Dec 2003

PNN Annual File—2003

PNN Pharmacotherapy Line
Jan. 2, 2003 Vol. 10, No. 1
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source: Jan. 1 issue of JAMA (www.jama.com; 2003; 289).

Sildenafil for Antidepressant-Associated Sexual Dysfunction: In 90 men with sexual dysfunction associated with antidepressant treatment with selective and nonselective serotonin receptor inhibitors, sildenafil improved sexual activity in 55–59% of patients (pp. 56-64). In a placebo-controlled, prospective study, subjects randomly received either placebo or sildenafil 50–100 mg before sexual activity for 6 weeks. Scores on the Clinical Global Impression–Sexual Function scale were much or very much improved in 54.5% and 4.4% of the sildenafil and placebo groups, respectively. “Erectile function, arousal, ejaculation, orgasm, and overall satisfaction domain measures improved significantly in sildenafil compared with placebo patients,” the authors write. “Mean depression scores remained consistent with remission ([Hamilton Rating Scale for Depression] score 10) in both groups for the study duration.... The maintained remission of depression supports the importance of maintaining medication adherence by managing treatment-emergent adverse effects to improve treatment outcomes. In everyday practice, less than 30% of patients complete a guidelines-recommended course of antidepressant treatment, discontinuing primarily for adverse effects, particularly sexual dysfunction.” (H. G. Nurnberg, geon@unm.edu)

ARB Prophylaxis of Migraine: “The angiotensin II receptor blocker candesartan provided effective migraine prophylaxis, with a tolerability profile comparable with that of placebo,” according to researchers who studied 60 adult patients with two to six monthly migraine attacks (pp. 65-9). During two 12-week treatment periods, patients received either placebo or candesartan 16 mg once daily. The mean number of days with headache was 18.5 with placebo and 13.6 with candesartan. Active therapy also significantly improved several secondary end points, including hours with headache (139 vs. 95), days with migraine (12.6 vs. 9.0), hours with migraine (92.2 vs. 59.4), headache severity index (293 vs. 191), level of disability (20.6 vs. 14.1), and days of sick leave (3.9 vs. 1.4). While the mechanism of action of ARBs in decreasing migraine occurrence is unknown, the rationale for this study was the prior demonstration of effectiveness of the ACE inhibitor lisinopril: “Candesartan reduces the effects of angiotensin II, which has several effects that may be relevant to migraine, such as direct vasoconstriction, increased sympathetic discharge, and adrenal medullary catecholamine release.” (E. Tronvik, St. Olavs Hosp., Trondheim, Norway; Erling.Tronvik@medisin.ntnu.no)

Binge Drinking: While binge consumption of alcohol is most common among college-age Americans, 69% of episodes occur in people 26 years and older (pp. 70–75). Based on annual telephone surveys conducted in 1993 through 2001 (sample sizes ranged from 102,263 to 212,510 each year), investigators found that 47% of binge-drinking episodes occurred among people whose alcohol consumption patterns were otherwise moderate, 73% of binge drinkers were moderate drinkers overall, binge drinkers were 14 times more likely to drive while impaired (compared with nonbinge drinkers), and binge drinking was common among women of child-bearing age. (T. S. Naimi, tbn7@cdc.gov).

>>>NEJM Highlights
Source:
Jan. 2 issue of the New England Journal of Medicine (content.nejm.org; 2003; 348).

Alpha-4 Integrin Therapy in Autoimmune Disease: Two studies (pp. 15-23, 24-32) and an editorial (pp. 68-72) discuss use of natalizumab, a recombinant monoclonal antibody against alpha-4 integrins, for treatment of multiple sclerosis and Crohn’s disease. Compared with placebo in a 6-month trial, natalizumab produced fewer inflammatory brain lesions and fewer relapses in patients with relapsing MS (D.H. Miller, Inst. of Neurology, London; d.miller@ion.ucl.ac.uk). Similar positive results were noted in a 4-week study of patients with active Crohn’s disease (S. Ghosh, Imperial College, London; s.ghosh@ic.ac.uk).

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 3, 2003 Vol. 10, No. 2
Providing news and information about medications and their proper use

>>>Adalimumab Approved for Rheumatoid Arthritis
In an earlier-than-expected decision, FDA on Tuesday approved adalimumab (Humira, Abbott) for reducing the signs and symptoms and inhibiting the progression of structural damage in adults with moderately to severely active rheumatoid arthritis who have had insufficient response to one or more traditional disease-modifying antirheumatic drugs. Given every other week by subcutaneous injection, the monoclonal antibody was approved for both monotherapy and combination treatment with one or more DMARDs.

Adalimumab is available in a prefilled syringe with plastic wings that facilitate self-administration by patients whose manual dexterity is reduced by rheumatoid arthritis. The usual dose is 40 mg, and in clinical trials 22% of patients had reduced signs and symptoms after as little as 1 week of therapy.

Adalimumab acts similarly to etanercept and infliximab, through inhibition of tumor necrosis factor alpha. A fourth biologic response modifier for rheumatoid arthritis, anakinra, exerts its effects through antagonism of interleukin-1 receptors. Like the other TNF-blocking agents, adalimumab has been associated with cases of tuberculosis and other serious infections or sepsis. Many patients were on concomitant immunosuppressive therapy when the infections occurred. Also, rare cases of demyelinating diseases have been linked to TNF-blocker therapy. Other frequent adverse events of adalimumab include upper respiratory infection (17% vs. 13% with placebo), injection site pain (12% vs. 12%), headache (12% vs. 8%), rash (12% vs. 6%) and sinusitis (11% vs. 9%).

>>>Eletriptan Added to Crowded Triptan Market
A sixth triptan has been approved for marketing in the U.S. Eletriptan (Relpax, Pfizer) was approved last week for acute treatment of migraine.

Like other agents in this category, eletriptan is a selective 5-hydroxytryptamine 1B/1D (5-HT1B/1D) receptor agonist that acts at serotonin 5HT1B receptors on intracranial blood vessels and 5HT1D receptors on sensory nerve endings to relieve the pain and associated symptoms of a migraine attack. The drug’s effectiveness and adverse effects (fatigue, somnolence, nausea, and dizziness) are similar to those of previously marketed triptans.

Relpax will be marketed in tablets containing 20, 40, and 80 mg. The maximum recommended single dose of the drug is 40 mg, and initially available information did not explain the purpose of the 80-mg tablet.

Eletriptan is contraindicated in patients with severe hepatic impairment, those who are older than 65 or younger than 18 years, and those who have taken potent cytochrome P450 inhibitors within 72 hours of triptan administration.

>>>>Diabetes Highlights
Source: Jan. Diabetes Care (www.diabetes.org; 2003; 26).

Cost Savings & DM Prevention: Compared with placebo, metformin and lifestyle interventions in patients with impaired glucose tolerance are associated with modest costs, according to an analysis conducted from the societal perspective (pp. 36-47). Analysis of direct medical, direct nonmedical, and indirect costs over 3 years shows that the cost of the metformin intervention was $2,191 per patient, compared with placebo. The per-patient cost of lifestyle intervention was $2,269 higher than the cost of placebo care. “The evaluation of costs relative to health benefits will determine the value of these interventions to health systems and society,” the authors conclude. (Diabetes Prevention Program Research Group, George Washington U., Rockville, Md.)

Sibutramine in Obese Patients with DM: Weights were reduced by a regimen of sibutramine among nearly one-half of 195 patients with type 2 diabetes mellitus and body mass indices greater than 27 kg/sq m (pp. 125-31). Among patients who lost 10% of their body weight, metabolic control was improved, with better glycemic control, A1c levels, fasting plasma glucose concentrations, HDL cholesterol levels, and plasma triglyceride concentrations. (S. J. McNulty, U. Hosp. Aintree, Liverpool, U.K.)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 6, 2003 Vol. 10, No. 3
Providing news and information about medications and their proper use

>>>Lancet Report
Source: Jan. 4 issue of Lancet (www.thelancet.com; 2003; 361).

Angioplasty vs. Thrombolysis for MI: Primary percutaneous transluminal coronary angioplasty was more effective than thrombolytic therapy in treatment of patients with ST-segment elevation acute myocardial infarction, according to a quantitative review of 23 published trials (pp. 13-20). The 7,739 patients received either PTCA (n = 3,872) or one of several thrombolytic agents (n = 3,867; either streptokinase or, more commonly, a fibrin-specific agent). Overall short-term death averaged 7% with primary PTCA, compared with 9% in those treated with thrombolysis. Significant advantages were also demonstrated for nonfatal reinfarction (3% vs. 7%, respectively), stroke (1% vs. 2%), and the combined endpoint of death, nonfatal reinfarction, and stroke (8% vs. 14%). These differences held over the long term, regardless of the type of thrombolytic agent used and whether patients were transferred for primary PTCA.

The authors conclude, “Our results are strengthened by the fact that they concur with those of a previous review; primary PTCA remains the best treatment option, despite changes in patients’ care over time between the earlier ten trials and the subsequent 13 trials. Consistent with the previous analysis, we noted that the beneficial effect of primary PTCA was similar irrespective of the thrombolytic regimen used (streptokinase or fibrin-specific).” (E. C. Keeley, Ellen.Keeley@UTSouthwestern.edu)

Accuracy of Pharmaceutical Advertisements in Journals: Caution is advised in evaluating claims made in advertisements for pharmaceuticals published in medical journals, note authors who studied promotions in six Spanish publications (pp. 27-32). In 264 different advertisements for antihypertensive drugs and 23 different advertisements for lipid-lowering drugs, a wide variety of problems were identified in 125 references cited to support promotional claims: 44.1% of promotional statements were not supported by the reference, usually because the drug was studied in a different patient group than stated in the ad; 18% of references or nonpublished data sources were unavailable; 63% of references were from journals with high impact-factor ratings; and 82% of references were from randomized controlled trials. (S. Peiró, Escuela Valenciana de Estudios para la Salud, Valencia, Spain; peiro_bor@gva.es)

“Readers should not take claims in journal adverts, with or without credible-appearing references, on face value,” concludes an editorialist commenting on this study. “Regulation of advertising claims is not strong or consistent enough to protect readers from misinformation. But then, neither should readers accept the conclusions of original research uncritically. Government regulators and editors do attempt to improve the accuracy of the content of medical journals, both articles and adverts. But readers must still take personal responsibility for judging the validity of assertions, especially those made in adverts.” (R. H. Fletcher, Robert_Fletcher@hms.harvard.edu)

>>>PNN JournalWatch
* Analgesic Effect of Breast Feeding in Term Neonates: Randomised Controlled Trial, in BMJ, 2003; 326: 13. Reprints: www.bmj.org; R. Carbajal, Poissy-Saint Germain Hosp., Poissy, France; carbajal@club-internet.fr

* Antithrombotic Therapy in Special Circumstances. I. Pregnancy And Cancer, in
BMJ, 2003; 326: 37–40. Reprints: www.bmj.org; B. Jilma.

* Prevalence of Obesity, Diabetes, and Obesity-Related Health Risk Factors, 2001, in
JAMA, 2003; 289: 76–9. Reprints: www.jama.com; A. H. Mokdad, ahm1@cdc.gov

* Selective Cyclooxygenase-2 Inhibition: A Target in Cancer Prevention and Treatment, in
Pharmacotherapy, 2003; 23: 9–28. Reprints: www.accp.com; D. Frame, David_G_Frame@rush.edu

* Tenofovir: A Nucleotide Analog for the Management of Human Immunodeficiency Virus Infection, in
Pharmacotherapy, 2003; 23: 29–43. Reprints: www.accp.com; T. Antoniou, Toronto; tonyantoniou@hotmail.com

* Adverse Drug Events Associated with Hospital Admission, in
Annals of Pharmacotherapy, 2003; 37: 5–11. Reprints: www.theannals.com; H. Peyriere.

* Reliability of a Modified Medication Appropriateness Index in Community Pharmacies, in
Annals of Pharmacotherapy, 2003; 37: 40–6. Reprints: www.theannals.com; R. Kassam.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 7, 2003 Vol. 10, No. 4
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: Jan. 7 issue of the Annals of Internal Medicine (www.annals.org; 2003; 138).

Diabetic Risk During HRT: Providing evidence for one of the few benefits of the use of hormone-replacement therapy, a study of 2,029 postmenopausal patients shows a reduced risk of diabetes during periods of HRT use (pp. 1-9). At baseline, 218 of the women had impaired fasting glucose, and the remainder were normoglycemic. Patients were assigned to take either placebo or conjugated estrogen 0.624 mg and medroxyprogesterone 2.5 mg for a mean of 4.1 years.

The risk of incident diabetes was significantly lower in patients taking HRT (relative hazard, 0.65). In the HRT group, 6.2% of patients developed diabetes, compared with 9.5% of women in the placebo arm of the study. The number needed to treat to prevent one case of diabetes was 30.

The authors conclude, “Postmenopausal women at high risk for incident diabetes, such as those with impaired fasting glucose, may benefit from hormone therapy. However, this potential benefit must be weighed against early risk for coronary events seen with initiation of hormone therapy, the threefold increased risk for venous thromboembolic events, and increased risk for breast cancer with long-term use. For these reasons, hormone therapy is not a viable approach to diabetes prevention in women with heart disease. This finding is consistent with current clinical guidelines stating that hormone therapy should not be used for secondary prevention of CHD.” (A. M. Kanaya, alkak@itsa.ucsf.edu)

Obesity & Mortality: Analysis of data from the Framingham Heart Study rates obesity as a “powerful predictor of death at older ages” (pp. 24-32). Among 3,457 participants who were 30–49 years of age at baseline in 1948, obese nonsmoking women and men lost 3.3 and 3.1 years of life expectancy, respectively, compared with normal-weight nonsmokers (based on an age of 40 at baseline). Compared with normal-weight smokers, obese smoking women and men lost 7.2 and 6.7 years, respectively. The combination of smoking and obesity reduced longevity by 13.3 years and 13.7 years in women and men, respectively.

The investigators observe, “Obesity and overweight in adulthood are associated with large decreases in life expectancy and increases in early mortality. These decreases are similar to those seen with smoking.... Because of the increasing prevalence of obesity, more efficient prevention and treatment should become high priorities in public health.” (A. Peeters, Erasmus Med. Ctr., Rotterdam, the Netherlands; peeters@mgz.fgg.eur.nl)

Genetic Predisposition to Obesity: In men, ACE I/D polymorphism is associated with being overweight and having abdominal adiposity (pp. 17-23). In a study of 959 adult men in the Olivetti factories of Naples, Italy, polymorphism of this renin– angiotensin system enzyme was measured along with anthropometric indexes, blood pressure, and serum glucose and insulin levels. “Overweight and abdominal adiposity were more common in men with the DD genotype, particularly among older participants (51.1% vs. 36.5% and 33.1% vs. 22.0%, respectively),” the researchers report. “Odds ratios were 1.82 (95% CI, 1.16 to 2.87) for overweight and 1.76 (CI, 1.06 to 2.90) for abdominal adiposity. Among 314 untreated men first examined 20 years earlier, those with the DD genotype had greater age-adjusted weight gain (1.45 kg [CI, 0.12 to 2.78 kg]) and change in diastolic blood pressure (2.83 mm Hg [CI, 0.39 to 5.28 mm Hg]). The relative risk for overweight was 2.34 (CI, 1.32 to 4.15) among participants with the DD genotype versus those with the ID or II genotype.” (P. Strazzullo, Federico II University, Naples, Italy; strazzul@unina.it)

BP& CHF: Pulse and systolic blood pressures are more accurate predictors of congestive heart failure than is diastolic blood pressure (pp. 10-6). Study authors conclude, “Increased pulse pressure may help identify hypertensive patients at high risk for overt CHF who are candidates for aggressive blood pressure control.” ( D. Levy, Framingham Heart Study, Framingham, Mass.)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 8, 2003 Vol. 10, No. 5
Providing news and information about medications and their proper use

>>>Circulation Highlights
Source: Jan. 7 issue of Circulation (circ.ahajournals.org; 2003; 107).

Atorvastatin–Clopidogrel Interaction: Atorvastatin competitively inhibits the activation of clopidogrel by the cytochrome P450 3A4 system, decreasing effectiveness of the platelet inhibitor (pp. 32 ff). After noticing a possible problem during point-of-care platelet testing, the authors tested clopidogrel alone or with atorvastatin or pravastatin (which does not affect 3A4) in 44 patients undergoing coronary artery stent implantation and 27 volunteers. Other 3A4 inhibitors (erythromycin or troleandomycin) and an inducer (rifampin) were also tested. The investigators report, “Atorvastatin, but not pravastatin, attenuated the antiplatelet activity of clopidogrel in a dose-dependent manner. Percent platelet aggregation was 34 ± 23, 58 ± 15 (P=0.027), 74 ± 10 (P = 0.002), and 89 ± 7 (P = 0.001) in the presence of clopidogrel and 0, 10, 20, and 40 mg of atorvastatin, respectively. Erythromycin attenuated platelet aggregation inhibition (55 ± 12 versus 42 ± 12% platelet aggregation; P = 0.002), as did troleandomycin (78 ± 18 versus 45 ± 18% platelet aggregation; P < 0.0003), whereas rifampin enhanced platelet aggregation inhibition (33 ± 18 versus 56 ± 20% platelet aggregation, P=0.001).” The authors conclude, “Use of a statin not metabolized by CYP3A4 and point-of-care platelet function testing may be warranted in patients treated with clopidogrel.” (W. C. Lau, weiclau@umich.edu)

HRT, DM, and MI: Similar to a report in yesterday’s Annals of Internal Medicine (see PNN, Jan. 7), a decreased risk of myocardial infarction resulted from use of hormone-replacement therapy in 24,420 women with diabetes mellitus (pp. 43). Current use of HRT was associated with a 16% reduction in MI risk. Unopposed estrogen therapy reduced MI risk by 12%, but the use of combined estrogen plus progestin was more effective, with a 23% reduction in risk. Lower to medium estrogen doses were effective, but women on doses above 0.625 mg of conjugated estrogens did not have a reduced MI risk. Also, in women who had had recent MIs, HRT increased the risk of MI. (A. Ferrara, axf@dor.kaiser.org)

>>>JAMA Highlights
Source: Jan. 8 issue of JAMA (www.jama.com; 2003; 289).

Deaths from Influenza or RSV: The importance of pharmacists’ immunization services is apparent in a report of increasing deaths from influenza over the past two decades (pp. 179-86). Comparing national viral surveillance data from 1976–77 and 1998–99 and estimates of influenza- and RSV-associated deaths in 1990–91 and 1998–99, the investigators found significantly increased deaths in the 1990s from pneumonia and influenza, underlying respiratory and circulatory deaths, and all-cause deaths. For the second category, 90% of influenza deaths and 78% of RSV deaths occurred in people aged 65 years or older. The group concludes that these deaths underscore “the need for better prevention measures, including more effective vaccines and vaccination programs for elderly persons.” (W. W. Thompson, wct2@cdc.gov)

Cholinesterase Inhibitors in AD: In patients with Alzheimer’s disease, treatment with cholinesterase inhibitors provides “a modest beneficial impact on neuropsychiatric and functional outcomes,” according to a meta-analysis of data from 16 trials (pp. 210-6). “Compared with placebo, patients randomized to cholinesterase inhibitors improved 1.72 points on the [Neuropsychiatric Inventory] (95% confidence interval [CI], 0.87–2.57 points), and 0.03 points on the [Alzheimer Disease Assessment Scale, noncognitive] (95% CI, 0.00-0.05 points),” write the authors. “For functional outcomes, 14 trials used [activities of daily living] and 13 trials used [instrumental activities of daily living] scales. Compared with placebo, patients randomized to cholinesterase inhibitors improved 0.1 SDs on ADL scales (95% CI, 0.00–0.19 SDs), and 0.09 SDs on IADL scales (95% CI, 0.01 to 0.17 SDs). There was no difference in efficacy among various cholinesterase inhibitors.” (K. Yaffe, kyaffe@itsa.ucsf.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 9, 2003 Vol. 10, No. 6
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source: Jan. 9 issue of the New England Journal of Medicine (content.nejm.org; 2003; 348).

Renal Etiology of Primary Hypertension: The number of nephrons is reduced in white patients with primary hypertension, shedding some light on the possible pathogenesis of this condition (pp. 101-8). The number and volume of glomeruli were measured in 20 middle-aged white people who had died in accidents. Compared with 10 normotensive matched controls, 10 patients with hypertension and/or left ventricular hypertrophy and renal arteriolar lesions had significantly fewer glomeruli per kidney (median of 702,379 vs. 1,429,200). Significantly greater glomerular volume was found in the patients with hypertension (median, 0.00650 cu mm vs. 0.00279 cu mm). However, very few obsolescent glomeruli were found. The investigators validated their counting method for intact and sclerosed glomeruli by examining kidneys in two elderly women who had died with severe hypertensive heart disease and nephrosclerosis.

The authors conclude, “The hypothesis that a reduced number of nephrons leads to primary hypertension is given further support by observations that the glomerular volume serves as a surrogate for the number of glomeruli and is very high in members of racial and ethnic groups with a predilection for renal failure over time. In this context, it is of note that the numbers of glomeruli are also significantly lower in spontaneously hypertensive rats than in normotensive controls.... Whether the reduced number of nephrons is caused by genetic or environmental factors is unclear. Several studies suggested that changes in the intrauterine environment lead to retarded renal growth before birth, low birth weight, and hypertension during adult life. A correlation between reduced birth weight and decreased formation of nephrons was recently found in experiments in rats. In humans, an association has been found between low birth weight and reduced renal volume, possibly indicating a reduced number of nephrons. All these data are consistent with the concept that the number of nephrons, which is determined during fetal development, is an important determinant of cardiovascular abnormalities during adult life. The present data, obtained at autopsy from white patients with primary hypertension, provide further evidence in support of this concept.” (K. Amann, U. Erlangen-Nürnberg, Erlangen, Germany; kerstin.amann@patho.imed.uni-erlangen.de)

Alcohol Consumption & Heart Disease: It’s the alcohol—not the other ingredients in wine—that reduces risks of myocardial infarction. That conclusion is evident from analysis of alcohol consumption patterns of 38,077 male health professionals between 1986 and 1998 (pp. 109-18). Regardless of the type of alcoholic beverage consumed or whether it was drunk with meals, men who consumed alcohol on 3–4 days per week had lower risks of myocardial infarction, compared with those who drank less than once per week. “The risk was similar among men who consumed less than 10 g of alcohol per drinking day and those who consumed 30 g or more,” the researchers report. “A 12.5-g increase in daily alcohol consumption over a four-year follow-up period was associated with a relative risk of myocardial infarction of 0.78 (95 percent confidence interval, 0.62 to 0.99).” (K. J. Mukamal, kmukamal@caregroup.harvard.edu)

Community-Based Treatment of Multidrug-Resistant TB: Community-based therapy of multidrug-resistant tuberculosis is feasible in resource-poor environments, according to a study conducted in Lima, Peru (pp. 119-28). Even though many have assumed that TB therapy is too expensive and not possible outside referral centers in low-income countries, 83% of 66 patients who completed 4 months of directly observed drug administration achieved probable cures. Five of the patients died during treatment. Only one patient had positive cultures after 6 months of therapy. Early initiation of appropriate therapy was important in the patients, whose pathogens were resistant to a median of six drugs when treatment was initiated. Pyrazinamide and ethambutol were included in regimens that were most often successful. (C. Mitnick, carole_mitnick@hms.harvard.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 10, 2003 Vol. 10, No. 7
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source: Jan. Pharmacotherapy (www.accp.com; 2003; 23).

Problems with Herbal Products: Unsafe and inaccurate advice was provided by employees of 12 health food stores in Mississippi, Tennessee, and Alabama, and St. John’s wort products purchased in those units were variable in their contents (pp. 64-72). Researchers approached the first employee they saw in each store and asked six specific questions about what to take for depression, how to take it and whether the labeled doses could be exceeded, what side effects to expect, whether the product could be taken with Prozac or Nardil, why the employee recommended a certain brand, and whether the product could be given to children and at what dose.

All 12 employees recommended St. John’s wort for depression. Based on analysis of employee responses by six medical professionals, the authors found that “numerous comments ... regarding St. John’s wort and the treatment of depression were unsafe and inaccurate.” High-performance liquid chromatographic analysis of 13 purchased products showed that no product contained within 10% of its labeled hypericin content. In fact, two products contained none of this key active ingredient of St. John’s wort. (H. E. Rogers, U. Miss., Jackson; he rogers@pharmacy.umsmed.edu)

Aspirin Use in Diabetic Patients: Pharmacy-directed interventions can increase prophylactic use of aspirin by patients with diabetes (pp. 73-9). Among 85 such patients of a rural primary care clinic, pharmacists reviewed medical records for use of or contraindications to aspirin use. At baseline, only 33% of eligible patients were taking aspirin. Pharmacists advised other eligible patients to begin enteric-coated aspirin 81 mg. A follow-up survey showed that 82% were “receiving daily aspirin or had accepted the recommendation to begin therapy,” the authors report. “The intervention, which has a simple, patient-focused design, serves as a template for improving aspirin prophylaxis among patients with diabetes in other ambulatory settings.” (J. J. Faragon, faragon@acp.edu)

Albumin Use in Critical Care: In a neurosurgical intensive care unit, albumin 5% or 25% was prescribed for about 25% of patients admitted during a 6-month period (pp. 88-92). The most common indications for use were vasospasm and maintenance of cerebral perfusion pressure. The authors also surveyed 78 members of the American Brain Injury Consortium about their opinions of albumin use. Respondents indicated that normal saline or albumin would be first-line drugs for vasospasm. Some 22% indicated their use of albumin declined following an FDA warning about the use of the agent in critically ill patients. (J. Hatton, U. Kentucky, Lexington)

Warfarin Therapy and Hip Fracture: Despite its inhibition of vitamin K, warfarin therapy does not affect elderly patients’ risk of hip fracture (pp. 1-4). Vitamin K is a necessary factor in the bone-modeling process, but in a analysis of Ontario health databases, the risk of hip fracture was not affected by warfarin treatment or thyroid replacement therapy. Using proton pump inhibitor therapy as a control, the adjusted relative risk of hip fracture was 0.94 among patients taking warfarin and 1.02 in patients on thyroid treatments. Use of oral corticosteroids significantly increased patients’ risk of hip fracture (aRR, 1.44). (M. Mamdani, Inst. for Clinical Evaluative Sci., Toronto; muhammad.mamdani@ices.on.ca)

>>>PNN NewsWatch
* Direct-to-consumer ads for prescription drugs were recalled by 77% of American adults in a recent National Consumer League survey, and 57% of that group took action as a result of promotions. Some 16% of consumers talked with their physicians immediately, 31% did so at their next office visit, and 26% sought additional information on their own (www.nclnet.org)

* A series of papers by prominent economists and analysts in the Jan/Feb issue of
Health Affairs explores the responsibilities of the government versus the private sector in controlling health spending (www.healthaffairs.org).

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 13, 2003 Vol. 10, No. 8
Providing news and information about medications and their proper use

>>>Lancet Report
Source: Jan. 11 issue of Lancet (www.thelancet.com; 2003; 361).

Adverse Events to Dietary Supplements: Ingestions of dietary supplements prompted 2,332 telephone calls to 11 U.S. poison control centers in 1998, and one third of reported symptoms were of greater than mild severity (pp. 101-6). In an article with several pharmacist authors, 489 cases of dietary supplement exposure are analyzed. New and previously reported associations included myocardial infarction, liver failure, bleeding, seizures, and death. “Most frequently associated with negative events were the botanical substances ma huang, guarana, ginseng, and St John’s wort, and non-botanical substances chromium, melatonin, and zinc,” the authors write.

Reasons for use of the agents included treatment of disease (28% of patients); dieting (14%); enhancing athletic performance (10%); aiding sleep (10%); stress adaptation, antioxidation, or nutrition (10%); suicide (9%); immune system stimulation (4%); recreational stimulation (2%); and enhancing cognitive performance (2%). “Increased symptom severity was associated with use of several ingredients, long-term use, and age,” writes the group. “Paediatric exposures were more often unintentional than were adult ingestions... Most products and ingredients were not identified in the information database (Poisindex) used by poison control centres, and specific adverse events were reported variably among five additional sources.” They conclude, “The difficulties we have described suggest the need for a comprehensive register of dietary supplements, strengthened surveillance (particularly mandatory reporting of adverse events), enforceable definitions of what constitutes a risk to safety, and what circumstances warrant product recall. Safety research should become a priority in investigations of dietary supplements to clarify hazards and possible risks for this recently defined class of foods.” (M. E. Palmer, Landspitali U. Hosp., Reykjavík, Iceland; mpalmer@landspitali.is)

Combined ACEI/ARB Therapy in Nondiabetic Renal Disease: In Japan, 263 patients with nondiabetic renal disease benefited from combination therapy with losartan 100 mg and trandolapril 3 mg daily, but disease in some patients still progressed (pp. 117-24). Using a combined end point of time to doubling of serum creatinine concentration or end-stage renal disease, the study shows that 11% of 85 patients on combination therapy reached the end point, compared with 23% of 85 patients on trandolapril alone. “Further strategies for complete management of progressive non-diabetic renal disease need to be researched,” the group concludes. (N. Nakao, Showa U., Fujigaoka, Aoba-Ku, Yokohama; nakao@ce.catv.ne.jp)

>>>PNN JournalWatch
* Stimulation of Staphylococcus epidermidis Growth and Biofilm Formation by Catecholamine Inotropes, in Lancet, 2003; 361:130–5. Reprints: www.thelancet.com; M. Lyte, lytex001@umn.edu

* Transfusion Medicine: Looking to the Future, in
Lancet, 2003; 361:161–9. Reprints: www.thelancet.com; L. T. Goodnough, Washington U., St. Louis; goodnough@labmed.wustl.edu)

* Platelet Responsiveness to Aspirin in Patients with Hyperlipidaemia, in
BMJ, 2003; 326: 82–3. Reprints: www.bmj.org; M. Miller, mmiller@heart.umaryland.edu

* Secondary Prevention Clinics for Coronary Heart Disease: Four Year Follow Up of a Randomised Controlled Trial in Primary Care, in
BMJ, 2003; 326: 82–3. Reprints: www.bmj.org; P. Murchie, U. Aberdeen, Foresterhill Health Centre, Aberdeen, U.K.; p.murchie@abdn.ac.uk

* Trends in Care by Nonphysician Clinicians in the United States, in
New England Journal of Medicine, 2003; 348: 130–7. Reprints: content.nejm.org; B. G. Druss, bdruss@emory.edu

* ACC/AHA 2002 Guideline Update for the Management of Patients With Chronic Stable Angina—Summary Article: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, in
Circulation, 2003; 107: 149–58. Reprints: circ.ahajournals.org, Committee on the Management of Patients With Chronic Stable Angina.

* Prescribing Oral Contraceptives for Women Older Than 35 Years of Age, in
Annals of Internal Medicine, 2003; 138: 54–64. Reprints: www.annals.org; C. Seibert, cseibert@facstaff.wisc.edu

* Protective Association of Aspirin/NSAIDs and Esophageal Cancer: A Systematic Review and Meta-Analysis, in
Gastroenterology, 2003; 124: 47–56. Reprints: www.gastrojournal.org; D. Corley, corley@itsa.ucsf.edu

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 14, 2003 Vol. 10, No. 9
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: Jan. 13 issue of Archives of Internal Medicine (www.archinternmed.com; 2003; 163).

SSRIs & GI Bleeding: Selective serotonin reuptake inhibitors increase patients’ risk of gastrointestinal bleeding, especially if they are also taking NSAIDs or low-dose aspirin, according to a study of prescriptions in a Danish county in 1991–95 (pp. 59-64). Hospitalizations among 26,005 users of antidepressant medications and nonusers were compared. The authors found, “During periods of SSRI use without use of other drugs associated with upper GI bleeding, we observed 55 upper GI bleeding episodes, which was 3.6 times more than expected (95% confidence interval, 2.7–4.7), corresponding to a rate difference of 3.1 per 1000 treatment years. Combined use of an SSRI and nonsteroidal anti-inflammatory drugs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1– 19.5) and 5.2 (95% confidence interval, 3.2–8.0), respectively. Non-SSRIs increased the risk of upper GI bleeding to 2.3 (95% confidence interval, 1.5–3.4), while antidepressants without action on the serotonin receptor had no significant effect on the risk of upper GI bleeding.” The role of serotonin in hemostasis is disrupted when the compound becomes depleted during SSRI use, the authors surmise. (S. O. Dalton, Danish Cancer Soc., Copenhagen, Denmark; sanne@cancer.dk)

Education About Patients with Hypercholesterolemia: To achieve adherence and meet treatment goals in patients with familial hypercholesterolemia, additional education of physicians and patients is necessary, conclude investigators who studied 747 individuals in the Netherlands (pp. 68-8). During the first 2 years after diagnosis of the genetic basis of elevated lipid levels, the overall percentage of patients under treatment increased from 37.6% to 92.5% at 1 year and then declined to 85.9% at 2 years. Patients’ physicians were often the reason for nontreatment or discontinuance, despite the patients’ high risk of cardiovascular disease. LDL cholesterol levels decreased by 30.1% in previously untreated patients, but mean levels were still 153 mg/dL. (J. C. Defesche, U. Amsterdam, Amsterdam, the Netherlands; j.defesche@amc.uva.nl)

Acyclovir Resistance: After 15 years of marketing, resistance to acyclovir remains low among immunocompetent patients, but researchers report a higher level of resistance among patients with HIV infection (pp. 76-80). Over an 18-month period ending in Apr. 1998, herpes simplex virus was isolated from 2,088 of 3,602 patients. HSV-2 was isolated in 90.2% of cases, and 15 of these strains were resistant to acyclovir. Twelve resistant isolates came from patients with HIV. The authors note, “Resistance was associated with oral acyclovir use (P<.001), duration of the current episode (P<.001), history of recurrent genital herpes (P<.01), and low CD4 cell count (P<.05).” (W. C. Reeves, wcr1@cdc.gov)

Celecoxib & Renal Papillary Necrosis:
The case of a 61-year-old woman who developed renal papillary necrosis during celecoxib therapy is presented (pp. 114-5). After diagnosis of rheumatoid arthritis in 1997, she was treated with naproxen and hydroxychloroquine. Celecoxib 200 mg replaced naproxen in Oct. 1999, and methotrexate was added. She had one episode of presumed urinary tract infection in Mar. 2000, and then presented in Aug. 2000 with papillary necrosis in the right kidney.

The investigators “believe that the renal papillary necrosis was most likely caused by celecoxib treatment” because none of her other conditions or medications are associated with the disease. They write, “The package insert for Celebrex notes that clinical trials with celecoxib have shown renal effects similar to those associated with comparator NSAIDs. Caution is recommended when initiating treatment in patients who are dehydrated and who have preexisting renal disease. Acute renal failure and interstitial nephritis have been listed as adverse reactions that occur rarely (in <0.1% of patients who take the drug) with celecoxib.” (R. J. Quinet, Ochsner Clinic Foundation, New Orleans; rquinet@ochsner.org)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 15, 2003 Vol. 10, No. 10
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Jan. 15 issue of JAMA (www.jama.com; 2003; 289).

LMWHs for ACS: Low molecular weight heparins could displace unfractionated heparin as antithrombotic agents of choice in a broad range of acute coronary syndromes, conclude authors of a systematic review article (pp. 331-42). A total of 31 studies on use of LMWHs in ACS and percutaneous coronary interventions were included in the analysis. “The LMWHs are recommended by the American Heart Association and the American College of Cardiology for treatment of unstable angina/non–ST-elevation myocardial infarction,” report the authors. “Clinical trials have demonstrated similar safety with LMWHs compared with unfractionated heparin in the setting of PCI and in conjunction with glycoprotein IIb/IIIa inhibitors. Finally, LMWHs show promise as an antithrombotic agent for the treatment of ST-elevation myocardial infarction.... More clinical data regarding the safety of these agents in elderly patients and in combination with potent platelet inhibitors such as thienopyridines and glycoprotein IIb/IIIa inhibitors are needed before their routine adoption in the setting of STEMI and PCI.” (R. P. Giugliano, TIMI Study Group, Boston; rgiugliano@partners.org)

Medicare Quality Improvement: Data on 22 quality indicators show improvement in fee-for-service care of Medicare beneficiaries between 1998–99 and 2000–1 (pp. 305-12). Using national and state-level data, the authors found, “The average relative improvement was 19.9% for outpatient indicators combined and 11.9% for inpatient indicators combined (P<.001). For all but one indicator, absolute improvement was greater in states in which performance was low at baseline than those in which it was high at baseline (median r = –0.43; range: 0.12 to –0.93). When states were ranked on each indicator, the state’s average rank was highly stable over time (r = 0.93 for 1998–1999 vs 2000–2001).” (S. F. Jencks, sjencks@cms.hhs.gov)

An editorialist reviews the bad apples/bad systems conundrum: “A critical issue is whether these errors represent failures of humans or systems.... Examining patient charts assumes that error derives from failure on the part of an incompetent or careless individual. Adverse events therefore identify bad apples for removal. This inspection model (‘name, blame, shame&rsquoWinking seeks to improve quality by cutting off one tail of the bell-shaped curve of human performance.

“In contrast, Deming’s continuous quality improvement (CQI) model assumes that most adverse events represent system failures and that design of work processes should detect and eliminate the human error that inevitably occurs... The CQI model seeks to improve quality by moving the entire bell curve to the left.” (D. Hsia, dhsia@ahrq.gov)

>>>Neurology Report
Source: Jan. 14 Neurology (www.neurology.org; 2003; 60).

AED Prophylaxis in Brain Trauma: Prophylaxis with phenytoin is effective in reducing the risk of early posttraumatic seizures in patients with severe traumatic brain injury, concludes the Quality Standards Subcommittee of the American Academy of Neurology (pp. 10-6). Published studies of patients with TBI who were treated with prophylaxis antiepileptic drugs were identified and graded (class I to IV).

“Pooled class I studies demonstrated a significantly lower risk of early post-traumatic seizures (those occurring within 7 days after injury) in patients given phenytoin prophylaxis compared to controls (relative risk 0.37, 95% CI 0.18 to 0.74),” writes the committee. “Pooled class I and class II studies demonstrated no significant difference in the risk of late post-traumatic seizures (those occurring beyond 7 days after injury) in patients given AED prophylaxis compared to controls (relative risk 1.05, 95% CI 0.82 to 1.35). Serum AED levels were suboptimal in these studies and adverse effects were mild but frequent.” Conclusions support use of prophylaxis with phenytoin in adult patients with severe TBI. The committee calls for studies addressing milder forms of TBI, use of newer AEDs, utility of EEG, and applicability of these findings to children. (Am. Acad. of Neurology, St. Paul, Minn.)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 16, 2003 Vol. 10, No. 11
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Jan. 16 issue of the New England Journal of Medicine (content.nejm.org; 2003; 348).

Leukemia-Like Disease with Retroviral Gene Therapy: In a letter to the editor, investigators describe the development of a leukemia-like disease in one of five patients treated with retrovirally mediated gene transfer for X-linked severe combined immunodeficiency (pp. 255-6; original study reported in PNN, Apr. 18, 2002). The patient developed hepatosplenomegaly and elevated lymphocyte counts between 30 and 34 months after gene therapy. A t(6;13) translocation was detected at that time that had not been present at 30 months. The patient has responded to treatment with a high-risk protocol for acute lymphocytic leukemia.
The authors write, “We interpret these findings as the consequence of the insertional mutagenesis event, a risk that is potentially associated with retrovirally mediated gene transfer and that has previously been considered to be very low in humans. For this reason, a thorough reassessment of the potential risk of retrovirally mediated gene therapy is warranted.” Gene therapy trials involving the technique have been halted pending investigation of the problem. (S. Hacein-Bey-Abina, Paris France)

An FDA official comments on the risks and benefits of gene therapy (pp. 193-4): “Because retroviral vectors are thought to insert themselves at random positions in the host genome, insertional mutagenesis as a potential risk of retroviral gene therapy has been debated for some years. That an instance of insertional mutagenesis first happened in humans during a clinical trial surprised some, but not those of us who regulate biologic products such as gene therapy. We take to heart the words of Robert Ingersoll: ‘In nature there are no rewards or punishments; there are consequences.’ Gene therapies are constructs derived from nature; they are not of nature. The manipulations needed to create genetic therapy add enormous complexity to considerations of safety and preclinical toxicity testing, and for every intended consequence of a complex biologic product, there are unintended consequences. Biologic products, like all products, carry risks along with benefits.” (P. Noguchi, FDA, Rockville, Md.)

>>>Psychiatry Report
Source:
Jan. issue of the American Journal of Psychiatry (ajp.psychiatryonline.org; 2003; 160).

Valproic Acid Safety in Hepatitis C: Increases in liver enzymes were no greater with valproic acid than with other medications in patients with hepatitis C infection (pp. 174-8). Valproic acid is “frequently not recommended for patients with hepatic dysfunction,” the authors explain. But their tests of 564 individuals who were beginning valproic acid therapy identified ALT elevations of approximately equal magnitude in hepatitis C-positive patients regardless of the medications they took. Infected patients had greater ALT elevations with valproic acid than did seronegative individuals, making monitoring necessary among hepatitis C-positive patients. (B. L. Felker)

Predicting Substance Abuse: The Gambling Task can be used to detect vulnerability to substance abuse among adolescents (pp. 33-40). The study included 64 adolescents aged 12 to 14 years, 31 of them healthy and 33 of them with externalizing behavior disorders, and 52 adults, 22 of them healthy and 30 of them with substance abuse. Healthy adolescents and adults performed similarly on the task, and adults with substance abuse performed more poorly than healthy adults at early stages of the task. Adolescents with behavior disorders performed more poorly in a second testing session but not in the first. The authors conclude that the task has potential utility in identifying adolescents at risk for substance abuse. (M. Ernst)

Omega-3 Fatty Acids in Borderline Disorder: Ethyl-eicosapentaenoic acid may be a useful monotherapy for women with borderline personality disorder (pp. 167-9). Aggression and depressive symptoms were diminished in 20 women who took 1 gram of the omega-3 fatty acid daily for 8 weeks, compared with 10 women on placebo. (M. C. Zanarini)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 17, 2003 Vol. 10, No. 12
Providing news and information about medications and their proper use

>>>Pediatrics Highlights
Source:
Jan. issue of Pediatrics (www.pediatrics.org; 2003; 111).

Low-Dose Aspirin in Pregnancy: Acetylsalicylic acid exerts antiplatelet effects in the fetus and newborn after low-dose aspirin therapy in the mother, according to researchers who studied 14 mother–infant pairs (e77–e81). The mothers were taking aspirin 100 mg daily for at least 4 weeks before maternal and umbilical cord plasma was analyzed using gas chromatography and mass spectrometry. Neonatal blood was also analyzed along with plasma from a control group. ASA and salicylic acid were detected in maternal/umbilical blood at 4 and 18–21 hours, respectively, after dosing. While ASA was not detected in newborns and salicylic acid was detectable in only one infant, platelet thromboxane A2 formation was suppressed for up to 2–3 days after birth.

The authors’ conclusion raises new concerns about the use of low-dose aspirin during pregnancy: “In pregnant women who are treated with [low-dose aspirin], acetylsalicylic acid is not completely inactivated in the portal circulation but reaches the uteroplacental circulation and exerts antiplatelet effects in the fetus and newborn.” (A. Leonhardt, Philipp’s U., Marburg, Germany)

ADHD Treatment & Substance Abuse: A study of 147 hyperactive children who were followed for 13 years into adulthood supports findings of 11 previous studies of children with attention-deficit/hyperactivity disorder: Stimulant treatment of children with ADHD does not lead to substance experimentation, use, dependence, or abuse by adulthood (pp. 97–109). Based on follow-up at age 15 and in adulthood (mean age, 21 years), the authors found, “Duration of stimulant treatment was not significantly associated with frequency of any form of drug use by young adulthood. Stimulant-treated children had no greater risk of ever trying drugs by adolescence or any significantly greater frequency of drug use by young adulthood. Stimulant treatment in high school also did not influence drug use in adulthood except for greater use of cocaine. This difference was no longer significant after controlling for severity of [ADHD] and conduct disorder in childhood, adolescence, and adulthood.” (R. A. Barkley, U. Massachusetts, Worcester)

In fact, report authors of a review article, the opposite is true: “Stimulant therapy in childhood is associated with a reduction in the risk for subsequent drug and alcohol use disorders” (pp. 179-85). Six studies that included 674 medicated subjects and 360 unmedicated subjects with ADHD estimated that the risk of substance use disorders is reduced by 1.9-fold among those treated with stimulants during childhood. “Studies that reported follow-up into adolescence showed a greater protective effect on the development of SUD (OR: 5.8) than studies that followed subjects into adulthood (OR: 1.4).” (T. E. Wilens, Mass. Genl. Hosp., Boston)

>>>PNN NewsWatch
* FDA yesterday proposed new warnings on the labels of OTC contraceptive products containing nonoxynol-9. The warnings would caution that the products do not protect against infection from HIV or other sexually transmitted diseases and that they may actually increase the possibility of transmitting HIV and other STDs from infected partners by irritating the vaginal lining.

* The Massachusetts Pharmacists Association yesterday called on the state legislature to repeal a new
prescription drug tax, saying that the tax is ill advised and has caused confusion and frustration among consumers and pharmacies. The tax, approved last July as part of the state budget, is $1.30 per non-Medicaid and non-Medicare prescription. It took effect on Jan. 1 even though the state had not issued regulations.

* Despite the
influence of pharmaceutical companies, the public seems unconcerned that their personal physician is swayed by marketing pitches. In a Wall Street Journal Online/Harris Interactive Health-Care poll, 67% of adult Americans indicated that they trust their physicians to pick the best medications, and they were largely unconcerned about company-sponsored educational programs.

*
PNN will not be published on Monday, Jan. 20, King Day.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 21, 2003 Vol. 10, No. 13
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: Jan. 21 issue of the Annals of Internal Medicine (www.annals.org; 2003; 138).

Heart Disease in Women: Medications for secondary prevention of coronary heart disease are underused in women, according to data from the Heart and Estrogen/progestin Replacement Study (pp. 81-9). Among 2,763 postmenopausal women with known coronary disease, the annual rate of myocardial infarction or death from CHD was 1.3% in women with no risk factors and 8.7% among women with five or more risk factors. The authors report, “At entry into HERS, 83% of participants were receiving aspirin or other antiplatelet agents, 33% were receiving beta-blockers, 18% were receiving angiotensin-converting enzyme inhibitors, and 53% were receiving lipid-lowering drugs. Women with more risk factors were less likely to be taking aspirin (P< 0.001) and lipid-lowering drugs ( P= 0.006).”

The authors conclude, “Women with coronary disease are at high risk for myocardial infarction or death from coronary heart disease even in the absence of other risk factors, and their risk increases up to sixfold when many risk factors are present. Established drugs for secondary prevention, including aspirin, beta-blockers, and lipid-lowering agents, are underused in these women, especially those at highest risk.” (E. Vittinghoff, UCSF, San Francisco)

Use of Chemotherapy in Women with Breast Cancer: Recommendations of an NIH consensus panel regarding use of chemotherapy in women with breast cancer are not being followed by many clinicians, especially in women older than 45 years (pp. 90-7). A cohort study included 5,101 women diagnosed with breast cancer in New Mexico between 1991 and 1997, and treatment as recommended by a 1990 NIH group was assessed. “Overall, 29% of women received chemotherapy,” the authors write. “The rate of chemotherapy use for women with stage I, stage II, or stage IIIA breast cancer was 11%, 47%, and 68%, respectively. Across all tumor stages, the use of chemotherapy decreased substantially with increasing age ( P< 0.001). Overall, 66% of women younger than 45 years of age received chemotherapy compared with 44% of women between 50 and 54 years of age, 31% of women between 55 and 59 years of age, and 18% of women between 60 and 64 years of age.” (X. L. Du, U. Texas Medical Branch, Galveston; xdu@utmb.edu)

Pravastatin in Patients with Renal Insufficiency: The statins appear useful in patients with cardiovascular risk factors and chronic renal insufficiency, according to results of the Cholesterol and Recurrent Events (CARE) study (pp. 98-104). Death from coronary disease or symptomatic nonfatal myocardial infarction was reduced by 28% among 1,711 patients who were followed for a median of 58.9 months. Side effects were similar in pravastatin and placebo groups. (M. Tonelli, U. Alberta, Edmonton)

>>>PNN JournalWatch
* Linezolid, in Annals of Internal Medicine, 2003; 138: I-44. Reprints: www.annals.org; R. C. Moellering, Jr.

* Effect of Recombinant Activated Factor VII on Perioperative Blood Loss in Patients Undergoing Retropubic Prostatectomy: A Double-Blind Placebo-Controlled Randomised Trial, in
Lancet, 2003; 361: 201–5. Reprints: www.thelancet.com; M. Levi, U. Amsterdam, Amsterdam, the Netherlands; m.m.levi@amc.uva.nl

* Drug-Eluting Stents in Vascular Intervention, in
Lancet, 2003; 361: 247–9. Reprints: www.thelancet.com; R. Fattori, Istituto di Cardiologia, Bologna, Italy; ross@med.unibo.it

* Systematic Review of Treatments for Recurrent Abdominal Pain, in
Pediatrics, 2003; 111: e1–e11. Reprints: www.pediatrics.org; J. A. Weydert, U. Arizona, Tucson.

* Diagnosis and Management of Lung Cancer: ACCP Evidence-Based Guidelines, in
Chest, 2003; 123(suppl). Reprints: www.chestjournal.org

* Cardiovascular Disease in Type 2 Diabetes Mellitus: Current Management Guidelines, in
Archives of Internal Medicine, 2003; 163: 33–40. Reprints: www.archinternmed.com; A. D. Mooradian, St. Louis U., St Louis; mooradad@slu.edu

* 2003 Clinical Practice Recommendations [for Diabetes Mellitus], in
Diabetes Care, 2003; 26. Reprints: www.diabetes.org; American Diabetes Assoc.

* Practice Parameter: Antiepileptic Drug Prophylaxis in Severe Traumatic Brain Injury, in
Neurology, 2003; 60: 10–6. Reprints: www.neurology.org

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 22, 2003 Vol. 10, No. 14
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Jan. 22/29 issue of JAMA (www.jama.com; 2003; 289).

Cannabis Use & Drug-Use Escalation: Use of cannabis by age 17 years is associated with increased risk for later use of other drugs, alcohol dependence, and drug abuse/dependence, according to a study of 311 fraternal and identical same-sex twin pairs (pp. 427-33). For all pairs, one twin used cannabis by age 17, while the other twin did not. The risks for later drug problems were 2.1 to 5.2 times higher for the twins who used cannabis early. “Controlling for known risk factors (early-onset alcohol or tobacco use, parental conflict/separation, childhood sexual abuse, conduct disorder, major depression, and social anxiety) had only negligible effects on these results,” write the investigators. “Associations between early cannabis use and later drug use and abuse/dependence cannot solely be explained by common predisposing genetic or shared environmental factors. The association may arise from the effects of the peer and social context within which cannabis is used and obtained. In particular, early access to and use of cannabis may reduce perceived barriers against the use of other illegal drugs and provide access to these drugs.” (M. T. Lynskey, Washington U., St. Louis; mlynskey@matlock.wustl.edu)

Shared Liability for Consumer Advertising: With pharmaceutical manufacturers increasingly using direct-to-consumer advertising to market prescription drugs, who bears the duty to warn patients of risks and the liability when warnings are not conveyed? That is the central question addressed in a legal review that explores new concepts of shared liability and the possible discarding of the learned intermediary rule. “The likely impact of a move to tort liability without the LIR is controversial. In the best-case scenario, drug manufacturers would continue their vigorous efforts to produce and market new drugs but would be deterred from providing inadequate warnings,” write the authors. “The economic consequences to manufacturers of increased tort liability would not be severe, because manufacturers would spread the costs over their entire customer base through price increases.” In bleaker legal scenarios, the authors predict that drug manufacturers would be “overdeterred by heightened tort liability,” leading them to reduce or discontinue consumer advertising, or even to situations in which they stop producing high-liability drug products such as vaccines.

Addressing the learned intermediary rule specifically, the group notes: “There is reason for some discomfort with the idea of a broad-scale abandonment of the LIR at this time. Shifting some of the tort liability from physicians to drug companies may have unintended effects on physician incentives to discuss risks and on patients’ incentives to seek out those discussions, and could well result in drug price increases. Such a sea change in the law should be supported by a more solid base of empirical evidence about the impacts of [direct-to-consumer advertising] than is presently available.” (M. M. Mello, JD, mmello@hsph.harvard.edu)

Conflicts of Interest in Research: Conflicts of interest among industry, scientific investigators, and academic institutions are common and affect biomedical research in important ways, conclude authors who studied 37 research articles in the published literature (pp. 454-65). Based on the prevalence and types of industry relationships, the authors made this assessment: “Approximately one fourth of investigators have industry affiliations, and roughly two thirds of academic institutions hold equity in start-ups that sponsor research performed at the same institutions. Eight articles, which together evaluated 1140 original studies, assessed the relation between industry sponsorship and outcome in original research. Aggregating the results of these articles showed a statistically significant association between industry sponsorship and pro-industry conclusions.... Industry sponsorship was also associated with restrictions on publication and data sharing.” Despite the dealings and journal policies for disclosing potential conflicts, few publications acknowledged the relationships. (C. P. Gross, cary.gross@yale.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 23, 2003 Vol. 10, No. 15
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Jan. 23 issue of the New England Journal of Medicine (content.nejm.org; 2003; 348).

Lead Exposure & Renal Disease: Repeated chelation therapy can reduce the progression of renal insufficiency caused by low-level exposure to lead, according to a study that followed 64 patients for 27 months (pp. 277-86). Lead-chelation therapy using calcium disodium EDTA produced increases in glomerular filtration rates (mean, 21 mL/min/1.73 sq m), while patients on placebo infusions had decreases in GFR (mean, –6.0 mL/min/1.73 sq m). The authors conclude, “This finding implies that treated patients might delay dialysis therapy by about three years, given the rate of decline in the glomerular filtration rate of approximately 3.0 ml per minute per year. The cost of this treatment for all 32 patients in the chelation group, including chelating agents, measurements of lead, frequent hospital visits, and staff salaries, was approximately $120,000 (or $3,750 per patient). However, the cost of three years of hemodialysis for this number of patients would be approximately $1,950,000 ($61,000 per patient). Thus, the treatment is likely to be cost effective.” (J-L Lin, Chang Gung Memorial Hosp., Taipei, Taiwan; jllin99@hotmail.com)

Hypervitaminosis A & Fracture: Subclinical hypervitaminosis A is associated with an increased risk of bone fractures in men, conclude authors of a longitudinal cohort study (pp. 287-94). A total of 2,322 men were enrolled in the trial at 49–51 years of age, and the group was followed for 30 years. During this time, 266 men suffered fractures. Multivariate analysis showed the highest risk of fracture in men in the highest quintile for serum retinol levels (>75.62 mcg/dL), with a 64% increased risk for any fracture and a 147% increased risk for hip fracture. Fracture risk was greater by sevenfold in men with retinol levels in the 99th percentile. The authors conclude: “Our findings, which are consistent with the results of studies in animals, as well as in vitro and epidemiologic dietary studies, suggest that current levels of vitamin A supplementation and food fortification in many Western countries may need to be reassessed.” (K. Michaëlsson, U. Hosp., Uppsala, Sweden; karl.michaelsson@surgsci.uu.se)

An editorialist surmises that the problem may be one of longevity in developed countries (pp. 347-9): “Vitamin A supplementation and fortification of food with vitamin A have been used to prevent xerophthalmia in [developing] countries. Although there are occasional reports of xerophthalmia in Western countries, it is usually associated with a markedly insufficient diet. Thus, the therapeutic window for vitamin A is narrow. Osteoporotic fracture due to excessive intake of vitamin A is a risk among adults, especially older persons, whereas eye disease due to vitamin A deficiency is a risk primarily among malnourished children. Th[is] study ... suggests that vitamin A supplementation and fortification of food with vitamin A may be harmful in Western countries, where the life expectancy is high and the prevalence of osteoporosis is increasing.” (P. Lips, Vrije Universiteit Med. Ctr., Amsterdam, the Netherlands)

Seizure Prophylaxis in Preeclampsia: “Magnesium sulfate is more effective than nimodipine for prophylaxis against seizures in women with severe preeclampsia,” conclude investigators who conducted an unblinded study of 1,650 women (pp. 304-11). Oral doses of nimodipine 60 mg every 4 hours were compared with intravenous magnesium sulfate solutions given according to institutional protocols. Monitoring lasted from enrollment to 24 hours after delivery. Overall, significantly more women taking nimodipine developed eclampsia (defined as a witnessed tonic-clonic seizure), compared with magnesium sulfate (2.6% vs. 0.8%). The two drugs were equivalent in the antepartum period, but the nimodipine group had significantly more observed seizures postpartum (1.1% vs. 0%). However, significantly more women taking magnesium required hydralazine for blood pressure control (54.3%% vs. 45.7%). (M. A. Belfort, Provo, Utah, uvmbelfo@ihc.com)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 24, 2003 Vol. 10, No. 16
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
Jan. issue of the Journal of the American College of Cardiology (www.cardiosource.com; 2003; 41).

Sirolimus-Eluting Stents: A 4-month study illustrates the major impact that drug-eluting stents are having in cardiac care. In a study of 16 patients with severe, recurrent in-stent restenosis, 26 sirolimus-eluting stents were successfully implanted (pp. 184-9). Four months later, 12 of the patients were doing well, three had angiographic evidence of restenosis (one in-stent and two in-lesion), and one patient had died. In-stent late lumen loss averaged only 0.21 mm, and quantitative angiographic and three-dimensional intravascular ultrasound showed that the volume obstruction of the stent was 1.1%. At 9 months, three patients had had experienced four major adverse cardiac events (two deaths and one acute myocardial infarction that required repeat target vessel angioplasty). (P. W. Serruys, U. Hosp. Dijkzigt, Rotterdam, the Netherlands)

Inappropriate Spironolactone Use: Clinicians are widely using spironolactone for heart failure without regard to the patient’s New York Heart Association class or their ejection fractions and without adequate background treatment with ACE inhibitors and beta blockers (pp. 211-4). The Randomized Spironolactone Evaluation Study (RALES) was released early by the New England Journal of Medicine (see PNN, July 20, 1999). Spironolactone reduced deaths by 30% over the first 24 months of RALES, leading researchers to stop the study early. In the current study, investigators analyzed the care of 104 patients who had been started on spironolactone after the highly publicized release of the RALES data. They write, “We found broader use, less intensive follow-up, and increased complications with spironolactone treatment compared with the RALES trial. Cardiologists provided more appropriate care than did primary care providers.... These data suggest that spironolactone is being used widely in HF without consideration of the NYHA class and ejection fraction, and without optimization of background treatment with angiotensin-converting enzyme inhibitors and beta-blockers. Clinical follow-up does not adhere to the RALES trial guidelines, resulting in higher complications. We conclude that long-term studies with further safety and efficacy data are needed.” (A. A. Knowlton, U. California, Davis)

Amiodarone & Bradyarrhythmia:
In elderly patients with atrial fibrillation and a previous myocardial infarction, the risk of bradyarrhythmia requiring a placement of permanent pacemaker is increased by use of amiodarone (pp. 249-54). In Quebec, a provincewide cohort of 8,770 patients 65 years of age or older with new diagnoses of AF was analyzed. Bradyarrhythmia requiring a permanent pacemaker occurred in 477 cases, and these were compared with 1,908 control patients. The authors found, “Amiodarone use was associated with an increased risk of pacemaker insertion ([odds ratio]: 2.14, 95% confidence interval: 1.30 to 3.54). This effect was modified by gender, with a greater risk in women versus men (OR: 3.86, 95% CI: 1.70 to 8.75 vs. OR: 1.52, 95% CI: 0.80 to 2.89). Digoxin was the only other medication associated with an increased risk of pacemaker insertion (OR: 1.78, 95% CI: 1.37 to 2.31).” (V. Essebag, Montreal)

Lifestyle vs. Medications in Improving Perfusion: In an era of highly effective lipid-lowering drugs, how important is it that patients focus on intense lifestyle changes? That question is addressed in a study of 409 patients with coronary artery disease who underwent myocardial perfusion imaging by dipyridamole positron emission tomography at baseline and after 2.6 years (pp. 263-72). During 5 years of follow-up, coronary events occurred in 6.6% of those on maximal treatment (diet, exercise, and lipid-lowering drugs), compared with 20.3% of patients on moderate treatment (diet plus drugs or strict low-fat diet without drugs) and 30.6% of patients on poor treatment (no diet or drugs, or patient smoked). The authors conclude that intense lifestyle interventions should accompany medication management of lipids in CAD patients. (K. L. Gould, U. Texas, Houston)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 27, 2003 Vol. 10, No. 17
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
Jan. 25 issue of Lancet (www.thelancet.com; 2003; 361).

IL-11 in Bacteremia: In 40 patients with hematologic malignant disease undergoing chemo-therapy, administration of recombinant human interleukin-11 50 mcg/kg reduced the frequency and load of bacteremia (pp. 275-80). Placebo or subcutaneous doses of IL-11 were administered beginning on the day before chemotherapy regimens and continued until neutropenia resolved or for 21 days, whichever was longer. Compared with placebo, patients who received IL-11 had significantly fewer episodes of bacteremia (65% and 25% had at least one positive blood culture). IL-11 especially seemed to decrease bacteremia of gastrointestinal origin, leading the researchers to write, “Our findings are, therefore, consistent with the notion that rhIL-11 inhibits bacterial translocation from the gastrointestinal tract into the blood by maintaining the integrity of the epithelium of the gut during chemotherapy. This idea is also supported by the reduction noted in the visually ascertained oral mucositis score, though the difference in score between the two groups was not significant.” (M. Ellis, UAE U., Al-Ain, United Arab Emirates; michael.ellis@uaeu.ac.ae)

Tamoxifen for Breast Cancer Prevention: While tamoxifen clearly reduces the risk of estrogen-receptor–positive breast cancer, it cannot be recommended for general use because of an associated increased risk of endometrial cancer and venous thromboembolic events (pp. 296-300). The only possible group for whom tamoxifen prophylaxis should be considered are women at very high risk of ER-positive breast cancer who also have a low risk of those side effects, the authors conclude. In addition, they support increased study of raloxifene and the aromatase inhibitors for breast cancer prevention. The group writes, “The tamoxifen prevention trials showed a 38% (95% CI 28–46; p<0.0001) reduction in breast-cancer incidence. There was no effect for breast cancers negative for oestrogen receptor (ER; hazard ratio 1.22 [0.89–1.67]; p=0.21), but ER-positive cancers were decreased by 48% (36–58; p<0.0001) in the tamoxifen prevention trials. Age had no apparent effect. Rates of endometrial cancer were increased in all tamoxifen prevention trials (consensus relative risk 2.4 [1.5–4.0]; p=0.0005) and the adjuvant trials (relative risk 3.4 [1.8–6.4]; p=0.0002); no increase has been seen so far with raloxifene. Venous thromboembolic events were increased in all tamoxifen studies (relative risk 1.9 [1.4–2.6] in the prevention trials; p<0.0001) and with raloxifene. Overall, there was no effect on non-breast-cancer mortality; the only cause showing a mortality increase was pulmonary embolism (six vs two).” (J. Cuzick, Wolfson Inst. of Preventive Med., London; jack.cuzick@cancer.org.uk)

PNN NewsWatch
* A large safety study of salmeterol xinafoate (Serevent, GSK) shows an increased risk of life-threatening asthma episodes or asthma-related deaths associated with use of the drug, especially in African American patients. The Salmeterol Multi-center Asthma Research Trial (SMART), a 28-week safety study, was initiated in 1996 after FDA received postmarketing reports of several asthma deaths associated with salmeterol and following publication of studies raising concern about the regular use of short-acting and long-acting beta agonists. GSK is stopping the study because of difficulties in enrollment and the likelihood the study would not give a clear result, even if fully enrolled. Among 26,000 subjects, a statistical trend emerged toward increased asthma deaths and serious episodes, although the difference was not significant.

>>>PNN JournalWatch
* Barriers to Accurate Diagnosis and Effective Management of Heart Failure in Primary Care: Qualitative Study, in BMJ, 2003; 326: 196 ff. Reprints: www.bmj.org; A. Fuat, Wolfson Res. Inst., U. Durham, Stockton-on-Tees, U.K.; ahmet@fuat.freeserve.co.uk

* Update on Glucocorticoid Action and Resistance, in
Journal of Allergy and Clinical Immunology, 2003; 111: 3–23. Reprints: www2.us.elsevierhealth.com; D. Y. M. Leung, Natl. Jewish Med. and Res. Ctr., Denver.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 28, 2003 Vol. 10, No. 18
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: Jan. 27 issue of Archives of Internal Medicine (www.archinternmed.com; 2003; 163).

Acetaminophen vs. Diclofenac for OA: Should acetaminophen be the agent of first choice for treatment of osteoarthritis? Authors who compared the analgesic with the NSAID diclofenac say no, at least not unless further comparisons of APAP with placebo support its effectiveness in patients with OA (pp. 169-78).
In a 12-week, placebo-controlled study, diclofenac sodium 75 mg twice daily was compared with acetaminophen 1000 mg 4 times daily in 82 subjects with symptomatic OA of the medial knee. Clinically and statistically significant improvements were observed in the diclofenac group at 2 and 12 weeks, compared with baseline. Acetaminophen failed to provide clinical or statistical improvements, compared with baseline, and the authors note that its “results were indistinguishable from those for placebo.”

In explaining why their results are different from the studies that showed APAP effectiveness for OA, the authors write, “The most compelling explanation for the disparate results of these studies (ie, whether acetaminophen is as effective as NSAIDs or, indeed, is an effective analgesic at all in patients with OA of the knee) may be the emphasis placed by the researchers on their interpretation of their results. The study by Bradley et al found a statistically significant pain response for acetaminophen in only 1 of 3 variables investigated, yet concluded that acetaminophen was equivalent to high-dose ibuprofen (which itself was significantly effective in all 3 variables). Similarly, Williams et al found acetaminophen effective in 1 of 2 variables and naproxen effective in both of them and superior to acetaminophen in 1 of them, yet concluded that efficacy was similar between the 2 drugs. The study by Pincus et al showed that diclofenac was more effective than acetaminophen, but does not indicate the presence or lack of statistical or clinical efficacy for either treatment arm alone and, like the study by Geba et al (and the studies by Bradley 1and Williams and colleagues), lacks a placebo control.” (J. P. Case, Rush U., Chicago; jcase@rush.edu)

Alcohol & Acetaminophen Hepatotoxicity: Authors of a research study that demonstrated safety of acetaminophen in patients who were chronic alcoholics (see PNN, Oct. 9, 2001) respond to letters to the editor that were published in the May 27 issue of Archives. Their bottom line is that no group of patients has been identified that is vulnerable to liver damage from doses lower than the labeled adult APAP dosage of 4 g/day: “Since acetaminophen is used by about 45 million people in the United States each week, it is striking that so few cases of alleged acetaminophen hepatotoxicity associated with therapeutic doses in alcoholic patients have been reported over the past 40 years. The few reports published have serious omissions and conflicting data, which question their validity.” (R. C. Dart, Denver)

ARBs After ACEI Sensitivity: Ten cases are reported in which patients who had confirmed angioedema associated with ACE inhibition were successfully switched to angiotensin II receptor blockers. “In all cases, the ARB was well tolerated and the patient’s subsequent course has been uneventful,” explain the authors. “Although this is by no means a rigorously controlled study, it should help alleviate the concerns of physicians who may be reluctant to use an ARB in such patients, despite anticipated benefits.” Patients in the series had a variety of causes of angioedema linked to ACE inhibitor therapy. These included 6 patients who had been taking ACEIs for more than 1 year before symptoms developed (including two patients who developed symptoms after 2 and 4 years of treatment with no other apparent cause); 2 patients in whom previously known allergens (mosquito bite soup and mushroom soup) produced major reactions when they had produced only minor reactions in the past; angioedema after switches from brand-name to generic ACEIs; and one patient who reacted to three different ACEIs in three different hospitals. (I. Gavras, Boston)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 29, 2003 Vol. 10, No. 19
Providing news and information about medications and their proper use

>>>Circulation Report
Source:
Jan. 28 issue of Circulation (circ.ahajournals.org; 2003; 107).

C-Reactive Protein: A national committee concludes that it is reasonable to measure high-sensitivity C-reactive protein in addition to other risk factors in assessing a patient’s coronary risk (pp. 499 ff). But, citing a “striking lack of Level A evidence (derived from multiple randomized clinical trials),” the committee recommends against use of hs-CRP as a screening tool in the entire adult population. The group, convened by the CDC and the American Heart Assoc., writes, “hs-CRP measurement appears to be best employed to detect enhanced absolute risk in persons in whom multiple risk factor scoring projects a 10-year CHD risk in the range of 10% to 20% (Evidence Level B). However, the benefits of this strategy or any treatment based on this strategy remain uncertain. The finding of a high relative risk level of hs-CRP (>3.0 mg/L) may allow for intensification of medical therapy to further reduce risk and to motivate some patients to improve their lifestyle or comply with medications prescribed to reduce their risk. Individuals at low risk (<10% per 10 years) will be unlikely to have a high risk (>20%) identified through hs-CRP testing. Individuals at high risk (>20% risk over 10 years) or with established atherosclerotic disease generally should be treated intensively regardless of their hs-CRP levels, so the utility of hs-CRP in secondary prevention appears to be more limited.

“In patients with stable coronary disease or acute coronary syndromes, hs-CRP measurement may be useful as an independent marker for assessing likelihood of recurrent events, including death, myocardial infarction, or restenosis after percutaneous coronary intervention. However, secondary preventive interventions with proven efficacy should not be dependent on hs-CRP levels. Further, serial testing of hs-CRP should not be used to monitor effects of treatment.” (AHA, 800-242-8721; reprint No. 71-0246)

Mini-reviews on CRP: Three brief reviews describe the clinical utility of high-sensitivity C-reactive protein as an indicator of cardiovascular disease risk. In outpatient settings, hs-CRP is most useful at the time of cholesterol screening, writes one author (pp. 363 ff). In patients whose LDL levels exceed 160 mg/dL and who should require therapeutic intervention based on ATP III guidelines, “an elevated CRP level should aggressively encourage physicians and patients to institute pharmacological therapy in those instances where none is currently being used or where compliance is poor,” the expert recommends. Elevated hs-CRP levels in patients with LDL levels of 130–160 mg/dL indicates the need for better adherence to treatment and other elements of ATP III guidelines. In patients who have reduced LDL levels below 130 mg/dL, an elevated hs-CRP level indicates a risk just as high as with overt hyperlipidemia. In these patients, careful adherence to ATP III lifestyle interventions is needed, and they should be monitored for metabolic syndrome and impaired glucose syndromes. (P. Ridker, pridker@partners.org)

CRP & Metabolic Syndrome: A research article provides evidence that the inflammatory properties of C-reactive protein are involved in development of the metabolic syndrome (pp. 391-7). In an 8-year study, 14,719 apparently healthy women were evaluated for characteristics of the metabolic syndrome (upper-body obesity, hypertriglyceridemia, low HDL, hypertension, and abnormal glucose). In the initial evaluation, 24% of the women had metabolic syndrome (three or more of the above characteristics), and median CRP levels were progressively higher as the number of characteristics increased. “At all levels of severity of the metabolic syndrome ... CRP added prognostic information on subsequent risk,” the authors noted. (P. M. Ridker, pridker@partners.org)

CRP & Alcohol Use: Moderate alcohol consumption was linked to lower levels of C-reactive protein in a study of 2,833 men and women (pp. 443-7). The effect was independent of alcohol-related effects on lipids. (M. A. Albert, maalbert@partners.org)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 30, 2003 Vol. 10, No. 20
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Jan. 30 issue of the New England Journal of Medicine (content.nejm.org; 2003; 348).

DM Interventions & CVD Risk: To cut their risk of cardiovascular and microvascular events by 50%, patients with type 2 diabetes and microalbuminuria need “a target-driven, long-term, intensified intervention aimed at multiple risk factors,” conclude authors of a 160-patient study (pp. 383-93). In the Steno-2 study, 80 patients received conventional treatment based on national guidelines, while the other 80 patients received “intensive treatment, with a stepwise implementation of behavior modification and pharmacologic therapy that targeted hyperglycemia, hypertension, dyslipidemia, and microalbuminuria, along with secondary prevention of cardiovascular disease with aspirin.”

Over a mean follow-up period of 7.8 years, the intensive-therapy group had a significantly greater decline in glycosylated hemoglobin values, systolic and diastolic blood pressures, fasting serum cholesterol and triglyceride levels, and urinary albumin excretion rates. Compared with the usual-care group, the intensive-therapy patients had significantly lower risks of cardiovascular disease (hazard ratio, 0.47), nephropathy (HR, 0.39), retinopathy (HR, 0.42), and autonomic neuropathy (HR, 0.37). (O. Pedersen, Steno Diabetes Ctr., Gentofte, Denmark; oluf@steno.dk)

An editorialist comments on the difficulty of achieving such results in the real world (pp. 457-9): “Despite the benefits of a multifactorial strategy, making it routine practice is not easy. Interventions similar to [these] are currently recommended but are underused for several reasons. They require education and time on the part of physicians. In addition, patients must be willing to follow a schedule of regular office visits and blood tests and often to take multiple medications, which may have side effects, at substantial expense for those who lack prescription-drug coverage.... Participants in trials are particularly motivated, yet at the conclusion of the current study, the target systolic blood pressure was reached in less than half the patients in the intensive-therapy group, and target glycosylated hemoglobin levels were achieved in less than a fifth. Although these findings point to the difficulty of achieving the targets in the real world, they also suggest the possibility of even greater benefits if the targets can be met more frequently.” (C. G. Solomon)

Smallpox Vaccination: The stark statistics of smallpox vaccination versus a variola attack on an unimmunized populace are presented using a model of outcomes under various control policies (pp. 416-25). Even though 25 deaths nationally can be expected from vaccination of health care workers, that step is recommended “unless the likelihood of any attack is very low,” the authors write. However, immunization of the general population is not advisable unless a national attack or multiple attacks are highly likely. Rather, vaccination of contacts along with effective isolation are recommended in the event of an attack. The anticipated mortality from vaccine or smallpox are 7 deaths “in a scenario involving the release of variola virus from a laboratory, 19 deaths in a human-vector scenario, 300 deaths in a building-attack scenario, 2735 deaths in a scenario involving a low-impact airport attack, and 54,729 deaths in a scenario involving a high-impact airport attack.” (S. A. Bozzette, RAND Health Care, Santa Monica, Calif.; sam_bozzette@rand.org)

Commenting on this and another article that minimizes the risk from smallpox (pp. 460-3), editorialists write (pp. 381-2): “As vaccination programs move forward ... we need effective teams ready to respond to any kind of bioterrorism, including that involving the many dangerous agents other than smallpox. The world’s developed countries must be prepared to help with outbreaks, perhaps accidental ones, in underdeveloped countries that are ill prepared to respond. And we must be prepared to hold to a steady course, with a rational response plan and vaccination policies, even if there is wide publicity about adverse effects of vaccinia or an outbreak of smallpox somewhere in the world.” (T. L. Schraeder)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 31, 2003 Vol. 10, No. 21
Providing news and information about medications and their proper use

>>>JAPhA Highlights
Source: Jan/Feb issue of the Journal of the American Pharmaceutical Association (www.aphanet.org; 2003; 43).

Iowa Pharmaceutical Care Program: Evidence continues to mount that pharmacists are unable to implement pharmaceutical care services effectively within the typical community pharmacy setting. In the Iowa Medicaid Pharmaceutical Case Management Program, about one half of 117 participating pharmacies “provided little or no PCM services within 3 months of notification of patient eligibility,” report authors who analyzed experiences during the first four quarters of the program (pp. 24-33). Nearly all of the 743 pharmacies in Iowa were eligible to participate in the program when it began in Oct. 2000. Pharmacists from the 117 participating pharmacies attended two live training sessions, and both they and the referring physician were paid $75 for the initial patient intervention and additional payments for follow-up visits.

Despite the pharmacists’ initial commitment to the program and its financial incentives and very effective implementation at a few pharmacies, two thirds of eligible patients never received PCM services. “The primary reasons given for the inability to provide services were patient access issues for 438 (23.2%) patients, pharmacy staffing or start-up issues for 419 (22.2%) patients, or no reason specified for 575 (30.4%) patients. A PCM intensity score was developed to represent the scope of services provided and the number of patients served. A higher intensity score indicated pharmacies that provided PCM to more patients and/or who offered higher levels of care (e.g., provided a written set of recommendations to the physician rather than simply assessing the patient without preparing or sending recommendations). Future evaluations will determine the validity of the score based on patient outcomes.” (B. L. Carter, barry-carter@uiowa.edu)

Pharmacists’ Roles in Public Health: Two articles and an editorial explore the contributions pharmacists can and do make to the public health of the nation. National health observances (e.g., Feb. is American Heart Month) provide “opportunities to work toward achieving Healthy People 2010 goals by advocating, facilitating, and/or providing education and screenings to patients,” maintain authors who provide lists of such observances and tips on appropriate programs. (J-V R. Goode, jrgoode@vcu.edu)

Another article details the general areas of the federal Healthy People 2010 program and lists specific objectives that present opportunities for pharmacists (pp. 56-60). “The message of
Healthy People 2010 is that the health of the individual is closely linked to the health of the community and hence the health of the nation,” the authors conclude. “Pharmacists, uniquely positioned as the most accessible health care providers in the community, can dedicate their considerable strengths toward using Healthy People 2010 as a tool to organize their own efforts and motivate their patients.” (V. J. Babb, babb@eber.fda.gov)

Authors of the second paper add this comment in an editorial (pp. 13-6): “In today’s economy, unmet needs will not go unaddressed for long. If pharmacists choose not to be active participants in protecting patients, elevating their level of understanding about their drug therapy and diseases, and addressing disparities in vaccination status as well as other health indicators, then rest assured that niche will be filled by other market-savvy health care providers. Despite the large hurdles that remain to be cleared, pharmacists can make dramatic progress in building a healthier nation in a relatively short period of time.”

>>>PNN NewsWatch
* For patients with severe sepsis and therefore at the highest risk of death, the cost of drotrecogin alfa is an acceptable $27,400 per quality-adjusted life-year, according to a study in the Jan. issue of Critical Care Medicine (Angus et al.; www.ccmjournal.com).

* Identifying areas of weakness and educating medical personnel about them improves
patient safety, according to two studies presented at this week’s Critical Care Congress (www.sccm.org).

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 3, 2003 Vol. 10, No. 22
Providing news and information about medications and their proper use

>>>Alefacept Approved for Chronic Plaque Psoriasis
Biogen announced on Friday the approval of alefacept (Amevive), a biologic therapy for treatment of adult patients with moderate-to-severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy. The agent is administered by intramuscular or intravenous injection weekly for 12 weeks, during which a prolonged remission is sometimes induced. This is followed by several months off therapy and, in some patients, in remission.

More than 1,000 patients at 100 sites in the United States, Europe, and Canada were enrolled in alefacept’s Phase III clinical trials. Patients were aged 16–84 years with chronic plaque psoriasis that covered at least 10% of their total body surface area. Response to treatment was defined as the proportion of patients with a reduction in score on the Psoriasis Area and Severity Index of at least 75% from baseline at 2 weeks following the 12-week treatment period. Response rates in these previously refractory patients were 14–21%, compared with 4–5% with placebo.

Because alefacept induces dose-dependent reductions in CD4+ and CD8+ T-lymphocyte counts, these cells should be monitored weekly during the 12-week dosing period and used to guide dosing. Alefacept is an immunosuppressive agent and could increase the risk of malignancies or infections. Adverse events commonly observed in the first course of placebo-controlled clinical trials with at least 2% or higher incidence in patients treated with alefacept compared with those treated with placebo were pharyngitis, dizziness, increased cough, nausea, pruritus, myalgia, chills, injection site pain, injection site inflammation, and accidental injury.

Alefacept will be available through direct distribution to a physician’s office or a specialty pharmacy (866-AMEVIVE; www.amevive.com). Physicians will administer alefacept to patients in their offices. Acquisition price will be $7,000–10,000 per course.

>>>BMJ Highlights
Source:
Feb. 1 issue of BMJ (www.bmj.org; 2003; 326).

VT & Third-Generation OCs: In the northern Netherlands, publicity in 1995 about the increased frequency of venous thrombosis with third-generation oral contraceptives produced a decrease in prescribing of the agents that lasted for 6 years (p. 254). While the majority of first-time pill users were placed on OCs containing gestodene or desogestrel in 1995, this figure dropped to less than 50% in 1996 and continued to decline through 2000. For women younger than 20, the change was most pronounced, with 73% being prescribed third-generation OCs in 1995 but only 11% receiving those agents in 2000. (L. de Jong-van den Berg, Groningen U., Groningen, Netherlands; jongltw@farm.rug.nl)

>>>PNN JournalWatch
* Thromboembolism Associated with the New Contraceptive Yasmin, in BMJ, 2003; 326: 257. Reprints: www.bmj.org; K. van Grootheest, Netherlands Pharmacovigilance Ctr., Hertogenbosch, Netherlands; ac.vangrootheest@lareb.nl

* Cholesterol Lowering Drugs and Risk of Age Related Maculopathy: Prospective Cohort Study with Cumulative Exposure Measurement, in
BMJ, 2003; 326: 255–6. Reprints: www.bmj.org; P. T. V. M. de Jong, Netherlands Ophthalmic Research Inst., Amsterdam, the Netherlands; p.dejong@ioi.knaw.nl

* Pathogenesis of Sepsis: New Concepts and Implications for Future Treatment, in
BMJ, 2003; 326: 262–6. Reprints: www.bmj.org; T. Calandra, Ctr. Hosp. U. Vaudois, Lausanne, Switzerland; Thierry.Calandra@chuv.hospvd.ch

* Folic Acid Supplements During Early Pregnancy and Likelihood of Multiple Births: A Population-Based Cohort Study, in
Lancet, 2003; 361: 380–4. Reprints: www.thelancet.com; R. J. Berry, rjberry@cdc.gov

* Fosmidomycin, a Novel Chemotherapeutic Agent for Malaria, in
Antimicrobial Agents & Chemotherapy, 2003; 47: 735–8. Reprints: aac.asm.org; B. Lell. U. Tübingen, Tübingen, Germany.

* ALLHAT—So What?, in
Journal of Informed Pharmacotherapy, 2003; 12: 1. Reprints: www.informedpharmacotherapy.com; J. McCormack.

* Maximizing Your Continuing Education Yield: Incorporating Streaming Media Into Your Oral Presentations, in
Journal of Informed Pharmacotherapy, 2003; 12: 500. Reprints: www.informedpharmacotherapy.com; R. M. Balen, U. British Columbia, Vancouver; rbalen@informedpharmacotherapy.com

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 4, 2003 Vol. 10, No. 23
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Feb. 4 issue of the Annals of Internal Medicine (www.annals.org; 2003; 138).

Posthospital Adverse Events: Follow-up contact by telephone with a clinical pharmacist within 5 days of discharge is one of the suggested solutions to problems identified in a study of 400 consecutive patients who were discharged from a general medical service of a tertiary care academic hospital (pp. 161-7). Of 76 patients (19%) who had adverse events after discharge, 23 had preventable problems (6%), and 24 had ameliorable adverse events (6%). Adverse drug events were the most common problem (66%), followed by procedure-related injuries (17%), nosocomial infections (5%), and falls (4%).

The authors write, “System problems contributed to all of the preventable and ameliorable adverse events. The most common deficit in the provision of discharge care was poor communication between the hospital caregivers and either the patient or the primary care physician (59% of preventable and ameliorable adverse events). Four principal aspects of the system were identified as requiring improvement: assessment and communication of unresolved problems at the time of discharge, patient education regarding medications and other therapies, monitoring of drug therapies after discharge, and monitoring of overall condition after discharge.” (D. W. Bates, dbates@partners.org)

HRT & Mammography: Use of hormone-replacement therapy probably affects the accuracy of breast mammography by increasing breast density, according to a study of 329,495 women aged 40–89 years (pp. 168-75). Screening mammography was more sensitive in women with fatty breasts (87.0%) and least sensitive in those with extremely dense breasts (62.9%), and sensitivity increased with age. HRT did not prove to be an independent predictor of accuracy, but “it probably affects accuracy by increasing breast density,” the authors conclude, and this make additional screening necessary to detect the presence of cancer. (P. A. Carney, Patricia.A.Carney@dartmouth.edu)

CAM Content of Medical School Curricula: Ten steps that medical schools can take toward improving their coverage of complementary and alternative medicine are presented in the latest installment of an ongoing CAM series (pp. 191-6). The steps apply equally well to pharmacy educators, including these: define a core curriculum in CAM, teach one medicine that includes the most solidly grounded information, establish a theme in the curriculum, incorporate CAM into cases, include an experiential component, and offer CAM content across the curriculum and into graduate education. (M. S. Wetzel, Harvard Med. Sch., Boston)

Assisted Suicide & Professional Associations: A position of “studied neutrality” would be preferable when it comes to professional associations’ positions on physician-assisted suicide, argue authors of a Perspectives article (pp. 208-11). The article lists links to nine groups’ Web sites (including those of APhA, state groups in Oregon, nursing and hospice groups, and medical students). “The question ‘Would you rather have excellent palliative care or access to physician-assisted suicide?’ offers a false dichotomy,” conclude the authors. “A better question might be something like ‘If you have access to excellent palliative care, and your suffering becomes intolerable, what options should you be able to pursue with your physician?’ Or, from a policy point of view, ‘Is it better to have an open, legally regulated response, or an underground, more idiosyncratic, passively prohibited process?’ As our multicultural society seeks to recognize and strengthen respect for different religious and cultural views, patients and physicians will sometimes have diverse opinions on this subject. Reinforcing our duty not to abandon while taking a position of studied neutrality on physician-assisted suicide simultaneously expresses respect for diversity and reinforces the importance of maintaining an ongoing commitment in the face of adversity.” (T. E. Quill, U. Rochester Med. Ctr., Rochester, NY)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 5, 2003 Vol. 10, No. 24
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Feb. 5 issue of JAMA (www.jama.com; 2003; 289).

Acetylcysteine for Contrast Nephropathy: In patients with moderate chronic renal insufficiency, oral acetylcysteine 600 mg twice daily protects against deterioration in renal function induced by contrast media, according to a study of 200 older Chinese patients (pp. 553-8). Acetylcysteine was administered on the day before and the day of angiography. The main outcome measure, a 25% increase in serum creatinine within 48 hours of the procedure, occurred in 12 control patients (12%) and 4 acetylcysteine patients (4%), a significant difference that reflected a 68% reduction in risk. Serum creatinine levels were significantly lower among patients who received prophylactic acetylcysteine (1.22 vs. 1.38 mg/dL), and creatinine clearances increased over the 2 days following angiography in the acetylcysteine group (44.8 vs. 58.9 mL/min). No major treatment-related adverse events occurred.

The authors conclude, “Oral acetylcysteine is a safe, effective, and inexpensive prophylactic treatment against acute renal dysfunction for patients with moderate chronic renal insufficiency undergoing coronary angiographic procedures. Additional larger studies will be required to determine if acetylcysteine reduces the morbidity (eg, acute dialysis) and mortality of nephrotoxicity following administration of contrast media.” (J. Kay, Grantham Hosp., Aberdeen, Hong Kong; flkay@netvigator.com)

While questioning some of the data that emerged from this study, an editorialist supports inclusion of acetylcysteine in management of renal patients undergoing angiography: “The findings of Kay and colleagues provide convincing support for the additional benefit of using acetylcysteine in addition to saline and nonionic contrast agents for patients with reduced renal function undergoing coronary angiography. This regimen is simple, inexpensive, and safe. Although the absolute clinical benefit is unproven, the reduction in length of hospitalization alone, with the associated costs and risk of nosocomial infection, is sufficient to recommend considering this approach for patients with reduced renal function who will undergo any procedure in which an intravenous or intra-arterial iodinated contrast agent will be administered.” (G. C. Curhan, gary.curhan@channing.harvard.edu)

Alcohol Consumption & Stroke: Heavy consumption of alcohol increases one’s risk of stroke, but light to moderate use appears to protect against all-cause and ischemic stroke, conclude authors of a meta-analysis of 35 observational studies (pp. 579-88). “Compared with abstainers, consumption of more than 60 g of alcohol per day was associated with an increased relative risk of total stroke, 1.64 (95% confidence interval [CI], 1.39–1.93); ischemic stroke, 1.69 (95% CI, 1.34–2.15); and hemorrhagic stroke, 2.18 (95% CI, 1.48–3.20), while consumption of less than 12 g/d was associated with a reduced relative risk of total stroke, 0.83 (95%, CI, 0.75–0.91) and ischemic stroke, 0.80 (95% CI, 0.67–0.96), and consumption of 12 to 24 g/d was associated with a reduced relative risk of ischemic stroke, 0.72 (95%, CI, 0.57–0.91),” the group reports. “Our study strongly suggests that reducing alcohol consumption in heavy drinkers should be an important approach to prevention of stroke in the general population. Our study also suggests that moderate alcohol consumption reduces risk of ischemic stroke. However, the implications of these findings should be examined cautiously. Any advice regarding the consumption of alcohol should be tailored to the individual patient’s risks and potential benefits.” (K. Reynolds; kreynol1@tulane.edu)

Alcohol & Formularies: Ethanol continues to be available on formularies of more than two thirds of major U.S. teaching hospitals, according to a survey. Beer and distilled spirits are most commonly dispensed, usually from pharmacies but sometimes from food services. “The availability of ethanol products for ‘therapeutic’ purposes may send the implicit message that alcohol is an appropriate remedy for illness,” the authors comment. (R. D. Blondell, U. Louisville)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 6, 2003 Vol. 10, No. 25
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Feb. 6 issue of the New England Journal of Medicine (content.nejm.org; 2003; 348).

From Pharmacogenetics to Pharmacogenomics: The “knowledge of genetic variations in proteins involved in the uptake, distribution, metabolism, and action of various drugs improves our ability to test for that variation and, as a result, to select the best drug at the optimal dose for each patient should also increase,” concludes an author of a review article (pp. 529-37). He writes, “The convergence of pharmacogenetics and rapid advances in human genomics has resulted in pharmacogenomics, a term used here to mean the influence of DNA-sequence variation on the effect of a drug. With the completion of the Human Genome Project and the ongoing annotation of its data, the time is rapidly approaching when the sequences of virtually all genes encoding enzymes that catalyze phase I and II drug metabolism will be known. The same will be true for genes that encode drug transporters, drug receptors, and other drug targets. As a result, the traditional phenotype-to-genotype pharmacogenetic-research paradigm ... is reversing direction to create a complementary genotype-to-phenotype flow of information.” (R. Weinshilboum, weinshilboum.richard@mayo.edu)

Drugs & Pharmacogenomics: In a review written by two pharmacists, steps that would accelerate the move of genomic-directed drug therapy into clinical practice are described (pp. 538-49). “One of the most important challenges in defining pharmacogenetic traits is the need for well-characterized patients who have been uniformly treated and systematically evaluated to make it possible to quantitate drug response objectively,” write the authors. “To this end, the norm should be to obtain genomic DNA from all patients enrolled in clinical drug trials, along with appropriate consent to permit pharmacogenetic studies. Because of marked population heterogeneity, a specific genotype may be important in determining the effects of a medication for one population or disease but not for another; therefore, pharmacogenomic relations must be validated for each therapeutic indication and in different racial and ethnic groups. Remaining cognizant of these caveats will help ensure accurate elucidation of genetic determinants of drug response and facilitate the translation of pharmacogenomics into widespread clinical practice.” (W. E. Evans, St. Jude Children’s Research Hosp., Memphis; william.evans@stjude.org)

Pharmacogenomics Exciting But Expensive: An editorialist cites specific examples of progress in pharmacogenomic research to show “that, with only rare exceptions, the translation of pharmacogenetic research into clinical practice will be intellectually challenging, time-consuming, and expensive” (pp. 553-6). “Basic research in pharmacogenetics deserves the support and the excitement that it has generated, but this excitement should not lead to unrealistic expectations about the rate at which medicines can be personalized according to genotype,” the author concludes. (D. B. Goldstein, U. Coll., London)

Cocaine-Associated Chest Pain: A 12-hour observation period in patients with cocaine-induced chest pain is sufficient to detect patients likely to have complications, according to a prospective study that confirms conclusions reached in retrospective analyses (pp. 510-7). Among 342 patients, 42 were admitted directly to the hospital because of the severity of their chest pain. The remaining 302 patients were observed in the emergency department for 9–12-hours and discharged if they had normal levels of troponin I and no new ECG indications of ischemia or cardiovascular complications. None of the patients died in the ensuing 30 days of a cardiovascular event, and, in 256 patients for whom detailed information was available, only 4 (1.6%) had nonfatal myocardial infarctions. The authors conclude, “Patients with cocaine-associated chest pain who do not have evidence of ischemia or cardiovascular complications over a 9-to-12-hour period in a chest-pain observation unit have a very low risk of death or myocardial infarction during the 30 days after discharge.” (J. E. Hollander, jholland@mail.med.upenn.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 7, 2003 Vol. 10, No. 26
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Feb. Pharmacotherapy (www.accp.com; 2003; 23).

Pharmacist Comanagement of Hypertension: Comanagement of hypertension by physician–pharmacist teams resulted in significantly better systolic blood pressures and visit costs, according to a randomized, controlled trial of 197 patients (pp. 209-16). In a staff model medical group, patients with uncontrolled hypertension were randomized to usual care or comanagement. Physicians in both groups participated in development of an evidence-based treatment algorithm and received group and individual education provided by the principal investigator (a physician) and clinical pharmacists. Systolic blood pressures were significantly lower in patients managed by the teams (–22 mm Hg, compared with –11 mm Hg in the usual care group). Reductions in diastolic blood pressure were similar (–7 and –8 mm Hg, respectively). The usual care group had significantly higher average visit costs per patient ($195, compared with $160 for the team-treated group). (J. E. Borenstein, Cedars-Sinai Health Syst., Beverly Hills, Calif.; jeff.borenstein@cshs.org)

Osteoporosis Treatment After Hip Fracture: In patients who were hospitalized for low-trauma hip fracture, osteoporosis was diagnosed and treated appropriately in only about one fourth of 118 individuals (pp. 190-8). A retrospective chart review conducted from 1993 through 1998 identified 43 men and 75 women with mean age of 70 years, and their care was reviewed for 1 year following hospital discharge. “Documented treatment of osteoporosis was uncommon, with approximately 75% of patients receiving no therapy for osteoporosis at discharge or follow-up,” the authors note. Subsequent fractures occurred in 12.5% of patients. (S. L. Follin, sheryl.follin@uchsc.edu)

Pneumococcal Vaccination Among Older Patients: Only one half of patients aged 65 years or older had been vaccinated against pneumococcal disease before hospital admission, according to interviews of 160 individuals (pp. 199-208). Predictors of immunization included patient awareness of the vaccine and physician recommendation, but access to care and health status had no effect. Of the unvaccinated patients, one half were willing to receive the vaccine after it was recommended by the interviewing pharmacist, but many preferred to receive it at their physician’s office. Nearly 40% had no preference or preferred to be vaccinated at the pharmacy. “Only half of the patients had interacted with a pharmacist in the past, and only 20% were aware that some pharmacists are certified to administer the vaccine,” explain the authors. (A. Wong-Beringer, anniewb@westernu.edu)

Perceptions of Pharmacists as Immunizers: A study of more than 400 patients in family medicine clinics reveals doubts that pharmacists are qualified to administer vaccines (pp. 248-54). “Only 43% [of patients] felt comfortable with having a community pharmacist administer a vaccine,” the authors write. Pharmacists have been actively involved in the clinics for more than 20 years, and 90% of health care professionals in the clinics believed it was appropriate for pharmacists to provide the service. However, 35% of professionals did not support provision of immunizations in local pharmacies. (M. M. Blair, Med. U. of South Carolina, Charleston)

Pharmacist Care of Dementia: In the nursing home setting, preliminary results indicate that “pharmacists can play an important role in the pharmacotherapy of [behavioral and psychological symptoms of dementia],” according to researchers who evaluated the care of 11 patients (pp. 217-21). Using trazodone at average doses of 70 mg/day in most patients, pharmacists enabled 30% improvements in scores on the Behavioral Pathology in Alzheimer’s Disease rating scale in 9 patients. (C. H. Rojas-Fernandez, carlosr@cortex.ama.ttuhsc.edu)

Herbal Use in Children: Of 117 caregivers, 20% had given herbal agents to children with attention-deficit/hyperactivity disorder or depression, usually without input from health professionals (pp. 222-30). (M. L. Crismon, crismonl@mail.utexas.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 10, 2003 Vol. 10, No. 27
Providing news and information about medications and their proper use

>>>Lancet Report
Source: Feb. 8 issue of Lancet (www.thelancet.com; 2003; 361).

Combination Treatment of COPD: Dual therapy with inhaled long-acting beta-2 agonists and corticosteroids yields better control of symptoms and lung function without increased risk of side effects, compared with use of either agent alone in patients with chronic obstructive pulmonary disorder (pp. 449-56). In a study of 1,465 patients in 25 countries, salmeterol 50 mcg twice daily, fluticasone 500 mcg twice daily, both, and placebo were compared. Pretreatment lung function was significantly improved by all three active medication interventions, but combination therapy provided the greatest increase along with the most improvement in health status and reduction of daily symptoms. “All treatments were well tolerated with no difference in the frequency of adverse events, bruising, or clinically significant falls in serum cortisol concentration,” the authors report. “There was no evidence of important cardiac side-effects with salmeterol, or any unanticipated problems with fluticasone.” (P. Calverley, U. Hosp., Aintree, Liverpool, U.K.; pmacal@liverpool.ac.uk)

An editorialist interprets these findings for the individual patient : “The key question of how the clinician should approach the COPD patient now has a two-part answer. First, an aggressively optimistic approach should be adopted as COPD patients can benefit from treatment. Multiple modalities, including bronchodilators and inhaled glucocorticoids, can contribute…. Guidelines suggest initiation of treatment with bronchodilator therapy with the inhaled route preferred. 14 If treatment with these agents is satisfactory, that is, patients are asymptomatic and exacerbations are largely prevented, this treatment may be adequate. If treatment goals are not met, inhaled glucocorticoids can be added. Second, COPD patients should be regularly evaluated to assess the response to drug(s) and adherence with other interventions including rehabilitation. Clinical trials such as TRISTAN report population-average responses. COPD patients are heterogeneous and must be managed individually. Many questions about treatment of COPD remain, but whether treatment can benefit patients is not among them.” (S. I. Rennard, U. Nebraska, Omaha; srennard@unmc.edu)

>>>PNN JournalWatch
* Comparison of Intermittent and Continuous Palliative Chemotherapy for Advanced Colorectal Cancer: A Multicentre Randomised Trial, in Lancet, 2003; 361: 457–64. Reprints: www.thelancet.com; R. J. Stephens, MRC Clinical Trials Unit, London; rs@ctu.mrc.ac.uk

* Practice Based, Longitudinal, Qualitative Interview Study of Computerised Evidence Based Guidelines in Primary Care, in
BMJ, 2003; 326: 314 ff. Reprints: www.bmj.org; M. Eccles, U. Aberdeen, Aberdeen, U.K.; martin.eccles@ncl.ac.uk

* Making Decisions About Hormone Replacement Therapy, in
BMJ, 2003; 326: 322–6. Reprints: www.bmj.org; J. Rymer, St. Thomas's Hosp., London; janice.rymer@kcl.ac.uk

* Problem Based Learning, in
BMJ, 2003; 326: 328–30. Reprints: www.bmj.org; D. F. Wood.

* Nicotinamide: An Oral Antimicrobial Agent with Activity Against Both
Mycobacterium tuberculosis and Human Immunodeficiency Virus, in Clinical Infectious Diseases, 2003; 36: 453–60. Reprints: www.journals.uchicago.edu/CID/journal/contents/ v36n4.html; M. F. Murray.

* American Heart Association Guide for Improving Cardiovascular Health at the Community Level: A Statement for Public Health Practitioners, Healthcare Providers, and Health Policy Makers From the American Heart Association Expert Panel on Population and Prevention Science, in
Circulation, 2003; 107: 645–51. Reprints: circ.ahajournals.org; T. A. Pearson.

* Acetylcholinesterase Inhibitors for Vascular Dementia and Alzheimer’s Disease Combined with Cerebrovascular Disease, in
Stroke, 2003; 34: 584–6. Reprints: stroke.ahajournals.org; J. V. Bowler.

* The Genetics of Inflammatory Bowel Disease, in
Gastroenterology, 2003; 124: 521–36. Reprints: www.gastroenterology.org; J. H. Cho, jcho@medicine.bsd.uchicago.edu

* Hepatitis C in the HIV-Infected Person, in
Annals of Internal Medicine, 2003; 138: 197–207. Reprints: www.annals.org; M. S. Sulkowski.

* Reducing Errors in Fluid Therapy Management , in
Pediatrics, 2003; 111: 424–5. Reprints: www.pediatrics.org; M. A. Holliday.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 11, 2003 Vol. 10, No. 28
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Feb. 10 issue of Archives of Internal Medicine (www.archinternmed.com; 2003; 163).

Alternative Therapies & IBS: Irritable bowel syndrome, a common condition with few effective therapeutic options, may respond to Chinese herbal agents and psychologic therapies, but other alternative medicine approaches lack supporting evidence (pp. 265-74). According to a systematic review, a randomized, double-blind, placebo-controlled trial showed that both individualized and standardized preparations of Chinese herbal products were significantly more effective than placebo in a 16-week trial of 106 patients. During a 14-week follow-up period, the individualized treatments showed greater sustained effectiveness than did the standardized product.

Trials of psychotherapy have shown effectiveness but have usually not been blinded. Other alternative medicine approaches—including elimination of offending foodstuffs, use of lactase or digestive aids such as peppermint oil, and use of probiotic and other approaches that alter the gut flora—lack sufficient evidence to support their use at this time, the authors conclude. (M. P. Jones, Northwestern Mem. Hosp., Chicago; mpjones@nmh.org)

Statins, Warfarin, & Stroke Outcomes: Secondary prevention efforts, including increased use of statins and warfarin, may have produced a decreased 1-year mortality rate and lower stroke readmission rates observed among older patients in Ontario during the 1990s (pp. 293-7). Linked administrative databases containing records of 91,419 patients discharged with a diagnosis of acute stroke were analyzed for 1992–99. Even though the average age of patients and the number of comorbidities increased, the median length of stay declined from 11 to 8 days, and risk-adjusted in-hospital mortality fell from 21.9% to 18.9%. The 30-day mortality rates declined only slightly (a nonsignificant fall from 19.7% to 19.0%), and the 1-year mortality rates fell slightly but significantly, from 34.1% to 32.0%. Stroke readmission rates were 12.1% at the beginning of time period and 9.9% at the end, a significant drop. The proportion of patients using warfarin increased from 14.6% to 19.6% during the period, and statin use jumped from 2.7% to 15.0%.

The authors conclude, “The continuing high mortality rates for these stroke patients suggest that although important advances in stroke management have occurred during the past 2 decades, their impact at a population-based level has been modest.” (J. V. Tu, Inst, for Clinical Evaluative Sci., Toronto; tu@ices.on.ca)

Depression & ADRs: More adverse drug reactions were identified among older patients with depression during stays in 23 Italian hospitals during 1998 (pp. 301-5). The odds ratio for ADRs was increased by 58% among patients with diagnoses of depression, compared with the overall population of 3,134 older patients. (G. Onder, Università Cattolica del Sacro Cuore, Rome; graziano_onder@rm.unicatt.it)

Improved Care for Pneumonia: Antibiotic administration in the emergency department or within 4 hours of hospital admission were two improved process steps taken by very small hospitals in Oklahoma to improve care of patients with pneumonia (pp. 326-32). A quality improvement organization-directed project implemented a number of initiatives in 20 small hospitals, and care for patients with pneumonia was compared with a control group of 16 similar hospitals for two time periods. Statistically significant improvements in care processes were recorded in intervention hospitals, including performance of sputum and blood cultures and the above improved antibiotic use. (D. W. Bratzler, Oklahoma Foundation for Medical Quality, Oklahoma City; okpro.dbratzler@sdps.org)

Clonidine Patch Ingestion: Deliberate ingestion of clonidine patches by patients in a detoxification unit is described (pp. 367-8). Three patients ate patches placed on their arms, two of whom said they thought it would lessen withdrawal symptoms. Clonidine can be abused by people seeking to avoid withdrawal symptoms, boost narcotic highs, or obtain the drug’s effects. (D. A. Rastegar, Johns Hopkins Bayview Med. Ctr., Baltimore; drastega@jhmi.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 12, 2003 Vol. 10, No. 29
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Feb. 12 issue of JAMA (www.jama.com; 2003; 289).

Early Beta-Blocker Use in Severe HF: In the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) study, benefits of beta blockers during the initiation of heart failure treatment were similar to those observed during long-term therapy (pp. 712-8). The multicenter study included 2,289 patients with symptoms of heart failure at rest or with minimal exertion who were clinically euvolemic and had left ventricular ejection fractions of less than 25%. In addition to their usual medications for heart failure, patients received either placebo or carvedilol 3.125 mg twice daily initially, with uptitration to target doses of 25 mg twice daily.

Compared with the patients on placebo, fewer patients on carvedilol died (hazard ratio, 0.75), died or were hospitalized (HR, 0.85), or were permanently withdrawn from treatment (HR, 0.83). The authors report, “These effects were similar in direction and magnitude to those observed during the entire study, and were apparent particularly in the 624 patients with recent or recurrent decompensation or a very depressed left ventricular ejection fraction. Differences in favor of carvedilol became apparent as early as 14 to 21 days following initiation of treatment. Worsening heart failure was the only serious adverse event with a frequency greater than 2% and was reported with similar frequency in the placebo and carvedilol groups (6.4% vs 5.1%).” (H. Krum, Monash U., Alfred Hosp., Melbourne, Victoria, Australia; henry.krum@med.monash.edu.au)

An editorialist supports routine use of beta blockers in heart failure: “Both beta-blockers and cardiac resynchronization improve well-being and prolong life in patients with severe congestive heart failure due to left ventricular systolic dysfunction. Hopefully, dissemination of the findings of the 2 studies in this issue [the above study and another one on cardiac resynchronization using pacemakers] will lead to more appropriate use of these therapies. Beta-blockade is now a mature therapy and should be prescribed to every patient without a strong contraindication.” (S. L. Pinski, Cleveland Clinic Florida, Weston, Fla.; pinskis@ccf.org)

Antibiotic Prescribing for Respiratory Infections: For patients with nonpneumonic acute respiratory tract infections, prescribing of broad-spectrum antibiotics is common, especially among internists and other physicians in the Northeast and South (pp. 719-25). Data from the 1997–99 National Ambulatory Medical Care Survey showed that 1,981 adults sought care for common cold and nonspecific upper respiratory tract infections (24%), acute sinusitis (24%), acute bronchitis (23%), otitis media (5%), pharyngitis, laryngitis, and tracheitis (11%), or more than 1 of the above diagnoses (13%). An antibiotic was prescribed for 63% of these patients, and of the antibiotics prescribed, 54% fell into the broad-spectrum category (quinolones, amoxicillin-clavulanate, second- and third-generation cephalosporins, azithromycin, clarithromycin). Compared with general and family physicians, internists were 2.4 times more likely to prescribe broad-spectrum antibiotics. Prescribing was lowest in the West, and physicians in the Northeast and South were 2.6 and 2.4 times more likely to order broad-spectrum antibiotics, respectively. The authors conclude, “These high rates of prescribing, wide variations in practice patterns, and the strong association of nonclinical factors with antibiotic choice suggest opportunities to improve prescribing patterns.” (M. A. Steinman, mstein@itsa.ucsf.edu)

Rebalancing Industry– Academia Relationships: Institutional partnerships with industry can be managed by physically separating some facilities, placing restrictions on information shared between investment and research staffs, and providing oversight by independent review panels whose members have expertise in intellectual property, finance, and research but are not financially or otherwise dependent on the institution, according to authors who call for a restoration of balance in such dealings (pp. 741-6). (M. Barnes, Ropes & Gray, New York City; mbarnes@ropesgray.com)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 13, 2003 Vol. 10, No. 30
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Feb. 13 issue of the New England Journal of Medicine (content.nejm.org; 2003; 348).

ACEIs vs. Diuretics for Hypertension: Especially in older men, initiation of antihypertensive therapy with ACE inhibitors rather than diuretics may have advantages that go beyond the reduction of blood pressure, according to an open-label comparison in 6,083 subjects (pp. 583-92). Patients, aged 65–84 years, were prospectively randomized to ACE inhibitors or diuretics while receiving care in 1,594 family practices. After following the patients for a median of 4.1 years, the investigators found: “Blood pressure had decreased to a similar extent in both groups (a decrease of 26/12 mm Hg). There were 695 cardiovascular events or deaths from any cause in the ACE-inhibitor group (56.1 per 1000 patient-years) and 736 cardiovascular events or deaths from any cause in the diuretic group (59.8 per 1000 patient-years; the hazard ratio for a cardiovascular event or death with ACE-inhibitor treatment was 0.89 [95 percent confidence interval, 0.79 to 1.00]; P=0.05). Among male subjects, the hazard ratio was 0.83 (95 percent confidence interval, 0.71 to 0.97; P=0.02); among female subjects, the hazard ratio was 1.00 (95 percent confidence interval, 0.83 to 1.21; P=0.98); the P value for the interaction between sex and treatment-group assignment was 0.15. The rates of nonfatal cardiovascular events and myocardial infarctions decreased with ACE-inhibitor treatment, whereas a similar number of strokes occurred in each group (although there were more fatal strokes in the ACE-inhibitor group).” (C. M. Reid, Baker Heart Res. Inst., Melbourne, Australia; chris.reid@baker.edu.au)

Noting the apparent contradiction of these findings with those of the recently published Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT; see PNN, Dec. 18, 2002), an editorialist asks, “What are we to believe?” (pp. 639-41): “First, measure blood pressure in all patients. Second, if blood pressure remains elevated, control it with medication so as to achieve the blood-pressure goal (systolic blood pressure of less than 140 mm Hg and diastolic blood pressure of less than 90 mm Hg). In selecting appropriate therapy, choose a drug or a combination of drugs for which there is strong evidence of effectiveness in persons with the type of problem found in the patient.

“We must not join the clamor of media and industry, allowing newscasts to declare immediately which class of drugs is best. Treatment of the individual patient with hypertension is complicated, requiring time and judgment. In choosing between a diuretic and an ACE inhibitor, the physician can make a reasonable selection by reviewing the patient's history and course. We must remember that trials describe population averages for the purposes of developing guidelines, whereas physicians must focus on the individual patient’s clinical responses.” (E. D. Frohlich, Ochsner Clinic, New Orleans)

Sorting Out HRT Confusion: Authors of a review article compile explanations for the differences between controlled and observational studies of hormone-replacement therapy, another area of confusion among clinicians and consumers trying to follow this topic from afar (pp. 645-50). “The observational data could be influenced by confounding bias, compliance bias, and in particular, a restricted ability to detect short-term effects,” write the authors. “Other explanations may be biologic and related to differences in the treatment regimens and in the subjects. But existing trials have limited ability to investigate the wide variety of hormone treatments available or to study effects in younger women who have just reached menopause—women who must make an important decision about whether to begin hormone therapy.”

The authors conclude that HRT should not be used for preventing cardiovascular disease or long-term (5 years or more) prevention of any chronic disease in women of any age. “The established increases in the risks of breast cancer, venous thromboembolism, and stroke are too high a price to pay,” they explain. (F. Grodstein, Channing Laboratory, Boston)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 14, 2003 Vol. 10, No. 31
Providing news and information about medications and their proper use

>>>Gastroenterology Report
Source:
Feb. Gastroenterology (www.gastro.org; 2003; 124).

GI Events with NSAIDs: Serious lower gastrointestinal events occur with both COX-2–selective and nonselective NSAIDs, conclude authors of a study of 8,076 patients with rheumatoid arthritis (pp. 288-92). In the randomized trial, patients were 50 years or older or, if they were taking corticosteroids, 40 years or older. Defining serious lower GI events as bleeding with a 2 g/dL drop in hemoglobin or hospitalization, or hospitalization for perforation, obstruction, ulceration, or diverticulitis, the authors found, “The rate of serious lower GI events per 100 patient-years was 0.41 for rofecoxib and 0.89 for naproxen (relative risk, 0.46; 95% confidence interval [CI], 0.22– 0.93; P= 0.032). Serious lower GI events accounted for 39.4% of all serious GI events (complicated upper GI event or lower GI event) among patients taking naproxen and 42.7% among those taking rofecoxib.” The group concludes, “Serious lower GI events occurred at a rate of 0.9% per year in rheumatoid arthritis patients taking the nonselective NSAID naproxen, accounting for nearly 40% of the serious GI events that developed in these patients. Serious lower GI events were 54% lower with the use of the selective COX-2 inhibitor rofecoxib.” (L. Laine, llaine@usc.edu)

Growth Hormone in Short-Bowel Syndrome: In patients with short-bowel syndrome who were dependent on home parenteral nutrition, 3 weeks’ treatment with low-dose growth hormone provided beneficial effects during an unrestricted hyperphagic western diet (pp. 293-302). Intestinal absorption of macronutrients was measured in 12 adult patients with an average of 48 cm of remaining small bowel. Compared with placebo, growth hormone (0.05 mg/kg/day) significantly increased intestinal absorption of energy (15%), nitrogen (14%), carbohydrates (10%), and fat (12%). “The increased food absorption represented 37% ± 16% of total parenteral energy delivery,” report the authors. “Body weight ( P< 0.003), lean body mass ( P< 0.006), d-xylose absorption ( P< 0.02), insulin-like growth factor 1 ( P< 0.002), and insulin-like growth factor binding protein 3 ( P< 0.002) increased, whereas uptake of GH binding protein decreased ( P< 0.01), without any major adverse effect.” (B. Messing, Hôpital Lariboisière—Saint Lazare, Paris, France; bernard.messing@lrb.ap-hop-paris.fr)

IBS Treatments: Both psychotherapy and paroxetine, used in treatment of severe irritable bowel syndrome, provide improvements in health-related quality of life with no additional cost, according to a cost-effectiveness analysis (pp. 303-17). In 257 patients who were treated and assessed at 3 months and 1 year after that, psychotherapy and paroxetine “were superior to treatment as usual in improving the physical aspects of health-related quality of life (SF-36 physical component score improvement, 5.2 [SEM, 1.26], 5.8 [SEM, 1.0], and –0.3 [SEM, 1.17]; P< 0.001), but there was no difference in the psychological component,” the paper states. “During the follow-up year, psychotherapy but not paroxetine was associated with a significant reduction in health care costs compared with treatment as usual (psychotherapy, $976 [SD, $984]; paroxetine, $1252 [SD, $1616]; and treatment as usual, $1663 [SD, $3177]).” (F. Creed, U. Manchester, Manchester, U.K.: francis.creed@man.ac.uk)

>>>PNN NewsWatch
* “New Paths to Recovery” is a community-education tour being presented in 14 cities with heroin and/or prescription-drug addiction problems (Baltimore, Boston, Chicago, Dallas, Detroit, Miami, New Orleans, New York City/Newark, Portland, Salt Lake City, San Francisco, Seattle, Wilmington/Philadelphia; and San Juan, Puerto Rico). Contact the Substance Abuse and Mental Health Services Administration for details (301/443-5052; www.samhsa.gov)

*
Multicultural pharmacy customers are less likely to receive medications for many conditions and are less satisfied with their treatment for many common conditions, according to a Wilson Health Information survey (215/ 862-4581; www.wilsonrx.com).

*
PNN will not be published on Mon., Feb. 17, Presidents’ Day.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 18, 2003 Vol. 10, No. 32
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
Feb. 15 issue of Lancet (www.thelancet.com; 2003; 361).

Interferons in MS: Recombinant interferons produce slight decreases in the number of exacerbations during the first year of treatment of patients with relapsing remitting multiple sclerosis, according to a systematic review (pp. 545-52). But any benefit beyond that is uncertain, primarily because of high patient dropout rates, the authors note. Seven trials between 1993 and 2002 met the review’s inclusion criteria, and these included 1,215 randomized patients. The relative risk of exacerbations was 0.73 during the first year. While the RR in the second year was a significant 0.81 and the risk of disease progression was reduced by 29%, “results were inconclusive after sensitivity analyses,” the paper states. “Data were insufficient to establish whether steroid use and admissions to hospital were reduced in the interferon group. Similarly, MRI outcome data could not be analysed quantitatively. Side-effects were common, and acute toxic effects adversely affected quality of life.” (G. Filippini, National Neurological Inst., “C Besta,” Milan, Italy; gfilippini@istituto-besta.it)

>>>BMJ Highlights
Source:
Feb. 15 issue of BMJ (www.bmj.org; 2003; 326).

Medication Adherence: Patients have many reasons for not taking medications as directed, note editorialists in calling for papers on the subject for a special BMJ issue this fall (pp. 348-9). “The difficulty for health professionals lies in acknowledging that it is the patients’ agendas and not their own that determine whether patients take medicines,” write the authors. “Patients have their own beliefs about their medicines and medicines in general. They have their own priorities and their own rational discourse in relation to health and care, risk and benefit. These may differ from and sometimes contradict those of the doctors. They are, however, no less cogent, coherent, or important.” (M. Marinker, Royal Pharm. Society of Great Britain, London)

>>>PNN NewsWatch
* Chronic hepatitis C virus may slowly progress to cirrhosis, produce scar tissue in the liver, and present a major risk factor for liver cancer, note authors of a study of 74 liver cancer patients with mild HCV and mild cirrhosis in today’s Annals of Internal Medicine (www.annals.org; 2003; 138: 299 ff). The study suggests that removing liver tumors by ethanol injection therapy, followed by interferon therapy to treat the HCV, may reduce the risk of tumor recurrence.

*
Interleukin-1, already implicated as a contributing factor in development of rheumatoid arthritis, may also encourage tumor growth, according to an animal study in yesterday’s Proceedings of the Natl. Academy of Sciences (article 7939). Mice that lacked the IL-1 gene and a control group were injected with skin, breast, or prostate cancer cells. Although all mice from the control populations developed tumors and died within 20 days, the knockout mice stayed tumor-free for much longer and in some cases never developed tumors. The cancer-free mice had no sign of angiogenesis. The scientists were able to prompt tumor angiogenesis in the knockout mice by injecting IL-1. Conversely, angiogenesis was arrested in the control mice by injecting IL-1ra.

>>>PNN JournalWatch
* In Search of a Better HIV Vaccine—The Heat Is On, in New England Journal of Medicine, 2003; 348: 643–4. Reprints: content.nejm.org; E. G. Phimister.

* The Importance of Indirect Costs in Primary Cardiovascular Disease Prevention. Can We Save Lives and Money With Statins?, in
Archives of Internal Medicine, 2003; 163: 333–9. Reprints: www.archinternmed.com; S. A. Grover.

* Macrophage Migration Inhibitory Factor: An Emerging Therapeutic Target in Rheumatoid Arthritis, in
Arthritis & Rheumatism, 2003; 48: 291–9. Reprints: www.rheumatology.org; E. F. Morand, eric.morand@med.monash.edu.au

* Intensive Blood Pressure Control Reduces the Risk of Cardiovascular Events in Patients With Peripheral Arterial Disease and Type 2 Diabetes, in
Circulation, 2003; 107: 757–61. Reprints: circ.ahajournals.org; W. R. Hiatt, Will.Hiatt@UCHSC.edu

* Statin Use and Leg Functioning in Patients With and Without Lower-Extremity Peripheral Arterial Disease, in
Circulation, 2003; 107: 757. Reprints: M. M. McDermott, mdm608@northwestern.edu

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 19, 2003 Vol. 10, No. 33
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Feb. 19 issue of JAMA (www.jama.com; 2003; 289).

Bivalirudin vs. Heparin During PCIs: In patients undergoing percutaneous coronary interventions, bivalirudin plus provisional glycoprotein IIb/IIIa blockade is as effective and causes less bleeding than heparin plus planned Gp IIb/IIIa blockade (pp. 853-63). In the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)–2 trial, about 6,000 patients undergoing elective or emergent PCI were randomly assigned to receive either bivalirudin (0.75 mg/kg bolus plus 1.75 mg/kg per hour for the duration of PCI) plus Gp IIb/IIIa as needed or heparin (65 U/kg bolus) with planned Gp IIb/IIIa inhibition (abciximab or eptifibatide) therapy. Both groups received daily aspirin and a thienopyridine for at least 30 days after PCI. In the provisional arm, Gp IIb/IIIb inhibitors were administered for procedural or angiographic complications at any time during the PCI.

At 30 days, the incidence of death, myocardial infarction, urgent repeat revascularization, or in-hospital major bleeding was 10.0% with heparin and 9.2.% with bivalirudin, not a significant difference. In-hospital major bleeding rates were significantly higher with heparin than with bivalirudin (4.1% versus 2.4%).

“The validation of bivalirudin therapy leaves little justification for the continued practice of treating some patients with heparin alone during contemporary percutaneous coronary revascularization,” the group concludes. “What remains to be investigated is whether outcome during PCI may be further optimized in a cost-effective manner by routine combination of bivalirudin and Gp IIb/IIIa blockade in high-risk patients.” (A. M. Lincoff, Cleveland Clinic Foundation, Cleveland, Ohio; lincofa@ccf.org)

Noting that the development of bivalirudin for this indication was precipitously suspended in 1994, an editorialist wonders if the drug can complete a comeback: “Whether bivalirudin should replace heparin in more elective PCI cases (about 56% of the REPLACE-2 trial population) will depend on whether interventionalists (and the US Food and Drug Administration) accept the quadruple primary end point, the definition of major bleeding, the definition of the noninferiority margin, and the dose–ACT range in the heparin group of REPLACE-2. Economic considerations are also likely to be important. The tradeoff appears to be fewer non–life-threatening bleeding events with bivalirudin compared with heparin at the cost of a few more moderately sized myocardial infarctions when Gp IIb/IIIa inhibitors are used provisionally rather than routinely.” (E. M. Antman, eantman@rics.bwh.harvard.edu)

Therapeutic Digoxin Range: For men with left ventricular ejection fractions of 45% or less, a lower than previously recognized range of serum digoxin concentrations may be needed, according to a study of 3,782 patients with low ejection fractions (pp. 871-8). Data from the Digitalis Investigation Group (DIG) trial were reanalyzed based on patients’ SDCs at 30 days (0.5–0.8 ng/mL, n = 572; 0.9–1.1 ng/mL, n = 322; and >1.2 ng/mL, n = 277). Mortality rates at 37 months were as follows: 29.9%, 38.8%, and 48.0% for men in the respective serum level groups listed above. “Given that no study has demonstrated any substantive clinical benefit for higher SDCs, prudent practice would support an SDC of 0.5 to 0.8 ng/mL as a revised therapeutic range,” the authors conclude. “The feasibility of achieving SDCs within this range in daily clinical practice is unclear. Only a randomized controlled trial can confirm this recommendation; however, we believe our data provide sufficient grounds for consideration of lower target SDCs for men with stable heart failure and left ventricular dysfunction.” (H. M. Krumholz, harlan.krumholz@yale.edu)

Tort Laws & Medical Monitoring: A law review assesses recent case law in which pharmaceutical manufacturers are required to provide monitoring for patients at risk of harm from pharmaceutical products (pp. 889-94). (D. M. Studdert, studdert@hsph.harvard.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 20, 2003 Vol. 10, No. 34
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Feb. 20 issue of the New England Journal of Medicine (content.nejm.org; 2003; 348).

Pediatric Cancer Treatment: Compared with standard chemotherapy, addition of ifosfamide and etoposide improved outcomes in patients with nonmetastatic forms of three cancers of children and young adults (pp. 694-701). Patients aged 30 years or less with Ewing’s sarcoma, primitive neuroectodermal tumor of bone, or primitive sarcoma of bone received 49 weeks of standard chemotherapy with doxorubicin, vincristine, cyclophosphamide, and dactinomycin or experimental therapy with these four drugs alternating with courses of ifosfamide and etoposide. Among 120 patients with metastatic disease, outcomes did not differ between the two treatment groups. But in the nonmetastatic groups, significantly more patients achieved 5-year event-free survival when treated with the experimental regimen (69%, compared with 54% of patients on standard therapy). (H. E. Grier, Dana–Farber Cancer Inst., Boston; holcombe_grier@dfci.harvard.edu)

An editorialist wonders whether current trends in pediatric cancer research bode well from an economic point of view (pp. 747-9): “If [patient] accrual is the lifeblood of a clinical-trials program, the actual interventions to be tested—the drugs, the diagnostics, and other innovative devices—are its heart. Currently, there is reason to wonder whether the progressive subdivision of even common adult tumors into a large number of molecularly specific subgroups will remove the large-market incentive that drives decision making in the pharmaceutical industry. However one regards this threat, it pales in comparison with the prospects for the discovery of drugs for pediatric cancers, an arena in which a market incentive has never existed. Pediatric cancer is a success story today because the chemotherapeutic agents of the past 50 years, brought to the clinic for testing mainly in adults, happened to work even better in children. Since the relevant molecular targets of the future are likely to differ between adult and childhood tumors, there is no reason to expect a similar ‘success by accident.’” (R. E. Wittes)

Antiretroviral Therapy & Associated Mortality: The adverse metabolic effects of some antiretroviral agents is not increasing patients’ rates of cardiovascular and cerebrovascular mortality, according to a retrospective analysis of 36,766 individuals who received care between 1993 and 2001 (pp. 702-10). Hospital admission rates for cardiovascular or cerebrovascular disease declined between 1995 and 2001 (from 1.7 to 0.9 per 100 patient-years), a period during which mortality fell precipitously (from 21.3 to 5.0 deaths per 100 patient-years). “Patient-level regression analyses indicated that there was no relation between the use of nucleoside analogues, protease inhibitors, or nonnucleoside reverse-transcriptase inhibitors and the hazard of cardiovascular or cerebrovascular events, but the use of antiretroviral drugs was associated with a decreased hazard of death from any cause,” the authors write. “Fear of accelerated vascular disease should not deter patients and providers from using the highest-quality care for HIV, as defined by the use of combination antiretroviral therapy that is compatible with current guidelines. HIV-infected patients are appropriate candidates for all usual methods of risk reduction and health maintenance.” (S. A. Bozzette, sbozzette@ucsd.edu)

Informed Consent in Clinical Trials: Readability scores of informed-consent forms fall short of institutional review boards’ standards (pp. 721-6). On the Flesch–Kincaid scale, informed-consent templates posted on the Web sites of 114 IRBs had average readability scores of 10.6. Readability standards posted on 61 of the Web sites requested 5th to 10th grade readability levels for informed-consent forms. At 52 schools that were subject to the oversight of the federal Office for Human Research Protections, readability scores were significantly lower than at other IRBs (10.2 vs. 10.9). (M. K. Paasche-Orlow, Johns Hopkins Med. Institutions, Baltimore; mpaasche@jhmi.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 21, 2003 Vol. 10, No. 35
Providing news and information about medications and their proper use

>>>Chest Highlights
Source:
Feb. issue of Chest (www.chestjournal.org; 2003; 123).

Adjusting Warfarin Doses for High INRs: In patients with mildly elevated normalized international ratios during warfarin therapy, adjustments in dose of 20% or less are preferred, and for some patients, no change at all is needed (pp. 499-503). A study included 231 outpatients who had isolated, asymptomatic, elevated INRs of 3.2–3.4; 103 patients were being managed by an anticoagulation services, while primary care physicians were caring for 128 individuals. Target INR was 2.5 for all patients. Median follow-up INRs were 2.7 for 148 patients who were kept on the same warfarin dose, 2.5 in 77 patients whose warfarin doses were lowered by 1–20%, and 1.7 in 6 patients who were on doses decreased by 21– 43%. Primary care physicians lowered warfarin doses for 47% of their patients, while the anticoagulation staff took this action in only 23% of patients. Despite this significant difference in doses, resulting INRs were similar: 2.7 in anticoagulation service patients and 2.6 in the physicians’ patients. (B. F. Gage, Washington U., St. Louis; bgage@im.wustl.edu)

Infections During Long-term Glucocorticoid Therapy: Fungi and gram-positive bacteria are most often involved with patients on long-term glucocorticoid therapy experience pulmonary infiltrates (pp. 488-98). A prospective study of 33 patients found Aspergillus spp. in 31% and Staphylococcus spp. in 21%. Reflecting the patients’ attenuated immunologic conditions, crude mortality was 45%. Factors associated with patient death were age greater than 64 years, bilateral involvement as demonstrated on radiographs, delay in diagnosis, inappropriate empirical treatment, elevated scores on a standard scale, and the need for mechanical ventilation. “Pulmonary infections were associated with an increase in the concentration of relevant inflammatory cytokines,” write the authors. “This local and systemic inflammatory response was attenuated when compared with the response observed in patients with pulmonary infections but without glucocorticoid treatment or receiving glucocorticoids for a short period of time (< 9 days).” (A. Torres, Hospital Clínic, Barcelona, Spain; atorres@medicina.ub.es)

Heroin as a Cause of Asthma: In an inner-city intensive-care unit, heroin insufflation proved a common cause of life-threatening asthma exacerbations (pp. 510-7). In an article that describes both a sequential case series and a retrospective case–control study of asthma and diabetic patients, authors report, “In the sequential ICU admissions, 13 of 23 patients (56%) described asthma exacerbations associated with heroin insufflation. In the case–control study, asthmatics were significantly more likely to report heroin use (41.3% vs 12.5%; p = 0.006) and had a significantly higher prevalence of [urine drug screen] results positive for opiates (60% vs 7%; p = 0.001) compared to subjects with [diabetic ketoacidosis]. The rates of cocaine use by history and UDS results did not differ significantly between the two groups.” (A. Krantz, Cook County Hosp., Chicago; akrantz@uic.edu)

>>>Neurology Report
Source:
Feb. issue of Archives of Neurology (www.archneurology.com; 2003; 60).

Diet, Vitamins, Hormones, & Risk of AD: Investigators report that high intake of dietary unsaturated fats may reduce one’s risk of developing Alzheimer’s disease (pp. 194-200). Diets high in saturated or hydrogenated fats may increase the risk of AD, according to data from 815 community residents aged 65 and older. (M. C. Morris, Rush-Presbyterian-St. Luke’s Med. Ctr., Chicago)

A second article shows that antioxidant vitamins are not linked to decreased risk of AD (pp. 203-8). In 980 elderly subjects who were initially free of dementia and were followed for an average of 4 years, consumption of carotenes or vitamins A and E either through diet or supplements had no effect on AD risk. (J. A Luchsinger, Columbia U., New York)

In a similar study of 120 postmenopausal women, hormone-replacement therapy had no effect of AD risk (pp. 209-12). (L. J. Thal, U. California, San Diego)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 24, 2003 Vol. 10, No. 36
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
Feb. 22 issue of Lancet (www.thelancet.com; 2003; 361).

Length of Antidepressant Therapy: A systematic review of randomized trials reveals that continuation of antidepressant therapy can reduce the risk of relapse in patients with recurrent depressive disorders (pp. 653-51). For treatment of acute episodes of depression, short- and medium-term therapy has been the standard of care, and this has been most commonly interpreted as continuation of treatment for 4–6 months following an episode. Based on data from 31 trials with 4,410 participants that lasted for the most part lasted for 12 months, the authors identified a 70% reduction in risk of relapse when antidepressant therapy was continued.

“The average rate of relapse on placebo was 41% compared with 18% on active treatment,” the group wrote. “The treatment effect seemed to persist for up to 36 months..., and so the evidence on longer-term treatment requires confirmation. Significantly more participants allocated [to] antidepressants withdrew from the trials than did those allocated to placebo (18% vs 15%, respectively; odds ratio 1.30, 95% CI 1.07-1.59): the treatment effect could be even greater in adherent patients. The two-thirds reduction in risk of depressive relapse seemed to be largely independent of the underlying risk of relapse, the duration of treatment before randomisation, or the duration of the randomly allocated therapy.” (J. Geddes, U. Oxford, Oxford, U.K.; john.geddes@psych.ox.ac.uk)

Buprenorphine for Heroin Addiction: “The combination of buprenorphine and intensive psychosocial treatment is safe and highly efficacious, and should be added to the treatment options available for individuals who are dependent on heroin,” conclude investigators who studied 40 patients (pp. 662-8). Patients who did not meet Swedish legal criteria for methadone maintenance were randomly allocated to daily buprenorphine 16 mg sublingually for 12 months or to a 6-day regimen of buprenorphine followed by placebo. Cognitive-behavioral therapy and weekly counseling sessions were provided for all participants. One-year retention rates were 75% and 0% in the buprenorphine and placebo groups, respectively. (Markus Heilig, Karolinska Inst., Huddinge U. Hosp., Stockholm, Sweden; markus.heilig@neurotec.ki.se)

>>>BMJ Highlights
Source:
Feb. 22 issue of BMJ (www.bmj.org; 2003; 326).

HRT & Mortality: Hormone-replacement therapy did not protect against ischemic heart disease, and women with diabetes had higher rates of all-cause mortality and IHD while taking the agents (pp. 426 ff). The hazard ratio for IHD and myocardial infarction were not significantly changed by HRT, and current users with diabetes had 3.2 times the risk of death, 4.2 times the risk of IHD, and 9.2 times the risk of MI. (E. Løkkegaard, Hvidovre U. Hosp., Hvidovre, Denmark; loekkegaard@dadlnet.dk)

>>>PNN JournalWatch
* Antibiotic Resistance Among Gram-Negative Bacilli in US Intensive Care Units: Implications for Fluoroquinolone Use, in JAMA, 2003; 289: 885–8. Reprints: www.jama.com; R. A. Weinstein, rweinste@rush.edu

* Corticosteroid Insufficiency in Acutely Ill Patients, in
New England Journal of Medicine, 2003; 348: 727–34. Reprints: content.nejm.org; P. M. Stewart, U. Birmingham, Birmingham, U.K.; p.m.stewart@bham.ac.uk

* A Case of Venlafaxine Abuse, in
New England Journal of Medicine, 2003; 348: 764–5. Reprints: content.nejm.org; S. P. Sattar, Omaha VA Med. Ctr., Omaha, Nebr.; shrink@prodigy.net

* Beneficial Effects of Weight Loss in Overweight Patients with Chronic Proteinuric Nephropathies, in
American Journal of Kidney Diseases, 2003; 41: 319–27. Reprints: www.ajkd.org; M. Praga, Hosp. 12 de Octubre, Madrid, Spain; mpragat@senefro.org

* Demographics and Trends in Overweight and Obesity in Patients at Time of Kidney Transplantation, in
American Journal of Kidney Diseases, 2003; 41: 480–7. Reprints: www.ajkd.org; A. N. Friedman, Indiana U., Indianapolis; allfried@iupui.edu

* Gene Therapy for Psychiatric Disorders, in
American Journal of Psychiatry, 2003; 160: 208–20. Reprints: www.psychiatry.org; Robert M. Sapolsky.

* Chronic Fatigue Syndrome: A Review, in
American Journal of Psychiatry, 2003; 160: 208–20. Reprints: www.psychiatry.org; N. Afari.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 25, 2003 Vol. 10, No. 37
Providing news and information about medications and their proper use

>>>Warfarin Study Released Early by NEJM
Long-term, low-intensity warfarin therapy reduced the incidence of recurrent venous thromboembolism by 64% among patients with idiopathic VT, according to a study released yesterday on the Web site of the New England Journal of Medicine. The study will appear in the Journal’s April 10 issue.

In the Prevention of Recurrent Venous Thromboembolism (PREVENT) trial, patients received full-dose anticoagulation therapy for a median of 6.5 months after an episode of idiopathic VT. They were then randomly assigned to placebo or low-intensity anticoagulation groups.

The trial was terminated early because of the pronounced benefits produced by anticoagulation. Among 508 patients followed for a mean of 2.1 years, 37 of 253 individuals taking placebo had recurrent VT (7.1 per 100 person-years), compared with 14 of 255 patients on low-dose warfarin (2.6 per 100 person-years), yielding a significantly lower hazard ratio (0.36). The authors write, “Risk reductions were similar for all subgroups, including those with and those without inherited thrombophilia. Major hemorrhage occurred in two patients assigned to placebo and five assigned to low-intensity warfarin (P=0.25). Eight patients in the placebo group and four in the group assigned to low-intensity warfarin died (P=0.26). Low-intensity warfarin was thus associated with a 48 percent reduction in the composite end point of recurrent venous thromboembolism, major hemorrhage, or death. According to per-protocol and as-treated analyses, the reduction in the risk of recurrent venous thromboembolism was between 76 and 81 percent.” (P. Ridker, Brigham and Women’s Hosp., Boston; pridker@partners.org)

Carefully managed anticoagulation services are needed, based on comments of an editorialist: “It is possible that newer, orally active antithrombotic agents will prove to have better safety and efficacy profiles than warfarin in the prevention of venous thromboembolism. However, all anticoagulants carry the risk of bleeding complications. The fundamental problem is that antithrombotic agents in current use or in development are unable to distinguish between a pathologic thrombus, which is potentially dangerous, and a hemostatic thrombus, which forms physiologically to restore and maintain vascular integrity and is therefore protective. Until a ‘magic bullet’ of antithrombotic therapy is found that specifically targets pathologic thrombi, we will continue to walk the tightrope of anticoagulant dosing.” (A. I. Schafer, U. Penn., Philadelphia)

>>>Internal Medicine Report
Source:
Feb. 24 issue of Archives of Internal Medicine (www.archinternmed.com; 2003; 163).

COX Inhibition & MIs: No differences in risk of acute myocardial infarction emerged among elderly patients taking the COX-2–selective inhibitors celecoxib and rofecoxib, the nonselective NSAID naproxen, or other nonnaproxen, nonselective NSAIDs (pp. 481-6). In a retrospective cohort study of health care data from Ontario, investigators identified 15,271 celecoxib users, 12,156 patients taking rofecoxib, 5,669 naproxen users, and 33,868 users of other nonselective NSAIDs, and 100,000 individuals not exposed to NSAIDs. Using multvariate Cox proportional hazards models, the group found “no significant differences in AMI risk for new users of celecoxib (adjusted rate ratio [aRR], 0.9; 95% confidence interval [CI], 0.7-1.2), rofecoxib (aRR, 1.0; 95% CI, 0.8-1.4), naproxen (aRR, 1.0; 95% CI, 0.6-1.7), or nonnaproxen nonselective NSAIDs (aRR, 1.2; 95% CI, 0.9-1.4).”

The authors conclude, “We observed no significant increased risk of AMI among users of celecoxib or rofecoxib, nor did we observe a significant protective effect for naproxen as these drugs are commonly used in clinical practice. While our findings relieve concerns about increased risks of AMI associated with celecoxib and rofecoxib, they call into question the cardioprotective benefits of naproxen observed in previous studies.” (M. Mamdani, Inst. for Clin. Eval. Sci., Toronto, Ontario, Canada; muhammad.mamdani@ices.on.ca)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 26, 2003 Vol. 10, No. 38
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Feb. 26 issue of JAMA (www.jama.com; 2003; 289).

Disclosing & Handling Medication Errors: Focus groups of 52 patients and 46 physicians reveals that both groups felt they would have unmet emotional needs if hypothetical medication errors occurred (pp. 1001-7). After qualitatively analyzing participants’ reactions to potential medication error situations [e.g., “insulin 10 U” being misinterpreted as “insulin 100 (units)” and development of medication-induced hyperkalemic arrhythmias that were not properly monitored by physicians], the authors report, “Patients wanted disclosure of all harmful errors and sought information about what happened, why the error happened, how the error’s consequences will be mitigated, and how recurrences will be prevented. Physicians agreed that harmful errors should be disclosed but ‘choose their words carefully’ when telling patients about errors. Although physicians disclosed the adverse event, they often avoided stating that an error occurred, why the error happened, or how recurrences would be prevented. Patients also desired emotional support from physicians following errors, including an apology. However, physicians worried that an apology might create legal liability. Physicians were also upset when errors happen but were unsure where to seek emotional support.” (T. H. Gallagher, thomasg@u.washington.edu)

U.S. Alcohol Consumption: Underage drinkers and adult excessive drinkers account for about one-half of alcohol consumption and expenditures in the U.S., according to an analysis of five data sets (pp. 989-95). The study combines data on 217,192 persons aged 12 years or older from three data sources with information from the census and on alcohol consumption and consumer expenditures. The proportion of underage individuals (ages 12–20 years) and adults (21 years and older) who drink was practically identical: 50.0% and 52.8%, respectively. Of 4.21 billion drinks that are consumed in the average month, 19.7% were consumed by underage drinkers, and 30.4% of the drinks were excessive (more than 2 drinks per day). Thus, of $116.2 billion spent on alcohol in 1999, underage drinkers were responsible for $22.5 billion, and adult drinkers spent $34.4 billion on excessive drinks.

The authors conclude, “These analyses show that it is not in the alcohol industry’s financial interest to voluntarily enact strategies to reduce underage or adult excessive drinking. These findings signal the need for parental engagement and vigilance to prevent underage drinking, for government action at the federal, state, and local levels to inform and educate the public, and to take other steps to curb underage and adult excessive drinking. These steps might include mounting aggressive public health campaigns similar to those that address smoking and illegal drug use; increasing taxes on alcohol; and enacting and enforcing tougher penalties on those who help minors obtain alcohol or on those who sell to minors. Action should also be taken to place restrictions on advertising and marketing of alcoholic beverages that target underage drinkers.” (S. E. Foster, Natl. Ctr. on Addiction and Substance Abuse, Columbia U., New York)

An editorialist adds, “Primary care practitioners should increase efforts to identify patients who are drinking to excess, conduct brief interventions for those who simply need to cut down, and refer those who may be dependent for further evaluation. Primary care practitioners can reduce problem drinking and its medical consequences by conducting brief interventions.” (G. R. Hanson, ghanson@mail.nih.gov)

From JAMA, 1903, the Origins of FDA: “If we can not depend on the dispenser for pure articles in our prescriptions the administration of medicine is a farce, and we had better go back to the old saddle bag or the more modern buggy case.... The foundation of a government drug laboratory, which would keep track of the standard preparations and check adulteration, would be a boon not only to the medical profession, but to its patrons.” (Originally published in JAMA, Feb. 28, 1903, pages 589-90.)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 27, 2003 Vol. 10, No. 39
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Feb. 27 issue of the New England Journal of Medicine (content.nejm.org; 2003; 348).

Adefovir & Hepatitis B: Two research papers and an editorial explore use of adefovir dipivoxil in treatment of antigen-negative and -positive chronic hepatitis B infection.
In 185 patients with hepatitis B e antigen–negative chronic hepatitis B, “48 weeks of adefovir dipivoxil treatment resulted in significant histologic, virologic, and biochemical improvement, with an adverse-event profile similar to that of placebo,” report authors (pp. 800-7). In the double-blind study, two-thirds of patients received adefovir dipivoxil 10 mg or placebo once daily. Liver-biopsy samples at 48 weeks showed improved histologic status in 64% of patients on active therapy, compared with 33% of those taking placebo. Serum HBV DNA levels dropped below 400 copies/mL in 51% of active-treatment patients (compared with none of those on placebo), and ALT levels normalized in 72% of adefovir patients (versus 29% of patients taking placebo). Resistance mutations were not found during the study, an important result given the need for long-term treatment of those with HBV. (S. J. Hadziyannis, Henry Dunant Hosp., Athens, Greece; hadziyannis@ath.forthnet.gr)

Similar conclusions were reached in a 48-week study of 515 patients with HBeAg-positive chronic hepatitis B (pp. 808-16). Comparing daily doses of 10 and 30 mg of adefovir dipivoxil with placebo, the authors found: “significantly more patients who received 10 mg or 30 mg of adefovir dipivoxil per day than who received placebo had histologic improvement [53%, 59%, and 25%, respectively], a reduction in serum HBV DNA levels (by a median of 3.52..., 4.76..., and 0.55 log copies per milliliter, respectively), undetectable levels (fewer than 400 copies per milliliter) of serum HBV DNA [21%, 39%, and 0%, respectively], normalization of alanine aminotransferase levels [48%, 55%, and 16%, respectively], and HBeAg seroconversion [12%, 14%, and 6%, respectively]. No adefovir-associated resistance mutations were identified in the HBV DNA polymerase gene. The safety profile of the 10-mg dose of adefovir dipivoxil was similar to that of placebo; however, there was a higher frequency of adverse events and renal laboratory abnormalities in the group given 30 mg of adefovir dipivoxil per day.” (P. Marcellin, Hôpital Beaujon, Clichy, France; marcellin@bichat.inserm.fr)

Editorialists are encouraged by the lack of mutations in these studies, given their occurrence in during lamivudine treatment of HBV (pp. 848-50). They conclude, “Although one cannot predict the duration of successful suppression of HBV replication by adefovir, we appear to be at the dawn of a new era. We hope that HBV vaccination, together with access to competitively priced lamivudine, adefovir, and other potent nucleoside analogues and, possibly, their use in combination, will herald the transformation of chronic HBV infection from a global scourge to a mere nuisance.” (M. E. Mailliard, U. Nebr. Med. Ctr., Omaha)

Growth Hormone & Aging: Two editorials address antiaging effects of growth hormone and related promotions of the dietary supplements industry. Vance reiterates advice she offered when GH first surfaced in 1990 as a potential antiaging agent (pp. 779-80): “There is no current ‘magic-bullet’ medication that retards or reverses aging. It remains to be determined whether growth hormone secretagogues that consistently increase endogenous production of growth hormone are beneficial in the elderly. Antiaging therapy with growth hormone has not yet been proved effective according to objective outcome criteria.” (M. L. Vance, U. Va. Med. Ctr., Charlottesville)

The journal’s Editor-in-Chief explains that promotional e-mails cite the above 1990 study as evidence that people should purchase “human growth hormone releaser” products (pp. 777-8). “Advertising is advertising,” he reminds readers. “The editors of the
Journal do not endorse any product for any commercial use. We strongly believe that when scientific information is communicated clearly and fairly, it speaks for itself.” (J. M. Drazen)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 28, 2003 Vol. 10, No. 40
Providing news and information about medications and their proper use

>>>Circulation Highlights
Source:
Feb. 25 Circulation (circ.ahajournals.org; 2003; 107).

Antioxidant Vitamins & Atherosclerosis: Six-year data from the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) study confirm 3-year results: Vitamin E and slow-release vitamin C supplementation slows the atherosclerotic process in men and women with hypercholesterolemia (pp. 947 ff). Among 520 smoking and nonsmoking men and postmenopausal women aged 45–69 years with mean serum cholesterol of 193 mg/dL, the slope of the mean intima–media thickness of the common carotid artery was reduced by 26% (33% in men and 14% in women) among those on vitamin supplements, compared with unsupplemented patients. Larger effects occurred in patients with low baseline vitamin C levels and with lower initial plaque thickness. (J. T. Salonen, U. Kuopio, Kuopio, Finland; jukka.salonen@uku.fi)

Acetylcysteine in ESRD: The antioxidant effects of acetylcysteine reduce cardiovascular complications among patients on maintenance hemodialysis, according to a study of 76 men and 58 women with end-stage renal disease (pp. 992 ff). The patients had been on hemodialysis a minimum of 3 months before the study began, average age was 62 years, acetylcysteine doses were 600 mg twice daily, and median length of treatment was 14.5 months (range, 1–24 months). The authors found a 40% reduction in the risk of a composite cardiac variable (fatal and nonfatal myocardial infarction, cardiovascular disease death, need for coronary angioplasty or coronary bypass surgery, ischemic stroke, peripheral vascular disease with amputation, or need for angioplasty), compared with patients taking placebo (28% of treated patients experienced one or more of these events, compared with 47% of control patients). No significant between-group differences were identified for any of the variables individually or for total mortality. (M. Tepel, Freie Universität Berlin, Berlin, Germany; Tepel@zedat.fu-berlin.de)

>>>Psychiatry Report
Source:
Feb. American Journal of Psychiatry (www.psychiatryonline.org; 2003; 160).

Reboxetine & Olanzapine-Induced Weight Gain: In a 6-week trial, reboxetine treatment reduced olanzapine-associated weight gain among 20 patients with schizophrenia (pp. 297-302). Compared with patients taking olanzapine 10 mg daily with a placebo, patients who took reboxetine 4 mg daily plus the antipsychotic agent had a significantly lower mean body weight gain (2.5 kg, compared with 5.5 kg). Only 2 of 10 patients completing the study gained at least 7% of their initial body weight when on combination treatment, while 7 of 10 patients in the placebo group did so. Reboxetine is a selective norepinephrine reuptake inhibitor marketed outside the U.S. (M. Poyurovsky)

Metabolic Effects of Antipsychotic Agents: Both typical and atypical antipsychotic agents produced elevations in blood glucose in substantial portions of 101 patients in a 14-week study, but only the atypical agents increased serum cholesterol values (pp. 290-6). The patients, whose baseline serum glucose levels were less than 125 mg/dL, were taking clozapine, olanzapine, risperidone, and haloperidol on fixed doses for 8 weeks and variable doses for an additional 6 weeks. The authors report, “There were significant increases in glucose levels at the end of the 8-week fixed-dose period for patients given clozapine (N=27) and those given haloperidol (N=25). The olanzapine group showed a significant increase of glucose levels at the end of the 6-week variable-dose period (N=22). Fourteen of the 101 patients developed abnormal glucose levels (>125 mg/dl) during the trial (six with clozapine, four with olanzapine, three with risperidone, and one with haloperidol). Cholesterol levels were increased at the end of the 8-week fixed-dose period for the patients given clozapine (N=27) and those given olanzapine (N=26); cholesterol levels were also increased at the end of the 6-week variable-dose period for patients given olanzapine (N=22).” (J-P Lindenmayer)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 3, 2003 Vol. 10, No. 41
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
Mar. 1 issue of Lancet (www.thelancet.com; 2003; 361).

Lowering Cardiovascular Risk: Personal and nonpersonal (e.g., governmental) health interventions could avert more than 21 million disability-adjusted life-years over the next 10 years, according to an analysis from the World Health Organization (pp. 717-25). Using effect sizes for factors such as systolic blood pressure and elevated cholesterol levels from published reviews and meta-analyses, an author estimates, “Non-personal health interventions, including government action to stimulate a reduction in the salt content of processed foods, are cost-effective ways to limit cardiovascular disease and could avert over 21 million DALYs per year worldwide. Combination treatment for people whose risk of a cardiovascular event over the next 10 years is above 35% is also cost effective leading to substantial additional health benefits by averting an additional 63 million DALYs per year worldwide.” (D. B. Evans; Evansd@who.int)

Defining HIV-Associated Lipodystrophy: A broad, inclusive model is needed to define HIV-associated lipodystrophy, according to an analysis of data from 1,081 adult outpatients (pp. 726-35). Models that included only clinical or clinical/metabolic variables were not as sensitive or specific as an inclusive model that included these variables: age, sex, duration of HIV infection, HIV disease stage, waist-to-hip ratio, anion gap, serum HDL cholesterol concentration, trunk to peripheral fat ratio, percentage leg fat, and intra-abdominal to extra-abdominal fat ratio. Sensitivity of the inclusive model was 79%, and specificity was 80%. “Our study serves as a model for the development of objective measures for other common, subjectively defined, adverse events associated with antiretroviral treatment, such as peripheral neuropathy, symptomatic lactic acidaemia, sexual dysfunction, and clinical hepatitis,” the authors conclude. (A. Carr, St. Vincent’s Hosp., Sydney , Australia; acarr@stvincents.com.au)

>>>BMJ Highlights
Source:
Mar. 1 issue of BMJ (www.bmj.org; 2003; 326).

Vitamin D Supplements: Oral administration of one vitamin D3 capsule (cholecalciferol) 100,000 IU every 4 months for 5 years is an effective preventive for preventing fracture among community-dwelling older patients (pp. 469 ff). Among 2,037 men and 649 women aged 65–85 years, relative risks of incident fractures in the vitamin D group were 0.78 for any first fracture and 0.67 for first hip, wrist or forearm, or vertebral fracture, compared with placebo. Mortality was reduced by 12% among patients taking vitamin D. The authors note, “Many interventions effective in high risk groups are not feasible in the general population owing to poor compliance or side effects or are not cost effective. In contrast, the cost of four-monthly oral 100,000 IU vitamin D is minimal.” (K. T. Khaw, U. Cambridge Sch. of Clin. Med., Cambridge, U.K.; kk101@med schl.cam.ac.uk)

>>>PNN JournalWatch
* Apolipoproteins Versus Lipids as Indices of Coronary Risk and as Targets for Statin Treatment [viewpoint], in Lancet, 2003; 361: 777–80. Reprints: www.thelancet.com; A. D Sniderman, Royal Victoria Hosp., Montreal; allan.sniderman@muhc.mcgill.ca

* Age Related Macular Degeneration, in
BMJ, 2003; 326: 485–8. Reprints: www.bmj.org; A. Chopdar, E. Surrey Hosp., Redhill, Surrey, U.K.; vision@nearpoint.fsnet.co.uk

* New Anti-Human Immunodeficiency Virus Type 1 6-Aminoquinolones: Mechanism of Action, in
Antimicrobial Agents & Chemotherapy, 2003; 47: 889–96. Reprints: aac.asm.org; M. Palumbo.

* High Variability of Plasma Drug Concentrations in Dual Protease Inhibitor Regimens, in
Antimicrobial Agents & Chemotherapy, 2003; 47: 889–96. Reprints: aac.asm.org; J.-B. Guiard-Schmid.

* Concomitant Psychotropic Medication for Youths, in
American Journal of Psychiatry, 2003; 160: 438–49. Reprints: ajp.psychiatryonline.org; D. J. Safer.

* Addressing Parents’ Concerns: Do Vaccines Cause Allergic or Autoimmune Diseases?, in
Pediatrics, 2003; 111: 653–9. Reprints: www.pediatrics.org; P. A. Offit, U. Penn., Philadelphia.

* Assessing Glycemic Control in Patients with Diabetes and End-Stage Renal Failure, in
American Journal of Kidney Diseases, 2003; 41: 523–31. Reprints: www.ajkd.org; D. Goldsmith, Guy’s Hosp., London; david.goldsmith@kcl.ac.uk

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 4, 2003 Vol. 10, No. 42
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Mar. 4 issue of the Annals of Internal Medicine (www.annals.org; 2003; 138).

Safety of Ephedra: Compared with other herbal products, ephedra produces a greatly increased risk of adverse reactions, according to an article posted early to the Annals’ Web site. A comparative case series assessed reports during 2001 to the American Association of Poison Control Centers Toxic Event Surveillance System Database. Ephedra-containing products accounted for 64% of all adverse reactions to herbs, even though they constituted only 0.82% of herbal product sales, the authors report. “The relative risks for an adverse reaction in persons using ephedra compared with other herbs were extremely high, ranging from 100 (95% CI, 83 to 140) for kava to 720 (CI, 520 to 1100) for Ginkgo biloba,” writes the group. “Ephedra use is associated with a greatly increased risk for adverse reactions compared with other herbs, and its use should be restricted.” (S. Bent, bent@itsa.ucsf.edu)

Vitamin Supplements & Infection: Adults aged 45 years and older, especially those type 2 diabetes, had a reduced incidence of infections when they took a daily multivitamin/mineral supplement (pp. 365-71). In a study of 130 community-dwelling adults, investigators found self-reported infectious illness in 73% of patients assigned to placebo but only 43% of those taking vitamins. The difference was more marked among patients with type 2 diabetes (n = 51): 93% of those taking placebo reported an infection, compared with 17% of those on a supplement. “These dramatic results warrant testing in a larger clinical trial, both for confirmation and to disentangle the effects of chronic disease status from those of other important factors, such as ethnicity and obesity, that serve as proxies for socioeconomic status and poorer nutrition,” the authors conclude. “Multivitamin and mineral supplements are convenient and relatively inexpensive. If our results are confirmed in a larger trial, the widespread implementation of this preventive measure could have a substantial economic impact and could ease the burden of suffering in our society.” (T. A. Barringer, Carolinas Med. Ctr., Charlotte, N.C.; tbarringer@carolinas.org)

An editorialist agrees with this assessment (pp. 430-1): “Vitamin supplements are inexpensive and might improve health status in settings where infections are major public health problems. In developed countries, infections pose important economic burdens. The potential impact of supplements merits further rigorous study, especially among diabetic persons and other vulnerable populations.” (W. Fawzi, Harvard Sch. of Public Health, Boston)

Benefits of Attempting Weight Loss: People who try to lose weight have lower mortality rates, even if they do not successfully reduce their body mass, according to a study of 6,391 overweight and obese persons aged 35 years and older (pp. 383-9). In a prospective cohort study, the individuals were assessed by self-report in 1989, and vital status was followed for 9 years. Among patients who intentionally lost weight, mortality rates were 24% lower, while they were 31% higher among patients who lost weight without trying to. “However, mortality rates were lower in persons who reported trying to lose weight than those in not trying to lose weight, independent of actual weight change,” the paper states. “Compared with persons not trying to lose weight and reporting no weight change, persons trying to lose weight had the following [hazard rate ratios]: no weight change, 0.80 (CI, 0.65 to 0.99); gained weight, 0.94 (CI, 0.65 to 1.37); and lost weight, 0.76 (CI, 0.60 to 0.97).” (E. W. Gregg, edg7@cdc.gov)

Homeopathy Deserves Chance But Needs Data: Homeopathy may be effective for influenza, allergies, postoperative ileus, and childhood diarrhea—and possibly for migraine, delayed-onset muscle soreness, and influenza prevention—according to an author who reviews the controversial practice (pp. 393-9). With data lacking for most conditions, the writer calls for an open-minded approach to the subject but adds that homeopathic remedies should not be substituted for proven therapies. (W. B. Jonas, Samueli Inst., Alexandria, Va.; wjonas@siib.org)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 5, 2003 Vol. 10, No. 43
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Mar. 5 issue of JAMA (www.jama.com; 2003; 289).

Preventable ADEs Among the Elderly: About one fourth of adverse drug events (including medication errors) among elderly patients could be prevented through better pharmaceutical care, according to researchers who analyzed Medicare enrollees cared for by a multispecialty group practice in 1999–2000 (pp. 1107-16). In 30,397 person-years of observation, 1,523 ADEs were identified, and 27.6% of those were considered preventable. The authors add, “Errors associated with preventable adverse drug events occurred most often at the stages of prescribing (n = 246, 58.4%) and monitoring (n = 256, 60.8%), and errors involving patient adherence (n = 89, 21.1%) also were common. Cardiovascular medications (24.5%), followed by diuretics (22.1%), nonopioid analgesics (15.4%), hypoglycemics (10.9%), and anticoagulants (10.2%) were the most common medication categories associated with preventable adverse drug events. Electrolyte/renal (26.6%), gastrointestinal tract (21.1%), hemorrhagic (15.9%), metabolic/endocrine (13.8%), and neuropsychiatric (8.6%) events were the most common types of preventable adverse drug events.” (J. H. Gurwitz, jerry. gurwitz@umassmed.edu)

Based on the new findings, an editorialist writes that “it is time to move beyond the illusion of medication safety to face the difficult reality of acknowledging the significant risk that medications pose to patients and implementing strategies to reduce it”: “Interventions to reduce ADEs need to be implemented. Several interventions have been demonstrated to improve ambulatory drug use in older persons, including curbing overuse of medications by identifying inappropriate medications and stopping their use and addressing underuse of beneficial medications. Patient nonadherence may be remedied through patient education, but commonly used approaches to ensure patient adherence often are not effective, and novel new methods to involve patients more directly in all aspects of their care are needed. In addition, several interventions effective at reducing medication errors in the inpatient setting could be generalized to the outpatient setting. These include computerized physician order entry of medications with decision support (ie, drug interaction checking, allergy checking, dose and frequency adjusting, and treatment duration limits), clinical pharmacist consultation services, and clinics for anticoagulation therapy.” (D. Classen, Salt Lake City, dckasseb@fcg.com)

Medical vs. Invasive Approaches for Angina: Even though invasive management of chronic coronary artery disease in the elderly produces better short-term outcomes, the two options produce similar outcomes at 1 year, conclude authors who studied 282 patients with chronic angina (pp. 1117-23). At 14 Swiss centers, patients randomly underwent coronary angiography followed by revascularization when feasible or received optimized medical therapy. Later hospitalization was less likely with revascularization (10% vs. 46% of those on medical therapy), but the invasive approach carried an early intervention risk. The authors conclude that “1-year outcomes in elderly patients with chronic angina are similar with regard to symptoms, quality of life, and death or nonfatal infarction with invasive vs optimized medical strategies based on this intention-to-treat analysis.” (M. Pfisterer, U. Hosp., Basel, Switzerland; pfisterer@email.ch)

Treatment of Aplastic Anemia: Antithymocyte globulin 40 mg/kg/day for 4 days and cyclosporine 10–12 mg/kg/day for 6 months produced “durable recovery and excellent long-term survival” in 122 patients with severe aplastic anemia (pp. 1130-5). In this uncontrolled trial conducted in 1991–98, response rates were 60% at 3 months, 61% at 6 months, and 58% at 1 year. Patients who responded early had better survival at 5 years (86% vs. 40%), and no deaths occurred among patients who survived to 3 years after treatment. Relapses occurred commonly, but they did not involve severe pancytopenia, and relapses did not affect survival. (N. S. Young, youngn@nhlbi.nih.gov)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 6, 2003 Vol. 10, No. 44
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Mar. 6 issue of the New England Journal of Medicine (content.nejm.org; 2003; 348).

Aspirin & Colorectal Cancer Risk: Two studies and a perspective article explore the role of daily aspirin in prevention of colorectal cancer.

In 517 patients with previous colorectal cancer, aspirin 325 mg/day reduced significantly the number of patients with adenomas during a median of 12.8 months after randomization (17% among those taking aspirin, compared with 27% of placebo recipients; pp. 883-90). A mean of 0.30 adenomas were found among those on aspirin, compared with 0.49 for the placebo group. Time to detection of first adenoma was also longer among those on aspirin, as reflected by a hazard ratio of 0.64. “Before aspirin use can be recommended for patients with colorectal cancer, the risks and benefits of the drug will need to be compared with those of alternative chemopreventive agents,” the authors advise. (R. S. Sandler, rsandler@med.unc.edu)

Low-dose aspirin—but not doses of 325 mg/day—had a moderate chemoprotective effect in a study of 1,121 patients with recent histories of adenomas (pp. 891-9). Compared with placebo, the unadjusted relative risk of any adenoma on colonoscopy at least 1 year after randomization was 0.81 for patients taking aspirin 81 mg/day but 0.96 for the 325 mg/day group. RRs for advanced neoplasms were 0.59 (significant) and 0.83 (not significant) for the two groups, respectively. The authors write, “It is not clear why a dose of 81 mg of aspirin per day, but not 325 mg, reduced the risk of adenomas in our study.... The 81-mg dose and the 325-mg dose appear to suppress colorectal prostaglandin levels to a similar extent and thus may have equivalent chemopreventive potency through cyclooxygenase-related mechanisms. Perhaps the most likely explanation for our finding is that a low threshold dose is required for chemoprotection and that the differences in effects between the low dose and the high dose were the result of chance.” (J. A. Baron, john.a.baron@dartmouth.edu)

The author of the Perspective article adds (pp. 879-80), “If aspirin were used for primary prophylaxis against colorectal cancer in adults at average risk, the lower base-line risk of neoplasia would mean that more people would need to be treated for a period of 10 to 20 years or longer.... The cumulative risk of major adverse effects most likely outweighs any benefit in the prevention of colorectal cancer, particularly when prevention due to screening is considered.... With the same side-effects profile, the benefit of aspirin in coronary artery disease is arguably much greater, yet the U.S. Preventive Services Task Force does not recommend aspirin unless the five-year risk of coronary artery disease is 3 percent or higher....

“Although aspirin may be of some benefit in preventing colorectal cancer, it cannot yet be recommended for this indication and is not a substitute for screening and surveillance.” (T. F. Imperiale, Indiana U., Indianapolis)

LHRH Agonists for Short Stature: In adolescents with very short stature, a luteinizing hormone–releasing hormone agonist significantly increased adult height but also produced substantial decreases in bone mineral density, according to a study of 18 boys and 32 girls (pp. 908-17). Among 47 patients followed to adult height, deslorelin 4 mcg/kg administered each evening by subcutaneous injection for 4 years produced an increase of 0.6 standard deviations for height and an increase of 4.2 cm over the initially predicted adult height. “Treatment with an LHRH agonist resulted in significantly greater adult height than did placebo in boys and girls, in adolescents with idiopathic short stature, and in those who had a growth-limiting syndrome,” the authors report. However, BMD among those on deslorelin was 1.6 SDs below the population mean at the time adult height was reached, compared with 0.3 SD below the mean for those who received placebo. “LHRH-agonist treatment cannot be routinely recommended to augment height in short adolescents with normally timed puberty,” concludes the group. (J. A. Yanovski, yanovskj@mail.nih.gov)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 7, 2003 Vol. 10, No. 45
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Mar. Pharmacotherapy (www.accp.com; 2003; 23).

Cefepime Dosing: Compared with the recommended dosage schedule for the fourth-generation cephalosporin cefepime, higher dosages or extended infusion times are needed when treating Pseudomonas aeruginosa infections (pp. 291-5). In 1,000 patients in medical and surgical intensive care units who were evaluated retrospectively, standard, maximum, nonstandard, and continuous doses had been administered. Patient data were used to derive steady-state pharmacokinetic profiles of cefepime against P. aeruginosa. Among patients with creatinine clearances of 120, 90, and 60 mL/min, the standard and maximum dosages achieved kinetic targets for 4–38% and 21–68% of patients, respectively. The nonstandard dosage, 2 g every 12 hours with each dose infused over 6 hours, increased the proportion of patients achieving the target to 18–63%. A continuous infusion of 4 g over 24 hours “offered the most promising pharmacodynamic target, attaining 65–81%,” the authors wrote. (G. L. Drusano, Ordway Res. Inst., Albany, N.Y.; gldrusano@aol.com)

Cefepime in the CNS: In patients with external ventricular drains, cefepime achieves concentrations in the central nervous system higher than the minimum inhibitory concentrations of many common nosocomial organisms, conclude authors who evaluated seven such patients (pp. 310-4). Based on serial serum and cerebrospinal fluid samples obtained concurrently after the fourth intravenous cefepime dose, a two-compartment model showed 4–34% penetration into the CNS based on area under the curve and 5–58% based on minimum concentrations, similar to values for other cephalosporins used to treat meningitis. (D. H. Rhoney, drhoney@wayne.edu)

Outpatient DVT Treatment: Shifting care of proximal deep-vein thrombosis from the inpatient to the outpatient setting is financially advantageous, according to a cost-minimization analysis (pp. 301-9). Compared with 49 historical inpatient controls who were treated with unfractionated heparin, mean cost of care was significantly reduced among 51 outpatients treated with low molecular weight heparin (in Canadian dollars adjusted for the differences in fiscal years, $248 vs. $2,826). Nursing time constituted 51% of outpatient costs, followed by monitoring laboratory tests (5%), drugs (2%), and other costs (diagnostic laboratory tests and medical imaging, 42%). (M. Boucher, Canadian Coordinating Office for Health Technology Assessment, Ottawa, Ontario, Canada)

Health Benefits from Diuretic Adherence: Patients with heart failure who took a greater proportion of their diuretic doses had lower risks of cardiovascular- and heart failure-related hospitalizations, according to a study of 42 individuals (pp. 326-32). All patients were prescribed a diuretic, usually furosemide (88% of patients). Electronic monitoring was used to detect their adherence to diuretic therapy (percentage of diuretic prescription container openings) and to scheduling (percentage of container openings within a specified time). The authors found a mean of 72% for adherence and 43% for scheduling, with wide ranges among the patients. “Log-linear models revealed that poor scheduling adherence was associated with increased cardiovascular-related hospitalizations ... and predicted more heart failure-related hospitalizations,” the group writes. “In contrast, neither measure was significantly associated with cardiovascular- or heart failure-related emergency department visits. We found a moderate correlation between scheduling adherence and taking adherence.” (M. D. Murray, Regenstrief Inst., Indianapolis; mmurray@regenstrief.org)

Bioavailability of Testosterone: Bioavailability of a new oral testosterone undecanoate formulation was increased by food in 16 healthy postmenopausal women (pp. 319-25). “For proper absorption, Andriol Testocaps must be taken with meals,” the authors conclude. (W. M. Bagchus, Organon, Oss, the Netherlands, wilma.bagchus@organon.com)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 10, 2003 Vol. 10, No. 46
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Mar. 8 issue of BMJ (www.bmj.org; 2003; 326).

Costs of MS Treatments: Prices of four disease-modifying treatments for multiple sclerosis drive their costs per quality-adjusted life-years to high levels, according to a cost-effectiveness evaluation (pp. 522 ff). Three dosage levels of interferon beta plus one regimen of glatiramer acetate were evaluated based on prices in the U.K. National Health Service. QALY costs ranged from 42,000 British pounds ($66,469) to 98,000 pounds, and the authors found that the probability of any treatment having a cost-effectiveness below 20,000 pounds at 20 years was below 20%.

The investigators comment, “Further research to establish the impact of these treatments by using robust and stable outcome measures would be of considerable value in improving the precision of estimates for cost effectiveness. It would also be extremely valuable to obtain real data on the progress of people once they have stopped treatment. Given the length of time that these drugs have been in use, it should be possible to gather such data. In the short term, the key modifiable determinant of the cost effectiveness of these drugs is their price.” (C. McCabe, U. Sheffield, Sheffield, U.K.; c.mccabe@sheffield.ac.uk)

>>>Lancet Report
Source:
Mar. 8 issue of Lancet (www.thelancet.com; 2003; 361).

Azithromycin for ACS: Despite evidence of an association between Chlamydia pneumoniae infection and coronary artery disease, short-term treatment with azithromycin had no effect on development of recurrent events in patients with acute coronary syndromes (pp. 809-13). A total of 1,439 patients hospitalized for unstable angina or acute myocardial infarction received either placebo or azithromycin 500 mg on the first day followed by azithromycin 250 mg daily for 4 days. During 6 months of follow-up, the investigators found no significant differences in the numbers of deaths, recurrent MIs, or recurrent ischemic episodes requiring revascularization. (B. Cercek, Cedars-Sinai Med. Ctr., Los Angeles; cercek@cshs.org)

Interferon alfa-2a for Japanese Encephalitis: Interferon alfa-2a administered in doses of 10 million units/sq m for 10 days failed to improve outcomes in 112 Vietnamese children with suspected Japanese encephalitis (pp. 821-6). Compared with placebo, active therapy did not affect mortality or development of severe sequelae. “Whether treatment with higher doses via alternative routes, perhaps in combination with other drugs, and possibly earlier in the disease, would be beneficial in flavivirus encephalitis remains to be seen—although the cost of such treatments in areas where Japanese encephalitis is endemic is likely to be prohibitive,” the authors write. “Despite the availability of vaccines, Japanese encephalitis continues to cause high morbidity and mortality in southern and eastern Asia.... There is an urgent need for more research into the treatment of flavivirus encephalitis.” (T. Solomon, U. Liverpool, Liverpool, U.K.; tsolomon@liv.ac.uk)

>>>PNN JournalWatch
* Diagnosis and Management of Scalp Ringworm, in BMJ, 2003; 326:539–41. Reprints: www.bmj.org; L. C. Fuller, King’s College Hosp., London, U.K.; claire.fuller@kcl.ac.uk

* Efficacy and Safety of Electroconvulsive Therapy in Depressive Disorders: A Systematic Review and Meta-analysis, in
Lancet, 2003; 361: 799–808. Reprints: www.thelancet.com; J. Geddes, Department of Psychiatry, U. Oxford, Oxford, U.K.; john.geddes@psych.ox.ac.uk

* Antiadrenergic Therapy of Chronic Heart Failure: Surprises and New Opportunities, in
Circulation, 2003; 107: 1100–2. Reprints: circ.ahajournals.org; M. Bristow.

* Contemporary Management of Paroxysmal Supraventricular Tachycardia, in
Circulation, 2003; 107: 1096–9. Reprints: circ.ahajournals.org; J. D. Ferguson.

* Nicotine Patch Therapy Based on Smoking Rate Followed by Bupropion for Prevention of Relapse to Smoking, in
Journal of Clinical Oncology, 2003; 21: 914–20. Reprints: www.jco.org; R. D. Hurt, rhurt@mayo.edu

* Bioterrorism: Pivotal Clinical Issues. Consensus Review of the Society of Infectious Diseases Pharmacists, in
Pharmacotherapy, 2003; 23: 274–90. Reprints: www.accp.com; B. M. Lamaestro, Albany Med. Ctr. Hosp., Albany, N.Y.; lomaesb@mail.amc.edu

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 11, 2003 Vol. 10, No. 47
Providing news and information about medications and their proper use

>>>Ephedra Study Released Early by JAMA
The evidence supporting use of ephedra for enhancing athletic performance and promoting weight loss is insufficient, according to an FDA-commissioned article released yesterday on the JAMA Web site (www.jama.com). But important health risks are strongly linked to use of the dietary supplement, authors note, including heart palpitations and psychiatric, gastrointestinal, and nervous system problems.

The RAND Corporation article, a meta-analysis of 52 controlled trials and 65 case reports of adverse events, will appear in the Mar. 26 issue of
JAMA (pp. 1537-45). Pooled results of clinical studies of ephedra, ephedrine, caffeine, and/or herbs containing caffeine showed that the products enabled patients to lose an average of 0.6–1.0 kg/month, depending on the formulation used.

“No trials of ephedra and athletic performance were found; 7 trials of ephedrine were too heterogeneous to synthesize,” write the authors. “Safety data from 50 trials yielded estimates of 2.2- to 3.6-fold increases in odds of psychiatric, autonomic, or gastrointestinal symptoms, and heart palpitations. Data are insufficient to draw conclusions about adverse events occurring at a rate less than 1.0 per thousand. The majority of case reports are insufficiently documented to allow meaningful assessment.” (P. G. Shekelle, RAND Corp., Santa Monica, Calif.; shekelle@rand.org)

In an accompanying opinion article, three
JAMA editors call for “new legislation ... for defining and regulating dietary supplements.” They specifically maintain that four steps are needed: (1) address the scope of categories of products included under the definition of dietary supplements, adding that it is currently too broad, (2) subject dietary supplements to more rigorous federal regulation, an action that was proposed last week by FDA, (3) establish formal systems for mandatory postmarketing surveillance and adverse event reporting, and (4) ensure that advertising for dietary supplements is accurate and not misleading. (P. B. Fontanarosa, phil_fontanarosa@ama-assn.org)

>>>Internal Medicine Report
Source:
Mar. 10 issue of Archives of Internal Medicine (www.archinternmed.com; 2003; 163).

Treating Hypertension in African Americans: In a consensus statement of the Hypertension in African Americans Working Group of the International Society on Hypertension in Blacks, experts call for a new approach to the management of high blood pressure in African Americans (pp. 525-41). “These strategies involve assessing cardiovascular risk; setting, achieving, and maintaining an appropriate blood pressure target; assisting patients to implement therapeutic lifestyle changes; and administering effective pharmacologic interventions early and persistently,” the group writes. “To reach appropriate blood pressure levels, most African Americans will require combination antihypertensive therapy. When combination therapy using agents from 2 major drug classes is required to achieve target blood pressure goals, the following combinations may be considered effective: beta-blocker/diuretic, ACE inhibitor/ diuretic, ACE inhibitor/[calcium-channel blocker], or [angiotensin II receptor blocker]/diuretic.” (J. G. Douglas, Case Western Reserve U., Cleveland; jgd3@po.cwru.edu)

Antihypertensive Adherence, Intolerance, & Psychiatric Illness: Patients with panic attacks, anxiety, or depression are more likely to have non–drug-specific intolerance to antihypertensive agents and to not adhere to regimens as a result (pp. 592-600). Among 233 patients with hypertension who had at least two episodes of intolerance during a 1-year period, 92% of 576 episodes were subjective (meaning that the patient was asymptomatic), and nearly one-half of these episode were not drug-specific. Patients with nonspecific intolerance had higher systolic blood pressures. “Physicians treating hypertensive patients need to recognize and manage the psychiatric aspects of intolerance to multiple antihypertensive drugs,” the authors conclude. (P. R. Jackson, Royal Hallamshire Hosp., Sheffield, U.K.; peter.r.jackson@sheffield.ac.uk)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 12, 2003 Vol. 10, No. 48
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Mar. 12 issue of JAMA (www.jama.com; 2003; 289).

Hyperhomocysteinemia & CHF: A study of 2,491 community-dwelling adults adds congestive heart failure to the list of conditions associated with elevated levels of homocysteine (pp. 1251-7). The patients, with a mean age of 72 years, had no history of myocardial infarction or CHF. They were followed for 8 years in the 1980s as part of the Framingham Heart Study. A first episode of CHF occurred in 88 women and 68 men. Plasma homocysteine levels were higher than the sex-specific median in patients with CHF, with adjusted hazard ratios of 1.93 in women and 1.84 in men.

The authors comment on their findings, “Our findings are consistent with the hypothesis that elevated plasma homocysteine levels are an important risk factor for CHF. The finding of a doubling of CHF risk in women with plasma homocysteine levels in the second quartile, at levels hitherto considered normal, is provocative. Given the novelty of our findings, we would like to underscore the need for additional studies to corroborate our results. Also, experimental investigations are required to clarify further the pathophysiological mechanisms underlying the observed association and the sex-related differences observed in our sample. If our observational findings are confirmed, additional studies (clinical trials) will be required to examine the possibility that lowering elevated homocysteine levels through vitamin therapy with folic acid, alone or in combination with pyridoxine hydrochloride and cyanocobalamin, may reduce the risk of CHF.” (R. S. Vasan, Framingham Heart Study, Framingham, Mass.; vasan@fram.nhlbi.nih.gov)

Handwashing Techniques & Anthrax: The new waterless handwashing gels performed poorly in a study that evaluated the efficacy of several techniques for removal of a Bacillus species from contaminated hands (pp. 1274-7). Hands of healthy adult volunteers were contaminated with 5 mL of a liquid inoculum of spores of B. atrophaeus, a surrogate for B. anthracis. Nonantimicrobial soap and water, 2% chlorhexidine gluconate, and chlorine-containing towels were all effective at removing the spores, but a waterless rub containing 61% ethyl alcohol failed to eliminate the spores at all times tested (10, 30, and 60 seconds). “Our data suggest that current recommendations for decontamination of exposed persons with soap and water is likely adequate,” the authors conclude. “Chlorhexidine gluconate, an agent with excellent antimicrobial activity against vegetative bacteria and viruses, did not provide improved elimination of spores compared with soap and water.... When soap and running water are not available in the field, waterless rubs containing ethyl alcohol should not be used, because they are ineffective in inactivating or removing spores. Rather, small amounts of water should be carried in rescue vehicles, allowing the use of chlorine-containing towels for handwashing.” (D. J. Weber, dweber@unch.unc.edu)

Translating Research into Practice: Commenting on a special Institute of Medicine report on “Central Challenges Facing the National Clinical Research Enterprise” (pp. 1278-87; N. S. Sung, Burroughs Wellcome Fund, Research Triangle Park, N.C.; nsung@bwfund.org), an editorialist writes, “An independent group, composed of the nation’s most prestigious investigators and clinicians, should alert the president and leaders of Congress about [the loss of life that results from our failure to bring research to the bedside]. A single short letter should point out the human consequences due to the present inefficient system of translating information from the laboratory to the bedside, request a meeting, and ask for the resources and authority to design a whole new system and approach. [This] inertia and inefficiency of the flow of scientific information from research laboratories ... to patients, as described in [this] report, is a national crisis of major proportions. A clarion call to action no different in scope than that described by Einstein and no less needed than the response to September 11 is required to save lives.” (R. N. Rosenberg, Roger.Rosenberg@utsouthwestern.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 13, 2003 Vol. 10, No. 49
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Mar. 13 issue of the New England Journal of Medicine (content.nejm.org; 2003; 348).

Immunologic Treatment of Peanut Allergy: Two articles address factors that cause and ways to treat peanut allergy.

Application of skin products that contain peanut oil to inflamed skin of infants and children is associated with development of peanut allergy, according to interview data from a cohort study of 13,971 preschool children (pp. 977-85). Children were 6.8 times more likely to develop peanut allergies after application of such products—mostly emollients used to treat diaper rash, eczema, dry skin, and inflammatory cutaneous conditions. Other significant factors included intake of soy milk or soy formula (odds ratio, 2.6) and presence of rash over joints and skin creases (OR, 5.2) or oozing, crusted rash (OR, 5.2). The authors surmise that the association between peanut allergy and use of soy products might be the result of common epitopes that produce cross-sensitization. (G. Lack, St. Mary’s Hosp; London)

Subcutaneous injections of a monoclonal antibody provided protection for peanut-sensitive patients at a level that could prevent reactions to accidental ingestions of small amounts of peanut protein (pp. 986-93). Peanut allergies affect 1.5 million Americans and cause 50–100 deaths annually. Many of these occur after people unknowingly ingest peanut protein present in many foods. The investigators tested three doses (150, 300, and 450 mg) of a humanized IgG1 monoclonal antibody against IgE that recognizes and masks an epitope in the CH3 region of IgE responsible for binding to the high-affinity Fc receptor on mast cells and basophils. At baseline, 84 peanut-sensitive patients reacted to from 178 (about one-half of a peanut) to 436 mg of encapsulated peanut flour in an oral food challenge. The highest subcutaneous dose of TNX-901 enabled patients to tolerate an average of 2,627 mg of peanut flour, equivalent to nearly nine peanuts. This “effect ... should translate into protection against most unintended ingestions of peanuts,” the authors conclude. (H. A. Sampson, Mount Sinai Sch. of Med., New York City; hugh.sampson@mssm.edu)

Imatinib for CML: For first-line therapy of newly diagnosed chronic-phase chronic myeloid leukemia, imatinib proved superior to interferon alfa plus low-dose cytarabine in a study of 1,106 patients (pp. 994-1004). The authors report, “After a median follow-up of 19 months, the estimated rate of a major cytogenetic response (0 to 35 percent of cells in metaphase positive for the Philadelphia chromosome) at 18 months was 87.1 percent (95 percent confidence interval, 84.1 to 90.0) in the imatinib group and 34.7 percent (95 percent confidence interval, 29.3 to 40.0) in the group given interferon alfa plus cytarabine (P<0.001). The estimated rates of complete cytogenetic response were 76.2 percent (95 percent confidence interval, 72.5 to 79.9) and 14.5 percent (95 percent confidence interval, 10.5 to 18.5), respectively (P<0.001). At 18 months, the estimated rate of freedom from progression to accelerated-phase or blast-crisis CML was 96.7 percent in the imatinib group and 91.5 percent in the combination-therapy group (P<0.001). Imatinib was better tolerated than combination therapy.” (S. G. O’Brien)

An editorialist adds transplantation to the therapeutic choices (pp. 1048-50): “For patients who have an adequate response and an appropriate donor, the question of when to consider transplantation arises. One approach would be to continue imatinib therapy in all such patients except the 10 to 15 percent with a low risk of death from transplantation (i.e., the youngest patients with sibling donors). Transplantation could be considered in the higher-risk patients only when signs of disease progression appeared. However, it remains unclear whether this approach would have an adverse effect on the outcome of transplantation, particularly if transplantation were performed more than 12 months after diagnosis and in many more patients with advanced disease as a result of this approach.” (K. Peggs, Royal Free and U. College London Med. Sch., London)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 14, 2003 Vol. 10, No. 50
Providing news and information about medications and their proper use

>>>Fusion Inhibitor Approved; Supply Is Low, Price High
FDA yesterday announced the accelerated approval of the first fusion inhibitor, enfuvirtide (Fuzeon; Roche, Trimeris), for use in combination with other anti-HIV medications to treat advanced HIV-1 infection in adults and children ages 6 years and older. But the widely anticipated approval came with anger and angst, as annual costs were expected to be $20,000.

Drugs in this class interfere with the entry of HIV-1 into cells by inhibiting the fusion of viral and cellular membranes. This inhibition blocks viral ability to infect certain components of the immune system. Enfuvirtide should only be used in patients who have previously used other anti-HIV medications and have ongoing evidence of viral replication. It is administered as a subcutaneous injection.

FDA based its accelerated approval of enfuvirtide on an analysis of 6 months of data from two ongoing clinical studies of enfuvirtide involving approximately 1,000 patients (see next article for summary of one of these trials). Addition of enfuvirtide to a combination of other anti-HIV medications reduced patients’ viral load more than did the combination of anti-HIV medications alone. The long-term effects of enfuvirtide are being evaluated in ongoing trials.

Patients must be monitored for signs and symptoms of pneumonia while taking enfuvirtide. Although bacterial pneumonia was uncommon in clinical study participants, more patients treated with enfuvirtide developed bacterial pneumonia than did other patients. Patients receiving enfuvirtide are advised to seek medical evaluation immediately if they develop signs or symptoms suggestive of pneumonia, such as cough with fever, rapid breathing, and shortness of breath.

In addition, enfuvirtide can cause serious systemic allergic reactions (difficulty in breathing, fever, skin rash, chills, vomiting, hypotension) that require prompt medical attention. Local skin reactions from enfuvirtide injections are very common, occurring in almost all patients, and may be painful. Patients must be careful that their skin does not become infected at the site of injection.

In lay media reports, Roche attributed the high price of the drug to its $600 million cost of development, a complicated manufacturing process that both limits supply and drives up costs, and the limited number of patients who can be treated with the small supply of available drug. As an agent used primarily when other anti-HIV therapies fail, enfuvirtide would be indicated for about 50,000–100,000 of the 850,000–950,000 Americans infected with the virus. This year, Roche can produce only enough drug for about 12,000–15,000 people, and about two thirds of that quantity will be distributed in the U.S. Supply will grow in 2004, with enough product for 32,000 people, and in 2005, when 39,000 patients can be treated, according to Associated Press.

>>>NEJM Releases Pivotal Study of Enfuvirtide
Significant antiretroviral and immunologic benefit was demonstrated through 24 weeks of therapy with the newly approved HIV drug enfuvirtide, according to results of one of the two pivotal studies of the agent. The New England Journal of Medicine posted the findings on its Web site (content.nejm.org) as the agent was approved. The article will appear in the May 29 print version of the Journal.

To be included in the study, patients had to have had at least 6 months of prior treatment with agents in three antiretroviral classes, resistance to drugs in these classes, or both, and at least 5,000 copies of HIV-1 RNA/mL of plasma. All received an optimized background regimen of three to five agents, and patients in the treatment group also received enfuvirtide. In 491 evaluable patients, viral load and CD4+ cell counts improved significantly among those receiving enfuvirtide, compared with control patients. Adverse reactions included injection-site reactions in 98% of patients in the treatment group, and pneumonia was more common among enfuvirtide-treated patients.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 17, 2003 Vol. 10, No. 51
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Mar. 15 issue of BMJ (www.bmj.org; 2003; 326).

Treatment of TB: The routine use of second- or third-line agents in directly observed treatment strategy might prevent deaths but could cause many more deaths overall if it resulted in “even minimal decreases in the effectiveness of treatment,” according to analysis using a DOTS model (pp. 574 ff.). The model assessed TB program effectiveness using DOTS with standard regimens and DOTS plus use of reserve drugs in scenarios with intermediate (3%) and high (10%) levels of primary multidrug-resistant TB. Over a 10-year period in a population of 100,000 people, the model predicted 276 deaths with DOTS and 272 with DOTS-plus under the 3% assumption.

However, the authors found that problems could ensue if the reserve medications prompted additional cases of resistance: “If implementation of DOTS-plus were to result in a decrease of just 5% in the effectiveness of DOTS, 16% more people would die with tuberculosis than under DOTS alone. In an area with 10% primary multidrug resistant tuberculosis, 10% fewer deaths would occur under optimal DOTS-plus than under optimal DOTS, but 16% more deaths would occur if implementation of DOTS-plus were to result in a 5% decrease in the effectiveness of DOTS.” (T. R. Sterling, Johns Hopkins U., Baltimore; tsterls@jhmi.edu)

>>>Chest Highlights
Source:
Mar. issue of Chest (www.chestjournal.org; 2003; 123).

Multidrug-Resistant TB in Pregnancy: A case report is used as a springboard to a literature review of cases of multidrug-resistant tuberculosis during pregnancy (pp. 953-6). In a woman at 23 weeks’ gestation, a 3-week course of rifampin, isoniazid, and ethambutol failed to improve cavitary TB. Treatment was changed to intravenous capreomycin, levofloxacin, para-aminosalicylic acid, pyrazinamide, cycloserine, and high-dose vitamin B6, and the patient delivered an uninfected child at 35 weeks’ gestation. After delivery, ethionamide was added, moxifloxacin replaced levofloxacin, and the patient’s sputum became smear-negative and culture-negative for TB. (K-D Lessnau, Cornell U., New York City; KLessnau@pol.net)

Treatment of ABECB: In 235 outpatients aged 35–75 years with acute bacterial exacerbations of chronic bronchitis, a 5-day macrolide regimen was just as effective as a fluoroquinolone given for 7 days (pp. 772-7). In the blinded comparison, oral azithromycin 500 mg on day 1 followed by 250 mg/day on days 2 through 5 was compared with oral levofloxacin 500 every 24 hours for 7 days. Clinical outcomes were similar (89% of azithromycin patients and 92% of levofloxacin patients were improved by day 4 of therapy), as were bacterial results (bacterial eradication rates of 96% and 85% in the two groups, respectively). “Despite increasing concerns over macrolide resistance and a higher incidence of Gram-negative pathogens, a standard 5-day course of oral azithromycin was clinically and bacteriologically equivalent to a 7-day course of oral levofloxacin in the treatment of patients with ABECB,” the authors conclude. (G. W. Amsden, Bassett Healthcare, Cooperstown, N.Y.; guy.amsden@bassett.org)

>>>PNN JournalWatch
* Chronic Cough and Gastroesophageal Reflux Disease: Experience with Specific Therapy for Diagnosis and Treatment, in Chest, 2003; 123: 679–84. Reprints: www.chestjournal.org; R. H. Poe, Highland Hosp., Rochester, N.Y.; Robert_ Poe@URMC.rochester.edu

* Transplantation of Cells for Cardiac Repair, in
Journal of the American College of Cardiology, 2003; 41: 711–7. Reprints: www.cardiosource.com; R. J. Hassink, U. Med. Ctr., Utrecht, The Netherlands.

* Risk for Myopathy with Statin Therapy in High-Risk Patients, in
Archives of Internal Medicine, 2003; 163: 553–64. Reprints: www.archinternmed.com; C. M. Ballantyne, Baylor Coll. of Med., Houston, Tex.; cmb@bcm.tmc.edu

* Management of Peripheral Arterial Disease in Primary Care, in
BMJ, 2003; 326: 584–8. Reprints: www.bmj.org; A. W. Bradbury, Heartlands Hosp., Birmingham, U.K.

* Oxidants and Antioxidants in Alcohol-Induced Liver Disease, in
Gastroenterology, 2003; 124: 778–90. Reprints: www.gastrojournal.org; G. E. Arteel, U. Louisville, Louisville, Ky.; gavin.arteel@louisville.edu

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 18, 2003 Vol. 10, No. 52
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Mar. 18 issue of the Annals of Internal Medicine (www.annals.org; 2003; 138).

Safety of Ephedra: Compared with other herbal products, ephedra produces a greatly increased risk of adverse reactions, according to an article that had been posted earlier to the Annals’ Web site (see PNN, Mar. 4). A comparative case series assessed reports during 2001 to the American Association of Poison Control Centers Toxic Event Surveillance System Database. Ephedra-containing products accounted for 64% of all adverse reactions to herbs, even though they constituted only 0.82% of herbal product sales, the authors report. “The relative risks for an adverse reaction in persons using ephedra compared with other herbs were extremely high, ranging from 100 (95% CI, 83 to 140) for kava to 720 (CI, 520 to 1100) for Ginkgo biloba,” writes the group. “Ephedra use is associated with a greatly increased risk for adverse reactions compared with other herbs, and its use should be restricted.” (S. Bent, bent@itsa.ucsf.edu)

Smallpox Vaccination Options: Risks and benefits of smallpox vaccination strategies are analyzed within the context of the natural course of the disease, the increased immunosuppression of the American population (compared with the 1960s), and the adverse effects of the vaccine itself (pp. 488-93). Because the smallpox virus spreads slowly , usually only among close contacts of the patient, the authors conclude that the immunization of medical workers is probably sufficient “in the absence of a known threat of a bioterrorist attack or the identification of a smallpox-infected person.” They conclude, “We could continue to pursue the current policy of avoiding mass vaccination while vaccinating small numbers of first responders and personnel who might be involved in the investigation and control of possible smallpox outbreaks. This should be and is being accompanied by an effort to build vaccine supplies, institutionalize vaccine production capacity, develop and expand laboratory expertise, and train public health authorities and first-response clinicians. While these options should be revisited periodically as new information comes to light, at present it seems prudent to continue the present policy and to initiate only modest increases in vaccination of first responders.” (J. M. Lane, CDC, Atlanta)

Preventing Ventilator-Associated Pneumonia: Semirecumbent positioning, sucralfate instead of H2 antagonists for stress ulcer prophylaxis in patients at low or moderate risk of gastrointestinal bleeding, and selective digestive tract decontamination are recommended as ways of preventing pneumonia in patients on ventilators (pp. 494-501). An evidence-based systematic review identified seven meta-analyses that included more than 20 randomized trials of methods of stress ulcer prophylaxis. Grade I evidence was found for sucralfate but not the H2 blockers. However, since sucralfate would not protect against GI bleeding, the authors recommend it only for patients at lower risks of bleeds (specifically those with no coagulopathy or need for prolonged mechanical ventilation). (H. R. Collard, U. Colorado, Denver; hal.collard@uchsc.edu)

Combination Therapy for Sepsis: In a perspectives article, an author concludes that “we may have reached the limits of adjunctive monotherapy” in the treatment of sepsis (pp. 502-5). In proposing a “new therapeutic paradigm based on improved recognition of the septic process, the authors argue, “A combination of therapies directed at many arms of the septic process, much like the strategy used for cancer and HIV infection, is required. Given the likelihood that sepsis represents an excessive innate immune response to microbial products, vigorous attempts must be made to develop rapid assays that reflect the level of innate immune activation. Such assays could be used to identify patients who would benefit from therapy and to monitor their response so that overtreatment does not completely abrogate host defense mechanisms and render these patients susceptible to fatal infection.” (A. S. Cross, U. Maryland, Baltimore; across@umm.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 19, 2003 Vol. 10, No. 53
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Mar. 19 issue of JAMA (www.jama.com; 2003; 289).

Alcohol & Dementia: Compared with abstention, consumption of 1–6 alcoholic drinks per week is associated with a lower risk of dementia among older adults, according to a case–control study (pp. 1405-13). In the Cardiovascular Health Study of 5,888 adults aged 65 years or older, 373 cases of incident dementia were compared with 373 controls. Adjusted odds ratios were reduced by 35% for those reporting less than 1 drink/week; 54% for 1–6 drinks/week; and 31% for 7–13 drinks/ week, compared with patients who self-reported that they never used alcohol. Dementia risks increased by 22% among patients who said they consumed 14 or more drinks in a typical week.

The authors add, “A trend toward greater odds of dementia associated with heavier alcohol consumption was most apparent among men and participants with an apolipoprotein E4 allele. We found generally similar relationships of alcohol use with Alzheimer disease and vascular dementia.” They conclude, “Given the many physiological effects associated with alcohol consumption and the observational nature of our study, our findings should be extrapolated to clinical care with great caution. However, our results are consistent with the hypothesis that light-to-moderate drinking has a protective effect on long-term cognitive function.” (K. J. Mukamal, Beth Israel Deaconess Med. Ctr., Boston; kmukamal@caregroup.harvard.edu)

>>>Pediatrics Report
Source:
Mar. issue of Pediatrics (www.pediatrics.org; 2003; 111).

Medication Concordance & Asthma:
For proper asthma therapy in children, educating the physician is not enough—the caregiver must also understand and agree with the therapy if it is to be used. That conclusion is apparent from results of a survey of 318 caregivers of inner-city children with asthma and their primary care physicians (e214-20). Investigators looked medication concordance—the degree to which caregivers and physicians agreed on what medications were being prescribed.
Even though 73% of caregivers reported that their children had persistent asthma, only 42% of physicians and 32% of caregivers reported prescription of a controller medication. “When the physician reported a controller prescription, 38% of the caregivers denied use of a controller,” wrote the authors. “Having a course of oral steroids in the past year (chi square = 9.85) and positive caregiver beliefs toward asthma care (chi square = 18.40) were associated with caregiver-physician concordance.” High caregiver scores on an asthma beliefs scale increased odds of concordance by nearly 10-fold. (K. A. Rieker, Johns Hopkins U., Baltimore)

Asthma & Atopic Dermatitis: Approaches and processes used in asthma therapy are appropriate for modification and use in treating atopic dermatitis, according to an expert panel of seven individuals (pp. 608-16). The specialists explain, “There are clear epidemiologic parallels in asthma and AD. Importantly, AD frequently is the first manifestation of an atopic diathesis, which occurs in genetically predisposed individuals and also includes asthma and allergic rhinitis. Up to 80% of children with AD will eventually develop allergic rhinitis or asthma later in childhood. This classic ‘atopic triad’ has numerous pathophysiologic elements in common, including cyclic nucleotide regulatory abnormalities, immune cell alterations, and inflammatory mediators and allergic triggers. New therapeutic options that target underlying immune mechanisms are available, and their place among treatments for AD is becoming established. Guidelines of care have been developed for asthma. The panel noted that the National Institutes of Health/National Heart, Lung, and Blood Institute guidelines for diagnosis and management of asthma, first issued in 1991, had a tremendous positive impact on many aspects of asthma treatment.... It is anticipated that AD therapy guidelines would have similar positive outcomes.” (L. F. Eichenfield, U. Calif., San Diego)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 20, 2003 Vol. 10, No. 54
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Mar. 20 issue of the New England Journal of Medicine (content.nejm.org; 2003; 348).

Obesity Gene: The clinical impact of mutations in the gene for the melanocortin 4 receptor (MC4R)—an allele that may control eating behavior—are explored in a study of the families of 500 patients with severe childhood obesity (pp. 1085-95). Of the 500 probands, 29 (5.8%) had mutations in the MC4R gene, including 23 patients who were heterozygous and 6 individuals who were homozygous. Among mutation carriers, several characteristics were common: severe obesity, increased lean mass, increased linear growth, hyperphagia, and severe hyperinsulinemia. Those with two copies of the mutant gene were more severely affected than heterozygous individuals. (S. O’Rahilly, Cambridge Inst. for Med. Res., Cambridge, U.k.; sorahill@hgmp.mrc.ac.uk)

In a second study, binge eating is shown to be a phenotypic characteristic of mutations in the
MC4R gene (pp. 1096-103). In 469 severely obese patients (mean body mass index, 44.1 kg/sq m), investigators sequenced several genes that interact to control eating behavior. Comparisons were made with 25 normal-weight control patients. The authors report, “Twenty-four obese subjects (5.1 percent) and one control subject (4 percent) had MC4R mutations, including five novel variants. Twenty of the 24 obese subjects with an MC4R mutation were matched for age, sex, and body-mass index with 120 of the 445 obese subjects without an MC4R mutation. All mutation carriers reported binge eating, as compared with 14.2 percent of obese subjects without mutations (P<0.001) and 0 percent of the normal-weight subjects without mutations. The prevalence of binge eating was similar among carriers of mutations in the leptin-binding domain of [a leptin receptor gene] and noncarriers. No mutations were found in the region of [the proopiomelanocortin gene] encoding melanocyte-stimulating hormone.” (F. F. Horber, Klinik Hirslanden, Zurich, Switzerland; genetics@obex.ch)

Editorialists comment on these two studies (pp. 1160-3): “MC4R clearly plays a part in regulating eating behavior. Some of the differences among studies of MC4R may be attributed to the genetic backgrounds of the studied subpopulations, among which there may be variation in the balance of susceptibility and compensatory genes that modify the phenotype of even a highly penetrant monogenic trait. Is
MC4R a reasonable candidate gene for binge-eating disorder...? A demonstration of abnormal molecular physiology constitutes the missing link between genes and behavior. Thus, although it is becoming clearer how hypothalamic neuropeptides control the amount we eat, further investigation is needed to establish the role of neuropeptides in determining the amount we eat at one sitting.” (Mass. Genl. Hosp., Boston)

>>>PNN NewsWatch
* Advances in
battlefield treatment of hemorrhage are among the new tools that will receive real-world testing in the now-underway Iraqi conflict, according to an article in this morning’s Wall Street Journal. Several new techniques for first aid are described, including bandages impregnated with human blood clotting factors or chitosan molecules; clotting powder; one-handed tourniquets; and an infusion device that plunges a needle into the bone marrow of the sternum.

* CDC announced yesterday that 11 suspected cases of
severe acute respiratory syndrome have now been identified in the U.S. The case definition for SARS is very broad: presence of fever of 38∞ C; travel to certain parts of China or Hanoi, Vietnam or contact with someone who has traveled there; plus at least one other nonspecific symptom (cough, shortness of breath, difficulty breathing, hypoxia, or radiographic findings of pneumonia or acute respiratory distress syndrome). CDC head Julie Gerberding says that this broad definition means many suspected cases probably have “garden variety” pneumonia rather than the emerging infectious disease, especially at this time of year.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 21, 2003 Vol. 10, No. 55
Providing news and information about medications and their proper use

>>>Psychiatry Highlights
Source:
Mar. issue of the American Journal of Psychiatry (ajp.psychiatryonline.org; 2003; 160).

Multiple Psychotropic Medications Among Youth: Concomitant use of psychotropic medications is common among youths with emotional and behavioral disorders, but the research into such therapies is inadequate, according to a review article (pp. 438-49). “In the mid-1990s, over 20% of outpatient youths treated in community mental health centers and over 40% of youths treated in inpatient psychiatric facilities were given concomitant psychotropic medication,” write the authors. “The rate has since increased. Psychiatrists more than primary care physicians prescribe concomitant psychotropic medication, and they show great variability in their prescribing habits. Youths with aggressive behavior, male gender, severe emotional illness, and disabling social maladjustment are most likely to receive concomitant psychotropic medication.” Data supporting this use include “almost exclusively ... case reports and small-scale, nonblind assessments,” the group adds. (D. J. Safer)

Antihypertensives & Schizophrenia: Risk of schizophrenia is increased in children of mothers who had hypertension during pregnancy and were treated with diuretics during the third trimester, conclude investigators who analyzed the Copenhagen Perinatal Cohort of people born between 1959 and 1961 (pp. 464-8). Of 7,866 individuals, 84 had schizophrenia. Logistic multiple regression analysis identified these significant predictors of the mental condition: maternal hypertension (odds ratio, 1.69), diuretic treatment during the third trimester (OR, 2.55), prenatal exposure to hypertension and diuretic treatment during the third trimester (OR, 4.01), and maternal schizophrenia (OR, 11.12). (H. J. Sørensen)

Psychotropic Medication Use Among HIV-Infected Patients: While many HIV-positive patients are prescribed psychotropic agents, about one-half of those with depression do not receive antidepressants, and African Americans are undertreated (pp. 547-54). Among 1,489 patients who completed detailed assessments in early 1996, 27.2% were taking some type of psychotropic medication that year. “Antidepressants were the most commonly prescribed drug class (20.9% of patients), followed by anxiolytics (16.7%), antipsychotics (4.7%), and psychostimulants (3.0%),” the authors determined. “Among patients with major depression or dysthymia, 43.2% reported receiving antidepressants, and 34.3% reported receiving anxiolytics. Psychiatric comorbidity was associated with greater use of psychotropics. Use of psychotropics in general, and antidepressants in particular, was significantly lower among African Americans than whites or Hispanics. Among patients with mood disorders, 61.0% of whites, 51.4% of African Americans, and 66.7% of Hispanics reported use of antidepressant medications or some type of psychosocial intervention.” (B. Vitiello)

>>>PNN NewsWatch
* The
California Poison Control System has received no state funding for the next fiscal year that begins July 1. Unless monies are restored, the state could become the only one without a poison control center at that point. Through four sites of operation, the system estimates that it reduced health care costs by $55 million in 2002, averting 61,000 emergency department visits.

* At the American Pain Society meeting, researchers reported pain and symptom relief when
levetiracetam was used in combination with tricyclic antidepressants, anticonvulsant drugs, and/or long-acting narcotics in 21 patients with multiple sclerosis and disabling neuropathic symptoms.

* Cost of the new HIV drug
enfuvirtide has been set at just under $20,000 per year in the U.S. Marketing partners Roche and Trimeris have also announced that during an initial period of insufficient supply of the drug (see PNN, Mar. 14), Chronimed/StatScript Pharmacy will be sole distributor of Fuzeon. Unrestricted distribution through pharmacies will follow when supply increases.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 24, 2003 Vol. 10, No. 56
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
Mar. 22 issue of Lancet (www.thelancet.com; 2003; 361).

Clindamycin & Preterm Delivery: Rates of late miscarriage and preterm delivery are reduced by treatment of bacterial vaginosis with oral clindamycin, according to a study of 6,120 pregnant women who were seen at 12–22 weeks’ gestation (pp. 983-8). During their first antenatal visit, the women were screened for asymptomatic abnormal vaginal flora and bacterial vaginosis, and 494 women with one of these conditions were randomly assigned to receive either clindamycin 300 mg or placebo orally twice daily for 5 days. For 485 women with complete outcome data, the authors report, “Women receiving clindamycin had significantly fewer miscarriages or preterm deliveries (13/244) than did those in the placebo group (38/241; percentage difference 10.4%, 95% CI 5.0-15·8, p=0.0003). Clindamycin also reduced adverse outcomes across the range of abnormal Nugent scores [for gram stains of vaginal smears], with maximum effect in women with the highest Nugent score of 10.” (A. Ugwumadu, St. George’s Hosp., London; aug wumad@sghms.ac.uk)

>>>BMJ Highlights
Source:
Mar. 22 issue of BMJ (www.bmj.org; 2003; 326).

Leukotriene Modifiers Versus Glucocorticoids for Asthma: In adults with mild or moderate asthma, inhaled glucocorticoids at doses equivalent to beclomethasone 400 mcg/day are more effective than are leukotriene receptor antagonists (pp. 621 ff). An author of a systematic review identified 13 randomized controlled trials, 12 in adults but only 1 in children. The author writes, “Patients treated with leukotriene receptor antagonists were 60% more likely to suffer an exacerbation requiring systemic glucocorticoids (relative risk 1.6, 95% confidence interval 1.2 to 2.2; number needed to treat 27, 13 to 81). A 130 ml greater improvement (80 ml to 170 ml) in forced expiratory volume in one second and a 19 l/min greater increase (14 l to 24 l) in morning peak expiratory flow rate were noted in favour of inhaled glucocorticoids. Differences in favour of inhaled glucocorticoids were also observed for nocturnal awakenings, use of rescue beta-2 agonists, and days without symptoms. Risk of side effects was no different between groups, but leukotriene receptor antagonists were associated a 2.5-fold increase risk of withdrawals due to poor asthma control (relative risk 2.5, 1.8 to 3.5).” (F. M. Ducharme, Montreal Children’s Hosp., Montreal, Quebec, Canada; Francine.ducharme@muhc.mcgill.ca)

BMI & Central Obesity: A study of British youths indicates that body mass index may be a poor proxy for central fatness, especially in girls (pp. 624). Comparing data from 1977, 1987, and 1997, the authors found significant increases in waist circumference for both boys (6.9 cm, 0.84 SD score units) and girls (6.2 cm, 1.02 SD score units). However, increases in body mass index were smaller, and the authors identified a systematic underestimation of obesity prevalence as measured by BMI. (H. D. McCarthy, London Metropolitan U., London; d.mccarthy@londonmet.ac.uk)

>>>PNN JournalWatch
* Management of Pain, in BMJ, 2003; 326: 635–9. Reprints: www.bmj.org; A. Holdcroft, Imperial College, London; aholdcro@ic.ac.uk

* Evidence of
Plasmodium falciparum Malaria Resistant to Atovaquone and Proguanil Hydrochloride: Case Reports, in BMJ, 2003; 326: 628–9. Reprints: www.bmj.org; A. Färnert, Karolinska Hosp., Stockholm, Sweden; anna.farnert@medks.ki.se

* COX-3: Just Another COX or the Solitary Elusive Target of Paracetamol [commentary]?, in
Lancet, 2003; 361: 981–2. Reprints: www.thelancet.com; J. M. Schwab, Inst. of Brain Res., Tübingen, Germany; jmschwab@med.uni-tuebingen.de

* Advances in Asthma, Allergy and Immunology, 2003, in
Journal of Allergy and Clinical Immunology, 2003; 111 (pt 2). Reprints: www2.us.elsevierhealth.com

* Preventing Complications of Central Venous Catheterization, in
New England Journal of Medicine, 2003; 348: 1123–33. Reprints: contents.nejm.org; M.K. Gould, VA Health Care System, Palo Alto, Calif.

* New Drugs of 2002, in
Journal of the American Pharmaceutical Assoc., 2003; 43: 207–48. Reprints: www.aphanet.org; D. A. Hussar, d.hussar@usip.edu

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 25, 2003 Vol. 10, No. 57
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Mar. 24 issue of Archives of Internal Medicine (www.archinternmed.com; 2003; 163).

Statin Monitoring: Routine monitoring of transaminase and creatine kinase levels may not be needed in patients taking statins in the primary care setting, according to a retrospective review of patients treated during 1998 at Boston’s Beth Israel Deaconess Med. Ctr. (pp. 688-92). Of 1,194 patients identified as receiving statins, 85% had one or more monitoring tests performed. Among these 1,014 patients, “10 (1.0%) had a significant elevation and 5 (0.5%) a moderate elevation of transaminase levels, but none of these abnormalities appeared to be related to statin use,” the authors report. “Moreover, 6 (0.9%) patients had at least 1 significantly abnormal CK value but it did not appear to be attributable to a statin; of the 14 (2.1%) patients who had a moderate CK elevation, it was potentially due to a statin in only 2. There were no documented adverse sequelae associated with these abnormal results.” The authors conclude, “In this study of statin use in a primary care practice, routine monitoring revealed no cases of significantly or moderately abnormal transaminase values attributable to statins. No significantly abnormal and only 2 moderately abnormal CK values were potentially attributable to statin use. This study questions the usefulness of routine measurement of transaminase and CK levels in all patients taking statins.” (C. C. Smith, Boston; csmith2@caregroup.harvard.edu)

In a related editorial, an author translates this advice for primary care practitioners (pp. 657-9): “Measuring CK, ALT, and AST at the beginning of statin therapy establishes baseline values for later comparisons. However, subsequent routine monitoring appears to add little to the prognostication of incipient toxic effects when patients are taking low doses of approved statins or are in a primary-prevention setting, are otherwise healthy, and are not taking multiple medications. Instead, the presentation of early symptoms consistent with toxic effects may be the best prompt for further testing; therefore, increasing patient awareness will be helpful. An unexpected pain in the muscles, weakness, flulike syndrome, general malaise, and the appearance of dark-colored urine should be explained as warning signs to patients when the drug is prescribed, with advice to discontinue the drug if these occur and to contact a physician immediately. In the case of hepatotoxicity, many of these adverse reactions are cholestatic, are generally benign, and are easily detected because patients become symptomatic with pruritus or jaundice before serious liver injury. Patients should be aware of possible drug–drug interactions, and the package inserts for statins will provide physicians with this relevant information.” (A. M. Gotto, Jr, Cornell U., New York City; amg_editorial@med.cornell.edu)

Lipid-Lowering Therapies & Stroke Prevention: Stroke incidence is reduced in patients whose total cholesterol is below 232 mg/dL (6.0 mmol/L), and this finding explains why the best results have been produced by statin therapy (pp. 669-76). In a meta-analysis of 38 trials involving 83,161 patients, lipid-lowering therapy significantly reduced the risk of stroke, by 17%. With statins, this relative risk reduction was 26%. Using statistical models, the authors demonstrated an association between stroke and total cholesterol levels, providing an explanation for the greater effectiveness of statins for stroke reduction. (P. Lechat, CHU Pitié-Salpêtrière, Paris; philippe.lechat@psl.ap-hop-paris.fr)

Addressing Systolic Hypertension: Lack of awareness of systolic hypertension is a “greater barrier to [blood pressure] control than cost of medications in Americans 50 years or older,” according to authors who interviewed 1,503 individuals (pp. 681-7). Patients indicated a preference for integrating traditional, complementary, and alternative treatment approaches. The authors conclude, “Education addressing limited awareness of systolic hypertension, policies facilitating a more holistic management approach, and research identifying the most effective innovations may improve outcomes.” (B. M. Egan, eganbm@musc.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 26, 2003 Vol. 10, No. 58
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Mar. 26 issue of JAMA (www.jama.com; 2003; 289).

Safety of Ephedra: The evidence supporting use of ephedra for enhancing athletic performance and promoting weight loss is insufficient, according to an FDA-commissioned article (pp. 1537-45) released previously on the JAMA Web site (see PNN, Mar. 11). Further, important health risks are strongly linked to use of the dietary supplement, authors note, including heart palpitations and psychiatric, gastrointestinal, and nervous system problems.

The RAND Corporation article is a meta-analysis of 52 controlled trials and 65 case reports of adverse events. Pooled results of clinical studies of ephedra, ephedrine, caffeine, and/or herbs containing caffeine showed that the products enabled patients to lose an average of 0.6–1.0 kg/month, depending on the formulation used.

“No trials of ephedra and athletic performance were found; 7 trials of ephedrine were too heterogeneous to synthesize,” write the authors. “Safety data from 50 trials yielded estimates of 2.2- to 3.6-fold increases in odds of psychiatric, autonomic, or gastrointestinal symptoms, and heart palpitations. Data are insufficient to draw conclusions about adverse events occurring at a rate less than 1.0 per thousand. The majority of case reports are insufficiently documented to allow meaningful assessment.” (P. G. Shekelle, RAND Corp., Santa Monica, Calif.; shekelle@rand.org)

In an accompanying opinion article (pp. 1568-70), three JAMA editors call for “new legislation ... for defining and regulating dietary supplements.” They specifically maintain that four steps are needed: (1) address the scope of categories of products included under the definition of dietary supplements, adding that it is currently too broad, (2) subject dietary supplements to more rigorous federal regulation, an action that has now been proposed by FDA, (3) establish formal systems for mandatory postmarketing surveillance and adverse event reporting, and (4) ensure that advertising for dietary supplements is accurate and not misleading. (P. B. Fontanarosa, phil_fontanarosa@ama-assn.org)

Blood Lead, Blood Pressure, & Osteoporosis: Skeletal lead stores appear to be an important source of blood lead in postmenopausal women, and increasing lead levels are linked to increased blood pressure and hypertension (pp. 1523-32). In a sample of 2,165 women aged 40– 59 years from the Third National Health and Nutrition Examination Survey conducted from 1988 to 1994, the authors found, “A change in blood lead levels from the lowest (quartile 1: range, 0.5– 1.6 µg/dL) to the highest (quartile 4: range, 4.0–31.1 µg/dL) was associated with small statistically significant adjusted changes in systolic and diastolic blood pressures.” Specifically, the risk of diastolic hypertension was increased by 3.4-fold in women in the highest quartile and by 8.1-fold among postmenopausal women in the highest quartile. (D. Nash, Health and Mental Hygiene, New York City; dnash@health.nyc.gov)

MS & EBV: Epstein–Barr virus infection may somehow be linked to development of multiple sclerosis, according to a nested case–control analysis of data from the U.S. Department of Defense (pp. 1533-6). For 83 individuals who were granted temporary or permanent disability because of MS and two matched controls, sera were analyzed for a number of EBV antigens and for cytomegalovirus. The risk of MS was 19.7 times greater among patients with the highest levels of antigen against EBV viral capsid antigen and 33.9 times greater in patients whose EBV nuclear antigen titers were in the highest category. (A. Ascherio, Alberto.Ascherio@channing.harvard.edu)

Vaccinia Transmission to Patients: Sizable proportions of patients in New York State hospitals were found in a study to be immunocompromised and therefore susceptible to vaccinia transmission from vaccinated health care workers for smallpox. The findings emphasize the importance of adhering to CDC-recommended infection-control guidelines for smallpox-vaccination sites. (Perry F. Smith, New York State Department of Health, Albany)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 27, 2003 Vol. 10, No. 59
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Mar. 27 issue of the New England Journal of Medicine (content.nejm.org; 2003; 348).

Imatinib Treatment of Hypereosinophilia: Nine of 11 patients with idiopathic hypereosinophilic syndrome responded for more than 3 months to treatment with imatinib (pp. 1201-14). The research led to the identification of a fusion gene that appears to be the cause of the syndrome. The gene, the result of deletion of material on chromosome 4, produces a fusion protein that is inhibited by imatinib. The authors explain, “Cloning of [this] gene rearrangement identified chromosomal interstitial deletion as a novel molecular mechanism for a gain-of-function fusion gene. Most investigations of the loss of heterozygosity in human tumors have focused on the loss of function of one or both alleles of a putative tumor-suppressor gene. Our data suggest that a comprehensive analysis of human tumors for small deletions that may result in gain-of-function fusion genes should be undertaken.” (D. G. Gilliland, gilliland@hihg.med.harvard.edu)

Oral Opioid Therapy for Neuropathic Pain: Higher strengths of oral levorphanol capsules proved more effective for pain relief than did lower strengths in 81 patients with refractory neuropathic pain, but adverse effects limited utility of the doses (pp. 1223-32). In an 8-week study, the potent mu-opioid agonist was tested in capsules of 750 or 150 mcg; patients could take up to 21 capsules of their assigned strength daily. Significantly greater pain relief was documented with higher strength capsules (36% reduction, compared with 21% for the lower strength dosage form), a level of pain reduction that is similar to that observed with tricyclic antidepressants and gabapentin in patients with neuropathic pain. Patients taking high-strength capsules took 11.9 capsules/day (8.9 mg/day), while patients in the lower-strength group took close to the maximum of 21 capsules (2.7 mg/day). Other variables were not significantly different between the groups (reductions in affective distress and interference with functioning, and improvements in sleep).

The most common reason for not completing the study was adverse effects of the opioid. A total of 15 patients reported physical or psychologic adverse events, including 12 in the high-strength group and 3 in the low-strength group. Treatment failure led 3 patients to leave the study, lack of protocol adherence was cited in 1 case, and other reasons were noted for 3 additional patients. Compared with patients who completed the study, those who withdrew rated themselves as less talkative, more restless, and more depressed. (M. C. Rowbotham, Pain Clinical Research Ctr., San Francisco)

An editorialist calls for increased research into effective ways to relieve neuropathic pain (pp. 1279-81): “This study adds to the expanding literature of randomized, placebo-controlled trials of opioids in patients with central or peripheral neuropathic pain that show that opioids work. The data show that patients with peripheral neuropathic pain seem to be more likely to have responses to opioids than those with pain from central lesions, and opioids appear selectively to reduce spontaneous and touch-evoked allodynia in trials using quantitative methods for sensory testing. Together, these studies challenge the traditional view that neuropathic pain is opioid-resistant and now provide the scientific basis for developing a rational approach to the opioid treatment of neuropathic pain....

“In addition to the biologic issues, concern on the part of both patients and physicians about addiction, physicians’ lack of knowledge about and training in pain management and opioid-drug therapy, scrutiny of physicians’ prescribing practices by drug regulators and insurance companies, and increased abuse of prescription drugs all serve as powerful disincentives influencing physicians’ decisions about trying opioids in patients with neuropathic pain. Given our lack of data about how to manage chronic neuropathic pain, we must focus urgent attention on the needs of suffering patients.” (K. M. Foley, Memorial Sloan-Kettering Cancer Ctr., New York City)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 28, 2003 Vol. 10, No. 60
Providing news and information about medications and their proper use

>>>Aprepitant Approved
Aprepitant (Emend, Merck)—the first substance P/neurokinin 1 receptor antagonist to reach the U.S. market—has been approved by FDA for use in combination with other agents to help prevent the acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including high-dose cisplatin. The oral capsule is taken once daily for 3 days. The recommended dosing regimen is 125 mg orally 1 hour before chemotherapy treatment (day 1) and 80 mg once daily in the morning on days 2 and 3.

In clinical studies, aprepitant was administered with a serotonin 5-HT3 antagonist and a corticosteroid. This regimen significantly improved protection for 5 days against both acute (within 24 hours of chemotherapy) and delayed nausea and vomiting, compared with standard therapy. In both studies, more patients on the regimen with aprepitant as compared with standard therapy had complete responses to therapy (defined as no vomiting and no use of rescue medicines). The improvement in overall complete response in each study was approximately 20 percentage points. More patients on the regimen with aprepitant reported minimal or no impact of nausea and vomiting on their daily lives.

The most commonly reported adverse effects with aprepitant have been tiredness, nausea, hiccups, constipation, diarrhea, and loss of appetite. Because it is a moderate inhibitor of the cytochrome P450 3A4 isoenzyme, aprepitant may increase serum levels of pimozide, terfenadine, astemizole, or cisapride, and its use in contraindicated in patients taking these agents. Drug interactions also potentially affect oral contraceptives and warfarin. Women who use oral contraceptives while taking the 3-day regimen of aprepitant should use an alternative or backup method of contraception. Chronic warfarin therapy should be monitored for 2 weeks after use of aprepitant.

Emend will be available beginning the week of April 14 at a price of $250 for the 3-day regimen. Merck has developed the Accessing Coverage Today (ACT) Program to provide patients with reimbursement information as well as to assist those who cannot afford aprepitant (866/EMENDrx).

>>>Acromegaly Agent OK’d
An injectable growth hormone receptor antagonist, pegvisomant (Somavert, Pharmacia) has been approved by FDA for treatment of acromegaly in patients who have had an inadequate response to surgery and/or radiation therapy and/or other medical therapies, or for whom these therapies are not appropriate. The agent acts by blocking the growth hormone-stimulated overproduction of insulin-like growth factor 1, which contributes to the disabling symptoms and the long-term health problems associated with acromegaly, an orphan disease affecting an estimated 40,000 people worldwide.

The first agent in this new class to be marketed in the U.S., pegvisomant was studied in a fixed-dose, randomized clinical trial and in a long-term, open-label, dose-adjusted study in patients with acromegaly. In the pivotal study, pegvisomant normalized IGF-I levels in up to 82% of patients, and in the long-term study, the agent normalized IGF-I concentrations in 92% of patients.

Elevations of liver enzymes (ALT and AST) greater than 10 times the upper limit of normal were reported in two patients (0.8%) exposed to pegvisomant in clinical trials. Serial monitoring of liver tests is necessary when beginning and during therapy. The most commonly reported adverse events with pegvisomant occurring in at least 10% of patients and at frequencies greater than placebo were infection, pain, diarrhea, nausea, flu syndrome, abnormal liver function tests, and injection-site reactions. The majority of reported adverse events were of mild or moderate intensity and limited duration. Pegvisomant is contraindicated in patients with hypersensitivity to any of its components. The stopper on the vial of Somavert contains latex, necessitating caution by patients sensitive to this substance.

Pricing and distribution details for Somavert have not been announced.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 31, 2003 Vol. 10, No. 61
Providing news and information about medications and their proper use

>>>Asheville Project Results Released at APhA2003
Short- and long-term results from the Asheville Project were released at a news conference yesterday during APhA2003 in New Orleans, where nearly 6,500 attendees have gathered. The Asheville results, focusing on 85 patients with diabetes who received pharmaceutical care services at 12 community pharmacies, show notable improvements in health indicators and patient outcomes. These included improved glycosylated hemoglobin, lower total health care costs, fewer days of missed work, and increased satisfaction with pharmacist’s services.

Complete project results are in four articles and an editorial in the March/April issue of the
Journal of the American Pharmaceutical Association, which can be accessed at www.aphanet.org.

APhA is marking the end of its sesquicentennial celebration and its final annual meeting as the American Pharmaceutical Association. On Wednesday, the name changes to the American Pharmacists Association, and the group unveiled a new tag line (Improving medication use. Advancing patient care.) and logo at a session on Saturday.

>>>BMJ Highlights
Source:
Mar. 29 issue of BMJ (www.bmj.org; 2003; 326).

I.V. Drug Errors High in U.K.: Nearly one-half of intravenous drug doses prepared and administered by nurses contained at least one error, according to a study of 10 wards in a teaching and a nonteaching hospital (pp. 684 ff). Among 430 i.v. drug doses, 249 errors were found in 212 doses. Three (1%) errors were potentially severe, 126 (29%) were potentially moderate, and 83 (19%) were minor. Errors most commonly involved bolus doses being given too quickly and preparation of drug products that required multiple steps. (K. Taxis, U. Tübingen, Tübingen, Germany; katja.taxis@uni-tuebingen.de)

Antihypertensive Therapy & Insulin Resistance: In men with hypertension, an insulin resistant state and metabolic effects of beta blockers and diuretics increase in the risk of myocardial infarction (pp. 681 ff). In 1,860 men who were examined in 1970 and 1980 and then followed for an average of 17.4 years, the risk of MI was significantly higher among those treated for hypertension (23% vs. 13.5%), and men who had MIs after age 60 were shown to have greater increases in blood glucose between ages 50 and 60. The link between MI and drug therapy was made based on a multivariate analysis. (K. Dunder, Uppsala U., Uppsala, Sweden; kristina.dunder@pubcare.uu.se)

>>>Lancet Report
Source:
Mar. 29 issue of Lancet (www.thelancet.com; 2003; 361).

Budesonide & Asthma: Severe exacerbations are reduced and asthma control improved in patients using long-term, once-daily, low-dose budesonide treatments (pp. 1071-6). In a 3-year study of 7,241 adults and children, patients on budesonide required fewer courses of systemic corticosteroids and had more symptom-free days, compared with placebo. Pulmonary function tests improved. Among children younger than 11 years on active therapy, 3-year growth was reduced by 1.34 cm, with reductions greater in year 1 (0.58 cm) than in years 2 and 3 (0.43 and 0.33 cm, respectively). (R. Pauwels, Ghent U. Hosp., Ghent, Belgium; romain.pauwels@rug.ac.be)

>>>PNN JournalWatch
* Important Triad in Cardiovascular Medicine: Diabetes, Coronary Intervention, and Platelet Glycoprotein IIb/IIIa Receptor Blockade, in Circulation, 2003; 107: 1556–9. Reprints: circ.ahajournals.org; A. M. Lincoff.

* In Vivo Pharmacodynamics of Antifungal Drugs in Treatment of Candidiasis, in
Antimicrobial Agents & Chemotherapy, 2003; 47: 1179–86. Reprints: aac.asm.org; D. Andes.

* Integrating Nutrition Therapy into Medical Management of Human Immunodeficiency Virus, supplement to
Clinical Infectious Diseases, 2003; 36 (suppl 2). Reprints: www.journals.uchicago.edu

* The Impact of United States Law on Medicine as a Profession, in
JAMA, 2003; 289: 1546–56. Reprints: www.jama.com; S. Rosenbaum, George Washington U., Washington, D.C.; sarar@gwu.edu

* Delivery on Demand — A New Era of Gene Therapy?, in
New England Journal of Medicine, 2003; 348: 1282–3. Reprints: content.nejm.org; J. T. Prchal, Baylor College of Medicine, Houston.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 1, 2003 Vol. 10, No. 62
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Apr. 1 issue of the Annals of Internal Medicine (www.annals.org; 2003; 138).

Tight Blood Pressure Control in Diabetes:
New guidelines from the American College of Physicians say that tight control of blood pressure should be a priority in managing people with type 2 diabetes and high blood pressure (pp. 587-92). Based on a review of the literature (see next item), the College makes these four recommendation:

* Blood pressure control must be a priority in the management of persons with hypertension and type 2 diabetes.
* Clinicians should aim for a target blood pressure of no more than 135/80 mm Hg for their patients with diabetes.
* Thiazide diuretics or ACE inhibitors can be used as first-line agents for blood pressure control in most patients with diabetes.
* Further studies are warranted on the relative contributions of glucose control and blood pressure control to clinical outcomes such as microvascular and macrovascular complications.

(V. Snow, American College of Physicians, Philadelphia; vincenza@acponline.org)

Hypertension Treatment in Diabetes: Randomized trials support use of thiazide diuretics, angiotensin II receptor blockers, and ACE inhibitors as first-line treatments for hypertension in patients with comorbid type 2 diabetes (pp. 593-602). “Other agents are usually necessary and goals may not be achieved even with three or four agents,” write the authors. “Treatment of hypertension in type 2 diabetes provides dramatic benefit. Target diastolic blood pressures of less than 80 mm Hg appear optimal; systolic targets have not been as rigorously evaluated, but targets of 135 mm Hg or less are reasonable. Studies that compare drug classes do not suggest obviously superior agents. However, it is reasonable to conclude that thiazide diuretics, angiotensin-II receptor blockers, and perhaps ... ACE inhibitors may be the preferred first-line agents for treatment of hypertension in diabetes. Beta-blockers and calcium-channel blockers are more effective than placebo, but they may not be as effective as diuretics, angiotensin-II receptor blockers, or ACE inhibitors; however, study results are inconsistent in this regard.” (S. Vijan, svijan@umich.edu)

Antibiotic Use in Community Practice: While overall antibiotic use is declining in U.S. communities, increasing and often illogical use of “expensive, broad-spectrum agents” may lead to increased antibiotic resistance, report investigators who assessed data from the National Ambulatory Medical Care Survey (pp. 525-33). Compared with prescribing patterns in 1991–92, antibiotics were used less frequently for acute respiratory tract infections such as common colds and pharyngitis in 1998–99. “Use of broad-spectrum agents increased from 24% to 48% of antibiotic prescriptions in adults (P< 0.001) and from 23% to 40% in children,” state the authors. “By 1998–1999, 22% of adult and 14% of pediatric prescriptions for broad-spectrum antibiotics were for the common cold, unspecified upper respiratory tract infections, and acute bronchitis, conditions that are primarily viral.... Increasing reliance on newer, largely broad-spectrum antibiotics may be breeding a new crisis in antibiotic resistance.” (M. A. Steinman, mstein@itsa.ucsf.edu)

In an accompanying editorial, writers express concern (pp. 605-6): “As we sound the alarm about the peril of rising antimicrobial resistance, we [in the public health community] may be inadvertently promoting inappropriate use of broad-spectrum agents. We should inform the public that drug resistance is a problem that has the potential to affect everyone’s health, but we must do this while making sure patients and prescribers understand when broad-spectrum agents are indicated and when they are not.

“We should be encouraged by the work being done to promote appropriate antimicrobial use... This work has undoubtedly been responsible for some of the declines in antimicrobial use reported by Steinman and colleagues. Now is the time to roll up our sleeves and start improving antimicrobial selection.” (R. E. Besser, rbesser@cdc.gov)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 2, 2003 Vol. 10, No. 63
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Apr. 2 issue of JAMA (www.jama.com; 2003; 289).

Hydroxyurea & Sickle Cell Anemia: Use of hydroxyurea was associated with a 40% reduction in mortality among 299 adult patients with sickle cell anemia who were followed for up to 9 years (pp. 1645-51). Patients who participated in the randomized controlled Multicenter Study of Hydroxyurea in Sickle Cell Anemia trial, conducted in 1992–95, were offered the choice of continuing, stopping, or starting hydroxyurea therapy during a follow-up study in 1996–2001. Among the 299 patients who enrolled in the follow-up study, 75 (28%) died from pulmonary toxicity. Cumulative mortality data showed that 28% of patients died when fetal hemoglobin levels were fetal hemoglobin levels were lower than 0.5 g/dL, compared with 15% when HbF levels were above this value. Other factors that were predictive for mortality included reticulocyte counts less than 250,000 cells/cu mm, hemoglobin levels lower than 9 g/dL, presence of acute chest syndrome, and annual occurrence of three or more painful episodes.

The authors conclude, “Whether hydroxyurea should be given to patients with [sickle cell anemia] and fewer vaso-occlusive events or to patients with [sickle cell hemoglobin] disease remains to be determined.... Underlying disease severity remains critical to determining the prognosis of adult [sickle cell anemia], but hydroxyurea may mitigate disease severity.” (M. H. Steinberg, Boston U., Boston; msteinberg@medicine.bu.edu)

Drug Interactions & Hospitalizations: Many hospitalizations of elderly patients appear to be the result of known drug interactions, according to investigators who analyzed an Ontario database from 1994 through 2000 (pp. 1652-8). In a case–control comparison, cases were patients hospitalized for drug-related toxicity who were aged 66 years or older and being treated with glyburide, digoxin, or an ACE inhibitor. Patients on glyburide were 6.6 times more likely to have been treated with sulfamethoxazole– trimethoprim in the week before hospitalization for hypoglycemia (n = 909). Likewise, 1,051 patients hospitalized for digoxin toxicity were 11.7 times more likely to have been treated with the interacting antibiotic clarithromycin, compared with control patients. Among 523 patients who were taking ACE inhibitors and hospitalized for hyperkalemia, the odds ratio for recent treatment with potassium-sparing diuretics was 20.3.

The authors offer these comments about their study, “Our findings emphasize the potential dangers of commonly used medications and highlight the need for more timely collaboration between the scientists who study drug–drug interactions and those who design the computer systems intended to prevent them. Physicians should be aware of these drug–drug interactions and consider prescribing alternative agents when appropriate. Alternatively, they should consider dose adjustments and monitor patients closely for evidence of drug toxicity.” (D. Juurlink, Sunnybrook and Women’s College Health Sciences Ctr., Toronto, Ontario, Canada; david.juurlink@ices.on.ca)

Statins & Nitrotyrosine: Treatment with statins modifies levels of nitrotyrosine, a marker for protein modification by nitric oxide-derived oxidants, according to a study of two tertiary-care referral centers (pp. 1675-80). The study had two parts, one a 100-patient case–control comparison and the other an interventional effort in 35 of those patients. Nitrotyrosine levels were significantly higher in patients with coronary artery disease (odds ratio, 6.1, in the upper quartile compared with the lowest quartile). In 35 patients whose nitrotyrosine levels did not fall adequately during nutrition and exercise modification, statin therapy reduced these levels by a significant 25%. In calling for further evaluation of the predictive value of nitrotyrosine levels, the authors write, “[These] results point toward promising potential clinical utility in use of nitrotyrosine levels as an adjunct for CAD risk stratification and monitoring of anti-inflammatory actions of statin therapy.” (S. L. Hazen, Cleveland Clinic Found., Cleveland, Ohio; hazens@ccf.org)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 3, 2003 Vol. 10, No. 64
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Apr. 3 issue and Web site of the New England Journal of Medicine (content.nejm.org; 2003; 348).

SARS: Two articles and two editorials on severe acute respiratory syndrome have been posted early on the NEJM Web site. The articles describe clusters of patient cases in Hong Kong and Canada, while the editorials assess syndrome causes and the response of the public health community.

Eplerenone & HF: The selective aldosterone blocker eplerenone reduced morbidity and mortality when added to standard therapy of post-myocardial infarction patients with left ventricular dysfunction and heart failure (pp. 1309-21). A total of 6,632 patients were admitted to the study at 3–14 days after MI. They were treated with optimal medical therapy, which could include ACE inhibitors, angiotensin-receptor blockers, diuretics, and beta-blockers, as well as coronary reperfusion therapy. Placebo or eplerenone 25 mg/day was administered for 4 weeks, after which eplerenone doses could be advanced to a maximum of 50 mg/day. Patients were excluded if they required treatment with potassium-sparing diuretics, if their serum creatinine concentrations exceeded 2.5 mg/dL, or if they had serum potassium levels greater than 5.0 mmol/L before randomization.

During a mean follow-up period of 16 months, mortality was reduced by 15% among those on eplerenone (478 deaths, compared with 554 deaths in the placebo group). Mortality from cardiovascular causes was reduced by 17%, and a 13% reduction was observed in the risk of death from cardiovascular causes or hospitalization for cardiovascular events, and the risk of sudden death was lowered by 21%. Serious hyperkalemia occurred more often among those taking eplerenone (5.5% vs. 3.9%), while hypokalemia was observed more often in the placebo group (13.1%, compared with 8.4% among patients in the eplerenone group). (B. Pitt, bpitt@umich.edu)

An editorialist comments (pp. 1380-2): “The introduction of eplerenone, a selective aldosterone antagonist with reportedly less cumbersome adverse effects than spironolactone, could theoretically increase the inappropriate use of this class of drug. Eplerenone will undoubtedly be more costly than generic spironolactone.... There is nothing in the results of [this and another trial] to suggest that eplerenone should be used preferentially before treatment with spironolactone has been tried. It is also critical to emphasize that hyperkalemia is just as likely to occur with eplerenone therapy as it is with spironolactone therapy....

“The use of aldosterone antagonists may be well worth the expense or extra effort required to monitor the potential adverse effects, but patients who are treated with them should be screened—and their cases managed—as carefully as those in the published studies. Supplementary trials are needed to determine whether this class of drug will be efficacious in patients with less severe symptoms, or in those with heart failure due to primarily diastolic dysfunction.” (M. Jessup, U. Pennsylvania, Philadelphia)

Flu Vaccine & Cardiovascular Disease: Health benefits of influenza vaccine go far beyond the prevention of this viral infection, according to a study that reports reductions in risks of hospitalization for heart and cerebrovascular disease (pp. 1322-32). Two groups of patients aged 65 years and older from three large managed-care organizations were studied, including 140,055 subjects in 1998–99 and 146,328 subjects in 1999–2000. In the two respective flu seasons, 55.5% and 59.7% of subjects were vaccinated against influenza. Even though vaccinated subjects had higher morbidity levels (they had higher rates of most coexisting conditions, outpatient care, and prior hospitalization for pneumonia) than did unvaccinated people, the vaccinated group had reduced risks of hospitalization (19% lower during both seasons), cerebrovascular disease (16% and 23% in the two respective years), and pneumonia or influenza (32% and 29%). In addition, all-cause death risk was lower in the vaccinated group (48% and 50%). (K. L. Nichol, nicho014@umn.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 4, 2003 Vol. 10, No. 65
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Apr. issue of Diabetes Care (care.diabetesjournals.org; 2003; 26).

Lipid Therapy in Diabetes: Increased efforts are needed in patients with diabetes to treat lipid disorders aggressively, note authors who assessed medical record data from 47,813 patients with coronary artery disease (pp. 991-7). Comparing data from 1996 and 1998, investigators found “impressive progress ... in outpatient lipid management of CAD patients.” However, those patients who also had diabetes were 26% less likely to have a lipid profile and 17% less likely to receive lipid-lowering medications, compared with those patients without diabetes. (M. W. Massing, Med. Rev. of North Carolina, Cary, N.C.)

Insulin Pump Therapy: Continuous subcutaneous insulin infusion therapy is more effective than traditional insulin therapies, and it provides advantages without significant adverse outcomes, according to a meta-analysis of 52 studies that included 1,547 patients (pp. 1079-87). The authors write, “Results indicate that CSII therapy is associated with significant improvements in glycemic control (decreased glycohemoglobin and mean blood glucose). A descriptive review of potential complications of CSII use (e.g., hypoglycemia, diabetic ketoacidosis [DKA], pump malfunction, and site infections) suggests a decreased frequency of hypoglycemic episodes but an increased frequency of DKA in studies published before 1993.” The group recommends that additional studies “further examine the relative risks of CSII therapy, including the potential psychosocial impact of this technologically advanced therapy.” (J. Weissberg-Benchell, Children’s Mem. Hosp., Chicago)

Pediatric Insulin Pump Therapy: In 95 children and adolescents treated for type 1 diabetes between 1990 and 2000, insulin pump therapy proved safe and effective (pp. 1142-6). Age range at initiation of therapy was 4–18 years, with 29% of patients younger than 10 years old. Median duration of follow-up was 28 months. A small but significant decrease in glycosylated hemoglobin was observed within the first 3–6 months of treatment (7.7% vs. 7.5%). Because A1c levels rise as children age, the data had to be adjusted to compare values over time, and values were considered lower after adjustment for duration and age (7.7% vs. 8.1%). Hypoglycemic events occurred less frequently after pump therapy began, while similar numbers of other complications (diabetic ketoacidosis, emergency department visits) were observed before and during pump therapy. (L. P. Plotnick, Johns Hopkins U., Baltimore)

ED in Diabetes: Sustained attention to erectile dysfunction is needed in men with comorbid diabetes (pp. 1093-9). In a study of 20 men with diabetes and ED and 90 men with ED but not diabetes, investigators found among patients with diabetes worse erectile function and intercourse satisfaction at baseline and greater impact on emotional life. “Although diabetic patients initially respond well to ED treatment, responses do not appear to be durable over time,” the authors report. “Therefore, clinicians must provide longer-term follow-up when treating ED in diabetic patients.” (D. F. Penson, VA Health Care System, Seattle)

Herb Therapy in Diabetes: Insufficient data preclude conclusions about the effects of herbal therapies and vitamin/mineral supplements for glucose control in patients with diabetes, according to a systematic study of 58 trials (pp. 1277-94). Most studies involved patients with type 2 diabetes, and 44 of the 58 trials showed that the agents under study had positive effects on glycemic control, and very few adverse effects were identified. The authors conclude, “The available data suggest that several supplements may warrant further study. The best evidence for efficacy from adequately designed randomized controlled trials ... is available for Coccinia indica and American ginseng. Chromium has been the most widely studied supplement. Other supplements with positive preliminary results include Gymnema sylvestre, Aloe vera, vanadium, Momordica charantia, and nopal.” (G. Y. Yeh, Harvard Med. Sch., Boston)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 7, 2003 Vol. 10, No. 66
Providing news and information about medications and their proper use

>>>Gemifloxacin Approved
Gemifloxacin (Factive, GeneSoft Pharmaceuticals), an orally active fluoroquinolone, has been approved by FDA for treatment of mild or moderate community-acquired pneumonia, and acute bacterial exacerbation of chronic bronchitis. In clinical trials with more than 11,000 subjects, the antibiotic was effective in 5-day regimens for AECB and when administered for 7 days in patients with CAP. Resistance did not emerge with the new agent, while that problem occurred with older agents used as comparators.

The most common adverse effects with gemifloxacin include diarrhea, rash, nausea, and headache. Rash is generally mild to moderate in nature and is more likely to occur if taken for longer than the recommended course.

GeneSoft (www.genesoft.com) acquired North American and European rights to gemifloxacin last Oct. after GlaxoSmithKline returned the product to its developer, LG Life Sciences of Seoul, Korea. FDA had issued to GSK a nonapprovable letter in 2000 for this drug. For GeneSoft, gemifloxacin is the upstart company’s first product. Founded in 1998, GeneSoft’s stated goal is to focus on anti-infective agents that can meet the challenges of drug-resistant bacteria.

>>>Lancet Report
Source:
Apr. 5 issue of Lancet (www.thelancet.com; 2003; 361).

Atorvastatin & Cardiovascular Disease: In a study that ran for a median of 3.3 years, atorvastatin therapy provided large reductions in cardiovascular events in 10,305 patients with hypertension, hyperlipidemia, and at least three other cardiovascular risk factors (pp. 1149-58). In the Anglo-Scandinavian Cardiac Outcomes Trial, atorvastatin 10 mg/day was compared with placebo. The study was stopped before the planned 5-year duration was reached because of a 36% reduction in risk of cardiovascular events with active therapy. Significant decreases were observed in fatal and nonfatal stroke (hazard ratio, 0.73), total cardiovascular events (0.79), and total coronary events (0.71). Mortality dropped by 13%, but the difference was not significant. (N. Poulter, Imperial College, London; n.poulter@imperial.ac.uk)

Hormonal Contraceptives & Cervical Cancer:
Long-term use of hormonal contraceptives is associated with increased risk of cervical cancer, according to a systematic review of 28 studies (pp. 1159-67). Among 12,531 women with cervical cancer and comparators, relative risks were determined through comparisons with never users of oral contraceptives. The authors report, “For durations of approximately less than 5 years, 5–9 years, and 10 or more years, respectively, the summary relative risks of cervical cancer were 1.1 (95% CI 1.1–1.2), 1·6 (1.4–1.7), and 2.2 (1.9–2.4) for all women; and 0.9 (0.7–1.2), 1.3 (1.0–1.9), and 2.5 (1.6–3.9) for HPV positive women.” (V. Beral, Radcliffe Infirmary, Oxford, U.K.)

>>>PNN JournalWatch
* Prevalence of Helicobacter pylori in Patients with Gastro-oesophageal Reflux Disease: Systematic Review, in BMJ, 2003; 326: 737 ff. Reprints: www.bmj.org; A. Raghunath, Wolfson Research Inst., Stockton on Tees, U.K.; raghu@nath.freeserve.co.uk

* Why Certain Systematic Reviews Reach Uncertain Conclusions, in
BMJ, 2003; 326: 756–8. Reprints: M. Petticrew, U. Glasgow, Glasgow, U.K.; mark@msoc.mrc.gla.ac.uk

* Treatment of Herpes Zoster and Postherpetic Neuralgia, in
BMJ, 2003; 326: 748–50. Reprints: R. W. Johnson, Bristol Royal Infirmary, Bristol, U.K.

* Guidelines for the Early Management of Patients With Ischemic Stroke: A Scientific Statement From the Stroke Council of the American Stroke Association, in
Stroke, 2003; 34: 1056–83. Reprints: stroke.ahajournals.org; H. P. Adams, Jr.

* ß-Blockers in Chronic Heart Failure, in
Circulation, 2003; 107: 1570–5. Reprints: circ.ahajournals.org; M. Gheorghiade.

* American Heart Association/American College of Cardiology Foundation Guide to Warfarin Therapy, in
Circulation, 2003; 107: 1692–711. Reprints: circ.ahajournals.org; J. Hirsh.

* Will the Genomics Revolution Revolutionize Psychiatry?, in
American Journal of Psychiatry, 2003; 160: 625–35. Reprints: ajp.psychiatryonline.org; K. R. Merikangas.

* Statin-Associated Myopathy, in
JAMA, 2003; 289: 1681–90. Reprints: www.jama.com; P. D. Thompson.

* Gene Vaccines, in
Annals of Internal Medicine, 2003; 138: 550–9. Reprints: www.annals.org; I. K. Srivastava.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 8, 2003 Vol. 10, No. 67
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Apr. Pharmacotherapy (www.accp.com; 2003; 23).

Beta Blockade in HF: Beta blockers are an important component of therapy of heart failure that assists in reversing the cardiac-remodeling process, explain authors of a review article (pp. 451-9). While their use was traditionally reserved for patients with mild or moderate HF, more recent data demonstrate their effectiveness in severe HF and those with left ventricular systolic dysfunction after myocardial infarction. Variations among beta blockers in pharmacology and dosing requirements affect treatment decisions and clinical measurements of drug effects. (J. H. Patterson, hpatterson@unc.edu)

Pharmacogenetics of PPIs: Genetic polymorphism in the cytochrome P450 2C19 isoenzyme could affect the success of therapy with proton pump inhibitors, according to a systematic review of 17 articles (pp. 460-71). However, virtually all available studies have been conducted in Japanese men; thus, clinical relevance of effects is unclear in women and non-Asian populations. “Although CYP2C19 genotyping is currently only a research instrument, it may be a valuable clinical tool in selecting patients to ensure optimal PPI therapy,” the authors conclude. (M. H. H. Ensom, Children’s and Women’s Health Ctr., Vancouver, B. C., Canada)

OTC Migraine Therapies: Pharmacists are in a prime position to assist patients with migraine select appropriate nonprescription medications and to recommend medical care when OTC agents are ineffective (pp. 494-505). Published trials of acetaminophen, aspirin, ibuprofen, and an aspirin–acetaminophen– caffeine combination have generally excluded patients “enduring morbidity with 50% or more of attacks and/or vomiting with 20% or more of attacks,” the authors write, and such patients should be referred to physicians. The best evidence supports an adequate trial of OTC therapies in patients with less severe cases of migraine. (R. G. Wenzel, Diamond Headache Clinic, Chicago; rwenz@hotmail.com)

>>>Psychiatry Highlights
Source:
Apr. issue of the American Journal of Psychiatry (ajp.psychiatryonline.org; 2003; 160).

Clozapine Weight Gain & Polymorphism: A study of 32 Chinese Han patients indicates that genetic polymorphism in the promoter region of the serotonin 5-HT2C receptor gene may be related to weight gain during clozapine therapy (pp. 677-9). In 10 patients with the –759T variant allele, significantly less weight gain occurred during 6 weeks of clozapine therapy for first-episode schizophrenia. The authors note that the effect was observed only in men. (G. P. Reynolds)

Nature vs. Nurture in Substance Abuse: A study of male twins shows that, while genetics influences the risk for use of illicit drugs and abuse/dependence of six substance classes, it has little or no influence over which of the drugs is used (pp. 687-95). Through interviews of both members of 1,196 male–male twin pairs, investigators determined, “High levels of comorbidity involving the different substance categories were observed for both use and abuse/dependence. One common genetic factor was found to have a strong influence on risk for illicit use and abuse/dependence for all six substance classes. A modest influence of substance-specific genetic factors was seen for use but not for abuse/dependence. Shared environmental factors were more important for use than for abuse/dependence and were mediated entirely through a single common factor.” (K. S. Kendler)

Suicide Rates in SSRI Clinical Trials: Concerns that patients taking SSRIs are at higher risk for completed suicide are refuted through an analysis of FDA summary reports of nine clinical trials (pp. 790-2). A total of 48,277 depressed patients participated in trials, and 77 of them committed suicide. Similar suicide rates were calculated for patients on SSRIs (0.59%), standard comparison antidepressant (0.76%), and placebo (0.45%), thus failing to support any difference in suicide risk in either treated or untreated subjects or among those on various types of antidepressants. (A. Khan)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 9, 2003 Vol. 10, No. 68
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Apr. 9 JAMA, a special theme issue on obesity research (www.jama.com; 2003; 289).

Zonisamide for Weight Loss: In a short-term, preliminary trial, addition of the antiepileptic drug zonisamide to hypocaloric diet increased weight loss among 60 obese patients (pp. 1820-5). The subjects, 55 women and 5 men, had a mean body mass index of 36.3 kg/sq m and a mean age of 37.0 years. All were prescribed a 16-week balanced hypocaloric diet that provided patients with a 500 kcal/ day deficit. Patients randomly received placebo or initial doses of zonisamide 100 mg/day that were gradually increased to 400 mg/day and, among patients who lost less than 5% of their body weight at the end of 12 weeks, to 600 mg/day.

Significantly greater weight loss occurred among patients on active therapy (5.9 kg, a 6% loss, compared with 0.9 kg, a 1% loss, with placebo). Of 30 patients taking zonisamide, 17 lost at least 5% of body weight, while only 3 of 30 individuals taking placebo did so. Further weight loss was recorded in 36 patients during a single-blind, 16-week extension (mean of 9.2 kg [9.4%] with zonisamide, compared with 1.5 kg [1.8%] on placebo). (K. M. Gadde, gadde001@mc.duke.edu)

Weight Loss with Ciliary Neurotrophic Factor: A neurotrophic factor that acts through leptinlike pathways produced significantly greater weight loss in a dose-ranging study than did placebo (pp. 1826-32). Genetically engineered recombinant human variant ciliary neurotrophic factor (rhvCNTF), administered subcutaneously, was tested in 173 randomized patients in daily doses of 0.3, 1.0, or 2.0 mcg/kg for 12 weeks. Mean body mass index was 41.1 kg/sq m among the patients, 82.6% of whom were women. Mean body weight increased by 0.1 kg in the placebo group and declined by 1.5, 4.1, and 3.4 kg in the three respective active therapy groups. rhvCNTF was generally well tolerated; adverse effects occurred in 75% of patients taking placebo and 78– 93% on active therapy. Mild injection site reactions were the most frequently reported adverse reaction. (H-P Guler, Regeneron Pharmaceuticals, Tarrytown, N.Y.; hans-peter.guler@regeneron.com)

Low-Carbohydrate Diets: Low-carbohydrate diets appear to work more by restricting caloric intake than a direct effect of lower carbohydrate intake, conclude authors of a systematic review (pp. 1837-50). After evaluating 107 articles that described 94 dietary interventions in 3,268 participants, the group wrote, “Among obese patients, weight loss was associated with longer diet duration (P= .002), restriction of calorie intake ( P= .03), but not with reduced carbohydrate content (P= .90). Low-carbohydrate diets had no significant adverse effect on serum lipid, fasting serum glucose, and fasting serum insulin levels, or blood pressure.” They conclude, “There is insufficient evidence to make recommendations for or against the use of low-carbohydrate diets, particularly among participants older than age 50 years, for use longer than 90 days, or for diets of 20 g/d or less of carbohydrates. Among the published studies, participant weight loss while using low-carbohydrate diets was principally associated with decreased caloric intake and increased diet duration but not with reduced carbohydrate content.” (D. M. Bravata, Ctr. for Primary Care and Outcomes Research, Stanford, Calif.; bravata@healthpolicy.stanford.edu)

An editorialist adds this assessment: “Although the truth of ‘a calorie is a calorie’ has been reaffirmed by the systematic review by Bravata et al, the question of whether patients can adhere more easily to one type of diet or another remains to be answered. One study suggesting that diet composition can make a difference came from a 9-month randomized study in which 25% of dietary fat was replaced with the fat substitute olestra to provide diets with 25% available fat. A standard diet with 25% fat initially produced weight loss, but this loss was not maintained. By replacing dietary fat with olestra, weight loss continued over the entire 9 months of the trial. Thus, the possibility remains that some dietary components may provide long-term effects.” (G. A. Bray, La. State U., Baton Rouge; brayga@pbrc.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 10, 2003 Vol. 10, No. 69
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Apr. 10 issue of the New England Journal of Medicine (content.nejm.org; 2003; 348).

Low-Intensity Warfarin for VT: In a study that had been released early on the NEJM Web site (see PNN, Feb. 25), long-term, low-intensity warfarin therapy reduced the incidence of recurrent venous thromboembolism by 64% among patients with idiopathic venous thromboembolism. In the Prevention of Recurrent Venous Thromboembolism (PREVENT) trial, patients received full-dose anticoagulation therapy for a median of 6.5 months after an episode of idiopathic VT. They were then randomly assigned to placebo or low-intensity (target INR, 1.5–2.0) anticoagulation groups.

The trial was terminated early because of the pronounced benefits produced by anticoagulation. Among 508 patients followed for a mean of 2.1 years, 37 of 253 individuals taking placebo had recurrent VT (7.1 per 100 person-years), compared with 14 of 255 patients on low-dose warfarin (2.6 per 100 person-years), yielding a significantly lower hazard ratio (0.36). The authors write, “Risk reductions were similar for all subgroups, including those with and those without inherited thrombophilia. Major hemorrhage occurred in two patients assigned to placebo and five assigned to low-intensity warfarin (P=0.25). Eight patients in the placebo group and four in the group assigned to low-intensity warfarin died (P=0.26). Low-intensity warfarin was thus associated with a 48 percent reduction in the composite end point of recurrent venous thromboembolism, major hemorrhage, or death. According to per-protocol and as-treated analyses, the reduction in the risk of recurrent venous thromboembolism was between 76 and 81 percent.” (P. Ridker, Brigham and Women’s Hosp., Boston; pridker@partners.org)

Carefully managed anticoagulation services are needed, based on comments of an editorialist: “It is possible that newer, orally active antithrombotic agents will prove to have better safety and efficacy profiles than warfarin in the prevention of venous thromboembolism. However, all anticoagulants carry the risk of bleeding complications. The fundamental problem is that antithrombotic agents in current use or in development are unable to distinguish between a pathologic thrombus, which is potentially dangerous, and a hemostatic thrombus, which forms physiologically to restore and maintain vascular integrity and is therefore protective. Until a ‘magic bullet’ of antithrombotic therapy is found that specifically targets pathologic thrombi, we will continue to walk the tightrope of anticoagulant dosing.” (A. I. Schafer, U. Penn., Philadelphia)

Pharmacogenetics of Multidrug Resistance in Epilepsy: Polymorphisms in a drug-transporter gene may somehow be linked to multidrug-resistant cases of epilepsy, according to a pharmacogenomic analysis of 315 patients (pp. 1442-8). Compared with 115 patients with drug-responsive epilepsy, 200 patients with drug-resistant conditions were 2.66 times more likely to have the CC genotype at ABCB1 3435 than the TT genotype. Because “the polymorphism fell within an extensive block of linkage disequilibrium spanning much or all of the gene,” the investigators suspect that “the polymorphism may not itself be causal but rather may be linked with the causal variant.” (S. M. Sisodiya, UCL Inst. of Neurol., London; s.sisodiya@ion.ucl.ac.uk)

An editorialist comments, “Whether intrinsic or acquired overexpression of multidrug transporters accounts for a few cases or many or whether it has only a supporting, perhaps minor role, the study of these transporters is a fruitful and exciting area of epilepsy research. Multidrug transporters exist normally in the brain, where they may be part of the barrier system that maintains a stable and normal extracellular milieu. The recognition that they are increased in epileptogenic areas opens potential new avenues for therapeutic intervention, such as the development of drugs that inhibit or bypass overexpressed transporters and implantable devices that can deliver high concentrations of antiseizure drugs directly into epileptogenic brain parenchyma.” (T. A. Pedley, Columbia U., New York City)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 11, 2003 Vol. 10, No. 70
Providing news and information about medications and their proper use

>>>SARS Agent Identified, Treatment Still Supportive
Important new articles about severe acute respiratory syndrome have been posted to journal Web sites this week.

The
New England Journal of Medicine released two studies yesterday (http://nejm.org/earlyrelease/sars.asp). Using clinical, cytopathological, microbiological, and immunologic testing, investigators confirm that a newly identified member of the single-stranded RNA coronavirus family is the causative agent of SARS. They place the new virus in context with other known coronaviruses, and they propose the virus be named Urbani SARS-associated coronavirus in memory of the WHO physician who contracted and died from SARS while caring for some of the first known patients in Hanoi, Vietnam.

Earlier this week,
Lancet also released SARS articles and commentaries, and one of them hints at possible treatment approaches (www.thelancet.com/ journal). Clinical management algorithms are provided for symptomatic patients with and without definite exposure to the virus, but these focus more on the need for isolation and use of protective garb by health care workers and family members than on specific treatments. The algorithm mentions coverage of patients for pneumonia with beta-lactam antibiotics and for atypical pneumonia with clarithromycin, azithromycin, or a fluoroquinolone. One article also mentions that patients who progressed to more serious cases of SARS received intravenous ribavirin and corticosteroids later rather than earlier in the course of the disease. However, CDC officials have recommended use of antibiotics and antiviral agents only when patients have concomitant conditions that require these other medications, and they emphasize only supportive care aimed at managing symptoms in patients with SARS.

>>>FDA Reviewing Approvals Of Menopause Products
A 1976 decision that allowed marketing of at least two marketed estrogen/androgen products for treating hot flashes of menopause is being reviewed by FDA, which announced the action in a Federal Register notice yesterday. In a news release, the agency noted, “FDA is acting because it does not believe there is substantial evidence that androgens contribute to the effectiveness of these combination products to treat hot flashes in menopausal women who do not find relief from these symptoms when using estrogens alone.”

Marketing of the products will continue while hearings are conducted and FDA reaches a final decision. While FDA did not name the products involved, one product that fits this description is Pharmacia’s Depo-Testadiol. FDA said that it is aware that the estrogen–androgen combinations it is reviewing are being used for female sexual dysfunction, an unlabeled use. It offered to work with manufacturers to design clinical trials of the products for this use, an action that would be needed for continued marketing if the menopausal-symptoms indication were eliminated.

>>>Oncology Group Struggles to Address Chemotherapy Problems
Acting in response to the case of Kansas City pharmacist Robert Courtney and other isolated reports of diluted chemotherapy admixtures, the American Society of Clinical Oncology has released a statement on use of outside services to prepare or administer chemotherapy drugs. Posted in advance of publication on the ASCO journal’s Web site (www.jco.org), the statement was approved by the organization’s Board on Mar. 1.

The two-page statement is quite general, in essence only calling for “the outside entity” to follow basic pharmacy laws regarding proper preparation, labeling, and handling. “To protect their patients, oncologists should administer drugs prepared by outside entities only if they are confident that the outside entities have adopted procedures that minimize the risk of error in complying with the oncologists’ prescriptions and preparing the drugs,” ASCO states. The group also notes that oncologists may want to use contracts to transfer the legal responsibility for admixtures to outside entities.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 14, 2003 Vol. 10, No. 71
Providing news and information about medications and their proper use

>>>Nephrology Report
Source:
Apr. issue of American Journal of Kidney Diseases (www.ajkd.org; 2003; 41).

Fat Distribution & Renal Impairment: Central fat distribution promotes development of renal impairment, even in lean subjects, concludes a study of 7,676 subjects without diabetes. Logistic regression showed that obese subjects (those with body mass index of greater than 30 kg/sq m) with central fat distribution had a greater risk of microalbuminuria (urinary albumin excretion of 30–300 mg/24 hr). Elevated filtration (2 SDs greater than the mean filtration in a nondiabetic lean group) was more common among obese subjects with either peripheral or central fat distribution. But the risk of similarly decreased filtration was 1.9 times greater among lean, overweight (BMI of 25–30 kg/sq m), and obese subjects in the study. The authors note that dividing the waist-to-hip ratio into quartiles shows that the higher this ratio, the greater the chances of diminished filtration, even when corrected for BMI. (S-J Pinto-Sietsma, U. Hosp., Maastricht, The Netherlands; pintosj@hotmail.com)

>>>Pediatrics Highlights
Source:
Apr. issue of Pediatrics (www.pediatrics.org; 2003; 111).

Medication Errors & ADRs: Computerized physician order entry with clinical decision support systems, ward-based clinical pharmacists, and improved communication among physicians, nurses, and pharmacists have the greatest potential to reduce medication errors in pediatric inpatients, according to a prospective cohort study was conducted in 1,020 patients (pp. 722-9). Data were gathered during a 6-week period in April and May 1999 at two academic medical centers. The investigators find, “Of 10,778 medication orders reviewed, 616 contained errors. Of these, 120 (19.5%) were classified as potentially harmful, including 115 potential adverse drug events (18.7%) and 5 preventable adverse drug events (0.8%). Most errors occurred at the ordering stage (74%) and involved errors in dosing (28%), route (18%), or frequency (9%).” Of the potentially harmful errors, 76%, 81%, and 86% could have been prevented by, respectively, CPOE, ward-based pharmacists, and improved communication, according to evaluations of an expert panel. (E. B. Fortescue, Children’s Hosp., Boston)

>>>PNN NewsWatch
* The menopause products described in an item in last Friday’s PNN have been identified in the lay media as Solvay’s Estratest and Estratest H.S. (esterified estrogens and methyltestosterone). An article in the Mar. 20 Wall Street Journal detailed how these and other products have fallen into a gray legal area as they were marketed after the 1962 drug amendments came into effect but were never approved by FDA. Instead, the agency has allowed their marketing to continue while “a handful” of FDA employees work on determining whether they are safe and effective.

* FDA on Friday approved the first
cyclosporine-sparing regimen for post-renal transplant patients. The action supports use of sirolimus (Rapamune, Wyeth) in new kidney transplant patients at low to moderate immunologic risk of organ rejection, who may now stop taking cyclosporine 2–4 months after transplantation. By substituting higher levels of sirolimus for cyclosporine, the agency said that kidney function might improve in these patients.

>>>PNN JournalWatch
* Sleep Apnea and Heart Failure: Part II: Central Sleep Apnea, in Circulation, 2003; 107: 1822–6. Reprints: circ.ahajournals.org; T. D. Bradley.

* Practice Recommendations for the Use of L-Carnitine in Dialysis-Related Carnitine Disorder National Kidney Foundation Carnitine Consensus Conference, in
American Journal of Kidney Diseases, 2003; 41. Reprints: www.ajkd.org; K. Willis, National Kidney Foundation, New York City, KerryW@kidney.org

* Cytosolic ß-Amyloid Deposition and Supranuclear Cataracts in Lenses from People with Alzheimer's Disease, in
Lancet, 2003; 361. Reprints: www.thelancet.com; A. I. Bush, bush@helix.mgh.harvard.edu

* Interleukin-2 Receptor Monoclonal Antibodies in Renal Transplantation: Meta-Analysis of Randomised Trials, in
BMJ, 2003; 326: 789 ff. Reprints: www.bmj.org; D. Adu, Queen Elizabeth Hosp., Birmingham; dwomoa.adu@uhb.nhs.uk

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 15, 2003 Vol. 10, No. 72
Providing news and information about medications and their proper use

>>>Internal Medicine Report I
Source:
Apr. 14 issue of Archives of Internal Medicine (www.archinternmed.com; 2003; 163).

Amiodarone for Sinus Conversion: The effectiveness of amiodarone for converting atrial fibrillation to sinus rhythm is confirmed in a meta-analysis of 21 studies, but the investigators find the safety data to be “too scarce for definitive conclusions” (pp. 777-85). Sinus rhythm was more easily achieved in patients with AF of more than 48 hours duration (relative risk, 4.33, compared with 1.40 in those with AF of less than 48 hours duration). The number needed to treat for both groups was 4. “We found that the size of the left atrium, presence of cardiovascular disease, and protocols of amiodarone administration did not influence the magnitude of effect,” the authors write. “Although it appears likely that amiodarone is safe when used in the short-term setting for the conversion of AF to sinus rhythm, one would require studies with more detailed exploration of [adverse events] to provide a definitive conclusion.... Amiodarone is effective and relatively rapid acting in converting AF to sinus rhythm in a wide range of patients. These features recommend its use as a first-line drug for stable patients without clinical thyroid disease or conduction abnormalities, particularly those who will require long-term antiarrhythmic treatment for preventing recurrence of AF.” (G. H. Guyatt, guyatt@mcmaster.ca)

Alendronate During HRT Withdrawal: In women discontinuing use of hormone-replacement therapy, alendronate 10 mg daily “increased or maintained both spine and hip bone mineral density and prevented the increase in bone resorption seen with withdrawal of HRT,” according to a trial of 144 subjects (pp. 789-94). In this 12-month study, alendronate produced mean increases of 2.3% in spine BMD (compared with a decline of 3.2% with placebo). “Greater hip and total body BMD preservation was also observed with alendronate use,” report the authors. “Bone turnover decreased significantly with alendronate (bone-specific alkaline phosphatase levels decreased by 20% and urinary N-telopeptide/creatinine ratio by 47%), but increased in the placebo group (by 18% and 36%, respectively). Alendronate was well tolerated, with no increase in adverse events compared with placebo.” (B. H. Ascott-Evans, U. Stellenboch Med. Sch., Tygerberg, South Africa)

>>>Internal Medicine Report II
Source:
Apr. 15 issue of the Annals of Internal Medicine (www.annals.org; 2003; 138).

CD4 Counts & Survival with Antiretroviral Treatment: In patients with HIV infection, earlier treatment of patients with low CD4+ cell counts results in reduced mortality, and the benefits may extend to patients with middle and high cell counts (pp. 620-6). In 340 patients who initiated antiretroviral therapy and 59 individuals who delayed ART, investigators identified mortality rates of, respectively, 15.4 and 56.4 deaths/1000 person-years in the low cell count group (0.201–0.350 X 109 cells/L), 10.0 and 16.6 deaths/1000 person-years in the middle cell count group (0.351–0.500 X 109 cells/L), and 7.5 and 3.1 deaths/1000 person-years in the high cell count group (0.501–0.750 X 109 cells/L). The group concludes, “These data provide strong evidence that earlier initiation of ART provides survival benefit for HIV-infected patients with [low] CD4+ cell counts.... Optimal timing of ART initiation is not entirely clear for those with CD4+ cell counts greater than 0.350 X 109 cells/L. Clinicians should consider these data when evaluating ART initiation for those with HIV infection.” (F. J. Palella Jr., f-palella@northwestern.edu)

Chemotherapy Use at the End of Life: Intravenous chemotherapy is used frequently during the last 3 months of life, note researchers who analyzed Medicare databases from Massachusetts and California (pp. 639-43). During the last month of life, 9% of patients received the agents, and 20–23% were given chemotherapy during the final 3 months. “The cancer’s responsiveness to chemotherapy does not seem to influence whether dying patients receive chemotherapy at the end of life,” write the authors. (E. J. Emanuel, NIH)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 16, 2003 Vol. 10, No. 73
Providing news and information about medications and their proper use

>>>Circulation Highlights
Source:
Apr. 15 Circulation (circ.ahajournals.org; 2003; 107).

Fatty Acids & Coronary Disease: In women with diabetes, higher consumption of fish and long-chain omega-3 fatty acids was associated with a lower coronary heart disease incidence and total mortality (pp. 1852 ff). The study included 5,103 women nurses who were diagnosed with type 2 diabetes but had no cardiovascular disease or cancer at baseline. Between 1980 and 1996, 362 incident cases of CHD were documented along with 468 deaths from all causes. Compared with women who seldom at fish (less than one serving per month), the adjusted relative risks of CHD were 0.70 for fish consumption one to three times per month, 0.60 for once per week, 0.64 for two to four times per week, and 0.36 for five or more times per week. Total mortality was also significantly lower among women who ate fish five times per week, and higher consumption of long-chain, omega-3 fatty acids showed a statistical trend toward lower incidence of CHD. (F. B. Hu, frank.hu@channing.harvard.edu)

An editorialist identified obstacles to further elucidation of these relationships (pp. 1834-6): “Use of N-3 fatty acids in preventive cardiology is at a crossroads. Expert opinion in the dietary field now favors moderate increases in intakes of plant-derived alpha-linolenic acid based on epidemiological evidence of benefit for [cardiovascular disease] risk reduction. The costs of such a clinical trial to confirm this reasonable recommendation would be prohibitive. The same is true for ‘increased fish intake,’ which likewise is based on epidemiological evidence. At the least, both of these recommendations are consistent with general dietary guidelines about ‘healthy eating patterns.’ The [American Heart Association’s] recent guideline for using fish-oil supplements for patients with established CHD is more problematic. Available evidence is suggestive of benefit in the immediate post-MI period, but a solid recommendation cannot be made without more definitive controlled clinical trials.” (S. M. Grundy, U. Texas Southwestern Med. Sch., Dallas)

Intracoronary vs. I.V. Abciximab: Major adverse cardiac events were reduced by intracoronary administration of abciximab 20 mg in 403 patients with acute myocardial infarction or unstable angina undergoing emergency coronary angioplasty, compared with intravenous administration of the drug (pp. 1840 ff). The incidence of death, MI, or urgent revascularization at 30 days was 10.2% among patients given the drug intracoronarily, compared with 20.2% among i.v. recipients. The authors conclude by encouraging that prospective, randomized trials be conducted to further assess this approach. (M. Höher, U. Ulm, Ulm, Germany; martin.hoeher@medizin.uni-ulm.de)

>>>Arthritis Highlights
Source:
Apr. issue of Arthritis & Rheumatism (www.rheumatology.org; 2003; 48).

Anakinra & RA:
The safety of anakinra was confirmed in a group of 1,399 patients with rheumatoid arthritis and numerous comorbid conditions similar to those likely to be found in clinical practice (pp. 927-34). In the 6-month study, 283 patients took placebo, while 1,116 individuals received the recombinant human interleukin-1 receptor antagonist. The authors report, “Serious adverse events occurred at a similar rate in the anakinra group and the placebo group (7.7% and 7.8%, respectively). Serious infectious episodes were observed more frequently in the anakinra group (2.1% versus 0.4% in the placebo group). The rate of withdrawal due to adverse events was 13.4% in the anakinra group and 9.2% in the placebo group.” (R. M. Fleischmann, St. Paul U. Hosp., Dallas; royfleischmann@radiantresearch.com)

Etanercept & JIA: Problems with etanercept therapy of juvenile idiopathic arthritis are identified in a study of 61 patients with this disease (pp. 1093-101). During a median of 13 months of treatment, most patients responded initially, but improvements were not sustained, and treatment failure was more common among those with systemic-onset JIA. (P. Quartier, Hôpital Necker-Enfants Malades, Paris; quartier@necker.fr)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 17, 2003 Vol. 10, No. 74
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Apr. 17 issue of the New England Journal of Medicine (content.nejm.org; 2003; 348).

ADEs in Ambulatory Care: Adverse drug events are common in the ambulatory setting, according to an analysis of two hospital-based and two community-based adult primary care practices in Boston (pp. 1556-64). Among 661 patients who received at least one prescription during a 4-week period, 162 patients (25%) had 181 ADEs (a rate of 27 per 100 patients). Thirteen percent of ADEs were serious, 28% were ameliorable, and 11% were judged preventable. “Of the 51 ameliorable events, 32 (63 percent) were attributed to the physician’s failure to respond to medication-related symptoms and 19 (37 percent) to the patient’s failure to inform the physician of the symptoms,” the authors write. “The medication classes most frequently involved in adverse drug events were selective serotonin-reuptake inhibitors (10 percent), beta-blockers (9 percent), angiotensin-converting–enzyme inhibitors (8 percent), and non-steroidal antiinflammatory agents (8 percent). On multivariate analysis, only the number of medications taken was significantly associated with adverse events.”

To improve patient–doctor communication in the outpatient setting, the investigators recommend “developing educational materials for patients, improving translation services, and increasing patients’ access to outpatient pharmacists (to discuss medications and side effects).” Web sites could help, they add, as could telephone calls from nurses or pharmacists to inquire about medication-related problems. (T. K. Gandhi, Brigham and Women’s Hosp., Boston; tgandhi@partners.org)

After describing an ADE involving his 80-year-old father on the day he was asked to write an editorial about the above article, a physician describes these possible roles for pharmacists in minimizing ADEs (pp. 1587-9): “Pharmacists should routinely inquire about drug-specific and nonspecific symptoms, instead of merely asking patients, ‘Do you have any questions?’ In addition, pharmacists and physicians should collaborate to improve pharmacotherapy. Murray et al. found that the use of an order-entry system for physicians, which sent electronic prescriptions to a hospital-based pharmacy, significantly reduced the time pharmacists spent recording prescription data and increased the time they spent counseling patients. Pharmacists could also collaborate with physicians on individualized (‘N of 1&rsquoWinking trials, which can help determine whether nonspecific symptoms can be attributed to specific drugs. Finally, outpatient practices could routinely screen patients for potential drug-related symptoms while the patients were in the waiting room, perhaps by using mobile computing devices, so that physicians would be alerted to a potential drug-related problem during the patient’s visit, when it could be addressed most effectively.” (W. M. Tierney, Indiana U., Indianapolis)

Paclitaxel-Eluting Stents: Combined with standard antiplatelet therapy in patients with coronary lesions, paclitaxel-eluting stents “effectively inhibit restenosis and neointimal hyperplasia, with a safety profile similar to that of standard stents,” according to a study of 177 individuals (pp. 1537-45). Control (drug-free), low-dose (1.3 mcg/sq mm) or high-dose (3.1 mcg/sq mm) stents were successfully placed in 176 patients (99%), and standard therapy was prescribed (aspirin with ticlopidine in 120 patients, clopidogrel in 18 patients, and cilostazol in 37 patient). The authors report the best results with the high-dose stent, “The high-dose group, as compared with the control group, had significantly better results for the degree of stenosis (mean [±SD], 14±21 percent vs. 39±27 percent; P<0.001), late loss of luminal diameter (0.29±0.72 mm vs. 1.04±0.83 mm, P<0.001), and restenosis of more than 50 percent (4 percent vs. 27 percent, P<0.001). Intravascular ultrasound analysis demonstrated a dose-dependent reduction in the volume of intimal hyperplasia (31, 18, and 13 cu mm, in the high-dose, low-dose, and control groups, respectively).” (S-J Park, Asan Med. Ctr., Seoul, South Korea; sjpark@amc.seoul.kr)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 18, 2003 Vol. 10, No. 75
Providing news and information about medications and their proper use

>>>Oncology Highlights
Source:
Apr. 1 issue of the Journal of Clinical Oncology (www.jco.org; 2003; 21).

MD vs NP Prescribing for Nausea and Vomiting: An interesting study of physician reactions to the need for guideline adherence analyzed patterns of physician and nurse practitioner prescribing for prevention of chemotherapy-induced nausea and emesis (CINE; pp. 1373-8). Institutional CINE guidelines were developed based on American Society of Clinical Oncology guidelines, but physician adherence to the suggestions was poor at baseline (mean of 0.87 omissions per chemotherapy administration) and after the guidelines were distributed, a lecture was presented by a visiting expert, and adherence data were shared. However, after a patient survey demonstrated problems with delayed CINE, particularly on day 3 after chemotherapy, the physicians “accepted the need for compliance and instituted nurse practitioner antiemetic prescribing, with almost complete compliance and concurrent measurable reduction in day 3 nausea,” the authors report. (W. C. Mertens, Baystate Regional Cancer Program, Springfield, Mass.; wilson.mertens@bhs.org)

End Points in Drug Approval: The end points used by FDA over the past 13 years in granting market approval of oncology drugs show a reliance on measures other than survival (pp. 1404-11). For the period of Jan. 1, 1990, through Nov. 1, 2002, the authors found, “The FDA grants either regular marketing approval or accelerated marketing approval for oncology drug applications. Regular approval is based on end points that demonstrate that the drug provides a longer life, a better life, or a favorable effect on an established surrogate for a longer life or a better life. Accelerated approval (AA) is based on a surrogate end point that is less well established but that is reasonably likely to predict a longer or a better life. Tumor response was the approval basis in 26 of 57 regular approvals, supported by relief of tumor-specific symptoms in nine of these 26 regular approvals. Relief of tumor-specific symptoms provided critical support for approval in 13 of 57 regular approvals. Approval was based on tumor response in 12 of 14 AAs.” (J. R. Johnson, Johnsonj@cder.fda.gov)

>>>Neurology Highlights
Source:
Apr. 8 Neurology (www.neurology.org; 2003; 60).

Headache Treatment: Reasons for treatment failure of headache fall into five categories, according to a review article (pp. 1064-70). These are: (1) the diagnosis is incomplete or incorrect; (2) important exacerbating factors have been missed; (3) pharmacotherapy has been inadequate; (4) nonpharmacologic treatment has been inadequate; and (5) other factors, including unrealistic expectations and comorbidity, exist. “Most refractory headache patients have a biologically determined problem and can be helped by accurate diagnosis or effective treatment,” write the authors. “Persistence in treating these patients can be very rewarding.” An orderly approach to treatment failure and a checklist for managing refractory patients are provided. (R. B. Lipton, Albert Einstein Coll. of Med., Bronx, NY; Rlipton@aecom.yu.edu)

B Vitamins and l-Dopa Therapy: Patients with Parkinson’s disease who are taking l-dopa may need B-vitamin supplements to avoid hyperhomocysteinemia, according to an analysis of 20 patients under treatment and 20 l-dopa–naive patients (pp. 1125-9). “The mean plasma homocysteine concentration was higher in the treatment group than in the controls (p = 0.018),” the article explains. “Plasma homocysteine was correlated with plasma folate, vitamin B12 ,and [pyridoxal-5'-phosphate] concentrations in the treatment group ( p = 0.007) but not in the controls.” The authors conclude, “l-Dopa can cause hyperhomocysteinemia in PD patients, the extent of which is influenced by B-vitamin status. The B-vitamin requirements necessary to maintain normal plasma homocysteine concentrations are higher in l-dopa-treated patients than in those not on l-dopa therapy. B-Vitamin supplements may be warranted for PD patients on l-dopa therapy.” (J. W. Miller, jwmiller@ucdavis.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 21, 2003 Vol. 10, No. 76
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
Apr. 19 issue of Lancet (www.thelancet.com; 2003; 361).

SARS: An analysis of 50 patients in Hong Kong with severe acute respiratory syndrome confirms that a novel coronavirus is the causative agent of this newly recognized disease (pp. 1319-25). This article, which discusses use of corticosteroids and ribavirin in managing the syndrome, was posted earlier to the journal’s Web site (see PNN, Apr. 11). However, use of ribavirin for treating SARS has since been discounted based on later tests of the virus in the laboratory.

“Patients’ age ranged from 23 to 74 years,” report the investigators. “Fever, chills, myalgia, and cough were the most frequent complaints. When compared with chest radiographic changes, respiratory symptoms and auscultatory findings were disproportionally mild. Patients who were household contacts of other infected people and had older age, lymphopenia, and liver dysfunction were associated with severe disease. A virus belonging to the family
Coronaviridae was isolated from two patients. By use of serological and reverse-transcriptase [polymerase chain reaction] specific for this virus, 45 of 50 patients with SARS, but no controls, had evidence of infection with this virus.”(J. S. M. Peiris, U. Hong Kong, Hong Kong, China; malik@hkucc.hku.hk)

CYP2S1 and Metabolism of Topical Drugs: Several agents used in the treatment of psoriasis induce expression of a recently identified cytochrome P450, CYP2S1, in psoriatic human skin, according to a study of 27 healthy volunteers and 29 patients with the condition (pp. 1336-43). Elucidating the role of CYP2S1 in mediating the response to photochemotherapy of psoriasis, the authors report, “Cutaneous expression of CYP2S1 was induced by ultraviolet radiation, [psoralen-ultraviolet A], coal tar, and all-trans retinoic acid; expression was significantly higher in lesional psoriatic skin than in adjacent non-lesional skin (geometric mean 3.38 [95% CI 2.64–4.34] times higher; p < 0.0001), which implies that topical drugs are differentially metabolised in psoriatic plaque and non-lesional skin. We showed that all-trans retinoic acid is metabolised by CYP2S1, which has higher cutaneous expression than CYP26, previously described as the specific cutaneous P450 retinoic-acid– metabolising enzyme.” (S. Ibbotson, Ninewells Hosp. and Med. Sch., Dundee, U.K.; s.h.ibbotson@dundee.ac.uk)

ADR Reporting by Nurses: Nurses appear more likely to report adverse drug reactions in the U.K.’s yellow card program than are physicians, and their reports are of acceptable quality (pp. 1347-8). Until Oct. 2002, nurses were not permitted to file ADR reports, which had to come from physicians, dentists, coroners, or pharmacists. Researchers assessed filing of reports by community and hospital nurses, finding that one in seven nurses reported ADRs, compared with one in eight doctors, and that similar proportions of nurse- and physician-filed reports were appropriate. (M. Pirmohamed, U. Liverpool, Liverpool, U.K.; munirp@liv.ac.uk)

>>>PNN JournalWatch
* Effectiveness of Anticholinergic Drugs Compared with Placebo in the Treatment of Overactive Bladder: Systematic Review, in BMJ, 2003; 326: 841 ff. Reprints: www.bmj.org; P. Herbison, U. Otago, Dunedin, New Zealand; peter.herbison@otago.ac.nz

* Outbreak of Severe Acute Respiratory Syndrome in Hong Kong Special Administrative Region: Case Report, in
BMJ, 2003; 326: 850–2. Reprints: www.bmj.org; M. Chan-Yeung, U. Hong Kong, Hong Kong, China; mmwchan@hkucc.hku.hk

* Bad Medicine: Low-Dose Dopamine in the ICU, in
Chest, 2003; 123: 1266–75. Reprints: www.chestjournal.org; K. R. Walley, McDonald Res. Lab., Vancouver, BC, Canada; kwalley@mrl.ubc.ca

* Alternate Treatments in Asthma, in
Chest, 2003; 123: 1254–65. Reprints: www.chestjournal.org; A. S. Niven.

* Management of Venous Thromboembolism: Past, Present, and Future, in
Archives of Internal Medicine, 2003; 163: 759–68. Reprints: www.archinternmed.com; T. M. Hyers, St. Louis U., St. Louis; Thyers@careinternet.com

* Descriptive Review of the Evidence for the Use of Metformin in Polycystic Ovary Syndrome, in
Lancet, 2003; 361. Reprints: Published online at http://www.thelancet.com/journal/vol361/iss9366/full/llan.361.9366.early_online_publication.25404.1

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 22, 2003 Vol. 10, No. 77
Providing news and information about medications and their proper use

>>>Neurology Highlights
Source:
Apr. issue of the Archives of Neurology (www.archneurol.com; 2003; 60).

Statins & Alzheimer’s Disease: The lowering of LDL cholesterol levels by statins partially explains the reduced risk of Alzheimer’s disease in people taking the drugs, according to a study of 44 patients (pp. 510-5). Of several possible effects of statins that could explain the relationship, the authors found, “Statin treatment reduced levels of plasma lathosterol by 49.5%, 24S-hydroxycholesterol by 21.4%, LDL cholesterol by 34.9%, and total cholesterol by 25%. The ratios of lathosterol-campesterol and 24S-hydroxycholesterol–LDL cholesterol were reduced significantly, but the ratio of 24S-hydroxycholesterol–total cholesterol was unchanged. Extended-release niacin also significantly reduced levels of 24S-hydroxycholesterol by 10% and LDL cholesterol by 18.1%. None of the agents lowered plasma concentration of apo E.” (G. L. Vega, Gloria.Vega@utsouthwestern.edu)

Vaccination & Neurologic Disease: Vaccination of adults against any of five diseases did not increase their risk of developing demyelinating neurologic disease in a study of members of three health-maintenance organizations (pp. 504-9). A total of 440 cases of patients aged 18–49 years with multiple sclerosis or optic neuritis were identified and matched with 950 control subjects. Odds ratios were not significantly different between cases and controls for hepatitis B vaccine (OR, 0.9), influenza vaccine (0.8), or measles, mumps, and rubella vaccine (0.8). Risks of neurologic disease were significantly lower in patients who received tetanus vaccination (0.6) or rubella vaccine (0.7); analysis by date of vaccination showed that the ORs were significantly lower only in patients who received those vaccines more than 5 years previously.

The authors conclude, “Our study adds to the weight of epidemiologic evidence that hepatitis B vaccine is not causally associated with MS. Our results also indicate that previous case reports of onset of demyelinating diseases shortly after receipt of several other vaccines probably represent coincidental temporal associations and not true causal associations.” (F. DeStefano, fdestefano@cdc.gov)

Anthrax Prevention & Treatment: A review of anthrax makes these observations about use of anthrax vaccine and treatment (pp. 483-8): “Although anthrax vaccines have been given to large numbers of military personnel without causing the commonly encountered major adverse effects, case reports are now emerging that describe occasional adverse effects. Optic neuritis was reported in a 39-year-old patient 1 month after booster vaccination, with good recovery after steroid treatment; a 23-year-old man had similar signs and symptoms within 2 weeks of the booster as well as retinal and nerve autoantibodies. A delayed hypersensitivity reaction was found in a 26-year-old man following 2 doses of anthrax vaccine.

“[For anthrax treatment, CDC recommends] ciprofloxacin ... on the basis of animal studies but that doxycycline should not be used for meningitis because of its poor central nervous system penetration. Further arguments against doxycycline for meningitis include in vitro resistance by
B anthracis Sterne; resistance to macrolides and quinolones has also been noted. The CDC stated that the bioterrorism-related strain of anthrax was sensitive to quinolones, rifampin, tetracycline, vancomycin, imipenem, meropenem, chloramphenicol, clindamycin, and aminoglycosides; resistant to third-generation cephalosporins, such as ceftriaxone sodium; and resistant to trimethoprim–sulfamethoxazole. The organization raised concerns for the induction of a penicillinase from the anthrax genome; they also cited the presence of a potential cephalosporinase and acknowledged that the issue is complicated. However, for inhalational anthrax, a multidrug regimen was advised to include either ciprofloxacin or doxycycline plus 1 or more traditional agents to which the organism is typically sensitive. They advocate that cutaneous anthrax could also be treated by ciprofloxacin or doxycycline.” (M. A. Meyer, Dent Neurol. Inst., Amherst, N.Y.; mmeyer@dentinstitute.com)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 23, 2003 Vol. 10, No. 78
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Apr. 23 issue of JAMA (www.jama.com; 2003; 289).

Verapamil in Hypertension: Antihypertensive therapy with verapamil is similar in effectiveness but not superior to treatment with diuretics or beta blockers, according to results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial (pp. 2073-82). At 661 centers in 15 countries, 16,602 patients with hypertension and 1 or more additional risk factors for cardiovascular disease were entered into the study. They received either controlled-onset extended-release (COER) verapamil 180 mg, atenolol 50 mg, or hydrochlorothiazide 12.5 mg, and data collection continued for a mean of 3 years after randomization.

Blood pressure reductions and most clinical outcomes were similar in the verapamil and atenolol or hydrochlorothiazide groups, but more nonstroke bleeds occurred in the patients taking verapamil. The authors report, “There were 364 primary cardiovascular disease– related events that occurred in the COER verapamil group vs 365 in atenolol or hydrochlorothiazide group (hazard ratio [HR], 1.02; 95% confidence interval [CI], 0.88–1.18; P= .77). For fatal or nonfatal stroke, the HR was 1.15 (95% CI, 0.90–1.48); for fatal or nonfatal myocardial infarction, 0.82 (95% CI, 0.65–1.03); and for cardiovascular disease–related death, 1.09 (95% CI, 0.87–1.37). The HR was 1.05 (95% CI, 0.95–1.16) for any prespecified cardiovascular disease–related event and 1.08 (95% CI, 0.93–1.26) for all-cause mortality. Nonstroke hemorrhage was more common with participants in the COER-verapamil group (n = 118) compared with the atenolol or hydrochlorothiazide group (n = 79) (HR, 1.54 [95% CI, 1.16– 2.04]; P= .003).” (H. R. Black, hblack@rush.edu)

Editorialists criticize the early termination of the CONVINCE study, which was ended “for commercial reasons” by sponsor Pharmacia (now Pfizer, but G. D. Searle at the outset of the study; pp. 2128-31). Had the study continued and the point estimates not changed, the editorialists note that “combining the atenolol and hydrochlorothiazide therapies into a single comparison group would no longer have been appropriate, and the primary results might have shown that while verapamil was slightly better than beta-blockers, diuretics were better than verapamil. Such a finding, although simply a projection from an aborted trial, would have been an important scientific contribution.” (B. M. Psaty, psaty@u.washington.edu)

Blood Pressure & Lifestyle Interventions: Recommended changes in lifestyle can effectively lower blood pressure in patients with stage 1 hypertension and other above-optimal BP readings (pp. 2083-93). Among 810 adults (mean age, 50 years; 62% women; 34% African Americans), three interventions were tested: established recommendations (weight loss, sodium reduction, increased physical activity, and limited alcohol intake), established recommendations plus the Dietary Approaches to Stop Hypertension (DASH) diet, and advice only. After 6 months, the investigators found, “Compared with the baseline hypertension prevalence of 38%, the prevalence at 6 months was 26% in the advice only group, 17% in the established group (P = .01 compared with the advice only group), and 12% in the established plus DASH group (P < .001 compared with the advice only group; P = .12 compared with the established group). The prevalence of optimal BP (<120 mm Hg systolic and <80 mm Hg diastolic) was 19% in the advice only group, 30% in the established group (P = .005 compared with the advice only group), and 35% in the established plus DASH group (P < .001 compared with the advice only group; P = .24 compared with the established group).” (L. J. Appel, Johns Hopkins Medical Inst., Baltimore; lappel@jhmi.edu)

An editorialist emphasizes weight more than diet (pp. 2131-2): “Weight loss has many benefits for obese and overweight individuals other than lowering blood pressure. For normal-weight individuals with hypertension, the DASH diet also may be beneficial.” (T. G. Pickering, Mount Sinai Med. Ctr., New York City; Thomas.pickering@msnyuhealth.org)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 24, 2003 Vol. 10, No. 79
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Apr. 24 issue of the New England Journal of Medicine (content.nejm.org; 2003; 348).

Obesity & Cancer: In a study of more than 900,000 American adults over a 16-year period, researchers identified increased mortality rates from cancer in patients with higher body mass indices (pp. 1625-38). Among men and women whose BMIs exceeded 40 kg/sq m, respective increases in risk of death from cancer were 52% and 62%. Higher rates of cancer deaths from specific types of cancer were also noted: “In both men and women, body-mass index was also significantly associated with higher rates of death due to cancer of the esophagus, colon and rectum, liver, gallbladder, pancreas, and kidney; the same was true for death due to non-Hodgkin’s lymphoma and multiple myeloma. Significant trends of increasing risk with higher body-mass-index values were observed for death from cancers of the stomach and prostate in men and for death from cancers of the breast, uterus, cervix, and ovary in women. On the basis of associations observed in this study, we estimate that current patterns of overweight and obesity in the United States could account for 14 percent of all deaths from cancer in men and 20 percent of those in women.”

The authors speculate on the mechanism through which obesity might cause cancer: “The International Agency for Research on Cancer (IARC) has concluded that there is sufficient evidence of a cancer-preventive effect of avoidance of weight gain for cancers of the colon, breast (in postmenopausal women), endometrium, kidney (renal-cell carcinoma), and esophagus (adenocarcinoma). Potential biologic mechanisms include increased levels of endogenous hormones (sex steroids, insulin, and insulin-like growth factor I) associated with overweight and obesity and the contribution of abdominal obesity to gastroesophageal reflux and esophageal adenocarcinoma. Our study supports the conclusion of the IARC.” (E. E. Calle, Am. Cancer Soc., Atlanta; jcalle@cancer.org)

Editorialists add these thoughts (pp. 1623-4): “Several important questions cannot be answered by the investigation by Calle et al. To what extent does the apparent effect of overweight and obesity on mortality due to cancer reflect an effect on the incidence of various types of cancer? In other words, does the likely detrimental effect of excess body weight on prognosis, given the presence of cancer, contribute to the observed pattern and, if so, to what extent? Do particular types of overweight or obesity, notably central obesity, have a differential effect in some, or in all, of the types of cancer related to excess body weight? And, of course, this important investigation raises the question of whether a documented excess risk of death due to cancer among overweight and obese persons will provide the necessary additional motivation for controlling body weight in the United States and around the world.” (H-O Adami, Karolinska Institutet, Stockholm, Sweden)

Skin Cancers After Organ Transplantation: As patients live longer after receiving solid-organ transplants, life-threatening skin cancers are emerging as the common tumors in these patients, according to a review article (pp. 1681-91): “Along with specific treatment, such tumors may require the tapering of immunosuppressive treatment. Squamous-cell carcinomas account for the majority of skin cancers in transplant recipients and are mainly related to sun exposure. Prevention of these tumors starts with adequate education of patients about the importance of strict protection from the sun. All patients must avoid direct exposure to the sun, use appropriate clothing for outdoor activities (i.e., a large-brimmed hat, long sleeves, and long pants), and apply sunscreens with a high sun-protection factor. An increasing number of transplantation units provide patients with detailed written recommendations for protecting themselves from the sun. Prevention also includes regular dermatologic monitoring for early detection and ablation of premalignant lesions. Such measures may prevent many skin cancers.” (S. Euvrard, Edouard Herriot Hosp., Lyons, France; sylvie.euvrard@numericable.fr)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 25, 2003 Vol. 10, No. 80
Providing news and information about medications and their proper use

>>>FDA Approves Enzyme for Treating Fabry Disease
Another orphan disease now has an FDA-approved treatment, thanks to yesterday’s approval of agalsidase beta (Fabrazyme, Genzyme). The intravenously administered enzyme, produced using recombinant DNA technology, is indicated for treatment of Fabry disease, which affects 1 in 40,000 males.

Because of a deficiency in an enzyme, alpha-galactosidase A, certain fats accumulate in the blood vessels of patients with Fabry disease over many years, leading to the involvement of various tissues and organs of the body, including the kidneys and the heart, which can then cause organ failure. As a result, patients with Fabry disease often must cope with significant pain and disability and typically have a shortened life span. While it is believed that fewer females suffer the most serious consequences of the disease, they can be similarly and seriously affected as well.

Agalsidase beta replaces the missing enzyme and thereby reduces a particular type of lipid accumulation in many types of cells, including blood vessels in the kidney and other organs. This reduction in fat deposition should prevent the development of life-threatening organ damage and have a positive effect on health.

Fabrazyme was approved under an accelerated or early approval mechanism. This policy allows for expediting the approval of therapies that treat serious or life-threatening illnesses when studies of the products indicate early favorable outcomes that are likely to predict clinical benefit. The approval is based on surrogate endpoints—laboratory measurements or physical signs likely to predict benefit for the patient.

In this case, Genzyme Corporation performed biopsies of cells lining the blood vessels within the kidney and other organs in patients with Fabry disease. Many but not all of the cells examined showed significant clearance of lipid deposits in patients treated with agalsidase beta.

Infusion reactions (fever, chest tightness, blood pressure changes, abdominal pain, and headache) are the main safety concern with agalsidase beta, and some of these can be severe. Most patients also develop antibodies to the product, and some patients who experience allergic reactions may need to be further evaluated. Because of the potential for these severe reactions, appropriate medical observation and support should be available when the drug is administered.

>>>PNN NewsWatch
* FDA this week approved two important medical devices with pharmacotherapeutic implications for marketing in the U.S. Cypher Sirolimus-Eluting Coronary Stent, made by Johnson & Johnson’s Cordis Corp., is placed in coronary arteries during angioplasty to keep the vessel open and slowly release sirolimus, which prevents the build-up of new tissue that could reclog the artery. Clinical studies show that use of the stent significantly reduces the need for revascularization procedures and the incidence of coronary events. Because the stent costs three times as much as an uncoated stent and Medicare may not increase its reimbursement rates sufficiently, hospitals could encounter financial pressures as the stent both increases their costs and reduces the number of these previously income-generating procedures.

*
Enteryx (Enteric Medical Technologies, a subsidiary of Boston Scientific), a device that is permanently implanted in the wall of the lower esophagus during endoscopy, is indicated for patients with GERD who require and respond to antisecretory medications. The device is a solution made up of a polymer and a solvent that is injected into the esophagus. After the injection, the solvent separates away and the polymer solidifies into a spongy material that is intended to help prevent the reflux. In a 12-month study of 85 patients, approximately 67% of the participants were able to discontinue all of their medications, 9% could reduce the dose by at least one half, and most patients (72%) noted an improvement in their symptoms when compared with taking no medications before implant. However, objective evaluations showed that, 12 months later, many patients still had subclinical reflux and inflamed tissues.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 28, 2003 Vol. 10, No. 81
Providing news and information about medications and their proper use

>>>Infectious Disease Report
Source:
May issue of Clinical Infectious Diseases (www.journals.uchicago.edu/CID/; 2003; 36).

SARS Bulletins: U. Hong Kong physicians are supplying updates on severe acute respiratory syndrome for posting to the CID Web site. Bulletins are published in the News section of the CID Electronic Edition [http:// www.journals.uchicago.edu/CID/ journal/news.html] 1-2 days after receipt.

Once-Daily HAART: Compared with conventional highly active antiretroviral therapy, once-daily HAART has at least equivalent virologic efficacy, good tolerability, and a low discontinuation rate, according to a systematic review (pp. 1186-90). The authors write, “Regimens [reviewed] included didanosine (ddI), emtricitabine (FTC), and efavirenz (EFV) (2 studies, 326 patients); ddI, lamivudine (3TC), and EFV (3 studies, 147 patients); ddI, 3TC, EFV, and adefovir dipivoxil (1 study, 11 patients); ddI, nevirapine, and EFV (1 study, 15 patients); and ddI, 3TC, indinavir, and ritonavir (1 study, 10 patients). Virological efficacy ranged between 70% and 91%. Preliminary randomized clinical trials showed that once-a-day regimens (ddI, 3TC, and EFV or ddI, FTC, and EFV) had a virological efficacy at least similar to that of conventional HAART.” (J. Ena, Marina Baixa Hosp., Villajoyosa, Alicante, Spain)

HIV Prevention Strategies: Discussing strategies for preventing HIV infection, authors note that “the expertise and energy that clinicians currently dedicate to diagnosis and treatment far exceeds that directed toward prevention” (pp. 1171-6). In an article that reviews prevention efforts and provides practical recommendations for behavioral counseling and medical interventions, the authors write, “Prevention of new HIV infections is an issue of increasing importance as the prevalence of HIV infection continues to increase. The integration of prevention and clinical care is recognized as a key element of future prevention activities. Prevention of HIV infection should extend beyond the traditional public health model to the clinical care site. The clinical care setting offers a unique opportunity to bring people with HIV disease into care and to establish relationships, thus creating a foundation for prevention-related activities.” (T. Schreibman, Yale Sch. of Med., New Haven, Conn.)

Treatment of Ventilator-Associated Pneumonia: Intravenous colistin provides a safe and effective alternative to imipenem for treating patients with ventilator-associated pneumonia (VAP) caused by multidrug-resistant Acinetobacter baumannii, according to a study of 35 patients (pp. 1111-8). Colistin was used to treat 21 patients, and imipenem–cilastatin was used in 14 individuals. “VAP was considered clinically cured in 57% of cases in both groups,” investigators report. “In-hospital mortality rates were 61.9% in the CO group and 64.2% in the IM group, and the VAP-related mortality rates were 38% and 35.7%, respectively. Four patients in the CO group and 6 in the IM group developed renal failure.” (J. Garnacho-Montero, Hospital Universitario Virgen Del Rocio, Seville, Spain)

>>>PNN JournalWatch
* Effect of Community-Based Promotion of Exclusive Breastfeeding on Diarrhoeal Illness and Growth: A Cluster Randomised Controlled Trial, in Lancet, 2003; 361: 1418–23. Reprints: www.thelancet.com; M. K. Bhan, All India Institute of Med. Sci., New Delhi, India; community.research@cih.uib.no

* Altitude Illness, in
BMJ, 2003; 326: 915–9. Reprints: www.bmj.org; P. W. Barry, pwb1@le.ac.uk

* ABC of Learning and Teaching in Medicine: Creating Teaching Materials, in
BMJ, 2003; 326: 921–3. Reprints: www.bmj.org; R. Farrow.

*
D,L-3-Hydroxybutyrate Treatment of Multiple Acyl-CoA Dehydrogenase Deficiency (MADD), in Lancet, 2003; 361: 1433–5. Reprints: www.thelancet.com; J. L. K. Van Hove, U. Hosp. Gasthuisberg, Leuven, Belgium; Johan.Vanhove@uz.kuleuven.ac.be)

* Statins Are Associated With a Reduced Incidence of Perioperative Mortality in Patients Undergoing Major Noncardiac Vascular Surgery, in
Circulation, 2003; 107: 1848. Reprints: circ.ahajournals.org; D. Poldermans, Erasmus Med. Ctr., Rotterdam, The Netherlands; d.poldermans@erasmusmc.nl

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 29, 2003 Vol. 10, No. 82
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Apr. 28 issue of Archives of Internal Medicine (www.archinternmed.com; 2003; 163).

Linking Lab & Pharmacy Records: “Greater improvement is possible through implementation of electronic order entry with real-time decision support incorporating linked laboratory and pharmacy data,” according to authors of a review article (pp. 893-900). “Pharmacotherapy could benefit from enhanced laboratory–pharmacy linkage with respect to (1) drug choice (laboratory-based indications and contraindications), (2) drug dosing (renal or hepatic, blood level– guided adjustments), (3) laboratory monitoring (laboratory signals of toxicity, baseline and ongoing monitoring), (4) laboratory result interpretation (drug interfering with test), and (5) broader quality improvement (surveillance for unrecognized toxicity, monitoring clinician response delays).” (G. D. Schiff, Cook County Hosp., Chicago; Gdschiff@aol.com)

Surgery in Patients on Oral Anticoagulants: Without change in their medication doses, patients taking oral anticoagulants can undergo a variety of surgical procedures, including dental procedures, arthrocentesis, cataract surgery, and diagnostic endoscopy, according to a systematic review article (pp. 901-8). Based the limited information available in 31 reports, the researchers found low rates of bleeds and thromboembolic events among patients undergoing the above procedures. “For other invasive and surgical procedures, oral anticoagulation needs to be withheld, and the decision whether to pursue an aggressive strategy of perioperative administration of intravenous heparin or subcutaneous low-molecular-weight heparin should be individualized,” writes the group. “The current literature is substantially limited in its ability to help choose an optimal strategy. Further and more rigorous studies are needed to better inform this decision.” (A. S. Dunn, andrew.dunn@mountsinai.org)

An editorialist concludes that the decision to continue or stop oral anticoagulation must be negotiated (pp. 881-3): “The physician managing the patient’s oral anticoagulation must arrive at an agreement with the physician planning to perform the procedure. For some surgeons or interventionalists, the risk of bleeding if anticoagulation is continued during a procedure may outweigh the concern for thromboembolism if anticoagulation is discontinued. Thus, even when the literature indicates that oral anticoagulation can be continued, I find the process to be one of negotiation and compromise, with the physician performing the procedure.” (J. E. Ansell, Boston U. Med. Ctr., Boston; jack.ansell@bmc.org)

Outpatient Bleeding Risk Index: The risk of bleeding in ambulatory patients who are receiving anticoagulants can be estimated accurately with an Outpatient Bleeding Risk Index, according to an 18.5-month study of 222 patients (pp. 917-20). “Bleeding rates were lower than expected, but the index did discriminate between low- and moderate-risk groups (P= .03, log-rank test),” the authors write. “The rate of major hemorrhage per 100 person-years was 0% (95% confidence interval, 0%-2.8%) in the low-risk group and 4.3% (95% confidence interval, 1.1%-11.1%) in the moderate-risk group. The rate in the high-risk group could not be defined because only 2 patients were at high risk.... The Outpatient Bleeding Risk Index discriminates between low- and moderate-risk patients, and could be used to guide decisions on the optimal duration of anticoagulant therapy.” (P. S. Wells, Ottawa Hosp. Civic Campus, Ottawa, Ontario, Canada; pwells@ohri.ca)

Medications & Fractures: “Community-dwelling older women taking narcotics have an increased risk for any nonspine fracture, and those taking antidepressants have a greater risk for nonspine fractures, including hip fracture,” concludes a study of 1,256 women who were followed for 4.8 years (pp. 949-57). The risk among women taking narcotics was 1.4 times higher than nonusers, while a 1.25-fold increase in risk was identified among those on tricyclic antidepressants and SSRIs. (K. E. Ensrud, ensru001@umn.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 30, 2003 Vol. 10, No. 83
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
May Diabetes Care (care.diabetesjournals.org; 2003; 26).

Polypharmacy & Medication Adherence: Unreported adverse drug effects and lack of patient confidence in specific medication benefits are more important factors in adherence than is the number of medications taken by patients with diabetes (pp. 1408-12). In a study of 128 randomly selected patients, investigators obtained opinions using a pharmacist-administered questionnaire about medication use. Responding patients were taking an average of 4.1 diabetes-related medications, and their mean 7-day adherence was 6.7 days. “Total number of medicines prescribed was not correlated with medication adherence,” report the authors. “Adherence was significantly lower for medicines not felt to be improving current or future health (6.1 vs. 6.9 days out of 7, P< 0.001). Among patients on three or more medicines, 71% (15 of 21 patients) with suboptimal adherence were perfectly adherent with all but one medicine. Side effects were the most commonly reported problem with medication use. Of 29 medicines causing side effects that interfered with adherence, 24 (83%) did so for >1 month, and only 7 (24%) were reported to the patient’s primary care physician.” (R. W. Grant, Mass. Genl. Hosp., Boston)

Electronic Transmission of Glucose Levels: Biweekly modem transmission of blood glucose levels can take the place of clinic visits, according to experiences of 63 patients in a 6-month study (pp. 1475-9). Decreases in glycosylated hemoglobin values were similar among 30 modem patients and 33 control patients when blood glucose data transmissions every 2 weeks replaced quarterly clinic visits. Frequency of mild or moderate hypoglycemia was similar between the two groups, and no instances of severe hypoglycemia occurred. Costs of clinic visits averaged $305, while modem transmission cost an average of $163 for the 6 months. (H. P. Chase, U. Colorado, Denver)

Electronic Reminders for Antiplatelet Medications: Among 15,343 high-risk patients with diabetes, reminders to physicians in electronic medical records increased prescribing of antiplatelet agents (pp. 1497-500). Compared with prescribing patterns among 150 control general practitioners, an equal number of intervention general practitioners were twice as likely to prescribe the medications for patients with at least one cardiovascular risk factor in addition to diabetes. “The effect of the electronic reminder was more relevant among those patients with one or more cardiovascular risk factors but without previous cardiovascular diseases (CVDs), compared with those with CVDs,” the group reports. (A. Filippi, Italian College of General Practitioners, Florence, Italy)

Resistance Training & Obesity: Progressive resistance training is an overall better option for “battling insulin resistance in elderly obese people with type 2 diabetes,” conclude authors of a review article (pp. 1580-8). “Aerobic exercise is hindered in many type 2 diabetic patients because of advancing age, obesity, and other comorbid conditions,” the authors explain. “PRT ... offers a safe and effective exercise alternative for these people. PRT promotes favorable energy balance and reduced visceral fat deposition through enhanced basal metabolism and activity levels while counteracting age- and disease-related muscle wasting.” The authors also note that benefits of PRT on insulin sensitivity, glycemic control, muscle mass, bone density, osteoarthritic symptoms, mobility impairment, self-efficacy, hypertension, lipid profiles, anxiety, depression, and insomnia in individuals with clinical depression. (K. A. Willey, U. Sydney, Lidcombe, Australia)

Antipsychotic Medications & Diabetes: “Careful collaboration between the psychiatric and diabetology teams is essential to minimize the risk of diabetes in patients taking atypical antipsychotic medication and for effective management when it develops,” conclude authors of a review article (pp. 1597-605). Body weights and blood glucose should be routinely monitored, and exercise encouraged. (M. E. J. Lean, U. Glasgow, Glasgow, U.K.)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 1, 2003 Vol. 10, No. 84
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
May 1 issue of the New England Journal of Medicine (content.nejm.org; 2003; 348).

Pneumococcal Vaccine Decreasing Disease: Both adults and children are benefitting from administration of pneumococcal conjugate vaccine in young children, conclude authors who examined population-based CDC data (pp. 1737-46). A 7-valent protein–polysaccharide pneumococcal conjugate vaccine (Prevnar, Wyeth Lederle Vaccines) was licensed in 2000, and authors looked at data from 1998 through 2001. They found large declines in invasive disease, defined as isolation of Streptococcus pneumoniae from a normally sterile site. While the largest decline was for children younger than 2 years (69% lower in 2001 than during baseline), declines were also found among adults (32% decrease in those aged 20–39 years, 8% for those aged 40–64 years, and 18% lower among patients aged 65 years and older). “The rate of disease caused by strains that were not susceptible to penicillin was 35 percent lower in 2001 than in 1999 (4.1 cases per 100,000 vs. 6.3 per 100,000, P<0.001),” the authors add.

The group concludes, “Multidrug-resistant pneumococci are a worldwide problem.... Our data indicate that conjugate vaccine is another effective tool for preventing infections caused by drug-resistant strains.... Whether vaccine use will slow the emergence of resistant pneumococci and whether disease due to pneumococci with nonvaccine serotypes will become more common are questions that do not yet have definitive answers. Although questions remain, our data indicate that the pneumococcal conjugate vaccine is working well in the U.S. population.” (C. G. Whitney, cwhitney@cdc.gov)

Pneumococcal Vaccine in Older Adults: While use of the pneumococcal polysaccharide vaccine prevents bacteremia in adults older than 65 years, alternative strategies are needed to prevent nonbacteremic pneumonia, conclude authors of a retrospective cohort study (pp. 1747-55). Based on data from 47,365 Group Health Cooperative members, the investigators identified 1,428 members hospitalized with community-acquired pneumonia, 3,061 with outpatient pneumonia, and 61 with pneumococcal bacteremia. The risk of pneumococcal bacteremia was significantly reduced, by 44%, among patients who had received pneumococcal vaccine, but those patients had a slightly increased risk in hospitalization for pneumonia (14%). The authors conclude, “Our results support the use of pneumococcal polysaccharide vaccine to prevent bacteremic disease in adults aged 65 years or over. The lack of evidence of effectiveness against pneumonia without bacteremia, however, underscores the critical need to evaluate other vaccine formulations for the prevention of noninvasive pneumococcal infections in adults. Two such possibilities are protein conjugate pneumococcal vaccines, such as the licensed 7-valent formulation recommended for use in young children, which may be effective against nonbacteremic pneumococcal pneumonia, and protein vaccines, such as pneumococcal surface protein A formulations, which may also offer the advantage of greater mucosal immunity than is conferred by polysaccharide vaccines.” (L. A. Jackson, Ctr. for Health Studies, Seattle; jackson.l@ghc.org)

Nitroprusside & Aortic Stenosis: Despite a contraindication in patients with severe aortic stenosis, nitroprusside was beneficial in 25 patients with decompensated heart failure from severe left ventricular systolic dysfunction and severe aortic stenosis (pp. 1756-63). “After six hours of therapy with nitroprusside (at which time the dose had been increased to a mean of 103±67 µg per minute), the cardiac index had increased to 2.22±0.44 liters per minute per square meter (P<0.001 for the comparison with base line). After 24 hours of nitroprusside infusion (dose, 128±96 µg per minute), the cardiac index had increased further, to 2.52±0.55 liters per minute per square meter (P<0.001 for the comparison with base line). Nitroprusside was well tolerated and had minimal side effects.... It provides a safe and effective bridge to aortic-valve replacement or oral vasodilator therapy in these critically ill patients.” (U. N. Khot, Indiana Heart Physicians, Beech Grove, Ind.; khot@cvresearch.net)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 2, 2003 Vol. 10, No. 85
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
May Pharmacotherapy (www.accp.com; 2003; 23).

ASA Dosage & Thromboxane Synthesis: A study of varying dosages of aspirin examines the relationship between drug dosages and serum and urinary markers of thromboxane synthesis (pp. 579-84). In 48 patients (mean age, 70 years) with vascular disease, levels of serum thromboxane B2 and urinary 11-dehydrothromboxane B2 (a marker of aspirin resistance) were measured after treatment with aspirin 81, 325, and 1300 mg/day for 4 weeks. Compared with other periods during which aspirin 325 mg/day was administered, serum TXB and urinary d-TXB were significantly higher in patients on the 81 mg/day dose of aspirin and significantly lower with the aspirin 1300 mg/day dose. (R. L. Talbert, talbert@uthscsa.edu)

High-Dose Hepatitis B Vaccine Before Transplantation: Administration of high doses of hepatitis B vaccine induced protective but suboptimal immune responses in 17 patients awaiting lung transplantation (pp. 555-60). Compared with 14 historical control lung transplant recipients who received the standard vaccine dose before the study, patients who received three doses of hepatitis B vaccine 40 mcg had a significantly higher response rate (9 patients versus 1 patient). “Four of six patients who received additional doses of vaccine seroconverted,” the group writes. “Two of them underwent transplantation shortly after completing the three-dose series.” However, because of the shortfalls in vaccine performance, the authors conclude, “Alternative immunization strategies should be studied.” (M. S. Hayney, mshayney@phar macy.wisc.edu)

Toxic Variations in Amphotericin B Brands: Differences in polyene or pyrogenic toxins among various brands of deoxycholate amphotericin B formulations likely explain observed variations in clinical responses to the products, according to authors of an in vitro study (pp. 572-8). Human mononuclear cells were exposed for 2 hours to amphotericin B products from six companies. The authors found substantial differences among the products in interleukin-1ß expression and ELISA-measured content despite identical spectrophotometric analyses of amphotericin A or B content. Since “amphotericin B is obtained from a fermentation plant and manufactured as a pharmaceutical at different facilities,” the authors surmise that the variability in toxicity of the products is related to their final concentrations of polyenes and other pyrogenic toxins. (J. D. Cleary, jcleary@medicine.umsmed.edu)

Illicit Methylphenidate Use: On college campuses, illicit use of methylphenidate presents a “potentially serious public health issue,” conclude authors who examined abuse patterns at a large university (pp. 609-17). Three percent of 2,250 students who responded to the Internet survey reported past-year illicit methylphenidate use. “Illicit methylphenidate users were significantly more likely to use alcohol and drugs and report adverse alcohol- and drug-related consequences than prescription stimulant users or students who did not use stimulants,” the group writes. “Undergraduate men and women were equally likely to report past-year methylphenidate use. Weekly party behavior was significantly associated with past-year illicit methylphenidate use.” (C. J. Teter, cjteter@umich.edu)

Antimicrobial Restriction Program: Ceftazidime use fell and judicious use of alternative antibiotics was achieved through an antimicrobial restriction program at a large university-affiliated medical center (pp. 618-24). The program was implemented in 1998, and retrospective analysis of patient data showed that ceftazidime use dropped by 44% in 1998–2001, compared with 1995–96. “Ceftazidime resistance [of Pseudomonas aeruginosa] fell from 32.5% to 18.5% (p< 0.001), whereas piperacillin resistance fell from 32.5% to 18.5% (p<0.001),” report the authors, noting that piperacillin use did not change appreciably after the program was implemented. They also found favorable trends in use of and resistance to the antipseudomonal agents imipenem and aztreonam. (R. E. Regal, U. Michigan, Ann Arbor)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 5, 2003 Vol. 10, No. 86
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
May 3 issue of BMJ (www.bmj.org; 2003; 326).

Opiate Detoxification: "Success" in opiate detoxification programs could prove fatal to patients, as their loss of opiate tolerance appears to place them at higher risk of death from drug overdose during the ensuing year (pp. 959-60). Investigators recruited 137 consecutive opiate addicts in an inpatient detoxification program and grouped them according to their opiate-tolerance status at the end of therapy. At the point patients left therapy, 43 were still tolerant as a result of not completing the 28-day program, 57 had reduced tolerance as they completed detoxification but left the program early, and 37 lost tolerance since they completed the entire program.

Five patients died in the 12 months after therapy: 3 lost tolerance patients died of drug overdoses, 1 lost tolerance patients died of end-stage renal failure, and 1 reduced tolerance patient died of infection. "The clustering of the deaths from overdose in the group of patients who had successfully completed treatment is counterintuitive and illogical unless it derives from loss of tolerance and consequent unpredictability of resumed heroin use," the authors write. "This study urgently requires replication, and if its results are confirmed these will need to be addressed within existing inpatient, residential, and custodial and associated aftercare programmes." (J. Strang, National Addiction Ctr., London; j.strang@iop.kcl.ac.uk)

>>>Lancet Report
Source:
May 3 issue of Lancet (www.thelancet.com; 2003; 361).

Immunosuppression After Transplantation: Clinical evidence supporting a new approach to posttransplant immunosuppression (see PNN, Aug. 27) is provided in a study of 82 patients (pp. 1502-10). Rabbit antithymocyte globulin 5 mg/kg was administered over several hours before patients underwent kidney, liver, pancreas, or intestinal transplantation. Only tacrolimus was used routinely after transplant. The author report, "Immunosuppression-related morbidity was virtually eliminated. 78 (95%) of 82 patients survived at 1 year and at 13-18 months. Graft survival was 73 (89%) of 82 at 1 year and 72 (88%) of 82 at 13–18 months. Of the 72 recipients with surviving grafts, 43 are on spaced doses of tacrolimus monotherapy: every other day (n=6), three times per week (11), twice per week (15), or once per week (11)." The group concludes, "The striking ability to wean immunosuppression in these recipients indicates variable induction of tolerance. The simple therapeutic principles are neither drug-specific nor organ-specific. Systematic application of these principles should allow improvements in quality of life and long-term survival after organ transplantation." (T. E. Starzl, U. Pittsburgh, Pittsburgh; mangantl@msx.upmc.edu)

Reduced Immunogenicity of Combination Vaccines: A case–control study adds clinical relevance to previous observations of reduced Haemophilus influenzae type b immunogenicity with combination vaccines that contain acellular pertussis (pp. 1521-3). Compared with control patients, 129 children with invasive Hib infection were more likely to have received two or three of their primary infant doses with the combination vaccine. The authors conclude, "Our results emphasise the importance of long-term surveillance of vaccine preventable diseases in the population, especially during changes to routine immunisation schedules." (J. McVernon, Communicable Disease Surveillance Ctr., London; jodie.mcvernon@hpa.org.uk)

>>>PNN JournalWatch
* Treating Dyslipidemic Patients with Lipid-Modifying and Combination Therapies, in Pharmacotherapy, 2003; 23: 625–37. Reprints: www.accp.com; C. R. Worz, Skilled Care Pharmacy, Mason, Ohio; chadw@skilleccare.com

* Targeting Bacterial Virulence: The Role of Protein Synthesis Inhibitors in Severe Infection: Insights from the Society of Infectious Diseases Pharmacists, in
Pharmacotherapy, 2003; 23: 638–42. Reprints: www.accp.com; E. A. Coyle, U. Houston, Houston; ecoyle@uh.edu

* Clinical Presentations and Outcome of Severe Acute Respiratory Syndrome in Children, in
Lancet, published online. Reprints: www.thelancet.com; K. L. E. Hon

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 6, 2003 Vol. 10, No. 87
Providing news and information about medications and their proper use

>>>Gefitinib Approved for Advanced Non-Small Cell Lung Cancer
Operating under its accelerated approval guidelines, FDA yesterday granted approval of gefitinib (Iressa, AstraZeneca) for single-agent treatment of patients with advanced non-small cell lung cancer. AstraZeneca has agreed to conduct three further studies of the drug to elucidate better its impact on clinical outcomes and assess its long-term safety.

Gefitinib’s mechanism of action is not fully understood, but it partly involves inhibition of several tyrosine kinase enzymes, included the one associated with epidermal growth factor receptor. FDA based the approval on the results of a study of 216 patients with NSCLC, including 142 patients with tumors resistant or unresponsive to two prior treatments. The response rate (50% or more tumor shrinkage lasting at least 1 month) was about 10%. More dramatic responses occurred in some patients, and the median duration of response was 7 months. Response rates were higher in some subsets of patients, including women (about 17%) and patients with adenocarcinoma, but lower in men (about 5%) and smokers.

Safety of gefitinib is at issue based on reports from Japan of serious and sometimes fatal interstitial lung disease in patients receiving the drug. In a news release, FDA noted, “After careful review of information from all sources, including a comprehensive analysis of updated toxicity information from clinical trials and the Iressa expanded access program, involving approximately 23,000 patients, FDA determined that the incidence of ILD was approximately 2% in the Japanese experience and approximately 0.3% in the United States expanded access program, with about one third of affected patients dying from this toxicity. FDA believes that this rare but serious toxicity of Iressa does not outweigh the benefits demonstrated in patients with advanced NCSLC.” Other common side effects of the drug include nausea, vomiting, diarrhea, rash, acne, and dry skin. Gefitinib may cause fetal harm when administered to pregnant women.

>>>Internal Medicine Report
Source:
May 6 issue of the Annals of Internal Medicine (www.annals.org; 2003; 138).

Warfarin Initiation: In the outpatient setting, therapeutic international normalized ratios can be safely achieved more quickly with a 10-mg warfarin nomogram than a 5-mg nomogram, according to a study of 201 patients with acute venous thromboembolism (pp. 714-9). Patients received subcutaneous low-molecular-weight heparin for a minimum of 5 days until therapeutic INRs were achieved. “Patients in the 10-mg group achieved therapeutic INR 1.4 days earlier than patients in the 5-mg group (P< 0.001),” write the investigators. “Eighty-three percent of patients in the 10-mg group achieved a therapeutic INR by day 5 versus 46% in the 5-mg group (P< 0.001). Fewer INR assessments were performed in the 10-mg group than in the 5-mg group (8.1 vs. 9.1; P= 0.04). There were no significant differences between the two groups in recurrent events, major bleeding, survival, and number of INR measurements greater than 5.0.” (M. J. Kovacs, London Health Sci. Ctr., London, Ontario, Canada; michael.kovacs@lhsc.on.ca)

Inappropriate Heparin Monitoring: Of 15 studies that included unfractionated heparin published between 1984 and 2001, only 3 used a validated activated partial thromboplastin time therapeutic range (pp. 720-3). “Therapeutic ranges of 1.5 to 2.5 times the control value are subtherapeutic for most modern aPTT reagents,” note the authors. “Only 3 studies stated that they used a validated aPTT therapeutic range; 10 studies used aPTT ranges that included values 1.5 times the control value. Only 2 studies reported a standardized protocol by which the unfractionated heparin dose was adjusted, and 4 studies reported the percentage of patients achieving therapeutic aPTTs. Ten studies reported the steady-state unfractionated heparin dose, and 7 of these documented a reduction in the unfractionated heparin infusion rate to less than 30,000 U/d in response to aPTT results.” (R. Raschke, Good Samaritan Regional Med. Ctr, Phoenix; robertraschke@bannerhealth.com)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 7, 2003 Vol. 10, No. 88
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
May 7 issue of JAMA (www.jama.com; 2003; 289).

Insulin Options:
Experiences with the use of human insulins and insulin analogues are detailed in an article that reviews 28 studies of type 1 diabetes mellitus, 18 trials of patients with type 2 DM, and 48 studies on the use of insulin plus oral therapies (pp. 2254-64). “In patients with type 1 DM, physiologic replacement, with bedtime basal insulin and a mealtime rapid-acting insulin analogue, results in fewer episodes of hypoglycemia than conventional regimens,” note the authors. “Rapid-acting insulin analogues are preferred over regular insulin in patients with type 1 DM since they improve HbA1C and reduce episodes of hypoglycemia. In patients with type 2 DM, adding bedtime neutral protamine Hagedorn (isophane) insulin to oral therapy significantly improves glycemic control, especially when started early in the course of disease. Bedtime use of insulin glargine results in fewer episodes of nighttime hypoglycemia than neutral protamine Hagedorn regimens. For patients with more severe insulin deficiency, a physiologic insulin regimen should allow lower glycemic targets in the majority of patients. Adverse events associated with insulin therapy include hypoglycemia, weight gain, and worsening diabetic retinopathy if hemoglobin A1C levels decrease rapidly.”

A related review of patient cases gives practical examples of how the newer insulins have resulted in great flexibility in insulin dosing (pp. 2265-9). The authors write, “Understanding physiologic insulin replacement and implementing new insulin strategies should allow clinicians and patients to reduce episodes of hypoglycemia and improve glycemic control. The combination of bedtime NPH or glargine [insulin] and an oral agent improves glycemic control in patients with type 2 DM and is easier and less costly to implement than often assumed. Basal–prandial insulin strategies are easy to use and often improve patients’ understanding and self-management skills, and increase dosing and mealtime flexibility.” (D. E. DeWitt, U. Melbourne, Shepparton, Victoria, Australia; ddewitt@unimelb.edu.au)

>>>FDA Approves Enzyme Therapy for Rare Disease
Replacement therapy for the enzyme that breaks down glycosaminoglycans is now available, thanks to last week’s FDA approval of laronidase (Aldurazyme, BioMarin Pharmaceuticals ). It is the first approved treatment for certain forms of the rare genetic disease MPS I, which includes Hurler syndrome. The build up of GAG in the cells of patients with MPS I results in progressive cellular damage that affects appearance, physical abilities, organ function, and, in some cases, mental development.

Laronidase helps prevent the build-up of GAG in the cells and has been shown to improve lung function and exercise ability. Its priority approval is for patients with Hurler and Hurler-Scheie forms of MPS I as well as patients with the Scheie form with moderate to severe symptoms. Hurler syndrome is the most severe of the MPS I forms. Affected children often die early from respiratory diseases and cardiac complications. Hurler-Scheie syndrome is less severe, but patients usually do not survive beyond their early 20s. Scheie syndrome is the mildest form with many patients living well into adulthood, but these patients can still have deformities, heart disease, and difficulty breathing.

Laronidase was studied in a randomized, placebo-controlled study of 45 MPS I patients, most of whom had Hurler-Scheie. After 26 weeks, patients receiving the product had improved lung function and walking capacity based on a 6-minute walk test. There is no evidence that the new product has any positive effects on CNS symptoms such as developmental delay and hydrocephalus.

The most serious adverse reaction reported with laronidase was anaphylactic reaction approximately 3 hours after infusion, and primary safety concerns are infusion-related flushing, fever, headache, and rash. Other adverse reactions were upper respiratory tract infection, rash, and injection site reactions.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 8, 2003 Vol. 10, No. 89
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
May 8 issue of the New England Journal of Medicine (content.nejm.org; 2003; 348).

HRT & QOL: An analysis of data from the Women’s Health Initiative indicates that estrogen and progestin supplementation has no clinically meaningful impact on postmenopausal women’s health-related quality of life (pp. 1839-54). The women, all of whom had an intact uterus, daily received either conjugated equine estrogens 0.625 mg plus medroxyprogesterone acetate 2.5 (n = 8,506) or placebo (n = 8,102). General health, vitality, mental health, depressive symptoms, and sexual satisfaction were unaffected by treatment, while small, statistically significant, but clinically irrelevant differences were found in the sleep disturbance, physical functioning, and bodily pain subscales after 1 year. After 3 years of treatment, no significant benefits in HRQOL were evident. In the subset of women aged 50–54 years with moderate-to-severe vasomotor symptoms at baseline, the authors report that “estrogen and progestin improved vasomotor symptoms and resulted in a small benefit in terms of sleep disturbance but no benefit in terms of the other quality-of-life outcomes.” The group concludes, “For most women, these small benefits do not outweigh the risks of heart attack, stroke, blood clots, and breast cancer associated with combined hormone therapy.” (J. Hays, Baylor College of Med., Houston; jhays@bcm.tmc.edu)

An editorialist calls for development of new treatments for treating the vasomotor symptoms of menopause(pp. 1835-7): “Postmenopausal therapy with estrogen and progestin results in increased risks of disease, does not make asymptomatic women feel better, and does not improve cognition. There is no role for hormone therapy in the treatment of women without menopausal symptoms. Women with vasomotor symptoms must weigh the risks associated with treatment against the benefit of symptom relief. Vasomotor symptoms occur in about two thirds of women and are very distressing in 10 to 20 percent. We clearly need to identify new treatments that are highly effective and safe.” (D. Grady, UCSF)

Stratifying Risk of Long-QT Syndrome: Mutations in the genes for the potassium and sodium channels can be used to stratify patients’ risk of long-QT syndrome, according to an analysis of 647 patients from 193 consecutively genotyped families (pp. 1866-74). Three loci of genes code for the channels: LQT1 and LQT2 code for potassium-channel genes, and LQT3 codes for the sodium-channel gene. The patients’ genotypes showed that “the incidence of a first cardiac event before the age of 40 years and before the initiation of therapy was lower among patients with a mutation at the LQT1 locus (30 percent) than among those with a mutation at the LQT2 locus (46 percent) or those with a mutation at the LQT3 locus (42 percent).” In multivariate analysis, QTc interval was a significant predictor of risk [of long-QT syndrome] among patients with mutations at LQT1 and LQT2 but not LQT3. On the other hand, patient gender was a significant predictor of risk in those with LQT3 mutations. Based on these findings, the authors propose a risk stratification scheme. (S. G. Priori, U. Pavia, Pavia, Italy; spriori@fsm.it)

Stem-Cell Rescue for High-Dose Chemotherapy of Multiple Myeloma: In patients younger than 65 years with multiple myeloma, high-dose chemotherapy with autologous stem-cell rescue is an effective first-line treatment, according to researchers who studied 407 previously untreated patients with the disease (pp. 1875-83). Rates of complete response were significantly higher in those treated with high doses of combination chemotherapy than among patients assigned to standard therapy (44% vs. 8%). Intensive therapy also produced significantly higher rates of overall survival and progression-free survival, and a trend toward greater survival was observed in patients with poor prognosis. Further intensified treatment strategies are under study that take advantage of emerging biologic rescue therapies. (J. A. Child, General Infirmary, West Yorkshire, U.K.; tony.child@leedsth.nhs.uk)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 9, 2003 Vol. 10, No. 90
Providing news and information about medications and their proper use

>>>Pediatrics Update
Source:
May issue of Pediatrics (www.pediatrics.org; 2003; 111).

Pharmacotherapy of Insomnia: Community-based pediatricians from six U.S. cities reported prescribing or recommending sedative-hypnotic agents for their patients, especially those with special needs such as mental retardation, autism, and attention-deficit/hyperactivity disorder (e628-35). Among 671 respondents to a mailed survey, more than 75% had recommended nonprescription medications (usually antihistamines) for treating insomnia, and more than 50% had prescribed sleep medications (most often alpha agonists). “Melatonin or herbal remedies had been recommended by approximately 15% of the respondents,” the authors write. “The likelihood of prescribing medication for sleep was 2- to 4-fold greater in respondents who treated children with attention-deficit/hyperactivity disorder for daytime behavioral problems or nocturnal sleep problems, respectively. Practitioners expressed a range of concerns about sleep medication appropriateness, safety, tolerance, and side effects in children.” (J. A. Owens, Brown Med. Sch., Providence, R.I.)

CSGM for Type 1 Diabetes: Use of Medtronic’s MiniMed continuous subcutaneous glucose monitoring system improved glycemic control and gave patients new insights and increased motivation, according to a study of 27 children and adolescents with type 1 diabetes mellitus (pp. 933-8). Patients were being treated with intensive insulin therapy (14 patients were using multiple daily injections, and 13 individuals had insulin pumps). Compared with a blind arm of the study in which changes in insulin dosages were based solely on blood glucose readings, use of CSGM enabled a significant decrease in glycosylated hemoglobin (from 7.70% to 7.31%, compared with declines from 7.75% to 7.65% in the blind arm). Low subcutaneous glucose occurred in 26 of the 27 patients, and all patients had at least one episode of low nocturnal subcutaneous glucose during the 6-month crossover study. (J. Ludvigsson, U. Hosp., Uddevalla, Sweden)

Herbal Use Among Pediatric Patients: In a convenience sample of 142 families presenting to a pediatric emergency department, 45% of caregivers reported giving their children herbal products (pp. 981-5). Children’s ages ranged from 3 weeks to 18 years (mean, 5.3 years), and 88% of caregivers had at least 1 year of college education. The authors found, “The most common therapies reportedly used were aloe plant/juice (44%), echinacea (33%), and sweet oil (25%). The most dangerous potential herbal and prescription medication combination reported was ephedra and albuterol in an adolescent with asthma. The most unusual products reportedly used included turpentine, pine needles, and cowchips. Of all people interviewed, 77% did not believe or were uncertain if herbal products had any side effects and only 27% could name a potential side effect. Sixty-six percent were unsure or thought that herbal products did not interact with other medications and only 2 people correctly named a drug interaction. Of the people who used these therapies, 80% reported either friends or relatives as their primary source of information. Only 45% of those giving their children herbal products report discussing the use with their child’s primary health care provider.” (S. L. Lanski, Emory U., Atlanta)

Growth Patterns in ADHD: In 124 female children with attention-deficit hyperactivity disorder, no growth deficits were associated with the disease itself or its treatment (pp. 1010-6). Compared with 116 female controls, 124 males with ADHD, and 109 control males, the girls with ADHD had “no deficits in age-adjusted height or age and height-adjusted weight,” the authors wrote. “Also, we found no association between growth measurements and psychotropic treatment, malnutrition, short stature, pubertal development, family history of ADHD, or psychiatric comorbidity, except for major depression: ADHD girls with major depression were on average 7.6 kg heavier than ADHD girls without depression, adjusting for age and height.” (J. Biederman, Mass. Genl. Hosp., Boston)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 12, 2003 Vol. 10, No. 91
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
May 10 issue of Lancet (www.thelancet.com; 2003; 361).

Antipsychotic Therapy: Atypical antipsychotic agents may hold little advantage over older, low-potency drugs in terms of extrapyramidal side effects, according to a meta-analysis of 31 studies with 2,320 patients (pp. 1581-9). Studies were included in the analysis if they met Cochrane quality criteria A or B, and the authors assessed the number of patients who had one or more EPS. Compared with low-potency conventional drugs, only clozapine was associated with fewer EPS and higher efficacy, the group reports.

“Reduced frequency of EPS seen with olanzapine was of borderline [statistical] significance,” write the authors. “Only one inconclusive trial of amisulpride, quetiapine, and risperidone and no investigations of ziprasidone and sertindole were identified, but some evidence indicates that zotepine and remoxipride do not lead to fewer EPS than low-potency antipsychotics. Mean doses less than 600 mg/day of chlorpromazine or its equivalent had no higher risk of EPS than new generation drugs. As a group, new generation drugs were moderately more efficacious than low-potency antipsychotics, largely irrespective of the comparator doses used.” (S. Leucht, Universität München, München, Germany; Stefan.Leucht@Lrz.tum.de)

Trial of Iron Chelator: ICL670, an orally active iron-chelating agent, was effective and reasonably well tolerated in a clinical trial of 24 patients at risk of transfusional iron overload secondary to beta-thalassemia (pp. 1597-602). In this dose-ranging study, three doses of the investigational agent improved net iron excretion. Skin rashes occurred in four patients on higher doses, and one patient developed grade 2 transaminitis. (D. G. Nathan, Dana-Farber Cancer Inst., Boston; david_nathan@dfci.harvard.edu)

>>>BMJ Highlights
Source:
May 10 issue of BMJ (www.bmj.org; 2003; 326).

Darvon & Suicide: Co-proxamol, the U.K. generic name for acetaminophen plus dextropropoxyphene, was a commonly used agent for suicide there in 1997–99 (pp. 1006-8). The combination was used in 5% of all suicides and in 18% of drug-related suicides. In comparison, tricyclic antidepressants were implicated in 22% of drug-related suicides, and acetaminophen alone was the agent used in 9% of cases. Further, patients who took co-proxamol were 2.3 and 28.1 times more likely to die than with tricyclic antidepressants and acetaminophen, respectively. (K. Hawton, U. Oxford, Oxford, U.K.; keith.hawton@psych.ox.ac.uk)

Suicide Rates & Antidepressant Prescribing: Use of selective serotonin reuptake inhibitors appears to have reduced suicide rates among older adults in Australia since the drugs were introduced in the early 1990s (pp. 1008 ff). Significant associations were noted between declines in suicide rates and increased SSRI prescribing. Rates fell among older adults, the group most heavily treated with antidepressants, but increased among young adults. (A. Mant, U. New South Wales, Sydney, Australia; a.mant@unsw.edu.au)

>>>PNN JournalWatch
* Efficacy and Tolerability of Selective Serotonin Reuptake Inhibitors Compared with Tricyclic Antidepressants in Depression Treated in Primary Care: Systematic Review and Meta-Analysis, in BMJ, 2003; 326: 1014 ff. Reprints: www.bmj.org; S. MacGillivray, U. Dundee, Dundee, U.K.; s.a.macgillivray@dundee.ac.uk

* Immune Tolerance After Long-Term Enzyme-Replacement Therapy Among Patients Who Have Mucopolysaccharidosis I, in
Lancet, 2003; 361: 1608–13. Reprints: www.thelancet.com; D. A. Brooks, Women’s and Children's Hosp., North Adelaide, Australia; douglas.brooks@adelaide.edu.au

* Diagnosis and Treatment of Rhinovirus Respiratory Infections, in
Chest, 2003; 123: 1664–72. Reprints: www.chestjournal.org; A. Anzueto, anzueto@uthscsa.edu

* Diabetic Autonomic Neuropathy, in
Diabetes Care, 2003; 26: 1553–79. Reprints: www.diabetes.org; A. I. Vinik, Eastern Va. Med. Sch., Norfolk.

* New Frontiers in Cardiology: Drug-Eluting Stents: Part I, in
Circulation, 2003; 107: 2274–9. Reprints: circ.ahajournals.org; J. E. Sousa.

* Effect of a Mental Health "Carve-Out" Program on the Continuity of Antipsychotic Therapy, in
New England Journal of Medicine, 2003; 348: 1885–94. Reprints: content.nejm.org; W. A. Ray, cindy.naron@mcmail.vanderbilt.edu

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 13, 2003 Vol. 10, No. 92
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
May 12 issue of Archives of Internal Medicine (www.archinternmed.com; 2003; 163).

Combo ARB/ACE Therapy in Diabetes: Authors of a review article encourage further testing of the initial treatment of patients with type 2 diabetes with a combination of ACE inhibitor and angiotensin receptor blockers (pp. 1025-9). Their rationale is as follows, “[Recent] studies leave us in a quandary as to the optimal initial treatment regimen for patients with type 2 diabetes mellitus and renal disease despite the recent recommendations from the American Diabetes Association.... Given the fact that many of these individuals will require administration of multiple antihypertensive agents, perhaps the initial treatment with a combination of an ARB and [ACE] inhibitor affords optimal cardiovascular and renal protection for patients with type 2 diabetes mellitus and renal disease.” (M. H. Rosner, Medical Associates of Savannah, Savannah, Ga.; rosner@medscape.com)

Fen–Phen Use: The number of Americans taking antiobesity medications increased fourfold in the mid-1990s, primarily the result of use of the combination of phentermine and fenfluramine, note researchers who analyzed 13,452 physician office visits from 1991 to 2002 (pp. 1046-50). Antiobesity medication use peaked in the second quarter of 1997, with 2.5 million Americans under treatment. “Phentermine has consistently been the most common antiobesity medication,” write the authors. “In 2002, an annualized 1.2 million mentions of phentermine use were noted (31% of drug-treated obese patients). Newly released medications, orlistat (0.6 million) and sibutramine hydrochloride (0.4 million), were used less often. Most antiobesity medication use occurs in patients without other reported medical conditions.” The group concludes, “Use of antiobesity medications increased rapidly with public and professional interest in fenfluramine-phentermine (fen–phen) combination therapy. Despite reports of adverse outcomes associated with fenfluramine agents (fen–phen and dexfenfluramine), the use of these medication therapies did not diminish until soon before their removal from the market in 1997.” (R. S. Stafford; rstafford@stanford.edu)

Chronic Headache & Stroke: Chronic headache may be a marker of underlying disease processes that lead to stroke, according to associations found among 35,056 randomly selected Finnish men and women aged 25–64 years (pp. 1058-62). Based on risk factor surveys conducted in 1972, 1977, 1982, and 1987, investigators found: “Women reported headache twice as often as men (16.7% vs 8.9%). Among men, the headache-associated hazard ratios (95% confidence intervals) for stroke were 4.08 (2.10–7.93), 1.86 (1.33–2.59), and 1.24 (1.05–1.47) during 1, 5, and a maximum of 23 years of follow-up, respectively. Adjustment for the other risk factors decreased the hazard ratios only slightly. Among women, there was also a direct but statistically nonsignificant association between headache and the risk of stroke.” (P. Jousilahti, National Public Health Inst., Helsinki, Finland; pekka.jousilahti@ktl.fi)

Medication Use Among Former Athletes: Compared with control patients, former top-level athletes take more vitamins and dietary supplements but fewer NSAIDs and medications for cardiac disease and asthma. That conclusion comes from an analysis of 2,026 male athletes who represented Finland in international events from 1920 through 1965 and 1,401 controls (pp. 1064-8). Age-adjusted hazard ratios were lower in the athletes for medication for cardiac insufficiency (HR, 0.61), coronary artery disease (0.72), asthma (0.47), hypertension (0.73), and diabetes (0.38). NSAID use of 52% lower among the athletes, and antacid use was similarly lower (51%). Vitamins A, B, and C, selenium, and iron supplements were taken about twice as often by the athletes as by the control subjects. The authors conclude, “Former Finnish athletes live a healthier life than controls.... The reduction in need for reimbursable medications and hospital care among athletes means lower costs for the public health care system.” (U. M. Kujala, Unit for Sports and Exercise Med., Helsinki, Finland; Urho.Kujala@helsinki.fi)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 14, 2003 Vol. 10, No. 93
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
May 14 issue of JAMA (www.jama.com; 2003; 289).

Hypertension More Common in Europe:
Compared with the U.S. and Canada, people in six European countries have significantly higher blood pressures and prevalences of hypertension, according to a study that compared data from national surveys (pp. 2363-9). Among men and women aged 35–74 years, BP averaged 136/83 mm Hg in Europe and 127/77 mm Hg in North America. The difference was present in young people who were largely untreated, and slope of the BP curve with aging was steeper in Europe. Using the 140/90 mm Hg threshold for defining hypertension, 28% of North Americans were affected, compared with 44% of those in the European countries. Hypertension prevalence was associated strongly with stroke mortality and more weakly with total cardiovascular disease. (R. S. Cooper, Loyola U., Maywood, Ill.; rcooper@lumc.edu)

Chronic Severe Pain & Substance Abuse: Substantial numbers of patients in substance abuse and methadone maintenance treatment programs have chronic severe pain, note authors of a study from New York State (pp. 2370-8). A total of 390 patients from two MMTPs and 531 inpatients from 13 short-term substance abuse programs completed a questionnaire. Chronic severe pain was identified in 37% of MMTP participants and 24% of inpatients. About four-fifths of patients reported pain during the previous week, and 65% of MMTP and 48% of inpatients who reported chronic severe pain indicated that it interfered with their physical and psychosocial functioning. Inpatients with pain were significantly more likely than the MMTP patients to have used illicit drugs and/or alcohol to treat their pain and were less likely to have been prescribed pain medications.

“The undertreatment of pain is a significant concern in populations with chemical dependency,” the authors write. “Given the number of barriers identified as potential reasons for inadequate pain management, it is appropriate to raise concerns about undertreatment and to investigate it further. The barriers are complex and may involve institutional practices, inadequate training and skills of clinicians, lack of access to health care, reluctance of physicians to prescribe opioids to individuals with a history of chemical dependency (especially opioid addiction), and reluctance on the part of the chemically dependent person to seek medical care because of stigma or fear of relapse.” (A. Rosenblum, National Development and Research Inst., New York City; rosenblum@ndri.org)

>>>PNN NewsWatch
* Clinical trials of efalizumab (Raptiva) for rheumatoid arthritis have been terminated by sponsors Genentech and Xoma Ltd. Lack of efficacy in Phase II trials was cited as the reason.

*
Illegal importation of prescription drugs between the U.S. and Canada undermines the patient–pharmacist relationship, said APhA, the Canadian Pharmacists Association, the National Association of Boards of Pharmacy, the Canadian National Association of Pharmacy Regulatory Authorities, and 44 other U.S. pharmacist groups in a cross-border communiqué released yesterday. “The U.S. and Canada each have regulatory systems in place to protect consumers,” stated John A. Gans, PharmD, executive vice president of APhA in a news release. “However, illegal importation undermines these regulatory systems. Most important is the severing of the bond between the individual patient and his or her pharmacist. The pharmacist, whether practicing in the U.S. or Canada, is responsible for the patient’s medication management. Medications are powerful; that’s why they work. There can be adverse reactions between one prescription medication and another—as well as over-the-counter medications and dietary supplements. The patient’s physical condition, ability to effectively understand and comply with a medication regimen, level of physical activity, diet, and other lifestyle issues come into play. Patient safety is primary to pharmacists, and illegal importation which threatens that for patients must be addressed through active law enforcement.”

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 15, 2003 Vol. 10, No. 94
Providing news and information about medications and their proper use

>>>JNC 7 Vying for Attention Of Patients, Clinicians
If you thought your blood pressure was OK, it may not be. And even if it is, you’ll probably someday have hypertension, if you live long enough.

While not stated that directly, those are some of the blunt messages your patients will hear as the lay media cover the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7). In an article scheduled for publication in next week’s JAMA and posted early on its Web site (www.jama.com), the key messages of JNC 7 are summarized this way:

* In persons older than 50 years, systolic blood pressure of more than 140 mm Hg is a much more important cardiovascular disease risk factor than diastolic BP.

* The risk of CVD, beginning at 115/75 mm Hg, doubles with each increment of 20/10 mm Hg; individuals who are normotensive at 55 years of age have a 90% lifetime risk for developing hypertension.

* Individuals with a systolic BP of 120–139 mm Hg or a diastolic BP of 80–89 mm Hg should be considered as prehypertensive and require health-promoting lifestyle modifications to prevent CVD.

* Thiazide-type diuretics should be used in drug treatment for most patients with uncomplicated hypertension, either alone or combined with drugs from other classes. Certain high-risk conditions are compelling indications for the initial use of other antihypertensive drug classes (ACE inhibitors, angiotensin-receptor blockers, beta blockers, calcium-channel blockers)

* Most patients with hypertension will require 2 or more antihypertensive medications to achieve goal BP (<140/90 mm Hg, or <130/80 mm Hg for patients with diabetes or chronic kidney disease).
n If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy with two agents, one of which usually should be a thiazide-type diuretic.

* The most effective therapy prescribed by the most careful clinician will control hypertension only if patients are motivated. Motivation improves when patients have positive experiences with and trust in the clinician. Empathy builds trust and is a potent motivator.

Pharmacy was represented on JNC 7 by Barry L. Carter, PharmD, U. Iowa, and Mark J. Cziraky, PharmD, Health Core, Newark, Del. The report notes that “involvement of nurse clinicians and pharmacists can be helpful” in the ongoing clinical management of patients with hypertension.

>>>Bortezomib Approved for Multiple Myeloma
The first proteasome inhibitor has been approved for U.S. marketing after only 4 months of FDA review. Bortezomib (Velcade, Millennium Pharmaceuticals) is indicated for treatment for multiple myeloma.

FDA evaluated the safety and efficacy of bortezomib based on a study of 202 patients who had received at least two prior therapies and demonstrated disease progression on their most recent therapy. Of 188 patients evaluated for response, 28% showed a response to bortezomib. The response lasted a median time of 1 year. Another trial in 54 patients with relapsed multiple myeloma showed similar responses. No studies have yet addressed survival rates and other harder clinical outcomes, but the manufacturer has agreed to complete ongoing trials and conduct other studies postapproval.

The most commonly reported adverse events with bortezomib have been nausea, fatigue, diarrhea, constipation, headache, decreased appetite, decreased platelets and erythrocyte counts, fever, vomiting, and peripheral neuropathy.

The injectable product will cost about $20,000 per course of treatment.

>>>PNN NewsWatch
* Today’s New England Journal of Medicine contains a number of articles on severe acute respiratory syndrome, most of which were released previously on the NEJM Web site (content.nejm.org).

* The page 1 cover story of this morning’s
USA Today has a good analysis of the growing problem of counterfeit pharmaceuticals in U.S. pharmacies.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 16, 2003 Vol. 10, No. 95
Providing news and information about medications and their proper use

>>>Allergy/Immunology Update
Source:
May Journal of Allergy and Clinical Immunology (www2.us.elsevierhealth.com; 2003; 111).

ASA-Induced Asthma: Aspirin desensitization followed by daily aspirin treatment is a useful option in managing patients with aspirin-induced asthma, conclude authors of a review (pp. 913-21). AIA occurs in some patients who develop a clinical syndrome consisting of eosinophilic rhinosinusitis, nasal polyposis, aspirin and other nonselective NSAID sensitivity, and asthma. “The disease runs a protracted course even if COX-1 inhibitors are avoided, and the course is often severe, many patients requiring systemic corticosteroids to control their sinusitis and asthma,” write the authors. Unless desensitization is successful, aspirin and NSAIDs should be avoided, and patients who need agents of this type should be treated with COX-2 inhibitors. “To prevent life-threatening reactions, patients with AIA should avoid ASA, all products containing it, and other analgesics that inhibit COX-1,” the authors write. “Thus, the education of physicians, pharmacists, and patients is important in the survival of patients with AIA.” (D. D. Stevenson, Scripps Clinic, La Jolla, Calif.)

Aspirin-Induced Asthma & COX-2 Inhibitors: Providing further evidence that COX-2 inhibitors can be used safely in patients with aspirin-induced asthma is a study of biochemical and clinical markers in 33 patients (pp. 1116-21). No changes were in lung function or extrapulmonary symptoms were observed with doses of celecoxib as high as 400 mg. “Large long-term studies of COX-2 inhibitors in AIA should be undertaken,” the authors conclude. (S-E Dahlén, Karolinska Institutet, Stockholm, Sweden)

Aspirin- and Other NSAID-Induced Intolerance & Chronic Urticaria: A study of 280 patients with acute urticaria provides further support for a relationship between NSAID intolerance and later development of chronic urticaria (pp. 1095-8). Clinical histories and oral challenge tests were used to identify 159 and 121 patients with intolerance to single or multiple NSAIDs, respectively. At follow-up visits occurring 1 to 10 years later, 93 (33%) of the patients had developed chronic urticaria. “NSAID intolerance might precede the onset of [chronic urticaria] by years,” the group concludes. “Both multiple and single NSAID reactors with a history of aspirin-induced urticaria seem at higher risk for [chronic urticaria] than patients with a history of single intolerance to NSAIDs other than aspirin.” (R. Asero, Clinica San Carlo, Paderno Dugnano, Italy)

Antihistamines & Impairment: The preferred antihistamine for all patients should be a nonsedating, nonimpairing agent, concludes an expert panel that convened to prepare a consensus document (pp. S835-42). “Many of the antihistamines used to treat allergic rhinitis, as well as the disease itself, may produce sedation, impairment, and reduced quality of life,” writes the Aventis-sponsored group. “Allergic rhinitis is more appropriately managed with the relatively nonimpairing second-generation antihistamines (eg, loratadine, desloratadine, cetirizine, and fexofenadine), because older agents (eg, diphenhydramine, chlorpheniramine, and brompheniramine) produce sedation and impairment and worsen sleep architecture. Although there is some debate surrounding the varying degrees of efficacy of second-generation antihistamines, it is known that some agents may produce varying levels of drowsiness or impairment, especially at higher than recommended doses. The differences with regard to safety among the second-generation antihistamines are smaller than are the differences between the first and second generations. A nonsedating, nonimpairing (even at higher than recommended doses), second-generation antihistamine is preferred for all patients, particularly those with a higher risk for the development of adverse effects. We recommend that primary care and specialist physicians, nurse practitioners, physician assistants, pharmacists, and all other health professionals involved in the diagnosis and treatment of allergic rhinitis follow this consensus document and share this information with patients for whom antihistamine therapy is recommended.” (T. B. Casale, tbcasale@creighton.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 19, 2003 Vol. 10, No. 96
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
May 17 issue of Lancet (www.thelancet.com; 2003; 361).

Topiramate for Alcohol Dependence: The antiepileptic agent topiramate may be effective in treatment of alcohol dependence, possibly through its actions on the dopamine and GABA neuronal systems of the brain (pp. 1677-85). In a 12-week trial, 150 individuals received either placebo or escalating doses of topiramate 25–300 mg/day along with standard medication compliance management. Compared with the placebo group, those patients taking topiramate had 2.88 fewer drinks per day, 2.10 fewer drinks per drinking day, and 26.2% more days abstinent. “Topiramate-induced differences in craving were also significantly greater than those of placebo, of similar magnitude to the self-reported drinking changes, and highly correlated with them,” the authors explain. “Our results provide evidence that topiramate is a safe and effective medication for treatment of alcoholism. Topiramate’s development for treatment of alcoholism should garner scientific interest, since few effective medications are available for this indication.” (B. A. Johnson, bjohnson@uthscsa.edu)

An editorialist adds (pp. 1666-7): “Most clinical trials in alcoholism are designed to randomise recently abstinent participants, to measure the effectiveness of the drug under study to prevent relapse, and to reduce the potential for adverse events related to acute withdrawal. Johnson and colleagues’ study is different, in that participants were not required to be abstinent from alcohol before starting the trial. Thus the study measures abstinence initiation rather than abstinence persistence. Importantly the results suggest that different pharmacotherapies could be targeted at different stages of alcoholism treatment—the initiation of abstinence, the maintenance of early abstinence, or the maintenance of prolonged abstinence.” (R. M. Swift, Providence VA Med. Ctr., Providence, R.I.; Robert_Swift@brown.edu)

Lung Pathology in SARS: The case definition for severe acute respiratory syndrome should be modified to acknowledge a wide range of pathologic changes in the lungs of patients infected by the coronavirus, according to authors of a case series article (published online, May 16). In postmortem samples of six patients who died of SARS and an open biopsy of one of those patients, the investigators found: “Diffuse alveolar damage was common but not universal. Morphological changes identified were bronchial epithelial denudation, loss of cilia, and squamous metaplasia. Secondary bacterial pneumonia was present in one case. A giant-cell infiltrate was seen in four patients, with a pronounced increase in macrophages in the alveoli and the interstitium of the lung. Haemophagocytosis was present in two patients....

“SARS is associated with epithelial-cell proliferation and an increase in macrophages in the lung. The presence of haemophagocytosis supports the contention that cytokine dysregulation may account, at least partly, for the severity of the clinical disease.” (J. M. Nicholls)

>>>PNN NewsWatch
* An FDA advisory panel on Friday recommended approval of
Xolair, an anti-IgE drug from Genentech, for treatment of asthma. Approval could come next month.

>>>PNN JournalWatch
* 25 Years of the WHO Essential Medicines Lists: Progress and Challenges, in
Lancet, 2003; 361: 1723–9. Reprints: www.thelancet.com; R.Laing, Boston U., Boston; richardl@bu.edu

* Systematic Review of Scope and Quality of Electronic Patient Record Data in Primary Care, in
BMJ, 2003; 326: 1070 ff. Reprints: www.bmj.org; K. Thiru, Fisher Med. Ctr., North Yorkshire, U.K.; krish.thiru@st-marys.nhs.uk

* Percutaneous Coronary Intervention. I: History and Development, in
BMJ, 2003; 326: 1080–2. Reprints: www.bmj.org; E. D. Grech, U. Manitoba, Winnipeg

* Are Critical Pathways Effective for Reducing Postoperative Length of Stay?, in
Medical Care, 2003; 41: 637–48. Reprints: www.lww-medicalcare.com; S. M. Dy, Johns Hopkins U., Baltimore; sdy@jhsph.edu

* New Frontiers in Cardiology: Drug-Eluting Stents: Part II, in
Circulation, 2003; 107: 2383–9. Reprints: circ.ahajournals.org; J. E. Sousa.

* Heart Failure, in
New England Journal of Medicine, 2003; 348: 2007–18. Reprints: content.nejm.org; M. Jessup.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 20, 2003 Vol. 10, No. 97
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
May 20 issue of the Annals of Internal Medicine (www.annals.org; 2003; 138).

Use of Coronary Stents: Might stents not make much of difference in patient care after all? That possibility is a real one, based on a hierarchical Bayesian meta-analysis of 29 trials involving 9,918 patients (pp. 777-86). The authors write, “There was no evidence for a difference between routine coronary stenting and standard [percutaneous transluminal coronary angioplasty] in terms of deaths or myocardial infarctions (odds ratio, 0.90 [95% credible interval [CrI], 0.72 to 1.11]) or the need for coronary artery bypass surgery (odds ratio, 1.01 [CrI, 0.79 to 1.31]). Coronary stenting reduced the rate of restenosis (odds ratio, 0.52 [CrI, 0.37 to 0.69]) and the need for repeated PTCA (odds ratio, 0.59 [CrI, 0.50 to 0.68]).”

Based on these findings, the group concludes, “In the controlled environment of randomized clinical trials, routine coronary stenting is safe but probably not associated with important reductions in rates of mortality, acute myocardial infarction, or coronary artery bypass surgery compared with standard PTCA with provisional stenting. Coronary stenting is associated with substantial reductions in angiographic restenosis rates and the subsequent need for repeated PTCA, although this benefit may be overestimated because of trial designs. The incremental benefit of routine stenting for reducing repeated angioplasty diminishes as the crossover rate of stenting with conventional PTCA increases.” (J. Brophy, McGill U., Montreal; james.brophy@mcgill.ca)

Cost Analysis of COX-2 Inhibitors: In average-risk patients with osteoarthritis or rheumatoid arthritis, the higher costs of rofecoxib and celecoxib are not offset by reduced or avoided costs of gastrointestinal complications, according to a cost-utility analysis (pp. 795-806). Using the perspective of a third-party payer and a lifetime incremental cost per quality-adjusted life-year gained, the authors found, “Using a coxib instead of a nonselective NSAID in average-risk patients cost an incremental $275,809 per year to gain 1 additional QALY.... The incremental cost per QALY gained decreased to $55,803 when the analysis was limited to the subset of patients with a history of bleeding ulcers. The coxib strategy became dominant when the cost of coxibs was reduced by 90% of the current average wholesale price. In probabilistic sensitivity analysis, if a third-party payer was willing to pay $150,000 per QALY gained, then 4.3% of average-risk patients would fall within the budget.... Unless the price of COX-2 inhibitors drops substantially, their benefits are worth the extra costs compared with naproxen only for patients who have had a previous bleeding ulcer. ” (I. M. Gralnek, igralnek@mednet.ucla.edu)

Heart Failure After TNF-Antagonist Therapy: The tumor necrosis factor antagonists etanercept and infliximab “might induce new-onset heart failure or exacerbate existing disease” in a subset of patients, according to an analysis of reports to the FDA’s MedWatch Program (pp. 807-11). In a case series analysis, investigators report, “After TNF antagonist therapy, 38 patients developed new-onset heart failure and 9 patients experienced heart failure exacerbation. Of the 38 patients with new-onset heart failure, 19 (50%) had no identifiable risk factors. Ten patients younger than 50 years of age developed new-onset heart failure after receiving TNF antagonists. After TNF antagonist therapy was discontinued and heart failure therapy was started in these 10 patients, 3 had complete resolution of heart failure, 6 improved, and 1 died.” (H. J. Kwon, kwon@cber.fda.gov)

>>>PNN NewsWatch
* The U.S. Supreme Court ruled yesterday that Maine’s discount-drug program for Medicaid can be implemented while its legality is debated in the lower courts. The ruling is a defeat for the Pharmaceutical Research and Manufacturers of America and major pharmaceutical companies. The court warned that the program could in the end be ruled unconstitutional or illegal, but the delay in such a decision could encourage other states to proceed more aggressively on similar cost-reduction plans in the meantime.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 21, 2003 Vol. 10, No. 98
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
May 21 issue of JAMA (www.jama.com; 2003; 289).

First-Line Antihypertensive Therapy: Low-dose diuretics are the most effective first-line treatment for preventing cardiovascular disease morbidity and mortality in patients with uncomplicated hypertension, according to a meta-analysis of 42 clinical trials (pp. 2534-44). Among the 192,478 patients in the studies, low-dose diuretics were significantly better at one or more measures of CVD prevention, compared with placebo, beta blockers, ACE inhibitors, calcium-channel blockers, alpha blockers, and angiotensin II receptor blockers. For example, compared with placebo, low-dose diuretics produced relative risks of 0.79 for coronary heart disease, 0.51 for congestive heart failure, 0.71 for stroke, 0.76 for CVD events, 0.81 for CVD mortality, and 0.90 for total mortality. No active therapy was significantly better than low-dose diuretics for any outcome. (B. M. Psaty, psaty@u.washington.edu)

These findings support recommendations of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), which are published in this issue (pp. 2560-71) along with a related editorial (pp. 2573-5; see PNN, May 15).

HRT & Alendronate for Bone-Loss Prevention: In women with severe bone loss or who have not responded to monotherapy, combining hormone-replacement therapy with alendronate may be an option (pp. 2525-33). In a 3-year study, 373 women aged 65–90 years took either hormone replacement (conjugated equine estrogens 0.625 mg/day, with or without medroxyprogesterone 2.5 mg/day), alendronate 10 mg daily, both agents, or neither, along with calcium and vitamin D supplements.

“Bone mineral density at 3 years was significantly greater at all femoral and vertebral sites in women treated with combination therapy than with monotherapy, with mean (SD) increases of 5.9% (3.8) at the total hip, 10.4% (5.4) at the posteroanterior lumbar spine, and 11.8% (6.8) at the lateral lumbar spine,” the authors write. “Mean (SD) increases in bone mass at the hip in women treated with alendronate alone were significantly greater than in those treated with hormone replacement therapy alone (4.2% [3.8] vs 3.0% [4.9]; P<.05, respectively), and alendronate resulted in more responders to therapy. All therapies were well tolerated and participant retention was 90% at 3 years.” (S. L. Greenspan, griffithsd@msx.dept-med.pitt.edu)

Muscle Training for Chronic Neck Pain: Strength training is a necessary component of care in patients with chronic, nonspecific neck pain, according to a study of 180 female office workers in Finland (pp. 2509-16). Compared with placebo, endurance exercises (dynamic neck exercises, which included lifting the head up from the supine and prone positions) increased significantly maximal isometric neck strength, flexion, rotation, and extension . But strength training (high-intensity isometric neck strengthening and stabilization exercises with an elastic band) provided even greater improvements. (J. Ylinen, Jyväskylä Central Hosp., Jyväskylä, Finland; jari.ylinen@ksshp.fi)

Clinical Trial Data Analysis: Two articles analyze important data-manipulation techniques used in clinical trials: factorial designs (pp. 2545-53) and composite outcomes (pp. 2554-9). Commenting on these papers, editorialists write (pp. 2575-7): “When mortality is considered, only all-cause mortality is a valid end point, while end points such as ‘cardiac death’ and ‘arrhythmic death’ should be actively discouraged. Composite end points may be appropriate, but may well be limited by biases related to differential associations of exposures and individual outcomes and related to competing risks. Nonfatal end points, such as myocardial infarction, should only be considered valid and reliable if assessed by a blinded clinical events committee or a core laboratory.... In addition, exposures, including treatments, should not be considered as isolated entities but rather as risk factors that may well interact with one another in a clinically important way.” (M. S. Lauer, Cleveland Clinic Foundation, Cleveland; Lauerm@ccf.org)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 22, 2003 Vol. 10, No. 99
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
May 22 issue of the New England Journal of Medicine (content.nejm.org; 2003; 348).

Management of Severe Emphysema: Compared with medical treatment for severe emphysema, lung-volume–reduction surgery provides a survival advantage only in patients with both predominantly upper-lobe emphysema and low baseline exercise capacity (pp. 2059-73). In a study of 1,218 patients, overall mortality was 0.11 death per person-year in both treatment groups, but mortality was 53% lower in the above subset of patients. “Patients previously reported to be at high risk and those with non–upper-lobe emphysema and high baseline exercise capacity are poor candidates for lung-volume–reduction surgery, because of increased mortality and negligible functional gain,” the authors conclude.

In a second article, the same research group explores the cost of the new surgery for emphysema (pp. 2092-102). Based on cost-effectiveness ratios of $190,000 and $53,000 per quality-adjusted life-year at 3 and 10 years, respectively, the group concludes, “Lung-volume–reduction surgery is costly relative to medical therapy. Although the predictions are subject to substantial uncertainty, the procedure may be cost effective if benefits can be maintained over time.” (S. Piantadosi, Natl. Emphysema Treatment Trial Research Group Coordinating Ctr., Baltimore)

“This trial provides yet another illustration of why it is important to test medical and surgical treatments rigorously,” note editorialists (pp. 2134-6). “As healers, we want to help our patients who have conditions that have adverse effects on their lives. It may be difficult to argue for research to test a new idea that seems to make physiological sense and ‘deserves to work,’ but testing is the right thing to do. It can be even more difficult to mount a research trial if there are vocal proponents of an approach who claim that the new treatment works and that failure to use it unfairly denies patients relief from suffering and longevity. As this trial shows, there are many steps between theory and its successful application to practice. Good research separates what we think should work from what we actually know does work. Our actions should be based on what we actually know; otherwise, we are just left with guesswork.” (J. M. Drazen,
NEJM, Boston)

Low-Carb vs. Low-Fat Diets: Among 132 severely obese subjects, a carbohydrate-restricted diet enabled significantly more weight loss over 6 months than did a low-fat, high-carbohydrate plan (pp. 2074-81). The patients included 77 blacks and 23 women. Their mean body mass index was 43 kg/sq m. In addition, the patients had a high prevalence of diabetes (39%) and metabolic syndrome (43%). Subjects on a low-carbohydrate diet lost 5.8 kg, compared with 1.9 kg in 6 months of a low-fat diet. Both insulin sensitivity among subjects without diabetes and triglyceride levels improved significantly among those on the low-carbohydrate diet. The authors caution, “This [weight-loss] finding should be interpreted with caution, given the small magnitude of overall and between-group differences in weight loss in these markedly obese subjects and the short duration of the study. Future studies evaluating long-term cardiovascular outcomes are needed before a carbohydrate-restricted diet can be endorsed.” (F. F. Samaha, VA Med. Ctr., Philadelphia, rick.samaha@med.va.gov)

A second study identified similar advantages for a low-carbohydrate, high-protein, high-fat (Atkins) diet at 3 and 6 months, but the advantage disappeared by 1 year (pp. 2082-90). Among 63 obese men and women on an Atkins diet, weight loss averaged 6.8, 7.0, and 4.4 kg at 3, 6, and 12 months, respectively, compared with 2.7, 3.2, and 2.5 kg among patients on conventional diets at those time points. “The low-carbohydrate diet was associated with a greater improvement in some risk factors for coronary heart disease,” add the authors. “Adherence was poor and attrition was high in both groups. Longer and larger studies are required to determine the long-term safety and efficacy of low-carbohydrate, high-protein, high-fat diets.” (G. D. Foster, fosterg@mail.med.upenn.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 23, 2003 Vol. 10, No. 100
Providing news and information about medications and their proper use

>>>Neurology Highlights
Source:
May 13 Neurology (www.neurology.org; 2003; 60).

Topiramate vs. Valproate: In 62 patients with partial seizures undergoing moderate dose escalation, the cognitive effects of topiramate were slightly worse than those of valproate (pp. 1483-8). Study drugs were titrated over 8 weeks to target doses of TPM 400 mg/day or VPA 2,250 mg/day, and these were compared with placebo over an additional 12 weeks. The authors found, “At the end of maintenance, effects of TPM and VPA were comparable, except for two variables ... in which TPM had greater negative effects relative to VPA. The statistical differences appeared to be due in large part to a small subset of patients who were more negatively affected by TPM. Cognitive effects of TPM relative to VPA were greater at the end of titration than at the end of maintenance.” (K. J. Meador, kjm32@georgetown.edu)

Stroke After Chiropractic Manipulation: Spinal manipulative therapy appears to be associated with occurrence of vertebral arterial dissection, according to results of a case–control study (pp. 1424-8). Compared with 100 control patients, 51 patients with dissection were more likely to have had this chiropractic procedure within 30 days (14% vs. 3%), to have had head or neck pain before stroke or symptoms (76% vs. 40%), and to consume alcohol (76% vs. 57%). (W. S. Smith, wssmith@itsa.ucsf.edu)

>>>PNN NewsWatch
* Imatinib mesylate has been approved for an additional indication by FDA: Treatment of Philadelphia chromosome–positive chronic myeloid leukemia in chronic phase in pediatric patients whose disease has recurred after stem-cell transplant or who are resistant to interferon alfa therapy.

* A study in the May issue of
Clinical Therapeutics pegs the 1998 cost of pharmaceutical industry marketing efforts at $12.7 billion. Free samples given to physicians totaled $6.6 billion of retail value, representing 51.9% of the drug promotion expenditures. Detailing costs totaled $3.5 billion, accounting for 27.8% of the total. Advertisements in medical journals totaled $540 million, 4.3% of total drug-promotion expenditures. Consumer-targeted drug advertising totaled $1.3 billion in 1998, 10.5% of all drug-promotion expenditures. In addition to sheer magnitude of this level of promotion, the authors emphasize that promotions were concentrated on a small number of drug products, with 51.6% of expenditures supporting the top 50 drugs. (www.clinicaltherapeutics.com; J. Ma, Stanford U., Palo Alto, Calif.)

* A variety of
medication-use problems are evident in studies reported in the May/June issue of the Journal of Managed Care Pharmacy. One study shows that patients on OxyContin used, on average, 22 mg/day more oral morphine equivalents than did those patients on Duragesic patches. The authors concluded that neither medication appears to be used in a manner consistent with standard recommendations in the package insert. An analysis of administrative claims data from three California health plans suggests that antibiotics are overused for the common cold and that drugs to treat asthma, depression and heart failure are underused. For example, only 55% of patients diagnosed with congestive heart failure received an ACE inhibitor, while only 28% of antidepressant drug users received the recommended 6 months of continuous therapy. (www.amcp.org)

* Medication problems in the elderly result from problems in the
“medication matrix,” according to a report from Medco Health. The average senior sees four or more physicians, and about one third of this group uses four or more different pharmacies. “The complex web of multiple physicians and multiple pharmacies is compounded by the fact that, among seniors covered by Medco Health who take medications, the average senior receives 25 prescriptions annually,” the PBM reports. “The leading types of medication categories being taken by this age group includes high blood pressure, antibiotics, cholesterol lowering agents and nonnarcotic pain relief.” (www.merckmedco.com)

*
PNN will not be published on Monday, May 26, Memorial Day.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 27, 2003 Vol. 10, No. 101
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
May 24 issue of BMJ (www.bmj.org; 2003; 326).

Treatment of Fever & Neutropenia: Broad-spectrum beta-lactams are sufficient for empiric treatment of fever and neutropenia and should be considered the standard of care, according to results of a structured review and meta-analysis (pp. 1111 ff). Assessing all-cause mortality in 47 trials with 7,807 patients, this research group found no significant differences in effectiveness between monotherapy with beta-lactams and combination therapy using beta-lactam antibiotics and an aminoglycoside. Rates of superinfection were also similar between the two groups, but adverse effects (including some that produced severe morbidity) were significantly more common in patients on dual therapy. (M. Paul, Rabin Med. Ctr., Petah-Tiqva, Israel; mica@zahav.net.il)

Stepped-Down Steroids in Asthma: Among 259 adult patients with chronic asthma, inhaled corticosteroid doses were successfully lowered by 50% in those with stable conditions (pp. 1115 ff). Patients were initially taking high doses, averaging 1,430 mcg of beclomethasone dipropionate per day. They were allocated to receive no dose reductions or a 50% reduction if they met criteria for stable asthma. Among stepped-down patients, asthma exacerbations, number of physician or hospital visits, generic measures of health status, and annual dose of oral corticosteroids were not significantly different than in the unchanged group. During the 1-year study, the stepped-down group took an average of 348 mcg of beclomethasone dipropionate less per day than did the control group, an achieved dose reduction of 25%. (N. C. Thomson, U. Glasgow, Glasgow, Scotland; n.c.thomson@clinmed.gla.ac.uk)

Treatment of Dyspepsia: Test and treat is a better primary care strategy for younger patients with dyspepsia and no alarm symptoms, compared with omeprazole therapy. That conclusion comes from a study of 219 patients younger than 45 years who were treated with omeprazole 20 mg/day or with a urea breath test followed by Helicobacter pylori eradication therapy in positive patients and omeprazole only in negative patients (pp. 1118 ff). Patients who failed the initial intervention underwent endoscopy. Significantly fewer patients in the test-and-treat group required endoscopy (55%, compared with 88% among untested patients who took omeprazole alone). “Eradication treatment allows resolution of symptoms in a large number of patients with dyspepsia and reduces the endoscopic workload,” conclude the authors. “After a trial of omeprazole, symptoms recur in nearly every patient. Such treatment is also likely to mask an appreciable number of peptic ulcers and cases of oesophagitis.” (G. Manes, Cardarelli Hosp., Naples, Italy; gimanes@tin.it)

>>>PNN JournalWatch
* Iron Supplementation for Unexplained Fatigue in Non-Anaemic Women, in BMJ, 2003; 326: 1124 ff. Reprints: ww.bmj.org; B. Favrat, U. Lausanne, Lausanne, Switzerland; bernard.favrat@hospvd.ch

* Clinical Progression and Viral Load in a Community Outbreak of Coronavirus-Associated SARS Pneumonia: A Prospective Study, in
Lancet, 2003; 361: 1767–72. Reprints: www.thelancet.com; K. Y. Yuen, U. Hong Kong, Hong Kong, Special Administrative Region, China; kyyuen@hkucc.hku.hk

* Aspirin and Clopidogrel in Acute Coronary Syndromes: Therapeutic Insights from the CURE Study, in
Archives of Internal Medicine, 2003; 163: 1145–53. Reprints: www.archinternmed.com; G. S. Francis, Cleveland Clinic Found., Cleveland, Ohio; francig@cesmtp.ccf.org

* The Growing Burden of Tuberculosis: Global Trends and Interactions with the HIV Epidemic, in
Archives of Internal Medicine, 2003; 163: 1009–21. Reprints: www.archinternmed.com; C. Dye, dyec@who.int

* Mechanisms of Actions of Inhaled Anesthetics, in
New England Journal of Medicine, 2003; 348: 2110–24. Reprints: content.nejm.org; S. A. Forman, saforman@partners.org

* Philadelphia Chromosome–Positive Leukemias: From Basic Mechanisms to Molecular Therapeutics, in
Annals of Internal Medicine, 2003; 138: 819–30. Reprints: www.annals.org; R. Kurzrock, rkurzroc@mdanderson.org

* Use of Focus Groups as a Tool to Enhance a Pharmaceutical Care Practice, in
Journal of the American Pharmacists Association, 2003; 43: 424–34. Reprints: www.japha.org; T. D. Sorenson, U. Minnesota, Minneapolis; soren042@umn.edu

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 28, 2003 Vol. 10, No. 102
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
May 28 issue of JAMA (www.jama.com; 2003; 289).

HRT & Cognition: More data from the Women’s Health Initiative argue against routine use of hormone-replacement therapy in postmenopausal women, this time with respect to development of dementia and lack of prevention against mild cognitive impairment (pp. 2551-62). Among 4,521 postmenopausal women who were free of dementia at the start of the study, 40 patients on HRT were later diagnosed with probable dementia, compared with 21 patients in the placebo group. During the mean follow-up period of 4.05 years, “the hazard ratio (HR) for probable dementia was 2.05 (95% confidence interval [CI], 1.21–3.48; 45 vs 22 per 10,000 person-years; P= .01),” the group reports. “This increased risk would result in an additional 23 cases of dementia per 10,000 women per year. Alzheimer disease was the most common classification of dementia in both study groups. Treatment effects on mild cognitive impairment did not differ between groups (HR, 1.07; 95% CI, 0.74–1.55; 63 vs 59 cases per 10 000 person-years; P= .72).” (S. A. Shumaker, Wake Forest U., Winston-Salem, N.C.; sshumake@wfubmc.edu)

HRT & Cognition in the Elderly: Cognitive problems were identified among women older than 65 years in the Women’s Health Initiative who took estrogen plus progestin (pp. 2663-72). Between June 1995 and the termination of this arm of the study in July 2002, cognitive function was measured at least once in 4,381 women. Compared with baseline, “more women in the estrogen plus progestin group had a substantial and clinically important decline (≥ 2 SDs) in Modified Mini-Mental State Examination total score (6.7%) compared with the placebo group (4.8%) (P= .008),” the authors report. “Results from this analysis within a large, randomized trial do not support the use of combined estrogen plus progestin treatment to protect cognition in older women. Moreover, while most women did not experience a negative treatment effect on cognition, a small increased risk of clinically meaningful cognitive decline occurred in the estrogen plus progestin group.” (S. R. Rapp, Wake Forest U., Winston-Salem, N.C.; srapp@wfubmc.edu)

HRT & Stroke Risk: Among 16,608 generally healthy postmenopausal women, estrogen plus progestin therapy for a mean of 5.6 years increased risk of ischemic stroke (pp. 2673-84). The hazard ratios for ischemic and hemorrhagic strokes were 1.44 (a significant increase) and 0.82 (a nonsignificant decrease), respectively. “Point estimates of the HRs indicate that excess risk of all stroke was apparent in all age groups, in all categories of baseline stroke risk, and in women with and without hypertension, prior history of cardiovascular disease, use of hormones, statins, or aspirin,” note the researchers. “Other risk factors for stroke, including smoking, blood pressure, diabetes, lower use of vitamin C supplements, blood-based biomarkers of inflammation, higher white blood cell count, and higher hematocrit levels, did not modify the effect of estrogen plus progestin on stroke risk.” (S. Wassertheil-Smoller, Albert Einstein Coll. of Med., Bronx, N.Y.; smoller@aecom.yu.edu)

HRT—Déjà Vu All Over Again: An editorialist notes that these data support last summer’s conclusions from the WHI study and that, in ongoing parts of the WHI study, unopposed estrogen is under study (pp. 2717-9): “The effect of unopposed estrogen on prevention of developing dementia and [Alzheimer’s disease] will be evaluated with the ongoing estrogen arm of [WHI].... In addition, current understanding of the CNS outcomes of selective estrogen receptor modulators, which act as estrogen agonists on some tissues and estrogen antagonists on others, is still rudimentary. Other questions such as timing and in particular—if there is a critical period for exposure to estrogen—duration of use and preparation of estrogen (oral vs patch) have emerged as women, clinicians, and researchers grapple with the discrepancies (primarily for cardiovascular disease and dementia) between the WHI results and the majority of observational studies.” (K. Yaffe, kyaffe@itsa.ucsf.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 29, 2003 Vol. 10, No. 103
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
May 29 issue of the New England Journal of Medicine (content.nejm.org; 2003; 348).

Enfuvirtide & HIV: Two articles and an editorial address the clinical utility of enfuvirtide, a recently approved fusion inhibitor approved for combination treatment of HIV-1 infection (see PNN, Mar. 14).

In the T-20 vs. Optimized Regimen Only Study 1 (TORO 1), enfuvirtide improved virologic and immunologic parameters over a 24-week period in 491 North and South American patients who had previously received multiple antiretroviral drugs and who had multidrug-resistant HIV-1 infection (pp. 2175-85). In patients on enfuvirtide, viral load decreased by 1.696 log 10 copies/mL, compared with a decrease of 0.764 log 10 copies/mL among patients on an optimized background regimen of three to five antiretroviral agents. CD4+ cell counts jumped by 76 and 32 cells/cu mm in the enfuvirtide and control groups, respectively. Nearly all patients receiving enfuvirtide reported injection-site reactions, and pneumonia was more common among those patients. (J. P. Lalezari, Quest Clinical Research, San Francisco; drjay@questclinical.com)

TORO-2, conducted in Europe and Australia, produced in 512 patients findings similar to those of TORO-1 (pp. 2186-95). Enfuvirtide lowered viral loads by 1.429 log 10 copies/mL among the heavily pretreated patients, compared with a decrease of 0.648 log 10 copies/ mL among those on a background antiretroviral regimen. The CD4+ cell count increased significantly among patients on the fusion inhibitor (65.5 cells/cu mm, compared with 38.0 cells/cu mm for the background regimen). (A. Lazzarin, San Raffaele Vita-Salute U., Milan, Italy; lazzarin.adriano@hsr.it)

Fusion inhibition is “a major but costly step forward in the treatment of HIV-1,” write editorialists in noting enfuvirtide’s $20,000 annual price tag (pp. 2249-50). They also elaborate on the adverse effects of the drug: “Of major concern are the potentially serious toxic effects associated with the administration of enfuvirtide. In the updated safety analyses, which included patients from both studies with a total of 1027 patient-years of exposure to enfuvirtide, pneumonia (primarily bacterial) occurred eight times as frequently in the combined enfuvirtide groups as in the combined control groups.... Furthermore, 2 of the 663 patients in the combined enfuvirtide groups had serious systemic hypersensitivity reactions to enfuvirtide....

“A less serious side effect derives from the fact that enfuvirtide is a large, 36-amino-acid peptide that must be administered by subcutaneous injection twice daily. Although the development at the injection site of painful, pruritic subcutaneous nodules with the histologic features of an interstitial granulomatous drug reaction was almost universal, less than 3 percent of patients withdrew from the trials because of injection-site discomfort.”

“Although these issues are important, they should not detract from the welcome demonstration of the effectiveness of this HIV-1 fusion inhibitor, the first successful inhibitor of viral entry. This new antiretroviral drug, when prescribed judiciously as a component of an optimized antiretroviral regimen, can be effective in persons who have previously received multiple antiretroviral drugs and whose therapeutic options are severely constrained by extensive resistance mutations against the available antiretroviral drugs.” (K. T. Tashima, Miriam Hospital, Providence, R.I.)

Preventing HIV Entry into Cells: “A new, diverse class of compounds designed or selected to inhibit the entry of HIV-1 into host cells is approaching clinical application,” write authors in a review article (pp. 2228-38). “Early clinical experience with some of these compounds has been favorable, and toxic effects or drug-resistance patterns that overlap with those of currently available therapies have not been observed.... As with all available antiretroviral agents, the clinical activity of viral-entry inhibitors will be limited by selection for drug-resistant viral variants unless the compounds can be used together with other effective drugs.” (J. M. Kilby, U. Ala., Birmingham; mkilby@uab.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 30, 2003 Vol. 10, No. 104
Providing news and information about medications and their proper use

>>>Neurology Report
Source:
May 27 Neurology (www.neurology.org; 2003; 60).

NSAIDs & Cognitive Function: Among 16,128 women aged 70–81 years, use of NSAIDs—especially nonaspirin compounds—was associated with reduced odds of low cognitive function and possibly less cognitive decline over a 2-year period (pp. 1591-7). Using data from the Nurses’ Health Study, researchers logged scores on six tests of cognitive function between 1995 and 2001. In multiple regression analyses, the relative risk for having a low baseline score on the Telephone Interview of Cognitive Status was 0.75 for women who were currently using aspirin and had been doing so for 15 or more years. For current use of NSAIDs (primarily ibuprofen) for 8 or more years, the RR was 0.79. Aspirin results were weaker on other baseline tests, but ibuprofen showed a protective effect in long-term users. Assessing the rates of substantial cognitive decline during the study, RRs were nonsignificant: 0.93 for long-term aspirin and 0.77 for long-term ibuprofen. (J. H. Kang, nhjhk@channing.harvard.edu)

Medication-Overuse Headaches: In 98 patients treated for headaches caused by overuse of medications, relapse rates were higher for tension-type headaches (73%) than for migraines (22%; pp. 1682-3). Relapse rates were lower for patients overusing triptans (19%) and ergots (20%) than for analgesics (58%). “The long-term success of withdrawal depends on the type of primary headache and the type of overused medication,” the authors conclude. (V. Limmroth, U. Hosp., Essen, Germany; volker.limmroth@uni-essen.de)

A patient page on medication-overuse headache is published in this issue of
Neurology (pp. 8-9).

>>>Infectious Diseases Report
Source:
June 1 issue of Clinical Infectious Diseases (www.journals.uchicago.edu/CID; 2003; 36).

Infections & Multidose Vials: Refrigeration of a multidose vial of lidocaine was linked to an outbreak of Staphylococcus aureus joint and soft-tissue infections in an outpatient setting (pp. 1369-73). An epidemiologic study of 17 patients who received therapeutic injections of lidocaine and/or triamcinolone linked infections to the lidocaine. The authors note: “A possible contributing factor was refrigeration after the use of MDVs of lidocaine; the manufacturer recommends storage at room temperature. An in vitro study of S. aureus in MDVs of lidocaine revealed prolonged survival at refrigerator temperatures. This outbreak highlights the importance of strict attention to aseptic procedures and carefully following manufacturers’ instructions when using MDVs.” (D. L. Kirschke, CDC, Atlanta)

Ring Wearing & Hand Hygiene: A study with implications for pharmacy sterile admixture preparation shows that wearing of rings by surgical intensive care nurses was associated with a 10-fold increase in median skin organism counts (pp. 1383-90). The odds ratios for contamination with transient organisms were 2.6 for those who wore one ring and 4.6 among those wearing multiple rings. Alcohol-based hand rubs were more effective at eliminating this contamination than was washing with plain soap and water or use of a medicated hand wipes. (W. E. Trick, CDC, Atlanta)

Antimicrobial Cycling in Hospitals: The “deliberate, scheduled removal and substitution of specific antimicrobials or classes of antimicrobials within an institutional environment (either hospital-wide or confined to specific units) to avoid or reverse the development of antimicrobial resistance” is unproven and should not replace other methods of influencing antibiotic choice, according to a review (pp. 1438-44). “True antimicrobial cycling requires a return to the antimicrobial(s) that were first used,” writes the author. “Testing of the hypothesis that cycling will result in a lower prevalence of resistance is ongoing, mostly occurs within intensive care units, and largely involves cycling regimens targeted for treatment of suspected gram-negative bacterial infections.... There has been insufficient study to determine whether any meaningful impact on resistance has occurred.” (S. K. Fridkin, CDC, Atlanta)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 2, 2003 Vol. 10, No. 105
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
May 31 issue of Lancet (www.thelancet.com; 2003; 361).

Enalapril & Systolic Dysfunction: Survival and life expectancy increased after long-term enalapril therapy in 6,797 patients with left ventricular systolic dysfunction (pp. 1843-8). In studies of left ventricular dysfunction (SOLVD), enalapril was used for 3–4 years for prevention in asymptomatic patients and treatment in symptomatic individuals. Survival after up to 12 years was improved in both groups (50.9% of those on enalapril died in the prevention trial, compared with 56.4% of placebo patients, and 79.8% of enalapril recipients in the treatment group died, compared with 80.8% of those taking placebo). In the combined trials, enalapril extended median survival by 9.4 months. “Benefits of ACE inhibitor treatment continued to accrue beyond the end of the trial,” the researchers conclude. “Thus, even a 4-year intervention trial with an ACE inhibitor could only provide an underestimate of the true benefit of lifelong treatment in high-risk patients.” (S. Yusuf, yusufs@mcmaster.ca)

Ciprofloxacin-Resistant Gonococci: Isolation of Neisseria gonorrhoeae resistant to ciprofloxacin tripled in England and Wales between 2001 and 2002 (pp. 1867-9). Of 2,204 isolates tested in 2002, 9.8% were resistant at an MIC of 1 mg/L, compared with 3.1% and 2.1% in 2001 and 2000, respectively. “These findings suggest that national and local treatment guidelines need to be reviewed urgently,” the authors write. (K. Fenton, Gonococcal Resistance to Antimicrobials Surveillance Programme [GRASP])

Probiotics & Atopic Disease: Perinatal administration of Lactobacillus GG provides protection against atopic eczema beyond infancy, according to a 4-year follow-up study (pp. 1869-71). In a group of patients studied previously for 2 years (see PNN, Apr. 9, 2001), the risk of atopic eczema at 4 years was reduced by 43% among those whose mothers had taken the probiotic agent for 4 weeks before expected delivery and who had received the agent for 6 months after birth. (M. Kalliomäki, Turku U. Hosp., Turku, Finland; markal@utu.fi)

Metformin & PCOS: The increasingly common clinical practice of using metformin in women with polycystic ovary syndrome “is ahead of the evidence,” according to authors of a review article (pp. 1894-901). “Close inspection of results from the adequately controlled studies shows that the benefits are modest,” the authors note. They call for more attention to adverse effects of metformin and more investigation into the benefits achievable with lifestyle modification. (N. Sattar, Glasgow Royal Infirmary U., Glasgow, U.K.; nsattar@clinmed.gla.ac.uk)

>>>BMJ Highlights
Source:
May 31 issue of BMJ (www.bmj.org; 2003; 326).

Stage-Based Smoking Interventions: The evidence for smoking-cessation interventions based on stage theories of behavior provide little evidence of increased effectiveness, according to a systematic review article. Among 23 studies, methodologic quality was mixed, and few validated their instruments for assessing readiness to change. Better studies are needed, the authors conclude. (R. P. Riemsma, U. York; rpr1@york.ac.uk)

>>>PNN JournalWatch
* Pharmaceutical Industry Sponsorship and Research Outcome and Quality: Systematic Review, in BMJ, 2003; 326: 1167–70. Reprints: www.bmj.org; J. Lexchin, joel.lexchin@utoronto.ca

* Evidence B(i)ased Medicine—Selective Reporting From Studies Sponsored By Pharmaceutical Industry: Review Of Studies In New Drug Applications, in
BMJ, 2003; 326: 1171–3. Reprints: www.bmj.org; H. Melander, Medical Products Agency, Uppsala, Sweden; hans.melander@mpa.se

* Maternal Lifestyle Factors in Pregnancy Risk of Attention Deficit Hyperactivity Disorder and Associated Behaviors, in
American Journal of Psychiatry, 2003; 160: 1028–40. Reprints: ajp.psychiatryonline.org; K. M. Linnet.

* An “Evidence-Based” Survey of Therapeutic Options for IgA Nephropathy, in
American Journal of Kidney Diseases, 2003; 41. Reprints: www.ajkd.org; F. P. Schena, U. Bari, Bari, Italy; gfmstrippoli@katamail.com

* Critical Review of Complementary Therapies for Prostate Cancer, in
Journal of Clinical Oncology, 2003; 21: 2199–210. Reprints: www.jco.org; S. Wilkinson, Weiss Memorial Hosp., Chicago; simonmwilkinson@hotmail.com

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 3, 2003 Vol. 10, No. 106
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
June 3 issue of the Annals of Internal Medicine (www.annals.org; 2003; 138).

Spinal Manipulation for Low Back Pain: Spinal manipulation for patients with low back pain is no more or less effective than general practitioner care, analgesics, physical therapy, exercise, or back school therapy, according to a meta-analysis of 39 randomized controlled trials (pp. 871-81). For acute back pain, spinal manipulation was superior to sham therapy and a variety of interventions judged to be ineffective or harmful (e.g., traction, corset, bed rest). “Results for patients with chronic low back pain were similar,” the authors report. “Radiation of pain, study quality, profession of manipulator, and use of manipulation alone or in combination with other therapies did not affect these results.” (P. G. Shekelle, RAND, Santa Monica, Calif.; shekelle@rand.org)

Treatments for Persistent Back Pain: For patients with persistent back pain, massage is an effective treatment, and it reduces the costs of care after an initial course of therapy, compared with spinal manipulation or acupuncture (pp. 898-906). A systematic review of 20 randomized controlled trials of acupuncture, 3 RCTs of massage, and 26 RCTs of spinal manipulation showed: “The effectiveness of acupuncture for treating acute or chronic back pain is unclear.... Massage ... is effective for subacute and chronic back pain.... Spinal manipulation for acute and chronic back pain ... was superior to sham therapies and therapies judged to have no evidence of a benefit but was not superior to effective conventional treatments.” (D. C. Cherkin, Group Health Cooperative, Seattle)

Treatment of HF with Renal Insufficiency: Little clinical information is available to guide treatment of patients with heart failure and renal insufficiency, notes an author of a review article (pp. 917-24). “At least one third of patients with heart failure have renal insufficiency, which is associated with substantially increased mortality,” notes the writer. “Although clinical trials have shown that several medications improve survival and reduce hospitalizations in patients with heart failure, most included few patients with moderate and severe renal insufficiency. Rather than rely on serum creatinine levels, clinicians should estimate [glomerular filtration rate] to categorize renal function. The available data indicate that ACE inhibitors offer a survival advantage in patients with heart failure and mild and moderate renal insufficiency; their use in patients with severe renal insufficiency requires caution because of the potential risk for adverse events.... The effect of beta-blockers on improved heart failure survival is less likely to differ by renal function, but the beta-blocker trials have not addressed the subgroup with moderate and severe renal insufficiency. The risk for hyperkalemia with spironolactone appears to be increased in renal insufficiency, and the safety of this drug has not been evaluated in patients with severe renal insufficiency. The safety of digoxin in patients with severe renal insufficiency is also unknown. Future studies of current and future medications in patients with renal insufficiency are needed to improve the evidence base for treatment in this vulnerable population.” (M. G. Shlipak, shlip@itsa.ucsf.edu)

>>>ASCO Convenes in Chicago
The 39th annual meeting of the American Society of Clinical Oncology is underway in Chicago. Among the highlights thus far are the following:

* In Phase III trials, bevacizumab (rhuMAb-VEGF, Avastin, Genentech) plus chemotherapy provided a 50% increase in survival rates in patients with previously untreated metastatic colorectal cancer, compared with chemo-therapy alone.

* The MOSAIC trial showed that the addition of oxaliplatin to the current standard of postoperative chemotherapy for colon cancer reduces the risk of recurrence by 23% in patients who have undergone surgery for their primary tumor.

* In patients with recurrent non-small cell lung cancer, Phase III data show significantly fewer side effects with pemetrexed (Alimta, Lilly) versus docetaxel.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 4, 2003 Vol. 10, No. 107
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
June 4 issue of JAMA (www.jama.com; 2003; 289).

SARS: In 144 Toronto-area patients treated for severe acute respiratory syndrome, ribavirin was commonly used but produced significant adverse effects, including hemolysis and decreases in hemoglobin (pp. 2801-9). Most of the patients were exposed to the SARS virus in the hospital setting (77%), and 126 patients (88%) were treated with ribavirin, usually within the first 48 hours of hospitalization for SARS. The most commonly used ribavirin regimen was a loading dose of 2 grams i.v. followed by 1 gram i.v. every 6 hours for 4 days and then by 500 mg i.v. every 8 hours for 3 days. Steroids, usually 20–50 mg/day of hydrocortisone for 10 days, were administered to 40% of patients, but few received these agents within the first 48 hours of hospitalization.

Of the patients treated with ribavirin, 49% had decreases in hemoglobin of 2 g/dL or more, with 76% of those patients having 1.5-fold increases in bilirubin or haptoglobin levels. Transaminases were elevated in 40% of those given ribavirin, and bradycardia (14%) and sore throat (4%) also occurred. While many of the patients in this series were treated with ribavirin, the researchers note that “recent reports suggest that most patients recover from SARS despite not receiving either ribavirin or steroids.” (A. S. Detsky, Mount Sinai Hosp., Toronto, Ontario, Canada; allan.detsky@uhn.on.ca)

In an editorial, authors note the challenges faced by health care workers who must care for patients with SARS (pp. 2861-3): “Accounts circulating from health care workers who have seen colleagues stricken and who have themselves developed this syndrome are reasons for concern. There is also concern that these workers represent a risk to their families in terms of spreading this nosocomial pathogen. Whether these health care workers were infected while taking proper precautions or whether they were inadvertently infected when the risk of exposure was not apparent or when the pressure of events precluded meticulous precautions remains to be determined.” (H. Masur, hmasur@cc.nih.gov)

NSAIDs & AD:
Lack of efficacy and increased number and severity of adverse drug effects led researchers to conclude that rofecoxib and low-dose naproxen were not effective in slowing cognitive decline in patients with mild or moderate Alzheimer’s disease (pp. 2819-26). Rofecoxib 25 mg once daily, naproxen sodium 220 mg twice daily, or placebo were given to 351 patients for 1 year. Scores on the Alzheimer Disease Assessment Scale-Cognitive subscale were not significantly different with active therapies, compared with patients taking placebo. Fatigue, dizziness, and hypertension were more common in active-treatment groups, and the number of serious adverse events was greater among patients who were taking the anti-inflammatory agents. (P. S. Aisen, psa@georgetown.edu)

Paroxetine & Hot Flashes: Controlled-release paroxetine reduced the frequency and severity of hot flashes in 165 menopausal women who were having at least two to three episodes per day at baseline (pp. 2827-34). By the end of the 6-week study, mean daily hot flash frequency had fallen “from 7.1 to 3.8 (mean reduction, 3.3) for those in the 12.5-mg/d and from 6.4 to 3.2 (mean reduction, 3.2) for those in the 25-mg/d paroxetine CR groups and from 6.6 to 4.8 (mean reduction, 1.8) for those in the placebo group,” the authors explain. “Mean placebo-adjusted reduction in hot flash composite scores [frequency times severity] were –4.7 (95% confidence interval, –8.1 to –1.3; P= .007) comparing 12.5-mg/d paroxetine CR with placebo; and –3.6 (95% confidence interval, –6.8 to –0.4; P= .03) comparing 25.0-mg/d paroxetine CR with placebo. This corresponded to median reductions of 62.2% for those in the 12.5-mg/d and 64.6% for those in the 25.0-mg/d paroxetine CR groups compared with 37.8% for those in the placebo group.” The researchers conclude that use of paroxetine CR or other antidepressants as first- or second-line therapies for hot flashes and the appropriate duration of such use remain unknown. (V. Stearns, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore; vstearn1@jhmi.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 5, 2003 Vol. 10, No. 108
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
June 5 issue of the New England Journal of Medicine (content.nejm.org; 2003; 348).

Microalbuminuria Regression & Type 1 DM: ACE inhibitor therapy appears to play little role in inducing regression of microalbuminuria in patients with type 1 diabetes mellitus, but a study of 386 individuals indicates that such regression occurs commonly, and this might mean that early diabetic nephropathy is reversible (pp. 2285-93). Patients with microalbuminuria (urinary albumin excretion of 30–299 mcg/ min) during an initial 2-year period were followed for 6 additional years. Regression of microalbuminuria occurred in 58% of patients at one or more times during the 6-year period. Regression analysis showed that ACE inhibitor therapy was not associated with regression, but several other factors were: microalbuminuria of short duration, salutary levels of glycosylated hemoglobin (less than 8%), low systolic blood pressure (less than 115 mm Hg), and low levels of both cholesterol and triglycerides (less than 198 mg/dL and 145 mg/dL, respectively). The odds of regression were 3-fold greater in patients with all of these positive factors, compared with patients with none of the factors.

“ACE inhibitors are now well established for prevention of the progression of microalbuminuria to proteinuria,” the authors explain. “However, in the present study, the use of ACE inhibitors was not associated with the regression of microalbuminuria. Moreover, detailed analysis found that the effect of low blood pressure in this study was independent of the use or nonuse of ACE inhibitors. Rather than a contradiction, it is possible that the beneficial pharmacologic effects of ACE inhibitors that prevent the progression of microalbuminuria do not influence the biologic mechanisms that underlie the regression of microalbuminuria.” (A. S. Krolewski, andrzej.krolewski@joslin.harvard.edu)

Intensive Diabetes Therapy & CVD: Progression of thickening of the carotid intima–media lining slowed during a 6-year period that followed intensive therapy during the Diabetes Control and Complications Trial (pp. 2294-303). Ultrasonography was conducted in 611 and 618 patients who received conventional and intensive diabetes therapy, respectively, and images from 1994–96 and 1998–2000 were compared. The investigators found: “The mean progression of the intima–media thickness was significantly less in the group that had received intensive therapy during the DCCT than in the group that had received conventional therapy (progression of the intima–media thickness of the common carotid artery, 0.032 vs. 0.046 mm; P=0.01; and progression of the combined intima–media thickness of the common and internal carotid arteries, –0.155 vs. 0.007; P=0.02) after adjustment for other risk factors. Progression of carotid intima–media thickness was associated with age, and ... base-line systolic blood pressure, smoking, the ratio of low-density lipoprotein to high-density lipoprotein cholesterol, and urinary albumin excretion rate and with the mean glycosylated hemoglobin value during the mean duration (6.5 years) of the DCCT.” (DCCT Research Group, dnathan@partners.org)

Genomics & Breast, Ovarian Cancer: Authors of a review article offer a positive view on the impact of advances in genomics of breast and ovarian cancer (pp. 2339-47). “The past decade has been a period of unparalleled discovery in the field of the genetics and genomics of breast and ovarian cancer. Two major susceptibility genes have been isolated, and subsequent work provided sufficient management information to allow genetic testing for BRCA1 and BRCA2 mutations to become a part of routine practice in many clinical centers. In addition, work has begun on the characterization of genetic variants that, although associated with a lower risk of cancer than germ-line BRCA1 and BRCA2 mutations, are far more common in the population and thus may have a substantial role in defining the risk of cancer.... A marked reduction in mortality from breast and ovarian cancer is a realistic goal for the next decade.” (R. Wooster, Wellcome Trust Sanger Inst., Cambridge, U.K.)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 6, 2003 Vol. 10, No. 109
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
June Pharmacotherapy (www.accp.com; 2003; 43).

Intracellular Interaction of Tenofovir and Didanosine: An in vitro study suggests that adjustment of didanosine doses is sufficient to compensate for that drug’s interaction with tenofovir (pp. 695-701). Radiolabeled tenofovir and didanosine were tested in human peripheral blood mononuclear cells. The presence of tenofovir did not affect phosphorylation of didanosine, and likewise the phosphorylation of tenofovir was not altered by didanosine. “This suggests that adjusting didanosine dosage, when given with tenofovir, to achieve similar didanosine plasma concentrations, may be sufficient to accommodate the systemic drug interaction” between these drugs, the authors write. (J. H. Rodman, john.rodman@stjude.org)

Osteoporosis in the Nursing Home: Better measurement and documentation of bone mineral density are needed in nursing homes, and new approaches to repletion of vitamin D should be considered, according to an analysis of 49 elderly women in a skilled-nursing facility (pp. 702-10). Calcaneal osteoporosis was documented in the medical records of only 4 of 23 patients whose bone mineral density and symptoms were consistent with the condition. Only 4% of the 49 patients had optimal vitamin D levels, and 60% of patients had concentrations associated with secondary hyperparathyroidism. Vitamin D deficiency was common even among patients on multivitamin supplements, leading to the authors’ suggestion that “practical new approaches for vitamin D repletion in this population are urgently needed.” (M. E. Elliott, meelliott@pharmacy.wisc.edu)

PPI Metabolism & H. pylori Eradication: Rabeprazole concentrations were significantly higher among poor metabolizers of the proton pump inhibitor in a study of 12 healthy volunteers, suggesting the possibility of greater efficacy of the drug when used for eradication of Helicobacter pylori (pp. 711-9). Compared with six individuals with extensive cytochrome P450 2C19 activity, six poor metabolizers had significantly higher levels of rabeprazole and rabeprazole thioether on days 1 and 4 of the multidose study. In addition, on day 4, plasma gastrin levels were significantly elevated among poor metabolizers; the authors suggest that this creates “advantageous conditions” for treating H. pylori infection with rabeprazole. (C-J Lin, Natl Taiwan U., Taipei)

Losartan & Polymorphisms: In 15 healthy volunteers with differing cytochrome P450 2C9 genotypes, losartan metabolism was not altered sufficiently to require dosage adjustments (pp. 720-5). Three genotypes, CYP2C9*1/*1, *1/*2, and *1/*3, were each present in five patients. After a single oral dose of losartan 50 mg, no significant effects of genotype were observed on blood pressure; losartan or metabolite areas under serum concentration– time curves or elimination half-lives; or losartan oral clearance. (C. R. Lee, craig_lee@unc.edu)

Statins & Cognition: The odds of a patient developing cognitive impairment appear to be reduced during lipid-lowering therapy, especially with the statins, according to an analysis based on seven published studies (pp. 726-30). Relative risks were reduced by 57% among patients on statins, a significant decline, and by a nonsignificant 38% among patients on any type of lipid-lowering therapy. “Randomized, controlled trials are needed to address the efficacy of these agents specifically in different types of dementia,” the group concludes. (A. Samii, asamii@u.washington.edu)

Review Articles: A number of interesting reviews are published in this issue:
* Risperidone-associated diabetes mellitus (pp. 735-44; P. M. Doraiswamy, Duke U.)
* Heparin-induced thrombocytopenia in critical care (pp. 745-53; M. Levine, U. Br. Columbia)
* Safety of antidepressant drugs in cardiac disease (pp. 754-71; W. Alvarez, Johns Hopkins U.)
* Factor Xa inhibition in orthopedic surgery (pp. 772-87; P. C. Comp, philip-comp@ouhsc.edu)
* Calcium-channel blockers in renal transplant patients (pp. 788-801; S. Baroletti, sbaroletti@partners.org)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 9, 2003 Vol. 10, No. 110
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
June 7 issue of Lancet (www.thelancet.com; 2003; 361).

Fluvastatin in Renal Transplantation: In 2,102 renal transplant recipients, fluvastatin lowered the number of cardiac deaths or nonfatal myocardial infarctions but failed to reduce rates of coronary intervention procedures or overall mortality (published online, June 3, 2003). During a mean follow-up period of 5.1 years, fluvastatin lowered LDL cholesterol concentrations by 32% and the number of cardiac deaths or nonfatal MIs by 35%. However, when the number of coronary interventions was incorporated into a composite endpoint that included the above two events, the risk reduction was only 17%, not a significant difference. (Assessment of LEscol in Renal Transplantation [ALERT] Study Investigators)

Neoadjuvant Chemotherapy for Invasive Bladder Cancer: Platinum-based combination chemotherapy regimens improved survival of 2,688 patients with invasive bladder cancer, according to a systematic review and meta-analysis of 10 trials (pp. 1927-34). A 13% reduction in the risk of death was identified along with an absolute increase of 5% in the 5-year mortality rate (it rose to 50% with the neoadjuvant regimens). While a statistical trend toward a benefit was observed with single-agent cisplatin, combination regimens reached significance and consistently outperformed single-agent regimens. The authors conclude, “This improvement in survival encourages the use of platinum-based combination chemo-therapy for patients with invasive bladder cancer.” (C. Vale, Med. Res. Council Clin. Trials Unit, London, U.K.; cv@ctu.mrc.ac.uk)

>>>BMJ Highlights
Source:
June 7 issue of BMJ (www.bmj.org; 2003; 326).

Effectiveness of Neuraminidase Inhibitors: Oseltamivir and zanamivir are clinically effective for treating and preventing flu, but the evidence supporting their use is limited in certain populations and for all prevention strategies, according to authors of a systematic review (pp. 1235-41) “Treatment of children, otherwise healthy individuals, and high risk populations with zanamivir reduced the median duration of symptoms in days respectively by 1.0 (95% confidence interval 0.5 to 1.5), 0.8 (0.3 to 1.3), and 0.9 (–0.1 to 1.9) for the intention to treat population,” report the authors. “The corresponding results, in days, for oseltamivir were 0.9 (0.3 to 1.5), 0.9 (0.3 to 1.4), and 0.4 (–0.7 to 1.4). The effect of giving zanamivir and oseltamivir prophylactically resulted in a relative reduction of 70–90% in the odds of developing flu, depending on the strategy adopted and the population studied.” (N. J. Cooper, U. Leicester, Leicester, U.K.; njc21@ le.ac.uk)

OTC Lice Treatments: Improper use and, outside the U.S., insecticide resistance are the chief causes of failure of over-the-counter products for treating head lice (p. 1257). Improper use can be caused by not using enough product to cover scalp and hair or not repeating the treatment after 7–10 days. Another common reason for “failure” is that the person does not have lice, with dandruff, dried hair spray, or pseudo-nits (peripilar keratin casts) being mistaken for nits. (I. Burgess, Insect Res. and Development, Cambridge, U.K.; ian@insectresearch.com)

>>>PNN JournalWatch
* Vaccination and Autoimmune Disease: What Is the Evidence?, in Lancet, published online June 3, 2003. Reprints: www.thelancet.com; D. C. Wraith.

* Unstable Angina and Non–ST-Elevation Myocardial Infarction: Initial Antithrombotic Therapy and Early Invasive Strategy, in
Circulation, 2003; 107: 2640–5. Reprints: circ.ahajournals.org; C. P. Cannon.

* Add-on or Step-up Trials for New Drug Development in Rheumatoid Arthritis: A New Standard?, in
Arthritis & Rheumatism, 2003; 48: 1481–3. Reprints: www3.interscience.wiley.com; M. Boers.

* Caspofungin, in
Clinical Infectious Diseases, 2003; 36: 1445–57. Reprints: www.journals.uchicago.edu; S. C. Deresinski, Stanford U., Stanford, Calif.

* Management of Complications in Patients Receiving Home Parenteral Nutrition, in
Gastroenterology, 2003; 124: 1651–61. Reprints: www.gastrojournal.org; L. Howard, Albany Medical College, Albany, N.Y.; howardl@mail.amc.edu

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 10, 2003 Vol. 10, No. 111
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
June 9 issue of Archives of Internal Medicine (www.archinternmed.com; 2003; 163).

Extended Fondaparinux Prophylaxis After Hip Fracture Surgery: Compared with placebo, a 4-week regimen of fondaparinux reduced venous thromboembolism events by 96% following hip fracture surgery (pp. 1337-42). Patients first received 6–8 days of fondaparinux therapy and were then randomized to fondaparinux sodium 2.5 mg or placebo for 19–23 days. Among 428 patients, VTE (detected by mandatory bilateral venography or documented symptomatic deep vein thrombosis or pulmonary embolism) occurred in 35% of those who received placebo and 1.4% of those on active therapy, a relative risk reduction of 95.9%. Incidence of symptomatic VTE was also reduced by fondaparinux, to 0.3% from 2.7% with placebo (relative risk reduction of 88.8%). A statistical trend toward more major bleeding was observed with fondaparinux, with the p value reaching 0.06. However, as in other studies of this agent, no differences in clinically relevant bleeding (leading to death, reoperation, or critical organ bleeding) were identified between placebo and fondaparinux. [PENTasaccharide in HIp-FRActure Surgery Plus (PENTHIFRA Plus) Investigators]

Extended LMWH Prophylaxis After Hip Arthroplasty: A systematic review of 14 studies indicates that “the absolute reduction in symptomatic venous thromboembolism attributed to extended [low molecular weight heparin] prophylaxis in some studies and meta-analyses seems to have been overestimated” (pp. 1362-6). “Knowledge of the results of [VTE] screening tests may have resulted in overdiagnosis of symptomatic venous thromboembolism in many of these studies,” the authors propose. Their respective absolute risk reduction and number needed to treat values were 1.56% and 64 for symptomatic VTE, 0.36% and 278 for symptomatic pulmonary embolism, and 0.09% and 1,093 for fatal PE. (M. O’Donnell, McMaster U., Hamilton, Ontario)

Length of Warfarin Prophylaxis After VTE: Following an initial venous thromboembolism event, prophylaxis with vitamin K antagonists for more than 3 months should be considered carefully, according to authors of a meta-analysis of 18 clinical trials (pp. 1285-93). Based on analysis of short, medium, and long treatment arms in the studies, the group found, “The monthly incidence immediately after discontinuation of treatment was high and declined rapidly thereafter. The monthly incidence after 9 months seemed independent of the treatment duration.” They conclude, “Continuation of treatment beyond 3 months should be considered with caution. In the debate about the optimal duration of treatment with vitamin K antagonists, it is also reasonable to take into account the burden of treatment experienced by the patient. It is questionable whether the reduced risk of a recurrent venous thromboembolic event when vitamin K antagonist treatment is prolonged can counterbalance the burden of treatment and the increased risk of bleeding, with its often far-reaching consequences for the quality of life for the patient.” (C. J. J. van Dongen, U. Amsterdam, the Netherlands; c.j.vandongen@amc.uva.nl)

Raloxifene–Levothyroxine Interaction: In a 79-year-old woman with chronic primary hypothyroidism, raloxifene reduced absorption of levothyroxine when the two agents were administered at the same time (pp. 1367-70). After noticing an increasing levothyroxine requirement during concomitant therapy, the investigators tested regimens in which administration of the two drugs were separated by about 12 hours and assayed blood samples when the agents were administered together and separately. “Hypothyroidism occurred in a reproducible fashion whenever levothyroxine and raloxifene were administered together and improved whenever they were taken separately,” write the authors. “Combined administration of levothyroxine and raloxifene resulted in lower levels of serum thyroxine compared with administration of levothyroxine alone. By a yet unknown mechanism, raloxifene caused malabsorption of levothyroxine in our patient when coadministered.” (E. S. Siraj, Cleveland Clinic Foundation, Cleveland)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 11, 2003 Vol. 10, No. 112
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
June 11 issue of JAMA (www.jama.com; 2003; 289).

Aspirin vs. Ticlopidine for CVD Prevention: For black patients, aspirin is a better choice for prevention of cardiovascular disease and death, compared with ticlopidine, according to a 1,809-patient study (pp. 2947-57). Stopped after running for 6.5 years when the likelihood that ticlopidine was superior dropped to less than 1%, the study provided patients with ticlopidine 500 mg/day or aspirin 650 mg/day for up to 2 years after noncardioembolic ischemic stroke. In the ticlopidine group, 14.7% of patients reached one element of a composite end point (recurrent stroke, myocardial infarction, or vascular death), compared with 12.3% of those who took aspirin, a nonsignificant difference. A statistical trend (p = .08) favored aspirin for prevention of fatal or nonfatal stroke. Serious neutropenia and thrombocytopenia occurred in similar numbers of patients on the two drugs. One case of possible thrombotic thrombocytopenic purpura occurred in a patient on ticlopidine who recovered after plasmapheresis.

“Our data call into question the superiority of the thienopyridine ticlopidine in black noncardioembolic ischemic stroke patients, and suggest that ticlopidine is unlikely to be superior to aspirin for prevention of recurrent stroke and major vascular events in these patients,” concludes the group. “Furthermore, ticlopidine may have a less favorable and potentially [serious adverse effects] profile. Therefore, aspirin is a reasonable first choice prevention agent in aspirin-tolerant black patients with noncardioembolic ischemic stroke.” (P, B. Gorelick, Rush Med. Coll., Chicago; Philip_B_Gorelick@rush.edu)

An editorialist laments the continued difficulties in stroke prevention among blacks (pp. 3005-7): “At present, control of stroke risk factors is still less than adequate, particularly in communities of lower socioeconomic status, who are less educated about the importance of these conditions and also have decreased access to health care for proper detection and management of these risk factors.... The number of blacks with uncontrolled hypertension, untreated diabetes, and elevated cholesterol levels as well as those who are stroke survivors and are not adequately protected from recurrent stroke is far too great. More innovative approaches are needed to translate the successes of clinical stroke research studies into the community. Effective stroke prevention continues to be elusive, and patients at highest risk present the biggest challenges.” (R. L. Sacco, rls1@columbia.edu)

HAART & Serum Lipids: Changes in serum lipid levels that are attributed to highly active antiretroviral therapy are at least in part due to normal effects of aging combined with persistent disease-related declines in HDL cholesterol concentrations, according to a study of 50 HIV-positive men (pp. 2978-82). Compared with preseroconversion lipid profiles, the men had notable declines in mean serum total cholesterol (–30 mg/dL), HDL-C (–12 mg/dL), and LDL-C (–22 mg/dL) after HIV infection. After HAART initiation, total cholesterol and LDL-C levels rose by an average of 51 and 21 mg/dL, respectively, while HDL-C levels remained depressed. This observed increase in LDL-C is only slightly higher than the increase that would be expected through normal aging over the time period involved (15 mg/dL), the authors note, adding, “Serum triglyceride levels after about 3 years of HAART were higher than would be expected based on [aging] data. The impact of HAART on triglyceride levels, especially with regimens containing ritonavir, needs further study. Likewise, data from women and minorities would be useful... Factors such as insulin resistance, fat redistribution, and smoking and diet may act synergistically ... in HAART-treated persons. These issues require further study; at the current time, standard guidelines for the treatment of hyperlipidemia should be followed. In the meantime, this study demonstrates the vital importance of comparing post-HAART lipid levels to preseroconversion levels whenever possible.” (S. A. Riddler, riddler@msx.dept-med.pitt.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 12, 2003 Vol. 10, No. 113
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
June 12 issue of the New England Journal of Medicine (content.nejm.org; 2003; 348).

Progesterone & Prevention of Preterm Delivery: In 463 women at high risk of recurrent preterm delivery, weekly injections of 17-alpha-hydroxy-progesterone caproate (17P) 250 mg significantly decreased the frequency of early delivery and occurrence of complications in infants (pp. 2379-85). In these women, all of whom had histories of spontaneous preterm delivery, injections were begun at 16–20 weeks’ gestation and continued until delivery or 36 weeks’ gestation. The risk of delivering before 32 weeks was reduced by 42% with 17P (11.4%, compared with 19.6% among women given placebo), and the risks of delivering before 35 and 37 weeks’ gestation were reduced by 33% and 34%, respectively.

Infants born to women treated with 17P had significantly lower rates of necrotizing enterocolitis, intraventricular hemorrhage, and need for supplemental oxygen, the authors report. But, they caution, “Our results may not be generalizable to women whose risk factors for preterm delivery are different from those of the women in this trial. In addition, although 17P significantly reduced the rate of preterm delivery among the women who received it, the rate of preterm delivery in this group remained very high (36.3 percent). Thus, the identification of other causes of preterm delivery and other methods of preventing it remains a pressing need.” (P. J. Meis, Wake Forest U., Winston-Salem, N.C.; pmeis@wfubmc.edu)

An editorialist calls some of these results into question, noting that the rate of preterm delivery among the placebo patients was unusually high and that a small trial of 17P had failed two decades ago (pp. 2453-5). He also questions whether sufficient supplies of 17P are available for preventing preterm labor in large numbers of women and whether “other progestational agents administered by less invasive routes [might] be equally efficacious and more tolerable.” (M. F. Greene)

Treatment of Advanced Hodgkin’s Disease: Increased-dose combination chemotherapy provided better tumor control and improved survival in a study of 1,195 patients with newly diagnosed advanced Hodgkin’s disease (pp. 2386-95). Patients with unfavorable stage IIB or IIIA or stage IIIB or IV conditions were randomly assigned to receive eight cycles of cyclophosphamide, vincristine, procarbazine, and prednisone alternating with doxorubicin, bleomycin, vinblastine, and dacarbazine (COPP-ABVD); bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP); or increased-dose BEACOPP, each followed by local radiotherapy when indicated. Filgrastim was used in patients on increased-dose BEACOPP, with doses beginning on day 8 of each cycle and continuing until leukocyte counts returned to normal. The COPP-ABVD arm was stopped early because of “inferior results,” the study group explains. Freedom from treatment failure at 5 years was significantly improved with increased-dose BEACOPP (87%, compared with 76% for BEACOPP and 69% for COPP-ABVD). Five-year survival rates were 91%, 88%, and 83% for the three respective groups, with increased-dose BEACOPP significantly better than COPP-ABVD and a statistical trend (p = .06) toward superiority of increased-dose BEACOPP over BEACOPP. (V. Diehl, Universität Köln, Cologne, Germany; v.diehl@uni-koeln.de)

Itraconazole & Chronic Granulomatous Disease: In 39 pediatric and adult patients with chronic granulomatous disease, itraconazole 100 or 200 mg/day for 1 year was effective for preventing fungal infections and was well tolerated (pp. 2416-22). Seven patients on placebo had serious fungal infections, compared with one nonadherent patient assigned to itraconazole. Five patients on placebo had superficial fungal infections, versus none on active therapy. Adverse effects were rash in one patient and elevated liver enzymes in another. Rigorous monitoring should be provided for longer-term therapy, the authors recommend. (J. I. Gallin, NIH, Bethesda, Md.)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 13, 2003 Vol. 10, No. 114
Providing news and information about medications and their proper use

>>>Infectious Disease Update
Source:
June 15 issue of Clinical Infectious Diseases (www.journals.uchicago.edu/CID; 2003; 36).

Low-Dose Ritonavir: Because of its pharmacokinetics, ritonavir can be used in low doses to boost the effectiveness of other antiretroviral agents, according to authors of a review article (pp. 1585-92). “The pharmacokinetics of protease inhibitors center around the microsomal enzyme cytochrome P-450 3A4,” the authors write. “As a potent inhibitor of this enzyme, ritonavir can increase the bioavailability and half-life of coadministered protease inhibitors.” Durable virological activity and immune reconstitution are improved when twice-daily, low-dose ritonavir is administered with lopinavir, indinavir, and saquinavir. Adverse effects are tolerable, although “gastrointestinal side effects, hepatotoxicity, and blood lipid abnormalities remain relevant issues,” the group concludes. (C. L. Cooper, Ottawa Hosp., Ottawa, Ontario)

Directly Observed Antiretroviral Therapy in Prisons: Directly observed antiretroviral therapy in 31 HIV-infected prison inmates failed to ensure adherence (pp. 1572-6). Adherence was measured in four different ways: self-report, pill counts, electronic monitoring caps, and, for DOT, medication-administration records. While the subjects reported taking all doses, pill counts showed a 90% adherence rate, while electronic monitoring caps indicated that 86% of doses were taken properly. Measured by electronic monitoring caps, adherence was greater than 90% for only 32% of the subjects. The authors add, “In 91% of cases, adherence, as measured by medication administration records, was greater than that recorded by electronic monitoring caps for the same medications administered by DOT.... Different methods used to measure adherence revealed significantly different levels of adherence.” (D. A. Wohl, U. North Carolina, Chapel Hill)

>>>Pediatrics Highlights
Source:
June issue of Pediatrics (www.pediatrics.org; 2003; 111).

Strangulation with I.V. Tubing: Two cases of nonintentional strangulation of young children by intravenous tubing, one of them fatal, are described (pp. 732–4). An 11-month-old boy with a history of prematurity and mild respiratory distress syndrome became entangled with tubing being used to administer antibiotics in a hospital. When nurses found the child, he was apneic and pulseless. Hemodynamics and cardiac rhythm were restored after 22 minutes, but the child later had seizures and required life support. He died 48 hours later after life support was withdrawn.

The second case was an 8.5-month-old boy hospitalized for streptococcal cellulitis secondary to chickenpox. Multiple problems were identified or developed during the hospital stay, and 1 month later, he was found with tubing to a central catheter wrapped tightly around his neck. He was apneic and pulseless, but resuscitation efforts were successful despite generalized clonic seizures during the effort. He recovered uneventfully. The authors recommend a number of possible strategies for decreasing the chances of children, especially those between 3 months and 3 years of age, becoming entangled in I.V. and other lines used in their care. (D. Garros, U. Alberta, Edmonton)

Methadone & Breastfeeding: Changes made by the American Academy of Pediatrics concerning doses of methadone that are appropriate for breastfeeding mothers have created “exciting possibilities for the most vulnerable of new mothers,” according to authors of a commentary article (pp. 1429-30). Previously, AAP recommended that breastfeeding women take no more than 20 mg/day of methadone, and this essentially eliminated breastfeeding for most women since high-dose therapy is used in the third trimester. The restriction was lifted in 2001, the authors note, allowing “infants [to] benefit from human milk [and their mothers to] be seen as essential to their infant’s care.... The empowerment this brings may help inspire them—and us—to make the most of this sensitive window to start a new life with implications for generations to come.” (B. L. Philipp, Boston U., Boston)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 16, 2003 Vol. 10, No. 115
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
June 14 issue of Lancet (www.thelancet.com; 2003; 361).

Statins in DM: Even in patients with no coronary disease or high serum cholesterol levels, cholesterol-lowering therapy provides benefits in those with diabetes mellitus, according to investigators in the MRC/BHF Heart Protection Study (pp. 2005-16). In the trial, 5,963 adults (aged 40–80 years) with diabetes and 14,573 adults with occlusive arterial disease but not diabetes randomly received either placebo or simvastatin 40 mg once daily. In patients with diabetes, simvastatin reduced the number of first major coronary events (nonfatal myocardial infarction or coronary death), stroke, revascularization by 22% (20.2% of patients on simvastatin versus 25.1% with placebo).

In subgroups of patients with diabetes but no pre-existing coronary disease or hypercholesterolemia, occurrence of the above events was reduced significantly, by 33% and 27%, respectively. The authors conclude, “Allocation to 40 mg simvastatin daily reduced the rate of first major vascular events by about a quarter in a wide range of diabetic patients studied. After making allowance for non-compliance, actual use of this statin regimen would probably reduce these rates by about a third. For example, among the type of diabetic patient studied without occlusive arterial disease, 5 years of treatment would be expected to prevent about 45 people per 1000 from having at least one major vascular event (and, among these 45 people, to prevent about 70 first or subsequent events during this treatment period). Statin therapy should now be considered routinely for all diabetic patients at sufficiently high risk of major vascular events, irrespective of their initial cholesterol concentrations.” (Heart Protection Study, Radcliffe Infirmary, Oxford; hps@ctsu.ox.ac.uk)

Antioxidant Vitamins & CVD: The routine use of vitamin E failed to reduce long-term cardiovascular morbidity and mortality, and use of beta-carotene and vitamin A (its metabolite) should be actively discouraged, conclude investigators who performed a meta-analysis of clinical trials of those antioxidant vitamins (pp. 2017-23). Seven trials of vitamin E used doses ranging from 50 to 800 IU, while eight trials of beta-carotene provided patients doses of 15–50 mg. The trials lasted for 1.4 to 12 years. Compared with control treatments, vitamin E did not affect mortality (11.3% with vitamin E, compared with 11.1% with controls), cardiovascular death (6% in each group), or cerebrovascular accident (3.6% vs. 3.5%, respectively). In patients taking beta-carotene, all-cause mortality was slightly but significantly increased (7.4% vs. 7.0%). (M. S. Penn, Cleveland Clinic Foundation, Cleveland; pennm@ccf.org)

>>>PNN JournalWatch
* Should Drug Companies Be Allowed To Talk Directly To Patients?: Yes or No, in BMJ, 2003; 326: 1302 and 1302–3. Reprints: www.bmj.org; T. Jones; W. Garlick.

* National Trends in the Treatment of Attention Deficit Hyperactivity Disorder, in
American Journal of Psychiatry, 2003; 160: 1071–7. Reprints: www.psychiatry.org; M. Olfson.

* Efficacy of the Branched-Chain Amino Acids in the Treatment of Tardive Dyskinesia in Men, in
American Journal of Psychiatry, 2003; 160: 1117–24. Reprints: www.psychiatry.org; M. A. Richarson.

* Risk Factors for Depression Among Elderly Community Subjects: A Systematic Review and Meta-Analysis, in
American Journal of Psychiatry, 2003; 160: 1147–56. Reprints: www.psychiatry.org; M. G. Cole.

* Topotecan Is an Active Agent in the First-Line Treatment of Metastatic or Recurrent Endometrial Carcinoma: Eastern Cooperative Oncology Group Study E3E93, in
Journal of Clinical Oncology, 2003; 21: 2110–4. Reprints: www.jco.org; S. Wadler.

* Multi-Institutional Randomized Phase II Trial of Gefitinib for Previously Treated Patients with Advanced Non–Small-Cell Lung Cancer, in
Journal of Clinical Oncology, 2003; 21: 2237–46. Reprints: www.jco.org; M. Fukuoka.

* Aromatase Inhibitors in Breast Cancer, in
New England Journal of Medicine, 2003; 348: 2431–42. Reprints: content.nejm.org; I. E. Smith, Royal Marsden Hosp., London, U.K.; ian.smith@rmh.nthames.nhs.uk

* Prolonged Therapeutic Hypothermia After Traumatic Brain Injury in Adults: A Systematic Review, in
JAMA, 2003; 289: 2992–9. Reprints: www.jama.com; L. A. McIntyre, Ottawa Hosp., Ottawa, Ontario, Canada; lmcintyre@ottawahospital.on.ca

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 16, 2003 Vol. 10, No. 115
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
June 14 issue of Lancet (www.thelancet.com; 2003; 361).

Statins in DM: Even in patients with no coronary disease or high serum cholesterol levels, cholesterol-lowering therapy provides benefits in those with diabetes mellitus, according to investigators in the MRC/BHF Heart Protection Study (pp. 2005-16). In the trial, 5,963 adults (aged 40–80 years) with diabetes and 14,573 adults with occlusive arterial disease but not diabetes randomly received either placebo or simvastatin 40 mg once daily. In patients with diabetes, simvastatin reduced the number of first major coronary events (nonfatal myocardial infarction or coronary death), stroke, revascularization by 22% (20.2% of patients on simvastatin versus 25.1% with placebo).

In subgroups of patients with diabetes but no pre-existing coronary disease or hypercholesterolemia, occurrence of the above events was reduced significantly, by 33% and 27%, respectively. The authors conclude, “Allocation to 40 mg simvastatin daily reduced the rate of first major vascular events by about a quarter in a wide range of diabetic patients studied. After making allowance for non-compliance, actual use of this statin regimen would probably reduce these rates by about a third. For example, among the type of diabetic patient studied without occlusive arterial disease, 5 years of treatment would be expected to prevent about 45 people per 1000 from having at least one major vascular event (and, among these 45 people, to prevent about 70 first or subsequent events during this treatment period). Statin therapy should now be considered routinely for all diabetic patients at sufficiently high risk of major vascular events, irrespective of their initial cholesterol concentrations.” (Heart Protection Study, Radcliffe Infirmary, Oxford; hps@ctsu.ox.ac.uk)

Antioxidant Vitamins & CVD: The routine use of vitamin E failed to reduce long-term cardiovascular morbidity and mortality, and use of beta-carotene and vitamin A (its metabolite) should be actively discouraged, conclude investigators who performed a meta-analysis of clinical trials of those antioxidant vitamins (pp. 2017-23). Seven trials of vitamin E used doses ranging from 50 to 800 IU, while eight trials of beta-carotene provided patients doses of 15–50 mg. The trials lasted for 1.4 to 12 years. Compared with control treatments, vitamin E did not affect mortality (11.3% with vitamin E, compared with 11.1% with controls), cardiovascular death (6% in each group), or cerebrovascular accident (3.6% vs. 3.5%, respectively). In patients taking beta-carotene, all-cause mortality was slightly but significantly increased (7.4% vs. 7.0%). (M. S. Penn, Cleveland Clinic Foundation, Cleveland; pennm@ccf.org)

>>>PNN JournalWatch
* Should Drug Companies Be Allowed To Talk Directly To Patients?: Yes or No, in BMJ, 2003; 326: 1302 and 1302–3. Reprints: www.bmj.org; T. Jones; W. Garlick.

* National Trends in the Treatment of Attention Deficit Hyperactivity Disorder, in
American Journal of Psychiatry, 2003; 160: 1071–7. Reprints: www.psychiatry.org; M. Olfson.

* Efficacy of the Branched-Chain Amino Acids in the Treatment of Tardive Dyskinesia in Men, in
American Journal of Psychiatry, 2003; 160: 1117–24. Reprints: www.psychiatry.org; M. A. Richarson.

* Risk Factors for Depression Among Elderly Community Subjects: A Systematic Review and Meta-Analysis, in
American Journal of Psychiatry, 2003; 160: 1147–56. Reprints: www.psychiatry.org; M. G. Cole.

* Topotecan Is an Active Agent in the First-Line Treatment of Metastatic or Recurrent Endometrial Carcinoma: Eastern Cooperative Oncology Group Study E3E93, in
Journal of Clinical Oncology, 2003; 21: 2110–4. Reprints: www.jco.org; S. Wadler.

* Multi-Institutional Randomized Phase II Trial of Gefitinib for Previously Treated Patients with Advanced Non–Small-Cell Lung Cancer, in
Journal of Clinical Oncology, 2003; 21: 2237–46. Reprints: www.jco.org; M. Fukuoka.

* Aromatase Inhibitors in Breast Cancer, in
New England Journal of Medicine, 2003; 348: 2431–42. Reprints: content.nejm.org; I. E. Smith, Royal Marsden Hosp., London, U.K.; ian.smith@rmh.nthames.nhs.uk

* Prolonged Therapeutic Hypothermia After Traumatic Brain Injury in Adults: A Systematic Review, in
JAMA, 2003; 289: 2992–9. Reprints: www.jama.com; L. A. McIntyre, Ottawa Hosp., Ottawa, Ontario, Canada; lmcintyre@ottawahospital.on.ca

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 17, 2003 Vol. 10, No. 116
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
June 17 issue of the Annals of Internal Medicine (www.annals.org; 2003; 138).

Basal Insulin Plus Oral Antidiabetic Agent: Glycemic control was better when oral glimepiride was combined with morning or bedtime insulin glargine, compared with bedtime doses of NPH insulin, according to a study of 695 patients with type 2 diabetes (pp. 952-9). All patients received glimepiride 3 mg plus either morning or bedtime insulin glargine or bedtime NPH insulin. The best glycemic control was exhibited with morning doses of insulin glargine (A1c levels improved by 1.24%, compared with 0.96% with bedtime insulin glargine and 0.84% with bedtime NPH insulin), and the number of nocturnal hypoglycemic episodes was significantly reduced with the insulin glargine regimens (17% and 23% of patients taking morning or evening glargine, respectively, had nocturnal hypoglycemia, compared with 38% of those on bedtime NPH insulin). “A simplified combination regimen with one injection of insulin glargine, one oral agent, and one self-monitored blood glucose measurement per day has been proven to be effective and well tolerated in patients with type 2 diabetes,” the authors conclude. (H-U Häring, Medizinische U., Tübingen, Germany; Hans-Ulrich.Haering@med.uni-tuebingen.de)

Cost-Effectiveness of Pneumococcal Vaccination: Current recommendations for pneumococcal vaccination of high-risk people younger than 65 years is supported by results of a cost-effectiveness analysis conducted from a societal perspective (pp. 960-8). Assuming a hypothetical cohort of patients ages 50–64 years with distributed like the 1995 U.S. population, the investigators found, “Vaccination saved medical costs and improved health among high-risk black people ($27.55 savings per vaccinee) and nonblack people ($5.92 savings per vaccinee), excluding survivors’ future costs. For low-risk black and nonblack people and the overall general population, vaccination cost $2477, $8195, and $3434, respectively, to gain 1 year of healthy life.... These results support the current recommendation to vaccinate high-risk people and provide useful information for considering extending the recommendation to the general population 50 through 64 years of age.” (J. E. Sisk, Mount Sinai Sch. of Med., New York City; jane.sisk@mssm.edu)

An editorialist supports this conclusion (pp. 999-1000): “It appears that at least for the next decade, we will need to use our current, imperfect product in the most judicious way. My vote is to follow the data of Sisk and colleagues and the new information about special risks related to ethnicity and cigarette smoking, to establish age 50 years as the time to initiate universal immunization with pneumococcal vaccine, and thereby to reunite the pneumococcal and influenza vaccine programs. In addition, recognizing that the risks for invasive pneumococcal disease continue to increase with age and that the vaccine has an excellent safety profile, I would support those who favor reimmunizing individuals every 5 to 10 years while waiting for better data or better vaccines.” (P. Gardner, NIH, Bethesda, Md.)

Inhaled Steroids for COPD: Inhaled corticosteroids failed to affect long-term decline in pulmonary function in patients with chronic obstructive pulmonary disease, authors conclude after analyzing results of six randomized controlled trials (pp. 969-73). Among 3,571 patients followed for 24–54 months, the rate of decline in forced expiratory volume was not significantly different between COPD patients on placebo versus corticosteroids. (K. B. Highland, Med. U. S. C., Charleston; highlakb@musc.edu)

Questioning whether “we [are] barking up the wrong tracheobronchial tree,” an editorialist writes (pp. 1001-2): “The answer is probably yes and no. Yes, because many of the inflammatory changes in COPD are unresponsive to corticosteroid therapy and because corticosteroids may actually encourage the persistence of inflammation through their antiapoptotic effect on neutrophils.... No, because many patients with COPD have at least an element of steroid-responsive eosinophilic inflammation that causes reversible bronchospasm.” (P. E. Epstein)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 18, 2003 Vol. 10, No. 117
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
June 18 issue of JAMA (www.jama.com; 2003; 289).

Epidemiology of Depression: Major depressive disorder is much more common among Americans than was previously understood, according to data from a nationally representative household survey (pp. 3095-105). In the 48 contiguous states, 9,090 household residents were administered the National Comorbidity Survey Replication in face-to-face interviews conducted between Feb. 2001 and Dec. 2002. The lifetime prevalence of major depressive disorder was 16.2%, indicating that 32.6–35.1 million adults in the U.S. have the condition at some point in their lives. Severity was estimated as mild in 10.4% of respondents, moderate in 38.6%, severe in 38.0%, and very severe in 12.9%. About three fourths of patients with depression had other comorbid mental conditions, including 59.2% with anxiety disorder, 24.0% with substance use disorder, and 30.0% with impulse control disorder. (R. C. Kessler, Harvard Med. Sch., Boston; NCS@hcp.med.harvard.edu)

Commenting on this study, an editorialist writes (pp. 3169-70): “The challenge for all physicians regarding depression is to learn to recognize it, in themselves as well as in their patients, and to surmount the obstacles against effective treatment. These obstacles include the feelings of hopelessness and worthlessness that are characteristic symptoms of depression, stigma about mental disorders and their treatment, and the institutionalized stigma that limits access to effective treatment for depression and other mental disorders.... Full remission should be the goal of treatment, a goal that assumes particular importance in the face of evidence that depression is usually a recurrent or chronic disease. Increasing the ability of physicians to attain that goal for more people who suffer from the multiple impacts of the illness of depression is surely a worthy endeavor for research, clinical practice, and social policy.” (R. M. Glass, richard_glass@ama-assn.org)

Cognitive–Behavioral Therapy for Post-MI Depression: In 2,481 depressed post-myocardial infarction patients, provision of cognitive–behavioral therapy with social support failed to significantly improve event-free survival, compared with usual care (pp. 3106-16). In the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) trial, SSRIs were prescribed for patients in the intervention group when scores on the Hamilton Rating Scale for Depression were greater than 24. Antidepressants could also be prescribed in the usual care group. The use of antidepressants ended up complicating the study, as a post-hoc analysis indicated significantly lower death or nonfatal MI among those on the medications. Since these patients were mixed into both the treatment and control groups, the beneficial effects of pharmacotherapy could have masked the benefits of group therapy and other nondrug interventions aimed at decreasing depressive symptoms. (S. M. Czajkowski, czajkows@nhlbi.nih.gov)

An editorialist observes: “The ENRICHD investigators have demonstrated that depressed [coronary artery disease] patients can be identified, randomized, properly treated with complex interventions, and followed up for long periods. This is a major accomplishment. However, depression remains a CAD risk factor in search of a successful intervention. Future trials should evaluate treatments with probable impacts on multiple cardiovascular and behavioral mechanisms. If reasonable sample sizes are to be envisaged, trials should also combine flexible interventions that respect patients’ individual treatment preferences with aggressive stepwise protocols. Although such multifaceted protocols will not permit the identification of active components, single-treatment studies with the goal of achieving realistic effect sizes on cardiac prognosis would need to be much larger.

“Regardless of whether rigorous studies will convincingly show that treating depression can influence cardiac prognosis, more trials are needed to find the best ways to improve care for patients with depression and CAD.” (N. Frasure-Smith, frsm@icm.umontreal.ca)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 19, 2003 Vol. 10, No. 118
Providing news and information about medications and their proper use

>>>Nasal Flu Vaccine Approved
FluMist (Influenza Virus Vaccine Live, Intranasal; MedImmune Vaccines, Wyeth) has been approved by FDA for use in healthy children older than 5 years, adolescents, and adults younger than 50 years, but, as expected, the product did not receive approval for the primary flu-vaccine target group of adults over age 50. Children 5–8 years old need two doses at least 6 weeks apart in their first year of influenza vaccination with FluMist, while individuals 9–49 years old need one dose.

The vaccine, the first nasally administered vaccine to reach the U.S. market and the first flu vaccine to contain live virus, was evaluated in 20,228 individuals, including more than 10,000 healthy children 5–17 years old. The efficacy of the vaccine in preventing influenza was approximately 87% among children included in the trial. In healthy adults ages 18–49 years, FluMist was effective in reducing severe illnesses with fever and upper respiratory problems possibly caused by influenza.

Like other live-virus vaccines, FluMist is contraindicated in immunosuppressed patients, including those with AIDS or cancer and people taking immunosuppressive medications. Rather than the nasal vaccine, the injectable product should be used in patients with chronic underlying medical conditions that predispose them to severe flu infections. Efficacy and safety of the vaccine in adults 50 or older have not been established.

The vaccine should not be used in patients with histories of asthma or other reactive airway diseases. In safety trials, children younger than 5 years old had an increased risk of asthma within 42 days of vaccination, compared with placebo recipients, and this finding led FDA to not approve the product in this age group.

Other contraindications for the vaccine include people with egg allergies and those who have had allergic reactions to this product previously. Common adverse reactions include nasal congestion, runny nose, sore throat, and cough.

>>>NEJM Highlights
Source:
June 19 issue of the New England Journal of Medicine (content.nejm.org; 2003; 348).

Safety & IT: Information technology must be incorporated into daily medical practice so that communications are improved, knowledge and key information made more accessible, and calculations and clinical decision making supported, according to authors who review IT’s progress and possibilities (pp. 2526-34). Pointing to successful models such as the Department of Veterans Affairs and Kaiser, the authors write, “The fundamental difficulty in modern medical care is execution. Providing reliable, efficient, individualized care requires a degree of mastery of data and coordination that will be achievable only with the increased use of information technology. Information technology can substantially improve the safety of medical care by structuring actions, catching errors, and bringing evidence-based, patient-centered decision support to the point of care to allow necessary customization. New approaches that improve customization and gather and sift through reams of data to identify key changes in status and then notify key persons should prove to be especially important.” (D. W. Bates, dbates@partners.org)

An editorialist calls for demonstration projects that “prove to ourselves that bold improvement is in fact possible” (pp. 2570-2). Noting three essential preconditions for quality improvement, the writer says that the
will to change and ideas for improvement are readily available, but the execution step is missing. “Improvement requires that changes be executed—put into practice, tried out in the real world, adjusted, and if they work, stabilized. Until real care actually changes for real patients in real beds, injury rates will stay the same,” the author writes. Roadblocks between will/ideas and execution include the low rate of observable injury at the local level, Neanderthal views of the cause of errors, the high cost of improvements in safety, and the difficulty of changing “dozens of habitual systems” that affect all members of the health care team. (D. M. Berwick, Inst. for Healthcare Improvement, Boston)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 20, 2003 Vol. 10, No. 119
Providing news and information about medications and their proper use

>>>FDA Studying Pediatric Paroxetine Suicide Risk
In a talk paper posted to its Web site, FDA confirmed yesterday that it is assessing reports of suicidal thinking and suicide attempts in children and adolescents under the age of 18 years while taking paroxetine for major depressive disorder. The action follows a recent call in the U.K. for an end to pediatric use of paroxetine for MDD. However, as patients hear this news through the lay media, they must be cautioned against abruptly stopping paroxetine because of the danger of withdrawal reactions.

Although FDA has not completed its evaluation of new safety data, it is also recommending that paroxetine not be used in children and adolescents for treatment of MDD. There is currently no evidence that paroxetine is effective in children or adolescents with MDD, and paroxetine is not currently approved for use in children and adolescents, the agency explained. Other approved treatment options are available for depression in children, and FDA noted that paroxetine was not any more effective than placebo in three well-controlled trials of pediatric patients with MDD.

The safety data cited by U.K. authorities in their action indicated a 1.5–3.2 times greater risk of harmful outcomes (e.g., episodes of self-harm, potentially suicidal behavior) in pediatric and adolescent patients taking paroxetine. None of the patients actually attempted or completed suicide. The chairman of the Committee on Safety of Medicines, Gordon Duff, added this comment about the drug’s use in adults, “Paroxetine has been demonstrated to be effective in adults with depressive illness and the CSM advises that the balance of risks and benefits of paroxetine remains positive. However, the implications of the new paediatric data on the safety of paroxetine in the adult population remains under close review by the CSM and its Expert Working Group.”

Paroxetine should be tapered when therapy is being stopped. The dose should be reduced very gradually, first using half tablets and then every-other-day dosing, to avoid withdrawal symptoms. Most adverse effects that occur during tapering will subside over a 2-week period, but if the patient finds them intolerable, the dose should be increased and then tapered more gradually.

>>>Diabetes Meeting Report
The 63rd Annual Scientific Sessions of the American Diabetic Association convened last weekend in New Orleans (www.diabetes.org/am03). Among the meeting highlights were these:

* Topiramate therapy improved four markers of neuropathy in an 8-week trial of 11 patients with type 2 diabetes, according to Vinik et al. of the Eastern Va. Med. Sch. in Norfolk. Doses of the anticonvulsant were titrated from very low doses (12.5 mg/day) to a maximum of 100 mg/day. By the end of the study, intraepidermal nerve fiber density, dendrite length, peroneal nerve amplitude, and total neuropathy scores had improved, as had total cholesterol, diastolic blood pressure, and A1c levels.

* Rosiglitazone appears to be useful for preventing restenosis in patients who have had stents placed after angioplasty, according to Choi et al., of the Yonsei U. Coll. of Med. in Seoul, Korea. The anti-inflammatory actions of rosiglitazone were tested in 101 patients with diabetes who underwent angioplasty for coronary artery blockages. After 6 months of rosiglitazone 4 mg daily, in-stent restenosis occurred in 12% of patients, compared with 47% of control patients. Highly sensitive C-reactive protein levels were significantly lower among patients in the rosiglitazone group, indicating that the drug might affect this marker of inflammation.

* Pioglitazone suppresses the amount of glucose produced by the liver, explained DeFronzo et al. of the U. Tex. Health Sci. Ctr. in San Antonio. In addition to declines in fasting plasma insulin concentrations, fasting plasma glucose, and A1c concentrations, basal hepatic glucose production declined significantly in 12 patients with type 2 diabetes who took pioglitazone 45 mg/day for 12 weeks. The results demonstrate an additional mechanism by which thiazolidinediones improve diabetes care.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 23, 2003 Vol. 10, No. 120
Providing news and information about medications and their proper use

>>>IgE Blocker Approved for Treatment of Asthma
Omalizumab (Xolair; Genentech, Novartis, Tanox) has been approved by FDA for subcutaneous treatment of moderate or severe persistent asthma in adults and adolescents (12 years of age and above) who have a positive skin test or in vitro reactivity to a perennial aeroallergen and whose symptoms are inadequately controlled with inhaled corticosteroids. The first humanized therapeutic antibody for treatment of asthma and the first approved therapy designed to target immunoglobulin E, omalizumab will be available next month.

Two 52-week Phase 3 trials provided the basis for FDA approval. Nearly 3,000 patients were randomized to receive subcutaneous weight-adjusted doses of omalizumab or placebo every 2 or 4 weeks. Doses were determined based on patients’ body weight and IgE level. Inhaled corticosteroid doses were kept stable over the initial 16 weeks of treatment (stable-steroid phase) and tapered during a further 12-week treatment period (steroid-reduction phase).

When used as an add-on therapy to inhaled corticosteroids, in both pivotal clinical trials, omalizumab reduced mean asthma exacerbations per patient by 33–75% during the stable-steroid phase and 33–50% during the steroid-reduction phase. Reduction in asthma exacerbations was confirmed by improvements in other measures of asthma control including symptom scores such as nocturnal awakenings and daytime asthma symptoms.

The most serious adverse reactions occurring in clinical studies with omalizumab were malignancies (0.5%, compared with 0.2% in placebo patients, not a significant difference) and anaphylaxis (less than 0.1% with omalizumab). Long-term studies will assess the relationship between omalizumab treatment and cancer. The most frequent adverse events included injection site reactions (45%), viral infections (23%), upper respiratory tract infections (20%), sinusitis (16%), headache (15%), and pharyngitis (11%). These events were observed at similar rates in omalizumab-treated patients and control patients.

>>>Atazanavir Approved
A seventh protease inhibitor has been approved for marketing by FDA. Atazanavir (Reyataz, Bristol-Myers Squibb), dosed once daily with food, will be used in combination with other antiretroviral agents for treatment of patients with HIV infection.

FDA based its approval of atazanavir on data from two Phase 2 48-week trials and from 24–48 week data from Phase 3 studies. Results from these trials showed a decrease in viral load and an increase in CD4 cell counts in patients taking atazanavir in combination with other antiretroviral agents. These treatment benefits were observed both in patients who had not been previously treated and in patients who had previously received other antiretroviral therapy.

The most common laboratory abnormality observed with the use of atazanavir is hyperbilirubinemia. This laboratory abnormality resulted in jaundice or scleral icterus in 15–24% of subjects taking atazanavir. This abnormality was reversible upon discontinuation of the drug. Hyperbilirubinemia did not appear to be associated with an increased risk of liver injury.

The most frequently reported adverse events among patients in the clinical trials were nausea, infection, headache, vomiting, diarrhea, abdominal pain, somnolence, insomnia, and fever.

>>>PNN JournalWatch
* Paclitaxel Plus Platinum-Based Chemotherapy Versus Conventional Platinum-Based Chemotherapy in Women with Relapsed Ovarian Cancer: The ICON4/AGO-OVAR-2.2 Trial, in Lancet, 2003; 361: 2099–106. Reprints: www.thelancet.com.

* Twice Weekly Fluticasone Propionate Added to Emollient Maintenance Treatment to Reduce Risk of Relapse in Atopic Dermatitis: Randomised, Double Blind, Parallel Group Study, in
BMJ, 2003; 326: 1367 ff. Reprints: www.bmj.org; J. Berth-Jones. U. Hosp., Coventry, U.K.; johnberthjones@aol.com

* Venous Thromboembolic Disease, supplement to
Circulation, 2003; 107 (suppl 1). Reprints: www.circ.ahajournals.org/content/vol107/23_suppl_1/

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 24, 2003 Vol. 10, No. 121
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
June 23 issue of Archives of Internal Medicine (www.archinternmed.com; 2003; 163).

Pharmacist’s Education of Patients, Interns: On cardiology wards of Duke University Hospital, identification and correction of medication errors had positive effects in two areas: improvement of patients’ knowledge of their outpatient medication regimens and education and support of new interns during initial months of training (pp. 1461-6). Between September 1, 1995, and February 18, 2000, a pharmacist made 14,983 interventions, with 4,768 of them related to medication errors (24 medication errors per 100 admissions). “The most common errors involved the wrong drug (36.0%) or wrong dose (35.3%), and cardiovascular medications were involved in 41.2% of the errors,” wrote the authors. “Prescribers were associated with most of the errors, and the transition from outpatient to inpatient was the most common point in the system for the occurrence of these medication errors. Higher numbers of errors were also identified during the transition period of house staff, and the total number of errors increased during the study period.” The avoided cost of adverse drug events was estimated at $5–11 million.

The investigators conclude, “These findings confirm the potential for pharmacist participation in physician rounds to identify and markedly decrease medication errors. These results are directly applicable to the approximately 400 teaching hospitals in the United States and are also likely to be pertinent to the remaining hospitals to the extent that medication errors occur outside of medical training settings.” (N. M. Allen LaPointe, Duke Clin. Res. Inst., Durham, N.C.)

Med Errors & CPOE/CDSS: Research is needed to evaluate commercially available computerized physician order entry and clinical decision support systems, conclude authors of a review article (pp. 1409-16). “Of [5] CPOE studies, 2 demonstrated a marked decrease in the serious medication error rate, 1 an improvement in corollary orders, 1 an improvement in 5 prescribing behaviors, and 1 an improvement in nephrotoxic drug dose and frequency,” the authors report. “Of the 7 studies evaluating isolated CDSSs, 3 demonstrated statistically significant improvements in antibiotic-associated medication errors or adverse drug events and 1 an improvement in theophylline-associated medication errors. The remaining 3 studies had nonsignificant results.” (R. Kaushal, rkaushal@partners.org)

Warfarin Adherence & Mortality: Full adherence to warfarin regimens can decrease patients’ risk of fatal coronary heart disease by 50%, according to a study of 5,499 men in the low-intensity Thrombosis Prevention Trial (target international normalized ratio was 1.5; pp. 1454-60). When patients were adhering to warfarin treatment, hazard ratios were 0.75 for all CHD and 0.49 for fatal cases of CHD. A retained benefit of warfarin was evident among former users, as the risk was reduced by 23% among these patients (HR, 0.77). “Expected survival time to a CHD event if patients randomized to warfarin had fully complied with treatment was 1.39 times greater (95% CI, 1.12–1.69) than if patients randomized to placebo had fully complied with placebo, whereas for fatal CHD the relative increase in survival time was 2.04 times greater for the former (95% CI, 1.43–2.86),” add the authors. (A. R. Rudnicka, Wolfson Inst. of Preventive Med., London; a.r.rudnicka@qmul.ac.uk)

Cholesterol Lowering by Green Tea Extract: Total cholesterol and LDL-cholesterol levels were significantly lowered by theaflavin-enriched green tea extract when used in conjunction with low-saturated-fat diet in 240 hypercholesterolemic adults (pp. 1448-53). Over 12 weeks, TC dropped by a mean of 11.3%, and LDL-cholesterol fell by 16.4% among green tea extract (375 mg) users, compared with patients taking placebo. HDL-cholesterol and triglyceride levels also improved, but not significantly so, and no adverse effects were associated with use of the extract. Extracts without theaflavins, derivatives of black tea, lack effect on cholesterol. (D. J. Maron, david.maron@vanderbilt.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 25, 2003 Vol. 10, No. 122
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
June 25 issue of JAMA (www.jama.com; 2003; 289).

Smallpox Vaccination: Mass smallpox vaccinations can be implemented safely and with fewer serious adverse events than previously believed, according to an analysis of 450,293 inoculations administered in 5.5 months under the Department of Defense’s military vaccination program (pp. 3278-82). Researchers looked at the number of vaccinations, rates of vaccination exemptions, symptoms, and adverse events. Data were collected via reports to DoD headquarters from fixed and field medical treatment facilities on multiple continents and ships at sea. Among the 70.5% of personnel who were primary vaccinees, 0.5% required short-term sick leave. In the 29.5% of people who were revaccinees, this leave was needed by 3.0% of patients. “Most adverse events occurred at rates below historical rates,” the authors write. “One case of encephalitis and 37 cases of acute myopericarditis developed after vaccination; all cases recovered.” The authors conclude, “Program implementation emphasized human factors: careful staff training, contraindication screening, recipient education, and attention to bandaging. Our experience suggests that broad smallpox vaccination programs may be implemented with fewer serious adverse events than previously believed.” (J. D. Grabenstein, john.grabenstein@us.army.mil)

Commenting on this and other related articles in this issue, editorialists write (pp. 3306-8): “Before 2002, virtually all that was known about the efficacy and safety of smallpox vaccination had been documented in studies conducted a minimum of 30 years earlier. This was an era prior to the availability of technological advances, such as flow cytometry, polymerase chain reaction, and magnetic resonance imaging and before modern-day computer systems made it possible to perform diagnostic surveillance and statistical analyses in close to real time. The continued application of these and other new technologies to this historic public health issue should be of great value in furthering the understanding of the nature of smallpox protection induced by vaccination.... By rapidly sharing the data from their smallpox vaccination experience with the general medical community, the Department of Defense has provided the civilian population with critical information pertaining to an important general public health issue and should be commended for this effort.” (A. S. Fauci, afauci@niaid.nih.gov)

HRT & Breast Cancer, Take 2: Continuing the string of negative reports over the past year about use of hormone-replacement therapy, Women’s Health Initiative data indicate that even short-term use of HRT can stimulate breast cancer and confound diagnosis by causing abnormal mammograms (pp. 3242-53). Among the 16,608 postmenopausal women in the WHI, the investigators found that, compared with placebo, combined estrogen plus progestin hormone therapy increased total breast cancers (245 cases vs. 185 cases) and invasive breast cancer (199 cases vs. 150 cases). Invasive breast cancers among women in the HRT group were larger and were diagnosed at a more advanced stage compared with those diagnosed in the placebo group. The researchers also found that after 1 year, the percentage of women with abnormal mammograms was substantially greater in the HRT group (716 [9.4%] of 7,656) compared with the placebo group (398 [5.4%] of 7,310), a pattern that continued throughout the study. (R. T. Chlebowski, UCLA Res. and Ed. Inst., rchlebowski@rei.edu)

A second study, from three counties in Washington State, shows that HRT increases the risk of breast cancer regardless of whether the progestin component is taken continuously or sequentially (pp. 3254-63). In the case–control analysis, women using unopposed estrogen had no increased risk of breast cancer, even during long-term use. But combined HRT produced increased risks of estrogen and progestin receptor–positive cases, with longer durations of therapy having higher rates of diagnosis. (C. I. Li, Fred Hutchinson Cancer Res. Ctr., Seattle; cili@fhcrc.org)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 26, 2003 Vol. 10, No. 123
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Web site and June 26 issue of the New England Journal of Medicine (content.nejm.org; 2003; 348).

Finasteride & Prostate Cancer: The 5-alpha reductase inhibitors may be useful for prevention of prostate cancer, but data from a just-released study indicate that when tumors do develop in men taking finasteride, they are more likely to be advanced (article released early on Web site). In the Prostate Cancer Prevention Trial, 18,882 men aged 55 years or older with a normal digital rectal examination and a prostate-specific antigen(PSA) level of 3.0 ng/mL or lower randomly received finasteride 5 mg/day or placebo for 7 years. Because PSA levels are affected by finasteride and this could interfere with detection of prostate cancer, all men not diagnosed with the disease by the end of the study were offered a prostate biopsy, regardless of their symptoms. Prostate cancer developed in 18.4% of men taking finasteride, compared with 24.8% of those on placebo, a significantly reduced risk. However, tumors of Gleason grade 7–10 were found in 37.0% of tumors in men on active therapy, compared with 22.2% of tumors in men in the placebo group. Sexual side effects were more common with finasteride, with about two-thirds of men reporting reduced ejaculate volume, erectile dysfunction, and loss of libido, compared with about one half of those on placebo. Urinary symptoms occurred more often in those taking placebo, but the differences between the groups were not large. (Southwest Oncology Group, San Antonio)

An editorialist argues that finasteride should not be recommended to men for lowering the risk of prostate cancer: “Although [finasteride] reduced the cumulative incidence of cancer in the PCPT trial, the reduction was relative to the incidence in a control group in which biopsy was recommended for all men, regardless of risk factors—an approach that is destined to lead to the overdetection of histologically identified cancers of little clinical significance. We do not know the malignant potential of such cancers and have no evidence that any benefit would be worth the risk associated with treatment. Furthermore, the study results suggest that finasteride may accelerate the growth of high-grade cancers, which may pose a threat to life and health if they are not treated successfully. Finally, the effects of finasteride on sexual function lessen the attractiveness of the drug as a preventive agent.” (P. T. Scardino, Memorial Sloan-Kettering Cancer Center, New York)

Bortezomib & Melanoma: In patients with relapsed, refractory myeloma [Editor’s note: corrected from melanoma in original edition], the recently approved agent bortezomib (see PNN, May 15) is active and relatively safe (pp. 2609-17). Of 193 evaluable patients in the Phase 2 study, 92% had been previously treated with three or more of the major classes of agents for myeloma, and 91% had disease refractory to the most recent therapy. Myeloma responded to bortezomib in 35% of these patients, and myeloma protein became undetectable in 7 individuals. Median overall survival was 16 months, and median duration of response was 12 months. Grade 3 adverse events were common, with thrombocytopenia occurring in 28% of patients, fatigue in 12%, and neutropenia in 11%. Grade 4 events included thrombocytopenia in 3% of patients, neutropenia in 3%, and febrile neutropenia in 1 person. (P. G. Richardson, paul_richardson@dfci.harvard.edu)

Oral Steroids & COPD: For treating patients discharged from the emergency department with an exacerbation of chronic obstructive pulmonary disorder, outpatient treatment with oral prednisone offers a small advantage over placebo, according to a 147-patient study (pp. 2618-25). The overall 30-day relapse rate was 27% with oral prednisone 40 mg/day for 10 days, compared with 43% with placebo. Active treatment improved pulmonary function at 10 days and clinical measures, but health-related quality of life did not improve significantly on the Chronic Respiratory Disease Index Questionnaire. (S. D. Aaron, saaron@ottawahospital.on.ca)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 27, 2003 Vol. 10, No. 124
Providing news and information about medications and their proper use

>>>Prescription Drug Bills Pass House, Senate
By a one-vote margin in the House of Representatives and a comfortable margin in the Senate, Congress early this morning passed bills that would create a federal prescription drug benefit for Medicare beneficiaries. While differences between the two houses’ versions must be worked out in conference, elderly Americans appear likely to have drug coverage beginning in 2006.

In the interim, Congressional Republicans are calling for a resurrection of drug-discount cards for Medicare patients, a plan opposed by organized pharmacy and, based on prior court rulings, one that would require Congress to pass enabling legislation.

The complexity of the proposed prescription drug benefit is just beginning to sink in among AARP members and other lobbying groups for the elderly. In particular, a “doughnut hole” in both bills’ coverage is unusual and sure to generate angst.

The House bill’s gap in coverage is between $2,000 and $4,900, while the Senate version leaves patients on their own between $4,500 and $5,800. The two bills have these provisions:

* Monthly premiums: House: $35; Senate: variable but beginning at $35
* Annual deductible: $250 (House), $275 (Senate)
* Coverage: 80% of costs between $250 and $2,000, then 0% between $2,000 and $4,900, then 100% (House); 50% of costs between $275 and $4,500, then 0% between $4,500 and $5,800, then 90%.

Thus, for a hypothetical drug bill of $500 per month ($6,000 per year) and assuming a monthly premium of $35, a patient’s out-of-pocket costs would be $3,920 under the House version and $4,127.50 under the Senate version. These amounts compare unfavorably with the relatively straightforward and lower copayments patients know from employer-sponsored plans.

For pharmacy, the devil of this plan will be in details that may not be clear until CMS issues regulations implementing it. Clearly, the last major group of cash-paying patients will be eliminated for community pharmacy, but unclear is exactly how much a law might restrict consumers’ choice of pharmacies, force use of mail-service pharmacies, and rely on pharmacy benefits managers to implement the plan. The bills contain elements favoring some privatization of Medicare and eliminating loopholes in the 1984 Hatch–Waxman Act under which Big Pharma companies have been able to delay entry of generic medicines onto the market. The Senate also passed a provision allowing pharmacists and wholesalers to import FDA-approved drugs from Canada, but its provisions are similar to those that have been deemed unsuitable by both the Clinton and Bush Administrations.

>>>PNN NewsWatch
* Health care spending per privately insured American jumped 9.6% in 2002, growing nearly four times faster than the overall U.S. economy, according to a study by the Center for Studying Health System Change published on the Web site of Health Affairs (www.healthaffairs.org). Outpatient spending grew at the fastest annual rate of the four major components of overall health spending, surpassing the annual growth rate of prescription drugs for the second year in a row. Spending on outpatient hospital care—which includes services provided by both hospital-based and freestanding outpatient facilities—grew 14.6% in 2002, accounting for 37% of the overall health care spending increase. Spending on prescription drugs rose 13.2%, slowing for the third year in a row and contributing 22% to the overall spending increase. Several factors help explain the slowdown, including increased use of three-tier copayment structures, a reduction in new drug introductions and greater availability of generic drugs. Spending for physician services increased 6.5%, accounting for 27% of the overall spending increase. Spending on inpatient hospital care increased 6.8% in 2002, accounting for 14% of the overall spending increase.

*
Correction: In yesterday’s PNN, the first sentence of the article on bortezomib should have stated myeloma, not melanoma.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 30, 2003 Vol. 10, No. 125
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
June 28 issue of BMJ (www.bmj.org; 2003; 326).

‘Polypill’ Cures Cardiovascular Ills: A tablet containing six medications could add an average of 11 years of life free of myocardial infarction or stroke if taken by all patients aged 55 years and older who have cardiovascular disease (pp. 1419 ff). Authors, using data from several meta-analyses they conducted (see next two summaries) and other sources, propose that simultaneous modification of LDL cholesterol, blood pressure, serum homocysteine, and platelet function could reduce ischemic heart disease events by 88% and stroke by 80%. The tablet, which the writers call the “Polypill,” would contain a statin (e.g., atorvastatin 10 mg or simvastatin 40 mg), three antihypertensive drugs at half standard doses (e.g., a thiazide, a beta blocker, and an ACE inhibitor), folic acid 0.8 mg, and aspirin 75 mg. Adverse effects could be expected in 8–15% of patients taking the tablet, the authors calculate, mostly aspirin-induced problems.

The authors conclude, “It is time to discard the view that risk factors need to be measured and treated individually if found to be ‘abnormal.’ Instead it should be recognised that in Western society the risk factors are high in us all, so everyone is at risk; that the diseases they cause are common and often fatal; and that there is much to gain and little to lose by the widespread use of these drugs. No other preventive method would have so great an impact on public health in the Western world.” (N. J. Wald, U. London, London; n.j.wald@qmul.ac.uk)

Statins & CVD Events: Use of statins can lower LDL cholesterol by an average of 1.8 mmol/L and thereby reduce the risk of cardiovascular disease events by some 60% and stroke by 17%, according to authors who conducted three meta-analyses of statin trials (pp. 1423 ff). In 58 trials, LDL cholesterol reductions of 1.0 mmol/L lowered the risk of ischemic heart disease events by 11% in the first year of treatment, 24% in the second year, 33% in years 3 to 5, and by 36% after that. (M. R. Law, U. London, London; m.r.law@qmul.ac.uk)

Low-Dose Antihypertensive Therapy: Cutting the doses of antihypertensive agents by 50% results in blood pressure reductions nearly as great as those achieved with full doses, conclude authors who conducted a meta-analysis of 354 studies of thiazides, beta blockers, ACE inhibitors, angiotensin II receptor antagonists, and calcium channel blockers (pp. 1427 ff). With standard and half doses, respectively, average reductions in blood pressure were 9.1 and 7.1 mm Hg for systolic readings and 5.5 and 4.4 mm Hg for diastolic values. Adverse effects were dose-related for thiazides, beta blockers, and CCBs, while side effects of ACE inhibitors (usually cough) were not related to dose. (M. R. Law, U. London, London; m.r.law@qmul.ac.uk)

>>>PNN JournalWatch
* Effect of Conjugate Pneumococcal Vaccine Followed by Polysaccharide Pneumococcal Vaccine on Recurrent Acute Otitis Media, in Lancet, 2003; 361: 2189–95. Reprints: www.thelancet.com; E. A. M. Sanders, U. Med. Ctr., Utrecht, the Netherlands; eam.sanders@planet.nl

* Burdens and Benefits of Placebos in Antidepressant Clinical Trials: A Decision and Cost-Effectiveness Analysis, in
American Journal of Psychiatry, 2003; 160: 1272–6. Reprints: ajp.psychiatryonline.org; S. Y. H. Kim.

* Cytochrome P450 CYP3A4/5 Expression as a Biomarker of Outcome in Osteosarcoma, in
Journal of Clinical Oncology, 2003; 21: 2481–5. Reprints: www.jco.org; L. H. Baker, bakerl@umich.edu

* The Platelet in Diabetes: Focus on Prevention of Ischemic Events, in
Diabetes Care, 2003; 26: 2181–8. Reprints: www.diabetes.org; R. W. Nesto, Lahey Clinic Med. Ctr., Burlington, Mass.; richard.w.nesto@lahey.org

* Do Antimicrobial-Impregnated Central Venous Catheters Prevent Catheter-Related Bloodstream Infection?, in
Clinical Infectious Diseases, 2003; 37: 65–72. Reprints: www.journals.uchicago.edu/CID/home.html; S. A. McConnell, U. Arkansas, Little Rock.

* Effects of Human Immunodeficiency Virus Infection on Recurrence of Tuberculosis After Rifampin-Based Treatment: An Analytical Review, in
Clinical Infectious Diseases, 2003; 37: 101–12. Reprints: www.journals.uchicago.edu/CID/home.html; E. L. Korenromp, WHO, Geneva, Switzerland.

* Antiretroviral Drug Resistance Testing in Adults Infected with Human Immunodeficiency Virus Type 1: 2003 Recommendations of an International AIDS Society USA Panel, in
Clinical Infectious Diseases, 2003; 37: 101–12. Reprints: www.journals.uchicago.edu/CID/home.html; M. S. Hirsch, Harvard Med. Sch., Boston.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 1, 2003 Vol. 10, No. 126
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
July 1 issue of the Annals of Internal Medicine (www.annals.org; 2003; 139).

Eczema & Smallpox Vaccination: Poor reporting of atopic dermatitis or eczema by patients and close contacts could cause problems during a mass preexposure smallpox vaccination campaign, according to a telephone survey from Wisconsin (pp. 1-7). Current recommendations call for exclusion of such patients and their close contacts because of the possibility of the patients developing eczema vaccinatum. The investigators sought to determine the prevalence of diagnosed atopic dermatitis or eczema and to test the sensitivity of questions that could be used to screen patient during a smallpox vaccination campaign. They found, “Among 94 adult respondents with atopic dermatitis, 55 (59%) correctly self-reported skin disease. Seventy-nine (60%) of 133 household contacts of adults with atopic dermatitis correctly reported the presence of skin disease in a household member. Parental recall of skin disease in children with atopic dermatitis was 70% (123 of 177).”

Because of this incomplete recall, the authors conclude, “Identifying dermatologic contraindications to smallpox vaccination by relying only on a self-reported history of rash illnesses is likely to miss a substantial proportion of individuals who should not receive smallpox vaccine in a preexposure vaccination campaign.” (E. A. Belongia, Marshfield Clinic Res. Found., Marshfield, Wisc.; belongia.edward@mcrf.mfldclin.edu)

Ig & Stem-Cell Transplantation: Prophylactic use of immunoglobulin is not recommended for allogeneic recipients of stem-cell transplant from HLA-identical sibling donors, based on the findings of a 200-patient study from 19 French centers (pp. 8-18). Compared with placebo, immunoglobulin 50, 250, or 500 mg/kg weekly from day 7 to day 100 after transplant provided no benefit, based on cumulative incidence of infection, graft-versus-host disease, veno-occlusive disease, interstitial pneumonia, transplantation-related mortality at 6 months, and overall survival at 2 years. In fact, grade 3 (severe) veno-occlusive disease occurred significantly more frequently among patients who received immunoglobulin. (C. Cordonnier, Hôpital Henri Mondor, Créteil, France; carlcord@club-internet.fr)

Extended Anticoagulation After PE: In 326 patients with a first episode of pulmonary embolism, recurrence occurred in only one patient while oral anticoagulation was being administered, compared with 32 patients in whom the medications had been stopped (pp. 19-25). All patients received 3 months of oral anticoagulation (target INR of 2.0 to 3.0) without recurrence or bleeding; those with transient risk factors for PE were randomly assigned to placebo or drug for 3 additional months, while patients with idiopathic PE were randomly assigned to placebo or drug for 9 additional months. Overall, 3.1% per patient-year of those on treatment had recurrent venous thromboembolism, compared with 4.1% per patient-year of those on placebo (not a significant difference). However, all but one of the recurrences occurred post-therapy, while only three major bleeding episodes were noted. Of 19 PE recurrences, two cases were fatal. The authors conclude, “Patients with [PE] have a substantial risk for recurrence after discontinuation of oral anticoagulation, regardless of treatment duration. Physicians should try to identify patients who are at high risk for recurrent venous thromboembolism and are therefore potential candidates for indefinite oral anticoagulant therapy.” (G. Agnelli, U. Perugia, Perugia, Italy; agnellig@unipg.it)

CPOE: Computerized physician order entry “is a promising technology that allows physicians to enter orders into a computer instead of handwriting them,” write authors who reviewed studies of CPOE (pp. 31-9). “This technology can yield many significant benefits and is an important platform for future changes to the health care system,” they note, despite the technology’s substantial start-up costs. “Organizational leaders must advocate for CPOE as a critical tool in improving health care quality.” (G. J. Kuperman, gkuperman@partners.org)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 2, 2003 Vol. 10, No. 127
Providing news and information about medications and their proper use

>>>Bexxar Approved for NHL
The approximately 100,000 U.S. patients with follicular non-Hodgkin’s lymphoma have a new therapeutic option if their condition proves refractory, thanks to FDA’s approval of tositumomab and Iodine I 131 tositumomab (Bexxar; Corixa, GlaxoSmithKline). The radiopharmaceutical agent is approved for treatment of patients with CD20-positive, follicular NHL, with and without transformation, whose disease is refractory to rituximab and has relapsed following chemotherapy.

Bexxar pairs the tumor-targeting ability of a cytotoxic monoclonal antibody, tositumomab, and the therapeutic potential of
131I radiation with patient-specific dosing. Combined, these agents form a radiolabeled monoclonal antibody (131I tositumomab) that is able to bind to the target antigen CD20 found on NHL cells, thereby initiating an immune response against the cancer and delivering a dose of radiation directly to tumor cells.

The efficacy of the Bexxar therapeutic regimen was examined in a multicenter, single-arm study of 40 patients with follicular NHL whose disease had relapsed following or had not responded to rituximab. The median age of patients in the study was 57 years (range, 35–78) and the median number of prior chemotherapies was 4 (range, 1–11). In the 88% of patients with rituximab-refractory disease, 63% of patients had a response to Bexxar, with a median duration of response of 25 months. A full 29% of patients had a complete response to Bexxar. The median duration of complete responses has not been reached after a median follow up of 26 months.

The Bexxar regimen consists of four components administered in two steps over 7–14 days. First, patients receive unlabeled tositumomab to improve the distribution of the subsequent radioactive antibody and increase its uptake in the tumor. A trace amount of
131I is then infused to allow calculation of the patient’s clearance rate. After 7–14 days have passed, the patient returns for the therapeutic step, which includes two infusions, again beginning with the nonradioactive antibody, followed by the calculated patient-specific radioactivity needed to deliver the targeted total body dose of radiation.

Neutropenia, thrombocytopenia, and anemia, sometimes prolonged and severe, are the most common adverse reactions to the radiopharmaceutical product. Nonhematologic side effects include asthenia, fever, nausea, infection, and cough.

>>>JAMA Highlights
Source:
July 2 issue of JAMA (www.jama.com; 2003; 290).

Contraindicated Antidiabetic Drugs in HF: Despite “explicit warnings” against their use in patients with heart failure, metformin and thiazolidinediones are prescribed for substantial numbers of Medicare patients with diabetes (pp. 81-5). Metformin is contraindicated in patients with diabetes who are under treatment for HF, while use of thiazolidinediones is not recommended in patients with symptoms of advanced heart failure. Based on discharge medications prescribed for Medicare beneficiaries who were hospitalized for diabetes and HF, the authors found, “In the 1998–1999 sample (n = 12,505), 7.1% of patients were discharged with a prescription for metformin, 7.2% with a prescription for a thiazolidinedione, and 13.5% with a prescription for either drug. In the 2000–2001 sample (n = 13,158), metformin use increased to 11.2%, thiazolidinedione use to 16.1%, and use of either drug to 24.4% (P<.001 for all comparisons). Similar increases were seen among patients of all age groups, all races, and both sexes.” (H. M. Krumholz, harlan.krumholz@yale.edu)

Benefits of Smoking Cessation: All-cause mortality drops when patients with coronary heart disease stop smoking, according to a systematic review of 20 clinical studies (pp. 86-97). Compared with patients who continued smoking, mortality risk fell by 36%, with improvements evident across many patient characteristics (age, sex, type of CHD, and the years in which studies took place). (J. A. Critchley, Liverpool School, Liverpool, England; juliac@liverpool.ac.uk)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 3, 2003 Vol. 10, No. 128
Providing news and information about medications and their proper use

>>> NEJM Highlights
Source:
July 3 issue of the New England Journal of Medicine (content.nejm.org; 2003; 349).

High-Dose Chemotherapy: In 885 women with stage II or III breast cancer, high-dose alkylating therapy improved relapse-free survival, especially in those with HER-2/neu-negative tumors (pp. 7-16). The patients were all younger than 56 years of age, had undergone surgery, and had 4–9 or 10 or more 10 tumor-positive axillary lymph nodes. All patients received fluorouracil, epirubicin, and cyclophosphamide (FEC) every 3 weeks for five courses, followed by radiotherapy and tamoxifen. Those in the intervention group also received high-dose chemotherapy (cyclophosphamide 6 g/sq m, thiotepa 480 mg/sq m, and carboplatin 1600 mg/sq m) and autologous peripheral-blood hematopoietic progenitor-cell transplantation instead of the fifth course of FEC.

Among patients treated with high-dose adjuvant chemotherapy, 65% lived for 5-years without relapse, compared with 59% of those in the control group (a statistical trend at p = .09). In women with 10 or more positive nodes, the respective survival rates were 61% and 51%, a significant difference. Relapse-free survival was also significantly longer in the group of women with HER-2/neu-negative tumors. (S. Rodenhuis, Netherlands Cancer Institute, Amsterdam, the Netherlands; sroden@nki.nl)

A second study came to different conclusions based on analysis of 511 women with primary breast cancer and at least 10 involved nodes (pp. 17-26). Patients received six cycles of adjuvant chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil (CAF) or CAF followed by high-dose chemotherapy with cyclophosphamide, thiotepa, and autologous hematopoietic stem-cell transplantation. No significant differences between the groups were observed in disease-free survival, overall survival, or time to recurrence. In addition, the authors add, “In the transplantation group, nine patients died of transplantation-related complications and a myelodysplastic syndrome or acute myeloid leukemia developed in nine.” (M. S. Tallman, m-tallman@northwestern.edu)

Neither of these studies is representative of current high-dose chemotherapy, writes an editorialist, noting that “high-dose chemotherapy should best be viewed as a launching pad from which to explore new methods of post-transplantation therapy to reduce the probability of relapse” (pp. 80-2). He adds, “There is a very large difference in the high-dose chemotherapy regimens used in the two studies. If the response of breast cancer to chemotherapy is dose-dependent, then the regimen studied by Rodenhuis et al., with three drugs, is 30 percent more dose-intensive than that studied by Tallman et al., with two drugs (according to my calculations, which are based on estimated maximal tolerated doses of the drugs in combination). Because dose–response curves have a sigmoid shape, it is possible that Tallman et al. tested a regimen with doses too low to reveal an effect that more dose-intensive regimens would produce.” (G. J. Elfenbein, Roger Williams Medical Center, Providence, R.I.)

>>>PNN NewsWatch
* The clinical laboratory community is opposing a provision in the Medicare prescription drug bills that would require copayments on all clinical laboratory tests. The “Campaign to Stop Medicare Laboratory Co-Pays” coalition includes the American Association of Clinical Chemistry, American Society for Clinical Laboratory Science, Quest Diagnostics, and other groups.

*
Sildenafil, many times obtained outside medical channels, is often used by men who engage in high-risk sex with other men, according to an article in the June Journal of Acquired Immune Deficiency Syndromes (2003; 33: 191-3). In a survey of 837 San Francisco men, Viagra use within the past 6 months was significantly associated with increasing age, white race or “other” ethnicity, being HIV-positive, illicit drug use, and unprotected anal intercourse with a partner of unknown serostatus.

*
PNN will not be published on Fri., July 4, Independence Day.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 7, 2003 Vol. 10, No. 129
Providing news and information about medications and their proper use

>>>Once-Daily NRTI Approved
Lowering the pill burden in treatment of HIV infection continues to be the focus of much research and development. Those efforts reached fruition again last week, with FDA’s approval of emtricitabine (Emtriva, Gilead), a once-daily, one-capsule nucleoside reverse transcriptase inhibitor, for treatment of HIV infection in adults in combination with other antiretroviral medications.

Licensed by Gilead from Emory U. in 1996, emtricitabine was evaluated in a Phase III trial of 571 treatment-naive patients. In combination with other antiretroviral medications, emtricitabine produced virologic responses in about 80% of patients, compared with 59% to 68% in other arms of the study. In a Phase III study of 440 treatment-experienced patients, 67% to 77% of emtricitabine-treated patients had virologic responses, statistically equivalent outcomes compared with 72% to 82% of patients who responded to control treatments.

The most common adverse events with emtricitabine have been headache, diarrhea, nausea, and rash, which were generally of mild or moderate severity. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination with other antiretroviral agents. In patients co-infected with HIV and chronic hepatitis B, exacerbations of hepatitis B have been reported in patients after discontinuation of emtricitabine. Patients with renal impairment should be carefully monitored and may require dose interval adjustments.

>>>Lancet Report
Source:
July 5 issue of Lancet (www.thelancet.com; 2003; 362).

Beta Blockers & HF: Carvedilol significantly reduced all-cause mortality among patients with chronic heart failure, compared with metoprolol (pp. 7-13). In a study of 1,511 patients with ejection fractions of less than 0.35, beta-1–selective metoprolol in doses of 25 mg twice daily was compared with 50 mg twice daily treatment with carvedilol, an agent that blocks beta-1, beta-2, and alpha-1 adrenergic receptors. Over the mean study duration of 58 months, all-cause mortality was 34% for carvedilol and 40% for metoprolol, yielding a hazard ratio of 0.83. Mortality or all-cause hospital admission occurred in 74% and 76% of the two respective groups, not a significant difference, and adverse effects and drug withdrawals were similar between the two groups. (P. A. Poole-Wilson, Imperial Coll., London; p.poole-wilson@imperial.ac.uk)

>>>BMJ Highlights
Source:
July 5 issue of BMJ (www.bmj.org; 2003; 327).

Nicotine Replacement & Long-Term Abstinence: Only 5% of participants in a nicotine-patch trial remained abstinent from tobacco 8 years later (pp. 28-9). Of 153 participants who were abstinent during the 1 year of the 1,625-patient, 83 were not smoking at the 8-year follow-up. “Finding more effective ways to help people to give up smoking remains an ongoing challenge,” the authors conclude. (P. Yudkin, U. Oxford, Oxford; U.K.; pat.yudkin@dphpc.ox.ac.uk)

>>>PNN JournalWatch
* Myocardial Viability as a Determinant of the Ejection Fraction Response to Carvedilol in Patients with Heart Failure (CHRISTMAS trial): Randomised Controlled Trial, in Lancet, 2003; 362: 14–21. Reprints: www.thelancet.com; J. G. F. Cleland, U. Hull, Kingston-upon-Hull, U.K.; g.m.porter@hull.ac.uk

* Decline in the AIDS and Death Rates in the EuroSIDA Study: An Observational Study, in
Lancet, 2003; 362: 14–21. Reprints: www.thelancet.com; A. Mocroft, Royal Free and U. Coll., London a.mocroft@pcps.ucl.ac.uk

* Cohort Study of Hepatotoxicity Associated with Nimesulide and Other Non-Steroidal Anti-Inflammatory Drugs, in
BMJ, 2003; 327: 18–22. Reprints: www.bmj.org; G. Traversa, National Institute of Health, Rome; giuseppe.traversa@iss.it

* Routine Vitamin Supplementation To Prevent Cancer and Cardiovascular Disease: Recommendations and Rationale, in
Annals of Internal Medicine, 2003; 139: 51–5. Reprints: www.annals.org; U.S. Preventive Services Task Force, www.preventiveservices.ahrq.gov or 800/358-9295.

* Statin-Associated Memory Loss: Analysis of 60 Case Reports and Review of the Literature, in
Pharmacotherapy, 2003; 23: 871–80. Reprints: www.accp.com; P. M. Doraiswarmy, dorai001@mc.duke.edu

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 8, 2003 Vol. 10, No. 130
Providing news and information about medications and their proper use

>>>Webster Dies at 56
R. Tim Webster, executive director of the American Society of Consultant Pharmacists since 1976, died of cancer on Sunday at age 56.

A 1969 pharmacy graduate of the Ohio State University, Webster devoted his professional career to improving the use of medications in the nation’s senior citizens, first in government regulatory affairs and then through ASCP. He oversaw growth of the Society—an upstart organization only 7 years old when Webster took the helm as the group’s fourth executive director—to a 6,500-member organization that today has a budget in excess of $8 million, a staff of 30, and its own headquarters building. Taking advantage of Webster’s unique vision of and insights into the role pharmacists should play in the lives of the elderly in long-term care and in all other settings, ASCP produced programs and publications that senior care pharmacists needed to advance their practices to higher levels, including reference materials, award-winning publications, a peer-reviewed journal, and Internet resources.

At ASCP’s Geriatrics ’03 conference 2 months ago, ASCP members and staff organized a tribute to Webster around the themes of “his tremendous ability to work with elected leaders; the energy and creativity he has brought to ASCP as an organization; the inspiration and influence he has had for and on pharmacy; and the example he provides to all of us, that work can be fun.”

A true “early adopter” of technology, Webster pushed his staff to explore the limits of their Apple Macintoshes from the earliest days of personal computers. He immediately grasped the power of communication and information delivery via fax, e-mail, and the Web, and he quickly incorporated their use in ASCP’s products and services. In fact, the creation of PNN as a daily information source written solely for pharmacists was the result of a March 1994 conversation with this unique pharmacist.

Services for Webster will be held Thursday in Alexandria, Va.

>>>Psychiatry Highlights
Source:
July issue of the American Journal of Psychiatry (ajp.psychiatryonline.org; 2003; 160).

Effectiveness of Newer Antipsychotic Medications: Use of newer antipsychotic agents reduces relapse rates, conclude authors of a review article (pp. 1209-22). Few trials were available for each individual drug, leading the authors to group the studies for analysis. They report: “Six placebo comparisons, involving a total of 983 patients, clearly demonstrated that new-generation antipsychotic drugs are effective for relapse prevention. Eleven studies with a total of 2,032 patients provided comparative data on relapse/treatment failure for new-generation and conventional antipsychotics. The analysis revealed that rates of relapse and overall treatment failure were modestly but significantly lower with the newer drugs. Whether this advantage was partly mediated by improved adherence to treatment remains unclear. No significant superiority in terms of fewer dropouts due to adverse events was found for the newer drugs. Furthermore, a number of methodological problems were identified.” (S. Leucht)

Depressive Relapse in Bipolar Illness: Recommendations that antidepressants should be discontinued within 6 months after remission in patients with bipolar disorders may be flawed, according to investigators who studied 84 subjects (pp. 1252-62). The patients had achieved remission following addition of an antidepressant to ongoing mood stabilizer regimens. During 1-year follow-up, the authors observed, “Patients who discontinued antidepressant treatment within the first 6 months after remission experienced a significantly shorter period of euthymia before depressive relapse over the length of 1-year follow-up. One year after successful antidepressant response, 70% of the antidepressant discontinuation group experienced a depressive relapse compared with 36% of [patients who continued antidepressants for longer time periods]. By the 1-year follow-up evaluation, 15 (18%) of the 84 subjects had experienced a manic relapse; only six of these subjects were taking an antidepressant at the time of manic relapse.” (L. Altshuler)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 9, 2003 Vol. 10, No. 131
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
July 9 issue of JAMA (www.jama.com; 2003; 290).

Tifacogin & Sepsis: Tifacogin (recombinant tissue factor pathway inhibitor) failed to affect all-cause mortality in a Phase III trial of 1,754 adult patients with severe sepsis and international normalized ratios of 1.2 or higher and 201 patients with severe sepsis and lower INR values (pp. 238-47). Compared with placebo, tifacogin 0.025 mg/kg/hr for 96 hours produced equivalent risk of mortality at 28 days in patients with high INRs (34.2% with drug and 33.9% with placebo). The authors note that an analysis of data on the first 722 of these subjects had shown a significant advantage for tifacogin, but later results favored placebo, producing the overall neutral results. In those with low INRs, overall mortality was lower with tifacogin (12%, compared with 22.9% with placebo), and this difference was significant when tested with a logistic regression model. Serious adverse events with bleeding occurred frequently in both groups, (6.5% tifacogin and 4.8% placebo for high INR; 6.0% tifacogin and 3.3% placebo for low INR). (E. Abraham, U. Colorado, Denver; edward.abraham@uchsc.edu)

An editorialist assesses the current state of severe sepsis care (pp. 256-8): “Important headway has been made in defining optimal care for the patient with or at risk for severe sepsis. Attention to head tilt in the patient who is ventilated, sterile precautions during central venous catheter insertion, hand washing, and appropriate stress ulcer prophylaxis all decrease the risk of developing nosocomial infection and sepsis. Once infection occurs, prompt diagnosis and initiation of appropriate antibiotics, along with surgical drainage when indicated, promotes optimal resolution of infection. Early goal-directed resuscitation can attenuate the progression of organ dysfunction and reduce mortality. Optimal organ support, including low tidal volumes for acute lung injury, daily ventilator weaning trials, tight blood glucose control, and sedation protocols all improve outcomes. In appropriately selected patients, manipulation of the innate immune response with activated protein C and corticosteroids may help to further decrease mortality of this common and frequently lethal condition.” (D. C. Angus, U. Pittsburgh, Pittsburgh; angusdc@ccm.upmc.edu)

Prescription Drug Costs & Medicare Patients: In a Medicare managed care plan that provided prescription drug coverage, substantial numbers of Medicare patients exceeded caps of $750 to $2,000 per year applied to the plan’s share of prescription costs (pp. 222-7). Among 438,802 patients who had at least one prescription filled during 2001, 22%, 14%, and 4% of Medicare patients exceeded caps of $750, $1,000, and $2,000, respectively. Monthly costs doubled or tripled when patients’ coverage ended, with median out-of-pocket costs climbing to $179–305 per month from $79–100 per month when coverage was in effect. Most medications for patients who exceeded the cap were for chronic conditions, and many had no lower-cost generic alternatives. (C-W Tseng, cwtseng@hawaii.edu)

Cost-effectiveness of HCV Therapy: Genotype and gender significantly affect the cost-effectiveness values for hepatitis C virus infection therapies, report investigators who analyzed monotherapy with standard or pegylated interferon alfa-2b and combination therapy with standard or pegylated interferon plus ribavirin (pp. 228-37). “The probability of patients with chronic HCV developing cirrhosis over a 30-year period ranged from 13% to 46% for men and from 1% to 29% for women,” write the authors. “The incremental cost-effectiveness of combination therapy with pegylated interferon for men ranged from $26,000 to $64,000 per [quality-adjusted life-year] for genotype 1 and from $10,000 to $28,000 per QALY for other genotypes; and for women ranged from $32,000 to $90,000 for genotype 1 and from $12,000 to $42,000 for other genotypes.” The group concludes that recent emphasis on screening programs could have the unintended effect of identifying patients whose infections present difficult therapeutic dilemmas in terms of costs and risks of care. (J. A. Salomon, jsalomon@hsph.harvard.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 10, 2003 Vol. 10, No. 132
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
July 10 issue of the New England Journal of Medicine (content.nejm.org; 2003; 349).

Secondary VT Prevention in Patients with Cancer: For preventing recurrence of venous thromboembolism in 672 patients with cancer, the low molecular weight heparin dalteparin proved more effective than and equally safe as oral coumarin compounds in a 6-month trial (pp. 146-53). All patients received an initial regimen of dalteparin 200 IU/kg once daily (maximum daily dose, 18,000 IU). Within 1 day, patients in the coumarin group began taking warfarin or, in the Netherlands and Spain, acenocoumarol, and doses were adjusted toward a target international normalized ratio of 2.5. Those in the dalteparin group were continued at the same LMWH doses for 1 month and then switched to doses of 75–83% of the full dose using prefilled syringes. Recurrent VT occurred in 9% of patients in the dalteparin group, significantly fewer than the 17% of those on warfarin (hazard ratio, 0.48). Adverse events and overall mortality were similar between the groups. The investigators conclude, “In patients with cancer, recurrent thromboembolism complicates management and diminishes the patients’ quality of life. Our study shows that the risk of symptomatic, recurrent thromboembolism among patients with active cancer is significantly lower with dalteparin therapy than with oral anticoagulant therapy. Although previous trials comparing low-molecular-weight heparins with warfarin for the secondary prophylaxis of venous thromboembolism did not find a difference in the risk of recurrent thrombosis, most of the trials were small and conducted primarily in patients without cancer.” (M. N. Levine, Henderson Hosp., Hamilton, ON, Canada)

In a perspectives article, an author endorses use of LMWHs in this clinical situation (pp. 109-11): “The cost of low-molecular-weight heparins has been overestimated. It is unnecessary to monitor the anticoagulant effect of these heparins, except in some patients with renal insufficiency, and the reduction in recurrences reduces the overall cost of medical care, easily compensating for the difference in cost between low-molecular-weight heparin and unfractionated heparin and in the cost, over a six-month period of prophylaxis, of monitoring the international normalized ratio in patients who receive warfarin. The multicenter trial reported by Lee at al. provides clear evidence that low-molecular-weight heparin should become the therapeutic and prophylactic agent of choice in cancer-associated thromboembolic disease.” (R. L. Bick, U. Texas Southwestern Med. Sch., Dallas)

Predicting Renal Allograft Survival: Aggressive therapy with antihypertensive or immunosuppressive medications might help salvage poorly performing renal allografts, based on findings of a study that shows a relationship between renal arterial resistance index at 3 months after transplantation and poor subsequent allograft performance and death (pp. 115-24). Renal segmental arterial resistance index—defined as the percentage reduction of the end-diastolic flow as compared with the systolic flow—was measured by Doppler ultrasonography in 601 patients at least 3 months after transplantation. In 122 patients with resistance indices of 80 or higher, decreases in creatinine clearance of more than 50%, need for dialysis, and death were more significantly more common than in patients with lower index scores. Drugs such as lisinopril, iloprost, and tacrolimus might be tested for their effects in patients with high resistance indices, the authors propose.

“Doppler ultrasonographic study performed three or more months after transplantation can predict long-term allograft outcomes,” the authors write. “Our data also suggest that longitudinal Doppler studies may be useful in monitoring interventions such as different immunosuppressive protocols or in comparing the capability of various antihypertensive drugs to improve allograft outcomes. Such studies may reduce the need for sequential renal biopsies, with their associated risks.” (J. Radermacher, Medizinische Hochschule Hannover, Hannover, Germany; radermacher.joerg@mh-hannover.de)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 11, 2003 Vol. 10, No. 133
Providing news and information about medications and their proper use

>>>Pharmacotherapy Update
Source:
July Pharmacotherapy (www.accp.com; 2003; 23).

4-Aminopyridine & Spinal Cord Injury: Motor function improved in 25 patients with long-term spinal cord injury after they received 12 weeks of treatment with 4-aminopyridine (pp. 823-34). Oral 4-AP therapy was begun at 5 mg/day and increased by 5 mg/ week to a maximum dosage of 30 mg/day in a double-blind, crossover, placebo-controlled fashion. Significant improvement in motor function was noted in 92% of patients on active therapy, compared with 46% of patients on placebo. Posterior tibial artery vasospasm occurred in 1 patient, and 25 milder adverse reactions were noted in 13 patients. About one fourth of patients had transient liver enzyme elevations. (I. Grijalva, Specialties Hosp., Mexico City, Mexico; igrijalvao@yahoo.com)

Lack of Didanosine–Amprenavir Interaction: Absorption of amprenavir was not affected by concurrent administration of either the buffered or enteric-coated formulations of didanosine in a study of 16 healthy volunteers (pp. 835-42). Area under the concentration–time curve during 12-hour amprenavir dosing intervals and serum concentration at 12 hours were similar under various concurrent didanosine administrations. The authors conclude that the two agents may be administered concurrently in fasting patients. (M. J. Shelton, GlaxoSmithKline, Res. Triangle Park, NC)

Alcohol Withdrawal in Surgical Patients: A standardized, symptom-triggered approach can be used to manage alcohol withdrawal syndrome in patients undergoing trauma, orthopedic, and general surgery, according to a pilot study of 72 patients (pp. 843-54). Compared with subjects managed using nonstandardized care, those treated with standardized approaches received a mean of 23 mg less benzodiazepines and 0.1 mg more clonidine, both significant differences, and 20 mg less haloperidol, a difference that reached a p value of 0.06. Fewer sitter hours were required in patients on standardized care, and the amount of time in restraints was decreased, approaching significance at a p value of 0.09. (K. M. Stanley, stanleyk@musc.edu)

Drug Allergy Errors in Hospitalized Patients: Based on patient interviews and analysis of medication error reports in a university teaching hospital, investigators conclude that a mechanism is needed “for ensuring that prescribers review each patient’s allergy profile before order entry” (pp. 855-60). Among 340 patients, 133 (39%) reported allergies, most often to beta-lactam antibiotics (12.6% of all patients), sulfonamides (9.1%), and opioid narcotics (14.4%). Beta-lactam antibiotics were most often involved in medication errors, with piperacillin–tazobactam accounting for one-half of the errors. (T. A. Jones, U. Ala. Hosp., tjones@uabmc.edu)

>>>PNN NewsWatch
* Rosuvastatin calcium (Crestor, AstraZeneca) has been recommended for approval by an FDA advisory committee. The “superstatin” is more potent for lowering of LDL cholesterol values than atorvastatin, but concerns about renal toxicities have slowed the medication’s progress through the drug-approval process.

* A new Medication Guide will provide patients with information about possible psychiatric reactions to the antimalarial agent
mefloquine hydrochloride. The Lariam Med Guide provides information on how patients can recognize psychiatric risks, including the possibility of sudden-onset symptoms, and take early action to prevent serious harm. Specifically, it instructs patients on the Roche drug who experience a sudden onset of certain psychiatric adverse events–anxiety, depression, restlessness or confusion–to contact a doctor or other health care provider because it may be necessary to stop taking mefloquine and use another malarial preventive agent.

* Amgen and Wyeth have applied for FDA approval of
etanercept for treatment of moderate to severe plaque psoriasis. Phase III trial results were presented in Mar. at the Am. Academy of Dermatology meeting and in June at the Intl. Psoriasis Symposium.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 14, 2003 Vol. 10, No. 134
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
July 12 issue of Lancet (www.thelancet.com; 2003; 362).

Tamoxifen & Ductal Carcinoma:
For treatment of women with ductal carcinoma in situ, tamoxifen therapy provides little benefit as a replacement for or adjunct to radiotherapy, according to a study of 1,701 subjects (pp. 95-102). Lesions were surgically excised in all patients, who then received radiotherapy, tamoxifen, both, or neither. Radiotherapy significantly reduced the incidence of ipsilateral invasive disease (by 55%) and of ipsilateral ductal carcinoma in situ (by 64%). Contralateral disease was not affected by radiotherapy. Tamoxifen failed to reduce the occurrence of ipsilateral invasive disease, although treatment reduced the recurrence of overall ductal carcinoma in situ. No interaction was observed between radiotherapy and tamoxifen therapy. “Trials of tamoxifen or of newer endocrine agents such as the aromatase inhibitors, perhaps with randomisation stratified by hormone receptor status, are needed to assess the true role of endocrine agents in prevention of ipsilateral recurrence and the prevention of contralateral disease,” the investigators conclude. (J. Houghton, Royal Free and U. College Med. Sch., London; j.houghton@ctg.ucl.ac.uk)

Cognitive Enhancement: From use of methylphenidate by students to the possibility of neuronal tissue implants and brain– computer interfaces, attendees at a recent conference explored the ethical concerns raised by emerging cognitive-enhancement strategies, according to a feature article (pp. 132-3). “Cognitive neuroscientist Lawrence Parsons, a Program Director at US grant-giving body the National Science Foundation, predicts that within the next 10 to 15 years some forms of cognitive enhancement will have become so widespread that it will be as contentious a social issue as stem-cell research and genetically modified foods are today,” the writer notes. Concerns noted at the conference included creation of population homogeneity and loss of diversity, loss of the perception of individual and self, and acceleration of society’s avoidance of suffering in the attainment of goals. The authors adds, “The personal experiences of Howard Gardner—a professor in cognition and education at Harvard University who discovered 10 years ago that his work was being used in a racially divisive way in Australia—helped cement the idea that the responsibility of the scientist does not end when he or she publishes. ‘Scientists have an obligation to monitor how their work is used and misused, and to speak up regarding misapplications, misinterpretations, and frank mischief,’ Gardner emphasised.” (J. Butcher)

>>>PNN NewsWatch
* A second brand of alpha-1– proteinase inhibitor has been approved by FDA. Zemaira (Aventis Behring) is indicated for long-term augmentation and maintenance therapy in individuals with alpha-1–proteinase inhibitor deficiency and clinical evidence of emphysema.

* Three lots (290122001, 290122002, and 290122003) of
Nortrel 7/7/7 – 28 day have been recalled because of incorrect placement of placebo tablets on the wrong row in some packages. In some affected packages, the lot numbers do not appear properly in the window; as a result, any package without a lot number is also recalled (www.fda.gov).

>>>PNN JournalWatch
* Pharmacogenetics and Clinical Gastroenterology, in Gastroenterology, 2003; 125: 240 ff. Reprints: www2.gastro journal.org; R. C. Givens, U. N. C., Chapel Hill; e.el-omar@abdn.ac.uk

* Cognitive-Behavioral Therapy Versus Education and Desipramine Versus Placebo for Moderate to Severe Functional Bowel Disorders, in
Gastroenterology, 2003; 125: 19 ff. Reprints: www2.gastrojournal.org; D. A. Drossman, U. N. C., Chapel Hill; Drossman@med.unc.edu

* Recent Advances and Future Frontiers in Treating Age-Related Cataracts, in
JAMA, 2003; 290: 248–51. Reprints: www.jama.com; R. Solomon.

* Preventing Fractures in Elderly People, in
BMJ, 2003; 327: 89–95. Reprints: www.bmj.org; A. D. Woolf, Peninsula Med. Sch., Royal Cornwall Hosp., Truro, U.K.; anthony.woolf@rcht.swest.nhs.uk

* Demographics and Concomitant Disorders in Heart Failure, in
Lancet, 2003; 362: 147–58. Reprints: www.thelancet.com; H. Krum, Monash U. Med. Sch., Prahran, Victoria, Australia; henry. krum@med.monash.edu.au

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 15, 2003 Vol. 10, No. 135
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
July 14 Archives of Internal Medicine (www.archinternmed.com; 2003; 163).

Glucosamine or Chondroitin in OA: Both glucosamine and chondroitin provide benefits to patients with osteoarthritis, according to a comprehensive meta-analysis (pp. 1514-22). After identifying and assessing some 500 research reports published in 1980 through March 2002, the authors identified eight studies of glucosamine and seven trials of chondroitin that met inclusion criteria. “Our results demonstrated a highly significant efficacy of glucosamine on all outcomes, including joint space narrowing and [Western Ontario MacMaster University Osteoarthritis Index],” write the authors. “Chondroitin was found to be effective on Lequesne Index, visual analog scale pain, mobility, and responding status. Safety was excellent for both compounds.... Further long-term studies are needed to confirm and evaluate the structural efficacy of chondroitin. Now that a structure-modifying effect has been demonstrated for glucosamine, further studies on the relationship between structural and symptomatic changes controlling for baseline characteristics, including osteoarthritis stage, and on the possible use in prevention are required to determine the role of this compound as a disease-modifying agent in osteoarthritis.” (J-Y Reginster, CHU–Centre Ville, Liege, Belgium; jyreginster@ulg.ac.be)

Glucosamine & DM: Oral glucosamine failed to affect glucose metabolism in 38 elderly patients with type 2 diabetes mellitus, but the agent may offer an alternative to NSAIDs in such patients (pp. 1587-90). In the 90-day study, subjects took either placebo or a combination of glucosamine hydrochloride 1,500 mg with chondroitin sulfate 1,200 mg per day, with two-thirds of the doses administered in the morning and one-third in the evening. Mean hemoglobin A1c concentrations were unaffected by the intervention (in both between-group and within-group comparisons), and no patient had any change in diabetes-related values. “Since patients with diabetes are at risk for toxic effects from some of the current treatments for osteoarthritis (NSAIDs in particular), glucosamine may provide a safe alternative treatment for these patients,” write the authors. “The present study has demonstrated that oral glucosamine supplementation does not adversely affect glycemic control when administered to patients with type 2 diabetes mellitus at doses recommended by the manufacturer.” (D. A. Scroggie, Daren.Scroggie@lackland.af.mil)

>>>More Internal Medicine
Source:
July 15 issue of the Annals of Internal Medicine (www.annals.org; 2003; 139).

Alternating HIV Regimens: Virologic failure in patients with HIV infections is delayed through use of alternating antiretroviral drug regimens, according to results of a 161-patient study (pp. 81-9). Patients continuously received stavudine, didanosine, and efavirenz (standard of care, regimen A) or zidovudine, lamivudine, and nelfinavir (standard of care, regimen B) until virologic failure, or alternated between those two regimens every 3 months while viral load was suppressed (regimen C). Results were equivalent in patients on regimens A and B, but with regimen C, virologic failure occurred at one-fourth the rate in those taking regimens A and B (1.2 versus 4.8 events/ 1000 person-weeks). The authors conclude, “Proactive switching and alternation of antiretroviral regimens with drugs that have different resistance profiles might extend the overall long-term effectiveness of first- and second-line treatment options without adversely affecting patients’ adherence or quality of life.” (J. Martinez-Picado, Hosp. Germans Trias i Pujol, Badalona, Spain; javiermp@ns.hugtip.scs.es)

Statins & Fractures: In 93,716 patients in the Women’s Health Initiative, statin use failed to improve fracture risk or bone density (pp. 97-104). Combining these findings with previously reported results, the authors conclude, “The cumulative evidence does not warrant use of statins to prevent or treat osteoporosis.” (A. Z. LaCroix, Fred Hutchinson Cancer Res. Ctr., Seattle)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 16, 2003 Vol. 10, No. 136
Providing news and information about medications and their proper use

>>>Chest Highlights
Source:
July issue of Chest (www.chestjournal.org; 2003; 124).

Lack of Adrenal Effects of Inhaled Triamcinolone: In 221 patients with chronic obstructive pulmonary disease who used either placebo or inhaled triamcinolone 1,200 mcg/day, no drug effects on adrenal function were evident at 1 and 3 years of treatment (pp. 57-62). As part of the Lung Health Study II, basal cortisol and cortisol levels at 30 and 60 minutes following cosyntropin injection were measured at study entry and at 1 and 3 years. The investigators found, “Basal cortisol levels in the placebo group were higher than in those receiving active drug at all time points and rose through the study period. There was no suppression of cortisol levels after cosyntropin stimulation at any study point in any subgroup.” (J. E. Connett, john-c@ccbr.umn.edu)

Serious Asthma Exacerbations with High-Dose Formoterol: Regular use of high-dose formoterol, a long-acting beta agonist, may be associated with more frequent serious asthma exacerbations (SAEs), according to pivotal clinical trial data that were analyzed and reported by FDA staff (pp. 70-4). Three prospective, randomized, placebo-controlled, double-blind clinical studies of formoterol at dosages of 12 mcg and 24 mcg twice daily in patients with asthma were analyzed, with these results:

* Study 1 (adults): 3% of 135 patients using formoterol 24 mcg b.i.d. had SAEs, compared with none of 136 patients on placebo.

* Study 2 (adults): 3.7% of 136 patients using formoterol 24 mcg b.i.d. had SAEs, compared with 1.4% of 141 patients on placebo.

* Study 3 (pediatrics): 6.4% of 171 patients on formoterol 24 mcg b.i.d. had SAEs, compared with none of 176 patients using placebo. (M. Mann, mannm@cder.fda.gov)

New Central Venous Catheters: A hypothetical cost-effectiveness analysis supports use of the newer antiseptic and antibiotic-impregnated central venous catheters, especially a product coated with rifampin and minocycline (pp. 275-84). In a cohort of 1,000 patients, the CEA model assumed a catheter-related bloodstream infection incidence of 3.3% and that the new catheters would reduce this risk by 60% (for CVCs coated with chlorhexidine silver sulfadiazine) and 85% (for the rifampin– minocycline models). Despite the higher cost of coated CVCs, their use saved about $10,000 per prevented case of catheter-related bloodstream infection, relative to standard catheters. Comparing the two new catheters, the one with rifampin and minocycline saved $9,600 per averted catheter-related bloodstream infection, or about $81 per patient overall. (A. F. Shorr, Walter Reed Army Med. Ctr., Washington; afshorr@dnamail.com)

Lipid Emulsions & ARDS: Lipid emulsions containing 50% long-chain and 50% medium-chain triglycerides improved oxygenation and oxygen delivery in 18 patients with acute respiratory distress syndrome (pp. 285-91). In crossover fashion, patients received 6-hour infusions of two 20% fat emulsions, one with 100% LCTs and one with the 50:50 ratio of LCTs and MCTs. No deleterious effects on oxygenation were observed with the LCT emulsion. The LCT/MCT product provided significantly better partial pressure of oxygen in arterial blood/fraction of inspired oxygen, and oxygen delivery was significantly improved, compared with baseline. “While a time-related increase in mean pulmonary artery pressure (p = 0.012) during lipid administration was found, no effect of the kind of lipid emulsion was observed,” the group adds. “The time-related increase in cardiac index (p = 0.002) was more marked when the patients received the LCT/MCT emulsion (p = 0.002). Pulmonary vascular resistances were not affected by the kind of lipid emulsion.” (L. Papazian, Hôpital Sainte-Marguerite, Marseille, France; laurent.papazian@ap-hm.fr)

>>>PNN NewsWatch
* In today’s JAMA, investigators debate the relationship between severe acute respiratory disorder and acute respiratory distress syndrome. Two case series (pp. 367-73 and 374-80) and an editorial (pp. 397-9) discuss the occurrence of ARDS in critically ill patients with the recently identified SARS (www.jama.com).

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 17, 2003 Vol. 10, No. 137
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
July 17 issue of the New England Journal of Medicine (content.nejm.org; 2003; 349).

Finasteride & Prostate Cancer: The 5-alpha reductase inhibitors may be useful for prevention of prostate cancer, but data from a study posted earlier on the NEJM Web site (see PNN, June 26) indicate that when tumors do develop in men taking finasteride, they are more likely to be advanced (pp. 215-24). In the Prostate Cancer Prevention Trial, 18,882 men aged 55 years or older with a normal digital rectal examination and a prostate-specific antigen (PSA) level of 3.0 ng/mL or lower randomly received finasteride 5 mg/day or placebo for 7 years. Because PSA levels are affected by finasteride and this could interfere with detection of prostate cancer, all men not diagnosed with the disease by the end of the study were offered a prostate biopsy, regardless of their symptoms. Prostate cancer developed in 18.4% of men taking finasteride, compared with 24.8% of those on placebo, a significantly reduced risk. However, tumors of Gleason grade 7–10 were found in 37.0% of tumors in men on active therapy, compared with 22.2% of tumors in men in the placebo group. Sexual side effects were more common with finasteride, with about two-thirds of men reporting reduced ejaculate volume, erectile dysfunction, and loss of libido, compared with about one half of those on placebo. Urinary symptoms occurred more often in those taking placebo, but the differences between the groups were not large. (Southwest Oncology Group, San Antonio)

An editorialist argues that finasteride should not be recommended to men for lowering the risk of prostate cancer (pp. 297-9): “Although [finasteride] reduced the cumulative incidence of cancer in the PCPT trial, the reduction was relative to the incidence in a control group in which biopsy was recommended for all men, regardless of risk factors—an approach that is destined to lead to the overdetection of histologically identified cancers of little clinical significance. We do not know the malignant potential of such cancers and have no evidence that any benefit would be worth the risk associated with treatment. Furthermore, the study results suggest that finasteride may accelerate the growth of high-grade cancers, which may pose a threat to life and health if they are not treated successfully. Finally, the effects of finasteride on sexual function lessen the attractiveness of the drug as a preventive agent.” (P. T. Scardino, Memorial Sloan-Kettering Cancer Center, New York)

Pharmacists & Direct Patient Care: An exchange in the letters to the editor illustrate both promises and problems when it comes to pharmacists emerging as a widely available source of direct patient care. A pharmacist, Dennis Snow of Arizona’s Scottsdale Healthcare, commented on a recent editorial that mentioned pharmacists as a potential solution to the problem of adverse events in outpatients (see PNN, Apr. 17): “It is time for a fundamental change. It is time for the role of the pharmacist in direct patient care to increase substantially. There are well-trained, board-certified clinical pharmacists who are willing to accept the responsibility—and liability—of the pharmacologic management of chronic diseases. But it will take a legislative change in pharmacists’ provider status and a willingness on the part of physicians to allow this to happen on a national scale.”

Physician William M. Tierney, of Indiana U. in Indianapolis and one of the authors of an earlier asthma study of pharmaceutical care in chain pharmacies that failed to show differences (see PNN, Oct. 2, 2002), replies: “I agree that as the last health care professionals to see patients before they take medicines, pharmacists have a key role in pharmacotherapy. Because many patients have more than one doctor but usually visit a single pharmacy, pharmacists can enhance the continuity of care. I also agree that changing pharmacists’ roles will require a fundamental transformation in the attitudes of the public, physicians, and pharmacists themselves.... The new paradigm of team-oriented health care should include pharmacists if such inclusion would improve pharmacotherapy and reduce the rate of adverse drug events. However, this hypothesis should be rigorously tested.”

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 18, 2003 Vol. 10, No. 138
Providing news and information about medications and their proper use

>>>Infectious Disease Update
Source:
July 15 issue of Clinical Infectious Diseases (www.journals.uchicago.edu/CID; 2003; 37).

Hospital Antibiotic Use Program: Multidisciplinary efforts at an Argentine hospital provided a cost-effective strategy for optimizing antibiotic prescribing (pp. 180-6). With pharmacy, internal medicine, and microbiology collaborating in introduction of a prescription form, providing prescriber education, and enforcing prescribing controls, costs were reduced by $913,236 and resistance of key pathogens to antibiotics was lowered. (C. Bantar, Hosp. San Martín, Paraná, Entre Ríos, Argentina)

Drotrecogin Alfa Use in Older Patients: Patients older than 75 years with severe sepsis had improved survival rates but more bleeding episodes when they were treated with drotrecogin alfa (pp. 187-95). Compared with patients who received placebo, drotrecogin alfa treatment provided absolute risk reductions in 28-day and in-hospital mortality of 15.5% and 15.6%, respectively. Long-term survival rates also improved, with significantly higher values at 2 years. “The incidences of serious adverse bleeding during the 28-day study period in the [drotrecogin alfa] and placebo groups were 3.9% and 2.2%, respectively (P= .34),” the authors write. “There was no interaction between age and bleeding rates (P= .97).” (E. W. Ely, Vanderbilt U., Nashville, Tenn.)

Smallpox Vaccination: In two invited reviews, authors discuss the unique technique used for smallpox vaccination and what normal and adverse reactions to expect following both primary vaccination and revaccination. (pp. 241-50 ,251-71; V. A. Fulginiti, U. Arizona, Tucson)

>>>Neurology Highlights
Source:
July 7 issue of Neurology (www.neurology.org; 2003; 61).

Smoking, Coffee, & PD: Patients who smoked cigarettes had lower risk of symptoms of Parkinson’s disease, compared with nonsmokers, while coffee and caffeine consumption were not related to presence of PD symptoms in a study of 1,339 Manhattan residents aged 65 years or more (pp. 24-8). Odds ratios for presence of parkinsonian signs were reduced by 42% among smokers, who also had lower mean parkinsonian sign scores than did nonsmokers. The authors offer two explanations, that the results “reflect a protective effect of smoking on age-related parkinsonian signs in the elderly or an aversion to smoking in elderly persons with mild parkinsonism.” (E.D. Louis, EDL2@columbia.edu)

Hypoalbuminemia & Steroid Psychosis: Among 92 patients with systemic lupus erythematosus, corticosteroid-induced psychosis in 5 patients was associated with low serum levels of albumin (pp. 104-7). Other factors predictive of psychosis included low serum levels of complement and creatinine, history of anxiety disorders, and a family history of psychiatric illnesses. But only hypoalbuminemia remained predictive after multivariate adjustment. (C. C. Mok, Tuen Mun Hosp., Hong Kong; ccmok@netvigator.com)

>>>PNN NewsWatch
* The risk of cardiovascular disease may be reduced by eating 1.5 ounces of hazelnuts each day, according to a new health claim approved by FDA. The claim states, “Scientific evidence suggests, but does not prove, that eating 1.5 ounces per day of most nuts, such as hazelnuts, as part of a diet low in saturated fat and cholesterol, may reduce the risk of heart disease.” Hazelnuts contain nearly 91% monounsaturated, mostly oleic fatty acid fat.

* Addressing the increasingly serious
drug counterfeiting problem, FDA this week announced a major new initiative and creation of an internal task force that will report back in 60 days and issue a final report within 6 months. The number of drug counterfeiting cases has averaged more than 20 for the past 2 years, after hovering at about 5 throughout the late 1990s. FDA has also observed a more sophisticated ability to introduce finished dosage counterfeits into the otherwise legitimate drug-distribution channels. Drug wholesalers and pharmacy groups expressed support of this effort to assure the integrity of the drugs being dispensed to patients.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 21, 2003 Vol. 10, No. 139
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
July 19 issue of BMJ (www.bmj.org; 2003; 327).

NSAIDs & AD: Long-term NSAID use reduced the risk of Alzheimer’s disease in older adults by 73%, according to a meta-analysis of nine published trials (pp. 128 ff). The studies, six cohort trials of 13,211 participants and three case–control studies of 1,443 participants, included adults older than 55 years. Overall, the relative risk of developing AD was 0.72 among NSAID users. Those using the agents for less than 1 month had no significant change in risk (0.95), nor did users for 2–24 months (0.83). But the risk dropped to 0.27 for those using NSAIDs for more than 24 months. Among patients who used aspirin (without regard to length of therapy), the relative risk was not significantly reduced (0.87).

The authors conclude, “In light of the growing evidence from observational studies and the current absence of evidence from randomised controlled trials, our systematic review lends support to the hypothesis that NSAIDs may protect against the development of [AD]. The appropriate dose, duration, and ratios of risk to benefit are still unclear.” (M. Etminan, Royal Victoria Hosp., Montreal; Canada; mahyar.etminan@mail.mcgill.ca)

ACE Modifier Interaction with Spironolactone: Patients with heart failure who are treated concomitantly with spironolactone plus ACE inhibitors or angiotensin II receptor antagonists are at increased risk of developing life-threatening hyperkalemia, according to a case series of 44 patients (pp. 147-9). Patients of advanced age were at greater risk of problems, as were those taking doses of spironolactone greater than 25 mg daily or having reduced renal function or diabetes mellitus type 2. The authors advise that “undetected hyperkalaemia may be suspected as a possible cause of sudden death in some patients treated for heart failure with spironolactone and ACE inhibitors or [ARBs].” (E. H. Wrenger, Otto-von-Guericke-U., Magdeburg, Germany; Eike.Wrenger@medizin.unimagdeburg.de)

>>>Lancet Report
Source:
July 19 issue of Lancet (www.thelancet.com; 2003; 362).

OC Use, Smoking, & Mortality: The all-cause mortality rate was twice as high among women who smoked 15 or more cigarettes per day between 1968 and 1974, compared with all subjects in a study of 17,032 women (pp. 185-91). The women—all of them white and all using oral contraceptives, diaphragms, or intrauterine devices—were recruited at 17 British family planning clinics. By 2000, 889 deaths had occurred. Women who had ever used OCs had increased mortality from cervical cancer (rate ratio, 7.2) but decreased mortality from other uterine and ovarian cancers (0.4).

Deaths from ischemic heart disease were more common among women who smoked 15 or more cigarettes per day. Considering deaths from all causes, the researchers found a rate ratio of 0.89 among ever-users of OCs and 1.24 among women who smoked 1–14 cigarettes per day, both nonsignificant differences. But deaths were significantly elevated (2.14) among women who smoked 15 or more cigarettes per day. Deaths were particularly high among smokers who were also users of OCs, products that, at that time, had higher hormone doses than do contemporary products. (Martin Vessey, U. Oxford, Oxford, U.K.; martin.vessey@dphpc.ox.ac.uk)

>>>PNN JournalWatch
* Therapeutic Potential of Phosphodiesterase 5 Inhibition for Cardiovascular Disease, in Circulation, 2003; 108: 239–44. Reprints: circ.ahajournals.org; T. Reffelmann.

* High-Density vs Low-Density Lipoprotein Cholesterol as the Risk Factor for Coronary Artery Disease and Stroke in Old Age, in
Archives of Internal Medicine, 2003; 163: 1549–54. Reprints: www.archinternmed.com; A. W. E. Weverling-Rijnsburger, Leiden U., Leiden, the Netherlands.

* Aspirin–Angiotensin-Converting Enzyme Inhibitor Coadministration and Mortality in Patients with Heart Failure: A Dose-Related Adverse Effect of Aspirin, in
Archives of Internal Medicine, 2003; 163: 1574–9. Reprints: www.archinternmed.com; M. Guazzi, Università degli Studi di Milano, Milano, Italy; maurizio.guazzi@unimi.it

* Versatility of Aminoglycosides and Prospects for Their Future, in
Clinical Microbiology Reviews, 2003; 16: 430–50. Reprints: cmr.asm.org; S. Mobashery, U. Notre Dame, Notre Dame, Ind.; mobashery@nd.edu

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 22, 2003 Vol. 10, No. 140
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
July 16 issue of the Journal of the American College of Cardiology (www.cardiosource.com; 2003; 42).

ESRD & MI: Aspirin, beta blockers, and ACE inhibitors are significantly less likely to be used in patients with end-stage renal disease after acute myocardial infarction, compared with post-AMI patients without ESRD, despite evidence that the drugs could lower the 30-day mortality rate in such patients (pp. 201-8). In the ESRD and Cooperative Cardiovascular Project databases, the investigators identified 145,740 patients without ESRD and 1,025 with ESRD who had had AMIs. They report, “Aspirin (67.0% vs. 82.4%, p < 0.001), beta-blockers (43.2% vs. 50.8%, p < 0.001), and angiotensin-converting enzyme (ACE) inhibitors (38.5% vs. 60.3%, p < 0.001) were less likely to be administered to ESRD patients than to non-ESRD patients.” However, relative risks of 30-day mortality were reduced by similar amounts in the ESRD and non-ESRD groups: Aspirin, 0.64 and 0.57, respectively; beta blockers, 0.78 and 0.70; and ACE inhibitors, 0.58 and 0.64. (A. K. Berger, U. Minnesota, Minneapolis)

Vitamin C Use & CHD Risk: In a study of 85,118 women nurses, vitamin C supplement use was associated with a lower risk of coronary heart disease (pp. 246-52). During 16 years of follow-up that included 1.24 million person-years of monitoring, 1,356 cases of nonfatal myocardial infarction or fatal CHD occurred. “After adjustment for age, smoking, and a variety of other coronary risk factors, we observed a modest significant inverse association between total intake of vitamin C and risk of CHD (relative risk [RR] = 0.73; 95% confidence interval [CI] 0.57 to 0.94),” the authors write. “Among women who did not use vitamin C supplements or multivitamins, the association between intake of vitamin C from diet alone and incidence of CHD was weak and not significant (RR = 0.86; 95% CI 0.59 to 1.26). In multivariate models adjusting for age, smoking, and a variety of other coronary risk factors, vitamin C supplement use was associated with a significantly lower risk of CHD (RR = 0.72; 95% CI 0.61 to 0.86).” (S. K. Osganian, Children’s Hosp., Boston)

>>>Rheumatology Update
Source:
July issue of Arthritis & Rheumatism (www.interscience.wiley.com/jpages/0004-3591/; 2003; 48).

Early Modification of RA: Earlier disease-modifying treatment is needed in those with rheumatoid arthritis, and therapy must be continued to maintain effectiveness, according to a study of 189 patients (pp. 1797-807). The study included patients recently diagnosed with RA. They received either pyramid treatment that began with NSAIDs for at least 1 year after inclusion or with immediate disease-modifying antirheumatic drugs. The authors observe, “Clinical results in favor of the early DMARD group, as observed after the first year, were not as evident after 5 years. This indicates that a more aggressive treatment approach in early RA is required, and that treatment should be continued for a prolonged period of time, in order to maintain the advantages obtained in the first year.” (S. M. M. Verstappen, U. Med. Ctr., Utrecht, the Netherlands; S.Verstappen@azu.nl)

Polymorphisms & Infliximab Therapy: Genotyping of the tumor necrosis factor-alpha gene may be “a useful tool in predicting response to infliximab treatment,” based on a study of 59 patients with rheumatoid arthritis (pp. 1849-52). The –308 position of the TNF gene was analyzed and matched with patients’ Disease Activity Scores in 28 joints at 22 weeks. The authors noted “that 42% of patients in the A/A and A/G group and 81% of patients in the G/G group had improvement of at least 1.2 in the DAS28 score (P= 0.0086)” They add, “The average improvement in the DAS28 score was 1.24 in the A/A and A/G patients and 2.29 in the G/G patients (P= 0.029).... These data suggest that patients with a TNF –308G/G genotype are better infliximab responders than are patients with A/A or A/G genotypes.” (J. Roudier, Faculté de Médecine, Marseille, France; jean.roudier@medecine.univ-mrs.fr)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 23, 2003 Vol. 10, No. 141
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
July 23 issue of JAMA (www.jama.com; 2003; 290).

Breast Cancer After Radiotherapy or Chemotherapy: Counter to some theories, less may be better when it comes to radiotherapy for Hodgkin’s disease if later occurrence of breast cancer is considered (pp. 465-75). In a case–control study of 3,817 female 1-year survivors of Hodgkin’s disease who were diagnosed at age 30 years or younger, radiation doses of 4 Gy or more delivered to the breast were associated with a 3.2-fold increase in breast cancer, compared with women who received lower radiation doses and no alkylating-agent chemotherapy. When doses of 40 Gy or more were delivered to the breast, relative risks jumped to 8.2; elevated breast cancer rates in these patients persisted for 25 years following treatment. The authors note, “Treatment with alkylating agents alone resulted in a reduced risk (RR, 0.6; 95% CI, 0.2–2.0) of breast cancer, and combined alkylating agents and radiotherapy in a 1.4-fold (95% CI, 0.6–3.5) increased risk. Risk of breast cancer decreased with increasing number of alkylating agent cycles (P= .003 for trend). Risk also was low (RR, 0.4; 95% CI, 0.1–1.1) among women who received 5 Gy or more delivered to ovaries compared with those who received lower doses.” (L. B. Travis, travisl@mail.nih.edu)

The study’s positive trends for chemotherapy treatment of Hodgkin’s disease prompted this passage by an editorialist (pp. 529-31): “This finding is not only biologically exciting, but also may encourage interventions to reduce hormonal stimulation of breast tissue during and after treatment. Recent data in women at high risk for developing breast cancer demonstrated that tamoxifen reduced risk of breast cancer by 38%. Tamoxifen should possibly be considered for patients with [Hodgkin’s disease] who have been treated with radiation that resulted in breast exposure.” (J. Yahalom, Memorial Sloan-Kettering Cancer Ctr., New York City; yahalomj@mskcc.org)

Antioxidant Vitamin Supplements & Cancer: Long-term mortality rates were higher among patients who took daily doses of beta-carotene 20 mg in a study of 25,563 male smokers aged 50–69 years, while supplementation with alpha-tocopherol 50 mg provided a statistical trend toward lower rates of prostate cancer (pp. 476-85). In the Finnish Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) study, postintervention analysis revealed that both beneficial and adverse effects of supplementation with the two antioxidant vitamins disappeared during 4–6 years of follow-up. “The recommendations made at the time our initial trial results were reported remain appropriate: the possible preventive effect of alpha-tocopherol on prostate cancer requires confirmation from other trials before public health recommendations can be made for vitamin E,” conclude the authors. “Also, beta-carotene supplementation should be avoided by smokers since it may be harmful to them.” (J. Virtamo, National Public Health Inst., Helsinki, Finland; jarmo.virtamo@ktl.fi)

Acarbose & CVD Risk: The risks of cardiovascular disease and hypertension are significantly reduced during acarbose treatment of patients with impaired glucose tolerance, according to findings of a 341-patient, 3-year study (pp. 486-94). “Decreasing postprandial hyperglycemia with acarbose was associated with a 49% relative risk reduction in the development of cardiovascular events ... and a 2.5% absolute risk reduction,” the authors report. “Among cardiovascular events, the major reduction [91%] was in the risk of myocardial infarction.... Acarbose was also associated with a 34% relative risk reduction in the incidence of new cases of hypertension ... and a 5.3% absolute risk reduction. Even after adjusting for major risk factors, the reduction in the risk of cardiovascular events [53%] and hypertension [38%] associated with acarbose treatment was still statistically significant.” The authors conclude that these results support the theory that postprandial hyperglycemia is a risk factor for cardiovascular disease and that patients should be screened and treated patients for impaired glucose tolerance. (J-L Chiasson, jean.louis.chiasson@umontreal.ca)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 24, 2003 Vol. 10, No. 142
Providing news and information about medications and their proper use

>>>Health Affairs Update
Source:
Posted July 23 on Health Affairs (www.healthaffairs.org).

Declines in Retirees’ Prescription Drug Benefits: The proportion of new retirees with employer-sponsored prescription drug benefits declined from 40% in 1996 to 35% in 2000 (Web exclusive article). In a study of about 12,000 Medicare beneficiaries per year in the 65–69 year old range, the investigators also find a decreasing level of employer-sponsored health insurance (46% in 1996 versus 39% in 2000).

Men were more affected by the trend than were women. The share of men receiving benefits from their own retirement policies fell 26% between 1996 and 2000. The rate of decline for men (nine percentage points) was three times that of women (three percentage points). The authors indicate that the erosion of retiree benefits would have been higher during the study period had men not increasingly sought coverage under their spouses’ policies (17% of men with retiree benefits obtained them from a spouse in 1996, compared with 25% in 2000).

With Congress considering waiting until 2006 for the new Medicare drug benefit to take effect, the authors worry that seniors may have difficulty protecting themselves in the meantime, since there is no evidence that reduction in offer rates for retiree medical and drug benefits has bottomed out. “All indications are that employer-sponsored benefits available to new retirees are going to erode,” the study’s lead author said in a news release from the journal. “This is especially alarming since any new prescription drug benefit sponsored by Congress won’t be available for several more years, and even those proposed benefits are likely to be far less than the benefits most retirees already receive.” (B. Stuart, bstuart@rx.umaryland.edu)

>>>NEJM Highlights
Source:
July 24 issue of the New England Journal of Medicine (content.nejm.org; 2003; 349).

Epidermal Growth Factor & Ulcerative Colitis: Combined with oral mesalamine, epidermal growth factor enemas were effective in treatment of active left-sided ulcerative colitis and proctitis (pp. 350-7). EGF, a potent mitogenic peptide produced by salivary glands, was administered to 12 patients in daily enemas of 5 mcg in 100 mL of an inert carrier for 14 days. For the 4 weeks that constituted the study duration, the patients also received oral slow-release mesalamine 1.2 g/day, or if they were already on this drug, their dose was increased by 1.2 g/day. Ten of the patients were in remission at 2 weeks, compared with 1 of 12 patients who received daily enemas with carrier only plus mesalamine. “At the 2-week assessment, disease-activity scores, sigmoidoscopic score, and histologic scores were all significantly better in the EGF group than in the placebo group (P < 0.01 for all comparisons), and this benefit was maintained at 4 weeks and at 12 weeks,” the authors write. “To determine optimal doses and delivery methods, larger studies that directly compare EGF with high-dose mesalamine or corticosteroids appear to be warranted.” (J. M. D. Nightingale, Leicester Royal Infirmary, Leicester, U.K.; jeremy.nightingale@uhl-tr.nhs.uk)

An editorialist cautions that this study used an unvalidated instrument for assessing disease severity and worries that “treating chronic ulcerative colitis with EGF enemas in concentrations 100 times as high as those normally found in gastric juice could induce malignant cell transformation in regenerating mucosal epithelium” (pp. 395-7; R. J. Farrell, Harvard Med. Sch., Boston).

Bone Strength Index: Because bone increases in size during the bone loss of menopause, a bone strength index is needed to help predict the risk of fracture, according to a 15-year study of 108 women (pp. 327-34). Bone mineral density declined by 1.9% per year, but increases in medullary bone diameter (1.1%) and periosteal diameter (0.7%) enabled the strength index to drop by only 0.7%. “Increased bone loss after menopause is associated with increased periosteal apposition, which partially preserves bone strength,” the authors note. (H. G. Ahlborg, U. Hosp., Malmö, Sweden; henrik.ahlborg@skane.se)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 25, 2003 Vol. 10, No. 143
Providing news and information about medications and their proper use

>>>Pediatrics Highlights
Source:
July issue of Pediatrics (www.pediatrics.org; 2003; 112).

Pneumococcal Vaccine in HIV-Infected Infants: Heptavalent pneumococcal conjugate vaccine proved immunogenic and well tolerated among 30 infants with HIV infection (pp. 66-73). Infants received PCV or placebo at 2, 4, 6, and 15 months, and immunogenicity was assessed after the third dose, before and after the 15-month booster dose, and at 24 months. The authors report, “Five severe acute reactions were experienced by 4 subjects: 3 in the PCV arm and 1 in the placebo arm; all occurred among subjects with symptomatic disease at study entry. No differences were found in the 2 arms with respect to the number or timing of new diagnoses through 24 months of age, including diagnoses of otitis media.... The primary immunogenicity measures were based on composites of 4-fold changes in serotype-specific immunoglobulin G titers from preimmunization levels. We found a highly significant difference between the vaccine and placebo arms, with the PCV arm showing higher rates of response. Asymptomatic and symptomatic subjects who received PCV had similar immunologic responses for all serotypes.” (Sharon Nachman, State U. New York Health Science Center, Stony Brook)

QOL & Childhood Migraines: Impairments in school and emotional functioning are prominent in children with migraines, according to a health-related quality of life study (e1-e5). Among 572 consecutive patients with headache, 99% had a clinical diagnosis of migraine, and 40% had chronic daily headaches. Total Pediatric Quality of Life Inventory scores were lowest among the children with daily headaches (70.5) and lower for the group as a whole (73.1) than for healthy norms (83.0). (S. W. Powers, Cincinnati Children’s Hosp. Med. Ctr.)

Opinions on Rotavirus Vaccine: Pediatricians in Wisconsin and Georgia would use a safer rotavirus vaccine, if such a product became available, according to a survey (e6-e10). Just 15% would administer the rhesus-based rotavirus tetravalent vaccine that was withdrawn from the market, if it were now available. But 94% of 319 respondents indicated they would use a safer alternative recommended by the American Academy of Pediatrics and the Advisory Committee on Immunization Practices for routine use among infants. “Barriers to reintroducing a rotavirus vaccine were fear of adverse reactions among 95% of pediatricians, followed by potential high vaccine cost (63%) and amount of time required to educate parents (57%),” the authors add. (M. Iwamoto, Emory U., Atlanta)

Diagnosis & Treatment of Otitis Media: In a study of 29 community pediatricians in St. Louis, overdiagnosis of acute otitis media was common, and broad-spectrum antibiotics were overused (pp. 143-9). Chart reviews and self-reports were used to assess compliance with CDC’s recommended diagnostic criteria and guidelines for antimicrobial selection. Chart audit indicated that diagnostic criteria were followed in 38% of cases, while self-reports yielded a 41% figure. Pediatricians reported they adhered to treatment guidelines for 100% of new-infection cases and 83% of treatment failures, but chart audit showed these respective figures were 68% and 50%. “Noncompliance was most frequently attributable to overuse of broad-spectrum antimicrobials,” the authors wrote. “Most patients treated with amoxicillin received a 10-day course (98%). Subtherapeutic dosing occurred in 26% of patients treated with amoxicillin.” (J. Garbutt, Washington U., St. Louis)

Care of the Newborn: Use of vitamin K in the newborn is the focus of a policy statement from the American Academy of Pediatrics Committee on Fetus and Newborn (pp. 191-2). It updates recommendations on use of vitamin K in prevention of early and late vitamin K deficiency bleeding. A clinical report assesses immunization practices for preterm and low birth weight infants, including modifications in the timing of hepatitis B immunoprophylaxis (pp. 193-8; T. N. Saari and the AAP’s Committee on Infectious Diseases).

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 28, 2003 Vol. 10, No. 144
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
July 26 issue of Lancet (www.thelancet.com; 2003; 362).

Coronavirus & SARS: SARS-associated coronavirus is confirmed in a macaque study to be the causative agent of severe acute respiratory syndrome (pp. 263-70). Combined with “the high prevalence of SARS-CoV infection in SARS patients,” the authors conclude that “replication in SARS-CoV-infected macaques of pneumonia similar to that in human beings with SARS fulfill the criteria required to prove that SARS-CoV is the primary cause of SARS.” (T. Kuiken, Erasmus Med. Ctr., Rotterdam, the Netherlands; t.kuiken@erasmusmc.nl)

SARS & Human Interferons: Tests of cell cultures indicate that human interferon beta might be effective in treatment of the coronavirus that causes severe acute respiratory syndrome (pp. 293-4). All three interferons tested —alpha, beta, and gamma— showed some effectiveness for treating the SARS-CoV, but “interferon beta was most potent, showing prophylactic protection and antiviral potential after infection.” The investigators conclude, “Interferon beta could be the drug of choice, alone or in combination with other antiviral drugs, in the treatment of SARS.” (J. Cinatl, Frankfurt U., Frankfurt; cinatl@em.uni-frankfurt.de)

Life Expectancy & Reduction of Risk Factors: Efforts to reduce risk factors could increase life expectancy in both developed and developing countries, according to an analysis of premature deaths and disease burden in 2000 (pp. 271-80). “[Twenty preventable risk factors] caused a substantial proportion of important diseases, including diarrhoea (92–94%), lower respiratory infections (55–62%), lung cancer (72%), chronic obstructive pulmonary disease (60%), ischaemic heart disease (83-89%), and stroke (70-76%),” authors wrote. “Removal of these risks would have increased global healthy life expectancy by 9.3 years (17%) ranging from 4.4 years (6%) in the developed countries of the western Pacific to 16.1 years (43%) in parts of sub-Saharan Africa.” (M. Ezzati, mezzati@hsph.harvard.edu)

>>>BMJ Highlights
Source:
July 26 issue of BMJ (www.bmj.org; 2003; 327).

Physician-Assisted Suicide: Analysis of 25 years of Dutch data shows that the number of patient requests for euthanasia and physician-assisted suicide has plateaued at about 5,000 per year (pp. 201-2). Requests increased during the first decade, reflecting liberalization and publicity, note the authors. “The importance of pain in such requests decreased significantly, paralleled by a proportional increase in the importance of deteriorating health,” the group adds. “Improvements in pain management and the increasing importance of feelings like self esteem are obvious reasons for these changes... Some people feared that the lives of increasing numbers of patients would end through medical intervention, without their consent and before all palliative options were exhausted. Our results, albeit based on requests only, suggest that this fear is not justified.” (R. L. Marquet, Netherlands Inst. for Health Services Res., Utrecht, the Netherlands; r.marquet@nivel.nl)

>>>PNN JournalWatch
* Heart Failure: The Frequent, Forgotten, and Often Fatal Complication of Diabetes, in Diabetes Care, 2003; 26: 2433–41. Reprints: care.diabetesjournals.org; D. S. H. Bell, U. Alabama, dbell@endo.dom.uab.edu

* Celecoxib, a Selective Cyclo-Oxygenase-2 Inhibitor, Enhances the Response to Preoperative Paclitaxel and Carboplatin in Early-Stage Non–Small-Cell Lung Cancer, in
Journal of Clinical Oncology, 2003; 21: 2645–50. Reprints: www.jco.org; N. K. Altorki, Cornell U., New York City; nkaltork@med.cornell.edu

* Combined-Modality Treatment of Solid Tumors Using Radiotherapy and Molecular Targeted Agents, in
Journal of Clinical Oncology, 2003; 21: 2760–76. Reprints: www.jco.org; L. L. Siu, Princess Margaret Hosp., Toronto; lillian.siu@uhn.on.ca

* Analgesic Use: A Predictor of Chronic Pain and Medication Overuse Headache: The Head–HUNT Study, in
Neurology, 2003; 61: 160–4. Reprints: www.neurology.org; J-A Zwart.

* Medical Errors on an Inpatient Neurology Service, in
Neurology, 2003; 61: 254–7. Reprints: www.neurology.org; S. Frank.

* Prostate Cancer, in
New England Journal of Medicine, 2003; 349: 366–81. Reprints: content.nejm.org; W. G. Nelson, Johns Hopkins U., Baltimore; bnelson@jhmi.edu

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 29, 2003 Vol. 10, No. 145
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
July 28 issue of Archives of Internal Medicine (www.archinternmed.com; 2003; 163).

Treatment of Superficial Vein Thrombosis: Use of preventive- or curative-dose enoxaparin or an investigational NSAID prevented thromboembolic complications in 427 adult patients with documented acute symptomatic superficial vein thrombosis of the legs, compared with placebo (pp. 1657-63). Once daily for 8 to 12 days, patients randomly received subcutaneous enoxaparin sodium 40 mg; subcutaneous enoxaparin 1.5 mg/kg; oral tenoxicam; or placebo. While 3.6% of patients on placebo had deep venous thromboembolism by day 12, ultrasonography demonstrated such problems in 0.9%, 1.0%, and 2.1% of those on the three respective active treatments (nonsignificant differences). Significant reductions were demonstrated in the combined incidence of deep and superficial VT (30.6%, 8.3%, 6.9%, and 14.9% in the placebo, enoxaparin 40 mg, enoxaparin 1.5 mg/kg, and tenoxicam groups, respectively). No deaths or major bleeding complications occurred during the study. (Superficial Thrombophlebitis Treated by Enoxaparin Study Group, H. Decousus, Hôpital Bellevue, Saint-Etienne, France; decousus@univ-st-etienne.fr)

Oseltamivir Use in Healthy and At-Risk Patients: Lower respiratory tract complications (LRTCs), antibiotic use, and hospitalizations were reduced among both healthy and at-risk adolescents and adults whose influenza infections were treated with oseltamivir, according to an analysis of prospectively collected data from 10 clinical studies (pp. 1667-72). A total of 3,564 subjects 13–97 years of age had influenza-like illness. Among those with proven influenza infections, “oseltamivir treatment reduced overall antibiotic use for any reason by 26.7% (14.0% vs 19.1% with placebo; P<.001) and the incidence of influenza-related LRTCs resulting in antibiotic therapy by 55% (4.6% vs 10.3% with placebo; P<.001), the authors report. “In those subjects considered at increased risk of complications, 74 (18.5%) of 401 placebo recipients developed an LRTC leading to antibiotic use compared with 45 (12.2%) of 368 oseltamivir recipients (34.0% reduction; P= .02). Hospitalization for any cause occurred in 18 (1.7%) of 1063 placebo recipients compared with 9 (0.7%) of 1350 oseltamivir-treated patients (59% reduction; P= .02).” Differences were not significant among patients who had influenza-like infection but without a confirmed diagnosis of influenza infection. (F. Hayden, fgh@virginia.edu)

Naltrexone & Alcohol Dependence: For patients whose alcohol dependence is managed through primary care rather than cognitive-behavioral approaches, naltrexone therapy provides an important therapeutic option (pp. 1695-704). In a nested sequence of three trials, naltrexone 50 mg/day yielded no significant difference among 197 patients who received either primary care management or cognitive–behavioral therapy in an initial 10-week trial (84.1% and 86.5% of patients in the two respective groups abstained from persistent heavy drinking).

In the second study, 53 patients who had responded to primary care management had better outcomes when naltrexone was continued for 24 weeks. While 80.8% of those on PCM plus naltrexone were abstinent, only 51.9% of those on PCM plus placebo continued to respond.

Continuation of cognitive– behavioral therapy for 24 weeks in 60 patients was successful both with or without naltrexone: 83.3% of those on CBT plus active therapy continued to respond, statistically similar to the 70.0% of those on CBT plus placebo. (S. S. O’Malley, stephanie.omalley@yale.edu)

Warfarin Underuse:
Among 11,699 Ohio Medicaid patients with nonvalvular atrial fibrillation, only 9.7% of all patients and 11.9% of those without apparent contraindications filled prescriptions for warfarin from 7 days preceding to 30 days after the development of AF (pp. 1705-10). Analysis of 1998–2000 data showed that several highly prevalent factors predicted against warfarin prescribing: alcohol or other drug abuse or dependence, psychiatric disease, homelessness or inadequate housing, and lack of a caregiver. (J. A. Johnston, jjohnston2@indy.rr.com)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 30, 2003 Vol. 10, No. 146
Providing news and information about medications and their proper use

>>>Pharmacy Faculty Focus of Recruitment Effort
Concluding that a shortage of pharmacy faculty is threatening efforts to meet the nation’s increasing demand for pharmacists, the American Foundation for Pharmaceutical Education yesterday announced a $12 million scholarship campaign aimed at recruitment of new teachers. Specifically, AFPE intends to fund up to:

* Thirty $5,000, 1-year, research project scholarships for pharmacy students who have demonstrated an aptitude for a career in academic pharmacy and research

* Ninety-five $25,000, 3-year, predoctoral fellowships for outstanding students at colleges and schools of pharmacy who seek a career in academic pharmacy and who are in their final stages of their PhD coursework and research

* Thirty $10,000, 1-year pharmacy faculty new investigator grants to help new pharmacy faculty establish their research programs and secure the government or private-sector research grants helpful in securing a tenured faculty position

A Dec. 2002 survey conducted by the American Association of Colleges of Pharmacy indicated an average of 6 vacancies at each of the nation’s pharmacy schools. Most of these were full-time positions in either pharmacy practice or pharmaceutical sciences. Pharmacy professors are leaving for higher-paying jobs at hospitals and in the pharmaceutical industry (32%) or moving to other pharmacy schools (29%). Retirements are forecast to increase the “brain drain” on U.S. colleges of pharmacy, with 37% of current pharmacy professors now older than 50 and 24% of pharmacy deans older than 60.

The AFPE effort coincides with a renewed push to pass the Pharmacy Education Aid Act of 2003, which would increase the ability of colleges and schools of pharmacy to educate more pharmacists. At a news conference held yesterday in Washington, AFPE exec Bob Bachman was joined by Sen. Jack Reed (D–RI), AACP exec Lucinda Maine, and Kurt Proctor, president of the NACDS Foundation.

>>>Circulation Highlights
Source:
July 29 Circulation (circ.ahajournals.org; 2003; 108).

Lotrafiban for Coronary and Cerebrovascular Disease: All-cause mortality was increased among 9,190 patients with atherosclerotic vascular disease when treated with lotrafiban, an orally administered glycoprotein IIb/IIIa inhibitor (pp. 399 ff). In a placebo-controlled, randomized trial, lotrafiban was dosed at 30 or 50 mg twice daily based on age and predicted creatinine clearance, and aspirin 75–325 mg/day was used at the clinicians’ discretion. Patients, who had cerebrovascular disease (41%) or coronary artery disease (59%), were followed for 2 years. Compared with placebo, lotrafiban produced a 33% increase in all-cause mortality (3.0% vs. 2.3% with placebo), with the cause of excess death vascular related. “Serious bleeding was more frequent in the lotrafiban group (8.0% compared with 2.8%; P<0.001),” the authors write. “Serious bleeding was more common among patients who received higher doses of aspirin (>162 mg/d), with or without lotrafiban.” (E. Topol, Cleveland Clinic Foundation, Cleveland; topole@ccf.org)

Predicting CHD Events & New-Onset Diabetes: Substitution of body mass index for waist circumference in a commonly used definition for metabolic syndrome enables prediction of coronary heart disease events and even new-onset diabetes, according to an analysis of data from the West of Scotland Coronary Prevention Study (pp. 414 ff). Investigators adapted the definition for metabolic syndrome of the National Cholesterol Education Program. “Men with 4 or 5 features of the syndrome had a 3.7-fold increase in risk for CHD and a 24.5-fold increase for diabetes compared with men with none (both P<0.0001),” the authors note. “C-reactive protein enhanced prognostic information for both outcomes... A modified NCEP metabolic syndrome definition predicts CHD events, and, more strikingly, new-onset diabetes, and thus helps identify individuals who may receive particular benefit from lifestyle measures to prevent these diseases.” (N. Sattar, Glasgow Royal Infirmary, Glasgow, Scotland; nsattar@clinmed.gla.ac.uk)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 31, 2003 Vol. 10, No. 147
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
July 31 issue of the New England Journal of Medicine (content.nejm.org; 2003; 349).

Drug-Induced Hepatotoxicity: The difficulties with identifying drugs that cause liver damage, monitoring known hepatotoxins, and managing patients once symptoms begin are reviewed (pp. 474-85). “Drug-induced hepatic injury is the most frequent reason cited for the withdrawal from the market of an approved drug, and it also accounts for more than 50 percent of the cases of acute liver failure in the United States today,” writes the author. “More than 75 percent of cases of idiosyncratic drug reactions result in liver transplantation or death....

“Case reports of toxic effects that appear in the first years after a drug is approved may help the FDA determine which new agents require closer scrutiny, as exemplified by some recent case reports of hepatotoxic effects of newer agents. Patients may not initially report taking complementary and alternative medications, which do not require prescriptions or FDA oversight. A careful inquiry by the physician may be necessary to identify the use of complementary medications and determine their role in liver injury. Monitoring aminotransferase levels on a monthly basis for the first six months of treatment has been suggested for patients taking medications that are known hepatotoxins, such as isoniazid or diclofenac. However, monitoring is unlikely to be effective in the case of a rare adverse reaction, such as that seen with terbinafine (incidence, 1 in 50,000). Monitoring is seldom performed consistently, and even if it were, it provides no guarantee of safeguarding the patient, since many drug reactions develop abruptly. Many deaths could be prevented if the offending drug were discontinued at the first sign of an adverse reaction.” (W. M. Lee, U. Texas Southwestern Med. Ctr., Dallas; william.lee@utsouthwestern.edu)

Bisphosphonate-Induced Osteopetrosis: In a 12-year-old boy, osteopetrosis was identified that had developed over a 2.75-year period that coincided with pamidronate administration (pp. 457-63). The patient’s case was complicated, with unusual and largely unexplained bone pain and trauma since age 6. However, none of the problems before bisphosphonate use were consistent with osteopetrosis. The authors conclude, “The amount of pamidronate our patient received is more than four times the amount that is typically administered during this time frame to children with osteogenesis imperfecta and other disorders. Had the cumulative dose been given over a longer period, the changes would most likely have been less pronounced. However, bisphosphonate treatment is often administered for years to children. To date, the therapeutic end points seem unclear for most pediatric conditions. Accordingly, more cases of bisphosphonate-induced toxicity may emerge.... On the basis of our finding of drug-induced osteopetrosis in a child, we caution that excessive doses of bisphosphonates may compromise skeletal quality in growing patients despite concomitant increases in bone density.” (M. P. Whyte, Shriners Hospitals for Children, St. Louis; mwhyte@shrinenet.org)

An editorialist adds (pp. 423-6): “Bisphosphonates should be used with caution in children and are best reserved for clinical trials or children with acute lytic lesions. Controlled trials should address the effect of bisphosphonates on functional mobility and lower-limb strength, as well as bone density, geometry, the risk of fractures, histologic features, and biomechanics. Whether predominantly trabecular vertebral bone and cortical bone in the arms and legs have different responses to bisphosphonates should be examined. These cautions do not preclude a role for bisphosphonates in pediatric bone disorders. The use of lower doses at longer intervals might provide a benefit without a long-term detriment in bone quality.... Alternating treatment periods with extended drug holidays could lead to a more normal bone quality than does continuous treatment. Finally, all these assessments of the safety and efficacy of bisphosphonates in children require validation with a better measure of bone quality than dual-energy x-ray absorptiometry.” (J. C. Marini, NIH, Bethesda, Md.)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Aug. 1, 2003 Vol. 10, No. 148
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Aug. issue of Diabetes Care (care.diabetesjournals.org; 2003; 26).

Insulin vs. Oral Therapy: Insulin therapy scored well in two studies, one of early insulin therapy and another that tested insulin care of refractory patients with type 2 diabetes.

Compared with glyburide, early insulin therapy temporarily prolonged endogenous insulin secretion and promoted better metabolic control, authors reported (pp. 2231-7). In 39 patients who had been diagnosed with islet cell antibody-negative type 2 diabetes within 2 years of study admission, two daily injections of premixed 30% soluble and 70% NPH insulin were compared with glyburide 3.5–10.5 mg daily. The glucagon-stimulated C-peptide response improved during the first year of therapy in the insulin-treated group but declined in glyburide patients, yielding a significant difference. After a second year of therapy, patients on insulin had significantly better fasting insulin levels and glycosylated hemoglobin values. (M. Alvarsson, Karolinska Hosp., Stockholm, Sweden; michael.alvarsson@ks.se)

At a lower cost and with better patient acceptance, insulin therapy was as effective as triple oral therapy for treating refractory patients (pp. 2238-43). The study of aggressive dose titration began with 188 patients with type 2 diabetes who did not respond sufficiently to two oral medications. They were randomized to treatment with either a third oral medication or an insulin 70/30 mix twice daily plus metformin. Those failing to achieve glycemic control targets were switched to alternate therapies. Over a 24-week period, patients in both groups showed similar improvements in glycosylated hemoglobin and fasting plasma glucose levels, but only about one-third of each group reached the A1c goal of 7%. Of 98 subjects on triple oral therapy, 10 were switched to insulin therapy because of poor response, and another four subjects dropped out of that arm of the trial because of adverse effects perceived to be drug related. “Only two of the subjects randomized to insulin plus metformin had to be switched to basal-bolus regimens (regular insulin and NPH insulin),” add the authors. “Cost analysis determined that insulin plus metformin (mean cost $3.20/day) provided efficacy equal to that of a triple oral drug regimen ($10.40/day).” (S. Schwartz, Diabetes and Glandular Disease Clinic, San Antonio; sschwartz@dgdclinic.com)

Combination Renoprotective Therapy: Compared with maximally recommended doses of ACE inhibitors, dual blockade of the renin–angiotensin system with angiotensin II receptor blockers and ACE inhibitors provides better short-term renoprotection, according to a study of 17 men and 3 women with type 2 diabetes and nephropathy (pp. 2268-74). The 8-week crossover trial added candesartan 16 mg daily to existing treatment with lisinopril or enalapril 40 mg daily or captopril 150 mg daily. Compared with treatment with ACE inhibitors alone, albuminuria was significantly decreased, ambulatory systolic and diastolic blood pressures over 24 hours were modestly but not significantly reduced, and glomerular filtration rate decreased slightly but not significantly during dual blockade. Changes in albuminuria did not correlate with changes in blood pressures. (K. Rossing, Steno Diabetes Ctr., Gentofte, Denmark; krossing@dadlnet.dk)

Low-Glycemic Index Diets: Use of low glycemic index foods produces “a small but clinically useful effect on medium-term glycemic control in patients with diabetes,” according to results of a meta-analysis of 14 studies that included 356 subjects (pp. 2261-7). The duration of trials was from 12 days to 12 months (mean, 10 weeks), and interventions were required for at least two meals per day. The authors found that low glycemic index diets reduced A1c levels by an average of 0.43 percentage points, and glycated proteins (A1c and fructosamine) were reduced by 7.4% more on low versus high glycemic index diets, benefits similar to those provided by pharmacological agents that also target postprandial hyperglycemia. (J. Brand-Miller, U. Sydney, Sydney, Australia; j. brandmiller@mmb.usyd.edu.au)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Aug. 4, 2003 Vol. 10, No. 149
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Aug. 2 issue of BMJ (www.bmj.org; 2003; 327).

Vitamin A & Infant Mortality: In a study conducted in southern India, vitamin A supplements reduced total mortality by 22% among 11,619 newborn infants (pp. 254 ff). Infants received either placebo or vitamin A 24,000 IU on days 1 and 2 after delivery. “Infants in the vitamin A group had a 22% reduction in total mortality (95% confidence interval 4% to 37%) compared with those in the placebo group,” the authors write. “Vitamin A had an impact on mortality between two weeks and three months after treatment, with no additional impact after three months.... Supplementing newborn infants with vitamin A can significantly reduce early infant mortality.” Vitamin A’s effects on mortality could be mediated through several mechanisms: providing a stimulus to rapid maturation of both gut and respiratory epithelium, making them more resistant to invasion by pathogens; development and maintenance of immunocompetence through effects on T cells, phagocytes, and antibodies; or enhancements of gene expression and cell differentiation. (J. M Tielsch, Johns Hopkins University, Baltimore; jtielsch@jhsph.edu)

Care of Young Adults with Type 1 Diabetes: A British study indicates that young people with type 1 diabetes have trouble attending clinics, placing them at greater risk for complications (pp. 260-1). Among 397 such patients (aged 16–25 years) seen at four diabetes clinics, the mean glycosylated hemoglobin level was 9.5%, and 34 patients (15% of those tested) were hypertensive. Of the patients with documented hypertension, 24 (71%) had been tested for albuminuria, with 10 (42%) positive results. Eight of those patients were taking ACE inhibitors. “For young adults with type 1 diabetes in this study, glycaemic control is generally poor, attendance at the clinic and screening for complications are suboptimal, and microvascular complications are common,” the researchers found. “Achieving good glycaemic control in youth yields future health, quality of life, and cost benefits but is difficult for many psychological and social reasons. Cooperation between paediatricians and diabetologists should provide a smooth transition of care from childhood to adulthood.” (C. J. Wills, Queen’s Med. Ctr., Nottingham; catherinewills1@hotmail.com)

>>>PNN JournalWatch
* Pain as a Complication of Use of Opiate Antagonists for Symptom Control in Cholestasis, in Gastroenterology, 2003; 125: 591–6. Reprints: www.gastro.org; D. E. J. Jones, U. Newcastle, Newcastle-upon-Tyne, U. K.; D.E.J.Jones@ncl.ac.uk

* Vitamin D, Cod-Liver Oil, Sunlight, and Rickets: A Historical Perspective, in
Pediatrics, 2003; 112: e132–e135. Reprints: www.pediatrics.org; K. Rajakumar, U. Pittsburgh, Pittsburgh.

* Otitis Media and Tympanostomy Tube Insertion During the First Three Years of Life: Developmental Outcomes at the Age of Four Years, in
Pediatrics, 2003; 112: 265–77. Reprints: www.pediatrics.org; J. L. Paradise, U. Pittsburgh, Pittsburgh.

* Treating Exacerbations of Asthma in Children: The Role of Systemic Corticosteroids, in
Pediatrics, 2003; 112: 382–97. Reprints: www.pediatrics.org; G. Rachelefsky, Allergy Research Foundation, Los Angeles.

* Fish Tank Exposure and Cutaneous Infections Due to
Mycobacterium marinum: Tuberculin Skin Testing, Treatment, and Prevention, in Clinical Infectious Diseases, 2003; 37: 390–7. Reprints: www.journals.uchicago.edu/ CID; F. M. T. Lewis, Dartmouth-Hitchcock Med. Ctr., Lebanon, N.H.

* Cholera, Diarrhea, and Oral Rehydration Therapy: Triumph and Indictment, in
Clinical Infectious Diseases, 2003; 37: 398–405. Reprints: www.journals.uchicago.edu/CID; R. L. Guerrant, U. Virginia, Charlottesville.

* Amphotericin B: Time for a New “Gold Standard,” in
Clinical Infectious Diseases, 2003; 37: 415–25. Reprints: www.journals.uchicago.edu/CID; L. Ostrosky-Zeichner, U. Texas Med. Sch., Houston.

* Detection of Viruses in Myocardial Tissues by Polymerase Chain Reaction: Evidence of Adenovirus as a Common Cause of Myocarditis in Children and Adults, in
Journal of the American College of Cardiology, 2003; 42: 466–72. Reprints: www.cardiosource.com; N. E. Bowles, Baylor Coll. of Med., Houston.

* Acute Decompensated Heart Failure: A Contemporary Approach to Pharmacotherapeutic Management, in
Pharmacotherapy, 2003; 23: 997–1020. Reprints: www.accp.com; C. M. White, Hartford Hosp., Hartford, Ct.; cmwhite@harthosp.org

* Management of Nephrotic Syndrome in Children, in
Pharmacotherapy, 2003; 23: 1021–36. Reprints: www.accp.com; R. F. Robinson, robinsonr@pediatrics.ohio-state.edu

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Aug. 5, 2003 Vol. 10, No. 150
Providing news and information about medications and their proper use

>>>FDA Issues Approvals
A trio of FDA approvals—of a new compound, a recombinantly produced agent, and a new indication—merit pharmacists’ attention.

Miglustat (Zavesca, Actelion) is the first oral treatment option for type 1 Gaucher disease and the first substrate reduction therapy, which reduces the amount of glycosphingolipid production to a level that can effectively be cleared by naturally occurring glucocerebrosidase in liver, spleen, and bone marrow cells. FDA approved miglustat for treatment of adult patients with mild or moderate type 1 Gaucher disease for whom enzyme replacement therapy is not a therapeutic option (e.g., because of constraints such as allergy, hypersensitivity, or poor venous access). Miglustat is contraindicated in women who are or may become pregnant.

Advate Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method (Baxter) has been approved to prevent and control bleeding episodes or to prepare persons with hemophilia for surgery. The factor VIII product is produced by genetically engineered Chinese hamster ovary cells, and avoidance of use of plasma and albumin makes the product safer than currently marketed recombinant factor VIII products. However, older natural products are also considered very safe, having been tested for HIV and hepatitis B and C viruses since 1987, and albumin-containing recombinant products are also available.

Porfimer sodium (Photofrin Injection, Axcan Scandipharm) has been approved for ablation of precancerous lesions (high-grade dysplasia) in Barrett’s esophagus patients who do not undergo esophagectomy. The clinical study supporting this new use showed that patients receiving this photosensitizing agent were more likely to achieve complete reversal of their precancerous lesions in Barrett’s esophagus compared with those who did not receive porfimer. The drug’s adverse effects include photosensitivity reactions and esophageal strictures. Product labeling includes information on precautions that should be taken to avoid exposure of skin and eyes to bright light.

>>>Internal Medicine Report
Source:
Aug. 5 issue of the Annals of Internal Medicine (www.annals.org; 2003; 139).

Losartan v. Atenolol for Stroke Reduction: Among 6,886 men and women patients with hypertension but with no clinically evident vascular disease, losartan was more effective than atenolol in preventing cardiovascular morbidity and death, especially stroke, independent of blood pressure reduction (pp. 169-77). The patients, 57% of whom were women, ranged in age from 55 to 80 years (mean, 66 years) and had a mean blood pressure was 174/98 mm Hg. While blood pressure was “reduced similarly by losartan and atenolol,” a composite end point of cardiovascular death, stroke, or myocardial infarction was reached in 282 losartan-treated patients (17.5 per 1,000 patient-years), compared with 355 atenolol-treated patients (21.8 per 1,000 patient-years), a significant reduction of 19%. Cardiovascular death was reduced by 20% with losartan (a nonsignificant reduction, given the smaller number of patients), while the number of MIs was higher with losartan than with atenolol (a nonsignificant increase of 14%). The risk of stroke, both fatal and nonfatal, was 34% lower with losartan, a significant reduction. In addition, fewer patients on losartan developed new-onset diabetes (173, compared with 254 of those on atenolol, a significant reduction of 31%). (R. B. Devereux, rbdevere@med.cornell.edu)

Cotreatment for Gonorrhea & Chlamydia: Current recommendations for empirical cotreatment for chlamydia in patients (and their sex partners) with gonorrhea continued to be justified based on frequent presence of both organisms (pp. 178-85). At five public STD clinics, 3,885 heterosexual men and women were tested. Among 411 men with gonorrhea, 20% also had chlamydia. In 151 women with gonorrhea, chlamydia was detected in 42%. Without the cotreatment recommendations, about one fifth of men and one third of women would not have been treated for chlamydia. (S. B. Lyss, CDC, Atlanta)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Aug. 6, 2003 Vol. 10, No. 151
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Aug. 6 JAMA, a theme issue on violence and human rights (www.jama.com; 2003; 290).

Sarin Toxicology: Clinical manifestations of sarin gas and management of patients exposed to this and other organophosphates during terrorist attacks are reviewed (pp. 659-62). “The ease of production, transport, and use of sarin and other chemical agents enhances their potential use as terrorist weapons,” writes the author. “Physicians and emergency response personnel must be prepared to deal with the clinical signs and symptoms of nerve agent poisoning and familiarize themselves with decontamination procedures and treatment. Hospitals must provide personal protective equipment, ventilation, and decontamination facilities to prevent secondary exposure to medical staff. Hospital and community organizations must coordinate disaster drills and disaster management planning.”

Sarin was first synthesized in 1937 in Germany, which produced but did not use large supplies during World War II. It was first used in wartime during the Iran–Iraq conflict of the 1980s.

Sarin is a highly volatile, high-potency nerve agent that presents both liquid and vapor hazards. It can produce death within minutes through acetylcholinesterase inhibition, and first responders are at risk if they breathe vapors or come into contact with contaminated clothing. Convulsions caused by sarin may be the result of a second possible mechanism of action, muscarinic-receptor antagonism that causes inhibition of GABA release.
Reviewing the events in the March 1995 sarin attack on the Tokyo subway system, the author notes that one hospital quickly used 700 ampules of pralidoxime chloride and 2,800 ampules of atropine sulfate and had to obtain additional supplies by airlift. That Tokyo attack, the largest disaster caused by nerve gas during peacetime, killed 12 people and injured less than 1,000 others. However, 4,973 people presented for care, emphasizing the need for sound disaster plans for directing and triaging large numbers of people at hospitals and emergency departments. (E. C. Lee, elee@hsph.harvard.edu)

Interventions for Students Exposed to Violence: A standardized 10-session cognitive–behavioral group intervention significantly decreased symptoms of posttraumatic stress disorder and depression among students who had been exposed to violence, according to a study of 126 sixth graders at two large middle schools in a socioeconomically disadvantaged, primarily Latino area of East Los Angeles (pp. 603-11). The Cognitive–Behavioral Intervention for Trauma in Schools incorporates cognitive–behavioral therapy skills in a group format (5–8 students per group) to address symptoms of PTSD, anxiety, and depression related to exposure to violence and emphasizes applying techniques learned in the program to the child’s own problems. (B. D. Stein, stein@rand.org)

Psychological Impact of Attacks in Israel: Despite the frequency and scope of terrorist attacks in Israel, psychological impact has been moderate, according to a results of a May 2002 telephone survey of 512 people residing there (pp. 612-20). A total of 16.4% of respondents had been directly exposed to an attack since they became continuous in Sept. 2000, and 37.3% had a family member or friend who had been exposed. Traumatic stress-related symptoms were reported by 76.7% of 510 respondents, but only 9.4% met the criteria for posttraumatic stress disorder. Stress symptoms and PTSD were more likely in respondents who were women, had a low sense of safety, and were using tranquilizers. The authors write, “The majority of respondents expressed optimism about their personal future (421/512 [82.2%]) and the future of Israel (307/509 [66.8%]), and expressed self-efficacy with regard to their ability to function in a terrorist attack (322/431 [74.6%]). Most expressed a low sense of safety with respect to themselves (307/509 [60.4%]) and their relatives (345/507 [67.9%]). Few reported a need for professional help (27/506 [5.3%]).” (M. Gelkopf, Lev-Hasharon Mental Health Ctr., Netania, Israel; l_mehkar@netvision.net.il)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Aug. 7, 2003 Vol. 10, No. 152
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Aug. 7 issue of the New England Journal of Medicine (content.nejm.org; 2003; 349).

Final WHI Results: The final results of the Women’s Health Initiatives support the interim advice offered last summer: Estrogen plus progestin should not be prescribed for the prevention of cardiovascular disease (pp. 523-34). The randomized, primary-prevention trial of conjugated equine estrogens 0.625 mg/day plus medroxyprogesterone acetate 2.5 mg/day included 16,608 postmenopausal women who were 50–79 years of age at base line. The risk of nonfatal myocardial infarction or death from coronary heart disease was increased by 24% in women taking combined hormone therapy (hazard ratio, 1.24; 95% confidence interval, 1.00–1.54; 95% CI after adjustment for sequential monitoring, 0.97–1.60). This risk climbed to 81% at 1 year of therapy (HR, 1.81; 95% CI, 1.09–3.01]).

“Although higher base-line levels of low-density lipoprotein cholesterol were associated with an excess risk of CHD among women who received hormone therapy, higher base-line levels of C-reactive protein, other biomarkers, and other clinical characteristics did not significantly modify the treatment-related risk of CHD,” the authors write. “Our trial documents that estrogen plus progestin does not have a beneficial effect on the risk of CHD among healthy postmenopausal women. Overall, the risks of treatment outweighed the benefits during 5.6 years of treatment. In view of the combined excess risk of CHD, stroke, venous thromboembolism, and breast cancer, which was not offset by the reduced risk of hip fracture and colorectal cancer, this treatment is not a viable intervention for primary prevention. Estrogen-plus-progestin therapy should not be initiated or continued for the prevention of cardiovascular disease.” (J. E. Manson, jmanson@rics.bwh.harvard.edu)

Hormones & Atherosclerotic Progression: Among 226 older postmenopausal women with at least one coronary artery lesion, 17-beta-estradiol alone or with sequentially administered medroxyprogesterone failed to affect the progression of atherosclerotic lesions (pp. 535-45). Patients’ average age was 63.5 years, the mean time from menopause to randomization was 18.2 years, 51% of the patients had diabetes, and 70% were members of racial or ethnic minority groups. Over 3.3 years of follow-up in 169 patients who had a pair of matched angiograms, percent artery stenosis increased by means of 1.89 percentage points among control patients, 2.18 percentage points in patients taking estrogen alone, and 1.24 percentage points among those on combined therapy (nonsignificant differences). (H. N. Hodis, watcher@usc.edu)

Hormone Therapy & Heart Disease: Editorialists put a positive spin on findings from the above two trials (pp. 519-21): “The good news is that rapid progress is being made in our understanding of the molecular and genetic determinants of estrogen biology and its rich array of physiological effects. In addition, variations in the type, timing of administration, or dose of estrogen agonists appear to modify the molecular, physiological, and possibly clinical responses to estrogen. For these reasons, the future remains bright: we may yet discover how to manipulate selected features of estrogen biology in ways that will be useful for the treatment and prevention of cardiovascular disease and, more broadly, for the advancement of public health.” (D. M. Herrington, Wake Forest U., Winston-Salem, N.C.)

In a second editorial, a writer adds these ideas based on HRT studies published over the past 18 years (pp. 521-2): “I have in my office a large sign that reads, ‘We never know as much as we think we do.’ Investigators must be especially wary of any tendency to misinterpret or overinterpret study results in which they have a professional or personal stake. Readers, too, are often overly enthusiastic about new research results, and both groups often seem reluctant to believe findings that are contrary to their previous beliefs. I believe that the current results are likely to hold up, but it will be interesting to see what we think we know in another 18 years.” (J. Bailar, U. Chicago, Chicago)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Aug. 8, 2003 Vol. 10, No. 153
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Aug. Pharmacotherapy (www.accp.com; 2003; 23).

Cost of Medicare Pharmacist Services: Had it been enacted, the Medicare Pharmacist Services Coverage Act of 2001 would have cost the federal government $13 billion over a 10-year period, a small amount compared with a calculated $1.5 trillion in drug costs for Medicare patients during a decade (pp. 955-65). The Pharmacist Provider Coalition funded this analysis, which used methodology consistent with that of the respected Congressional Budget Office. The act would have created new types of covered services under Medicare, beginning in 2004, and recognized pharmacist practitioners as providers. The first-year cost would have been $427 million, and costs would have risen in subsequent years, leading to the calculated 10-year total of $13 billion. (V. H. Poole, Moran Co., Arlington, Va.; vhpoole@themorancompany.com)

Antifungal Agents & Histamine Release: Infusion-related reactions are likely mediated by histamine when caspofungin is being administered, but amphotericin B effects do not appear to be the result of histamine release (pp. 966-73). In vitro tests on cells from five healthy volunteers showed that histamine concentrations and histamine N-methyltransferase activity did not change when amphotericin B deoxycholate was present. But addition of caspofungin induced a significant release of histamine from peripheral blood cells as well as mast cells. “Similarly, histamine N-methyltransferase activity in peripheral blood was not affected by amphotericin B deoxycholate, but was significantly decreased by caspofungin,” the researchers report. (J. D. Cleary, U. Miss., Jackson)

Physiologic Effects of Tobacco: Smokeless tobacco induces just as much impairment in a marker of endothelial dysfunction as does tobacco smoking, according to a study of 17 apparently healthy volunteers (pp. 974-8). For 1 year, the subjects had been smoking at least 10 cigarettes/day, had been using at least two containers of smokeless tobacco per week, or had been abstinent from tobacco. “Mean [brachial artery flow-mediated dilation] over baseline was 4.1% ± 0.7% in subjects who used smokeless tobacco, 3.9% ± 5.1% in cigarette smokers, and 12.2% ± 5.7% in nonusers of tobacco (p=0.01),” the group writes. “Endothelium-independent dilation induced by nitroglycerin was not statistically different among the three groups.” (M. C. Granberry)

Digoxin & Grapefruit Juice: The genetically controlled balance between a person’s intestinal drug uptake and efflux transport appears to account for interindividual variability in the effects of grapefruit juice on digoxin pharmacokinetics (pp. 979-87). In healthy volunteers (4 men and 3 women), “grapefruit juice significantly reduced the digoxin absorption rate constant (3.0 ± 2.4 to 1.2 ± 1.0 hr-1, p<0.05) and increased absorption lag time (0.32 ± 0.12 to 0.53 ± 0.34 hr, p<0.05),” the authors note. Peak digoxin concentrations, area under the curve, elimination half-life, and renal clearance of digoxin were unaffected, although the first two variables were substantially different among individuals. Higher digoxin Cmax, AUC, and absorption rate constant were evident among subjects who were homozygous for the C allele of multidrug-resistance-1 gene, compared with those who carried the T allele. (R. B. Parker, U. Tenn., Memphis)

>>>PNN NewsWatch
* Oxcarbazepine has been approved by FDA for monotherapy in children with partial seizures 4 years of age and older, making it the first antiepileptic drug approved as monotherapy in children since 1978. The indication is based on data from four multicenter, randomized, double- blind, controlled trials. The safety profile in children was established from data in more than 1,000 children from 20 studies. Adverse effects in children have been similar to those in adults. Because 25–30% of patients with prior allergic reactions to carbamazepine will experience allergic reactions to oxcarbazepine, patients should be asked about their prior use of that drug.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Aug. 11, 2003 Vol. 10, No. 154
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
Aug. 9 issue of Lancet (www.thelancet.com; 2003; 362).

Breast Cancer & HRT: In the U.K., about 20,000 cases of breast cancer were induced in the past decade by use of hormone-replacement therapy, especially therapy that includes estrogens and progestins, according to findings from the Million Women Study (pp. 419-27). Looking at the effects of specific types of HRT on incident and fatal breast cancer among 1,084,110 women aged 50–64 years, investigators found a 66% increased risk of breast cancer among current HRT users and a 22% increased risk of dying from breast cancer. Past HRT users did not have increased risk of either incident or fatal breast cancer. While the incidence of breast cancer was somewhat higher among women on estrogen-only preparations (adjusted relative risk, 1.30, a significant increase), those taking estrogen–progestin combinations accounted for more cases (RR, 2.0). Oral, transdermal, and implanted HRT products all produced increased cases of breast cancer (respective RRs were 1.32, 1.24, and 1.650. (V. Beral, Radcliffe Infirmary, Oxford, U.K.)

Oral vs. Transdermal HRT: Among 155 postmenopausal women in France, oral but not transdermal estrogen-replacement therapy was associated with increased risk of idiopathic venous thromboembolism (pp. 428-32). Compared with 381 matched control patients, current users of oral ERT had a 3.5-fold elevated risk of VTE, while current users of transdermal ERT had a slight, nonsignificant lowering of risk (odds ratio, 0.9). “Oral but not transdermal ERT is associated with risk of VTE among postmenopausal women,” the researchers conclude. “This pattern of association is biologically plausible. Our finding could be important in assessment of the risk–benefit profile of ERT. The effects of transdermal ERT on health outcomes should be assessed in randomised trials.” (P-Y Scarabin, INSERM Cardiovascular and Metabolic Epidemiology, Villejuif, France; scarabin@vjf.inserm.fr)

>>>BMJ Highlights
Source:
Aug. 9 issue of BMJ (www.bmj.org; 2003; 327).

Heroin for Treatment-Resistant Addicts: “Coprescription of heroin is feasible, more effective, and probably as safe as methadone alone in reducing the many physical, mental, and social problems of treatment resistant heroin addicts,” conclude authors of a 549-patient study (pp. 310 ff). Over 12 months, use of inhalable and injectable heroin produced a 94% adherence rate. Combination therapy with heroin plus methadone was more effective than methadone alone in the inhalable heroin arm of the study, but discontinuation of heroin resulted in rapid deterioration in 82% of patients. (W. van den Brink, Central Committee on the Treatment of Heroin Addicts, Utrecht, the Netherlands; w.vandenbrink@amc.uva.nl)

>>>PNN JournalWatch
* Acute Low Back Pain: Systematic Review of Its Prognosis, in BMJ, 2003; 327: 323 ff. Reprints: www.bmj.org; R. D. Herbert, U. Sydney, Lidcombe, Australia; R.Herbert@fhs.usyd.edu.au

* Analgesia in Patients with ESRD: A Review of Available Evidence, in
American Journal of Kidney Diseases, 2003; 42: 217–28. Reprints: www.ajkd.org; G. M. Chertow, chertowg@medicine.ucsf.edu

* Analgesics and Renal Disease in the Postphenacetin Era [editorial], in
American Journal of Kidney Diseases, 2003; 42: 217–28. Reprints: www.ajkd.org; P. Schnuelle, U. Hosp., Heidelberg, Germany.

* Short-Term Use of Estradiol for Depression in Perimenopausal and Postmenopausal Women: A Preliminary Report, in
American Journal of Psychiatry, 2003; 160: 1519–22. Reprints: ajp.psychiatryonline.org; L. S. Cohen.

* Clozapine as a First Treatment for Schizophrenia, in
American Journal of Psychiatry, 2003; 160: 1514–6. Reprints: ajp.psychiatryonline.org; M. G. Woerner.

* Cochrane Review: Dipyridamole for Preventing Major Vascular Events in Patients with Vascular Disease, in
Stroke, 2003; 34: 2072–80. Reprints: A. Algra, U. Med. Ctr., Utrecht, the Netherlands; a.algra@azu.nl

* Ethical, Legal, and Social Implications of Genomic Medicine, in
New England Journal of Medicine, 2003; 349: 562–9. Reprints: content.nejm.org; E. W. Clayton, Vanderbilt U., Nashville.

* Pharmacy and Immunization Services: Pharmacists' Participation and Impact, in
Journal of the American Pharmacists Association, 2003; 43: 470–82. Reprints: www.japha.org; S. S. Madhaven, smadhaven@hsc.wvu.edu

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Aug. 12, 2003 Vol. 10, No. 155
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Aug. 11 issue of Archives of Internal Medicine (www.archinternmed.com; 2003; 163).

Quality of Pharmacist Collaboration: An expert panel agreed with 94.2% of pharmacists’ interventions in an analysis of 5,780 drug therapy problems among 2,524 patients receiving pharmaceutical care (pp. 1813-20). Experiences since 1999 at the Fairview Clinics System of Minneapolis–St. Paul were analyzed. A 12-member panel of physicians and pharmacists used randomly selected patient records to assess the quality of therapeutic determinations made by pharmacists within this collaborative practice of pharmaceutical care.

The authors report, “The rate of therapeutic goals achieved increased from 74% at the time of patients’ initial pharmaceutical care encounters to 89% at patients’ latest encounters. In this quality assessment analysis panel members performed a total of 4,779 evaluations of clinical decisions. Panelists indicated agreement with the evaluations in 94.2% of cases, expressed a neutral opinion in 3.6% of cases, and disagreed in 2.2% of cases. Intraclass correlation coefficients ranged from 0.73 to 0.85.” The group concludes, “This study provides data demonstrating the clinical credibility of the therapeutic outcome determinations of pharmaceutical care practitioners when they collaborate with physicians to provide drug therapy management services. Patients, health care providers, employers, third-party payers, and policymakers can use these data to make better-informed decisions about the value and role of collaboration in reducing drug-related morbidity and achieving therapeutic goals.” (B. J. Isetts, isett001@umn.edu)

Argatroban in HIT: “Argatroban therapy ... improves outcomes, particularly new thrombosis and death due to thrombosis, in patients with heparin-induced thrombocytopenia.” conclude investigators who studied 418 patients and 185 historical controls (pp. 1849-56). I.V. argatroban 2 mcg/kg/min therapy was adjusted to maintain the activated partial thromboplastin time at 1.5–3 times baseline value for a mean of 5–7 days in patients with HIT. A composite endpoint of all-cause death, all-cause amputation, or new thrombosis was reached in 28.0% of argatroban patients over a 37-day observation period, compared with 38.8% of historical control patients, a significant difference. In patients with HIT with thrombosis, the composite endpoint was reached in 41.5% of argatroban-treated patients and 56.5% of historical controls, a statistical trend (p = .07). (J. G. Kelton, McMaster U., Hamilton, Ontario, Canada; keltonj@mcmaster.ca)

Amoxicillin–Clavulanate in Rhinosinusitis:
Patients with clinically diagnosed acute rhinosinusitis benefit little from antibiotic treatment with amoxicillin– clavulanate and are more likely to have adverse effects, according to a study of 252 patients (pp. 1793-8). Patient with histories of purulent nasal discharge and maxillary or frontal pain for at least 48 hours were given placebo or amoxicillin 875 mg and clavulanate 125 mg twice daily for 6 days. Times to cure were similar between antibiotic- and placebo-treated patients, but diarrhea was more common among those on amoxicillin–clavulanate patients. (H. C. Bucher, Basel Inst. for Clin. Epidemiology, Basel, Switzerland; hbucher@uhbs.ch)

Achilles Tendon Rupture with Quinolones: Especially among elderly patients who are also being treated with corticosteroids, current use of fluoroquinolones increases patients’ risk of Achilles tendon rupture, report authors who analyzed information from 1988–98 in the U.K. General Practice Research Database (pp. 1801-7). Compared with control patients, 1,367 cases with first-time Achilles tendon rupture were 4.3 times more likely to be taking quinolones and 2.4 times more likely to have used the agents recently. Odds ratios were 6.4 and 20.4 for patients aged 60–79 years and 80 years or older, respectively. In the elderly, odds ratios were 28.4, 3.6, and 14.2 for current exposure to ofloxacin, ciprofloxacin, and norfloxacin, respectively. In the elderly, 2–6% of Achilles tendon ruptures are likely caused by quinolone exposure, the researchers calculate. (B. H. Ch. Stricker, Erasmus Med. Ctr., Rotterdam, the Netherlands)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Aug. 13, 2003 Vol. 10, No. 156
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Aug. 13 issue of JAMA (www.jama.com; 2003; 290).

Guggulipid for Hypercholesterolemia: A standardized guggul extract failed to lower cholesterol levels and possibly produced dermatologic hypersensitivity reactions in an 8-week, placebo-controlled trial of 103 ambulatory, community-dwelling, healthy adults with hypercholesterolemia (pp. 765-72). Guggul is an extract from resin of the mukul myrrh tree, and its possible biologically active contents, guggulsterones, have been shown to be potent antagonists of two nuclear hormone receptors involved in cholesterol metabolism.

In this trial, patients took either placebo, normal 1,000-mg doses of a standardized guggul extract (guggulipid, containing 2.5% guggulsterones), or 2,000-mg doses of the guggul extract three times daily for 8 weeks. LDL-C levels dropped by 5% among patients taking placebo, but they rose by 4% and 5% among patients on normal- and high-dose guggulipid, for net changes of 9% and 10%, respectively. No other changes in total cholesterol or subfractions were significantly different among the groups. Six patients on guggulipid developed hypersensitivity rash, compared with none in the placebo group. “In a typical American population of adults with hypercholesterolemia and eating a typical Western diet, using this standardized guggulipid product did not reduce and actually raised levels of LDL-C compared with placebo, and in a subset of patients caused a hypersensitivity drug reaction,” write the authors. “These results do not support the use of dietary supplements containing guggulipid for reduction of LDL-C levels by the general population.” (P. O. Szapary, szapary@mail.med.upenn.edu)

Curative vs. Palliative Care in HIV Infection: “The emerging biomedical paradigm of highly active antiretroviral therapy ... as the cornerstone of treatment has helped to transform HIV into a manageable chronic disease, yet at the same time has resulted in a more narrow focus and a de facto separation between disease-specific ‘curative’ and symptom-specific ‘palliative’ care for patients with HIV/AIDS,” note the authors of a Clinician’s Corner article (pp. 806-14). “The chronic nature of the HIV disease course and the increasing burden of cumulative HIV-related morbidity and treatment-related toxic effects pose new challenges to the care of patients over time. Uncertainties about prognosis and the promise and limitations of rapidly evolving therapies have made decision making about advance care planning and end-of-life issues more complex and elusive than when the disease course was more uniform, rapid, and predictable.... As patients survive longer in the latter stages of progressive HIV disease, they may in fact have increasing need for comprehensive symptom management as well as wide-ranging need for psychosocial, family, and care planning support. In the HAART era, the false dichotomy of curative vs palliative care for patients with HIV/AIDS must be supplanted by a more integrated model to provide comprehensive care for patients with advanced HIV disease and their families.” (P. A. Selwyn, Albert Einstein Coll. of Med., Bronx, N.Y.; selwyn@aecom.yu.edu)

Single-Payer Health Care in the U.S.: Creation of a single-payer national health insurance program for the U.S. could provide care to the nation’s currently uninsured citizens and still save $200 billion per year by eliminating profit, overhead, and marketing costs of the private sector, claims the Physicians’ Working Group for Single-Payer National Health Insurance (pp. 798-805). The proposal, endorsed by nearly 7,800 physicians and medical students, calls for expansion of Medicare to include all citizens and recognition that health care is a needed social service and not a “commodity [that is] distributed according to the ability to pay.” The authors add, “Other wealthy countries manage to provide universal health care at half the cost we pay.... The problems in the United States are systemic. Incremental changes cannot solve them; further reliance on market-based strategies will exacerbate them. What needs to be changed is the system itself.” (D. U. Himmelstein, Harvard Med. Sch., Cambridge, Mass.; Dhimmelstein@challiance.org)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Aug. 14, 2003 Vol. 10, No. 157
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Aug. 14 issue of the New England Journal of Medicine (content.nejm.org; 2003; 349).

Low-Intensity Warfarin for Secondary Prophylaxis: For preventing recurrence of venous thromboembolism, conventional-intensity warfarin therapy is more effective and just as safe as low-intensity regimens, according to a 738-patient study (pp. 631-9). Patients completed 3 months of warfarin therapy after unprovoked VT and then were randomly assigned to continue warfarin therapy with target international normalized ratios of 2.0–3.0 or 1.5–1.9. Patients were followed for a mean of 2.4 years.

Patients on low-intensity therapy were significantly more likely to have recurrent VT than were those on conventional-intensity warfarin (16 vs. 6 patients; 1.9 vs. 0.7 events per 100 person-years; hazard ratio, 2.8). Yet major bleeding episodes occurred with similar frequencies in the two groups (9 and 8 events with low- and conventional-intensity therapy, respectively). “Long-term conventional-intensity warfarin therapy is very effective at preventing recurrent thrombosis and is associated with a low frequency of bleeding,” the authors conclude.

Editorialists offer these insights into the duration of anticoagulation in prevention of recurrent VT (pp. 702-4): “Besides the complex assessment of the risk of recurrent venous thromboembolism, including consideration of this catch-up phenomenon, two other elements dominate the decision about how long to continue treatment with vitamin K antagonists. The first concerns the risk of bleeding, and the second the patient’s valuation of health states related to venous thromboembolism and its treatment with vitamin K antagonists. The frequency of major bleeding is about 1 episode per 100 person-years, whereas the risk of nonmajor, but still clinically relevant, bleeding is four to five times as high. In order to obtain optimal efficacy and safety with vitamin K-antagonist therapy, it is mandatory to perform careful and regular laboratory monitoring with subsequent adjustments of the dose, which makes this therapy inconvenient. On the basis of the balance between the risk of recurrence and the risk of bleeding, the current recommendation is to provide secondary prophylaxis with vitamin K antagonists to patients with unprovoked venous thromboembolism for a period of 6 to 12 months.” (H. R. Büller, U. Amsterdam, Amsterdam)

Long-Term Anticoagulant Therapy: A case-based review article assesses current thinking about warfarin prophylaxis, including evidence about optimal intensity and duration of therapy, drug interactions, reversal of anticoagulation, and anticoagulation during surgery (pp. 675-83). The author offers these conclusions: “The benefit of anticoagulation with vitamin K antagonists has been convincingly demonstrated for patients with mechanical prosthetic heart valves, mitral-valve disease, atrial fibrillation, and venous thromboembolism. The intensity of anticoagulation and the duration of treatment should be tailored according to the indication for treatment and the presence or absence of risk factors. For a patient with atrial fibrillation and other risk factors for thromboembolism, as in the case described in the vignette, oral anticoagulation with a vitamin K antagonist is appropriate and should be targeted to achieve an INR of 2.0 to 3.0. It is preferable to use a nomogram to determine the appropriate initial dose and not to give concomitant heparin. Dose adjustments to maintain the INR in the therapeutic range may be facilitated by the use of a nomogram or another supportive tool; once the INR appears to be stable, monthly tests of the prothrombin time should be sufficient.” (S. Schulman, Karolinska Hosp., Stockholm, Sweden; sam.schulman@ks.se)

Treatment of Plaque Psoriasis: Methotrexate and cyclosporine are equivalent therapies for treatment of moderate or severe chronic plaque psoriasis, conclude authors of an 88-patient study (pp. 658-65). Over 16 weeks of treatment, efficacy outcomes were similar with each drug. Twelve patients on methotrexate discontinued therapy because of reversible liver-enzyme elevations, while one patient on cyclosporine stopped therapy because of hyperbilirubinemia. (M. A. de Rie, U. Amsterdam, Amsterdam)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Aug. 15, 2003 Vol. 10, No. 158
Providing news and information about medications and their proper use

>>>Rosuvastatin Approved
The long-awaited approval of the first “superstatin” came this week, as FDA ruled that AstraZeneca had successfully overcome concerns about renal toxicity with rosuvastatin (Crestor, AstraZeneca). The question is now just how much of the $20 billion worldwide market the new agent will garner.

Rosuvastatin was approved by FDA as an adjunct to diet to reduce elevated total cholesterol, LDL-C, ApoB, non–HDL-C, and triglyceride levels and to increase HDL-C in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson Type IIa and IIb); as an adjunct to diet for the treatment of patients with elevated serum TG levels (Fredrickson Type IV); and to reduce LDL-C, total cholesterol, and ApoB in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments (such as LDL apheresis) or if such treatments are unavailable.

The dose range for rosuvastatin is 5–40 mg once daily. The recommended usual starting dose of 10 mg once daily in patients with hypercholesterolemia and mixed dyslipidemia. Initiation of therapy with 5 mg once daily may be considered for patients requiring less aggressive LDL-C reductions or who have predisposing factors for myopathy. For patients with marked hypercholesterolemia (LDL-C >190 mg/dL) and aggressive lipid targets, a 20-mg starting dose may be considered . The 40-mg dose should be reserved for those patients who have not achieved goal LDL-C at 20 mg. After initiation and/or upon titration of rosuvastatin, lipid levels should be analyzed within 2–4 weeks and dosage adjusted accordingly.

Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with rosuvastatin and other drugs in this class. Liver function tests should be performed before and at 12 weeks following both the initiation of therapy and any elevation of dose, and periodically (e.g., semiannually) thereafter. The drug should be prescribed with caution in patients with predisposing factors for myopathy, such as renal impairment.

>>>Infectious Disease Update
Source:
Aug. 1 issue of Clinical Infectious Disease (www.journals.uchicago.edu/CID; 2003; 37).

Limb Swelling After Vaccination: Postvaccination extensive limb swelling occurs occasionally in all age groups and with a broad variety of vaccines, write authors who analyzed reports to FDA’s Vaccine Adverse Event Reporting System (pp. 351-8). They write, “A case of ELS was defined as any report of edema extending at least to the elbow or knee of a vaccinated extremity. Four hundred ninety-seven cases were identified, with some describing swelling from the shoulder to the hand or the hip to the foot. Patient age ranged from 0.1 to 91 years. The proportion of reports of ELS associated with a given vaccine, among all VAERS reports received for that vaccine, varied substantially among vaccines. Most reactions began within 1 day after vaccination and involved other signs of inflammation.” (E. J. Woo, FDA, Rockville, Md.)

Levofloxacin-Resistant Pneumococci: “In immunocompromised patients with suspected or proven pneumococcal infection, it may be prudent not to use fluoroquinolone monotherapy empirically when the patient has a history of fluoroquinolone therapy in at least the past 4 months,” conclude authors who report the cases of four patients who had 15 episodes of community-acquired pneumonia (pp. 376-81). “The initial episode of CAP in each patient was due to a levofloxacin-susceptible strain,” explain the investigators. “One of 4 reinfections and 5 of 6 relapses were due to levofloxacin-resistant strains.... The time between episodes of pneumonia varied from 1 to 4 months.” (K. B. Anderson, Summa Health System, Akron, Ohio)

>>>PNN NewsWatch
* According to a study commissioned by and reported on Wednesday by the Wall Street Journal, Performance Marketing tablets sold on the Internet for penis enlargement contain high amounts of Escherichia coli and other contaminants.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Aug. 18, 2003 Vol. 10, No. 159
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
Aug. 16 issue of Lancet (www.thelancet.com; 2003; 362).

Smoking & Mortality: Smoking increases the incidence of clinical tuberculosis and causes death in about one half of men with the disease, according to an case–control study of Indian men who died from medical causes at ages between 25 and 69 years (pp. 507-15). Smokers of cigarettes or Indian bidis were twice as likely to die as were nonsmokers (risk ratio, 2.1). Respiratory disease, especially TB (RR, 4.5), vascular disease (RR, 1.8), cancer (RR, 2.1), and alcoholism/cirrhosis (RR, 3.3) were most often implicated in deaths, and smoking accounted for 61%, 24%, 32%, and 0% of deaths in each of those respective categories. “Smoking probably caused about 700,000 deaths in India during the year 2000, including about 550,000 among middle-aged men and about 110,000 among older men (with much smaller numbers among women, due to their low prevalence of smoking),” note the authors. “The number of deaths from tobacco among Indian men just at ages 25–69 years will, if present smoking patterns persist, reach 1 million per year by about 2025, with an average of about 20 years of life lost for each such death.” (V. Gajalakshmi, Epidemiological Res. Ctr., Chennai, India; gajaerc@rediffmail.com)

Prevalence & Mortality of Diabetes: Studies need to take into account the possibility of declining mortality from diabetes as they attempt to analyze rising prevalence figures for the disease, according to an analysis from Denmark (pp. 537-8). Prevalence of diabetes increased over the 1993–99 period (odds ratios: women, 1.026; men, 1.041), but mortality declined by similar amounts (ORs: women, 0.976; men, 0.966). (H. Støvring, U. Southern Denmark, Aarhus, Denmark; hstovring@health.sdu.dk)

An editorialist comments (pp. 503-4): “The ‘diabesity’ pandemic is a useful message for the diabetes community to broadcast, not least when funding is at stake, but this report reminds us that the rising prevalence of type 2 diabetes is complex and deserves more detailed examination. Make no mistake, obesity and diabetes are indeed on the increase, a problem big and deadly enough to need no supporting rhetoric, but not all increases are sinister. Let us take some comfort from the hint that, in some populations at least, the prevalence of type 2 diabetes may have risen mainly because people are being picked up and treated earlier or are living longer.” (E. A. M. Gale, Southmead Hosp., Bristol, U.K.; Edwin.Gale@bristol.ac.uk)

>>>PNN JournalWatch
* Prevention of Venous Thromboembolism After Major Orthopaedic Surgery: Is Fondaparinux an Advance [commentary]?, in Lancet, 2003; 362: 504–5. Reprints: www.thelancet.com; G. D. O. Lowe, U. Edinburgh, Edinburgh, Scotland; gdl1j@clinmed.gla.ac.uk

* Exposure to Non-Steroidal Anti-Inflammatory Drugs During Pregnancy and Risk of Miscarriage: Population Based Cohort Study, in
BMJ, 2003; 327:368 ff. Reprints: www.bmj.org; D-K Li, dkl@dor.kaiser.org

* The Epidemiology of Burn Wound Infections: Then and Now, in
Clinical Infectious Diseases, 2003; 37: 543–50. Reprints: www.journals.uchicago.edu/ CID; C. G. Mayhall, U. Texas, Galveston.

* Advertising Strategies to Increase Public Knowledge of the Warning Signs of Stroke, in
Stroke, 2003; 34: 1965 ff. Reprints: stroke.ahajournals.org; F. Rubini, Heart and Stroke Foundation of Ontario, Toronto; frubini@hsf.on.ca

* Thrombolysis with Recombinant Tissue Plasminogen Activator and Tirofiban in Stroke, in
Stroke, 2003; 34: 1932 ff. Reprints: stroke.ahajournals.org; R. J. Seitz, U. Hosp., Düsseldorf, Germany; seitz@neurologie.uni-duesseldorf.de

* Leptin: A Novel Link Between Obesity, Diabetes, Cardiovascular Risk, and Ventricular Hypertrophy, in
Circulation, 2003; 108: 644–6. Reprints: circ.ahajournals.org; S. Sader.

* Randomized Trial of the Adenosine A2a Receptor Antagonist Istradefylline in Advanced PD, in
Neurology, 2003; 61: 297–303. Reprints: www.neurology.org; R. A. Hauser, U. South Fla., Tampa; rhauser@hsc.usf.edu

* Adenosine A2a Receptor Antagonist Treatment of Parkinson’s Disease, in
Neurology, 2003; 61: 293–6. Reprints: www.neurology.org; T. N. Chase, chaset@ninds.nih.gov

* Sex hormones and Systemic Lupus Erythematosus: Review and Meta-analysis, in Arthritis & Rheumatism, 2003; 48: 2100– 10. Reprints: www.interscience.wiley.com/jpages/0004-3591/; R. W. McMurray; Robert.McMurray@med.va.gov

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Aug. 19, 2003 Vol. 10, No. 160
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Aug. 19 issue of the Annals of Internal Medicine (www.annals.org; 2003; 139).

Treatment of Bleeding Ulcers: Endoscopic hemostasis plus omeprazole was significantly more effective at preventing recurrent bleeding than was omeprazole alone in 156 patients who had upper gastrointestinal bleeding with nonbleeding visible vessels or adherent clots (pp. 237-43). Endoscopic hemostasis involved thermocoagulation and epinephrine injection. Combination therapy was superior to omeprazole alone for several measures: recurrence of ulcer bleeding before hospital discharge (0% vs. 9%), recurrent bleeding within 30 days (1.1% vs. 11.6%), and fewer transfusions (difference in median units of blood transfused, 1 unit). In the omeprazole group, 4 patients died with 30 days, compared with 2 combination patients. (J. J. Y. Sung, Prince of Wales Hosp., Shatin, Hong Kong; joesung@cuhk.edu.hk)

An editorialist comments on the possibility of therapy of g.i. bleeds with proton pump inhibitors alone (pp. 294-5): “Although Dr. Sung’s group showed that combined therapy was superior, the rates of rebleeding in patients receiving intravenous PPIs alone were much lower than in past studies. These unexpectedly low rates of rebleeding reported with medical treatment might tempt some physicians to treat nonbleeding visible vessels and adherent clots with intravenous PPIs alone. I recommend strongly against this practice, as do the authors. Sung and colleagues’ results would be much more convincing if they had included a comparison group receiving standard medical therapy (such as intravenous H
2-antagonists or oral PPIs). Comparison with standard therapies is not only scientifically warranted but ethical and should include measures of patient preference and a cost-effectiveness analysis, since intravenous PPI infusions are inconvenient and costly....

“I agree with the authors’ recommendation to use high-dose PPI infusion and epinephrine plus thermal coagulation when upper gastrointestinal endoscopy shows a nonbleeding vessel or adherent clot. It is too early to adopt intravenous PPIs as an alternative to combined medical and endoscopic therapy.” (D. M. Jensen, VA Healthcare Ctr., Los Angeles)

Blood Pressure Control & Proteinuria: In patients with urine protein excretion of more than 1 gram/day, systolic blood pressure goals of 110–129 mm Hg appear optimal, according to authors of a patient-level meta-analysis (pp. 244-52). Merging the data of 11 randomized, controlled trials of antihypertensive regimens both with and without ACE inhibitors, the authors found: “Systolic blood pressure of 110 to 129 mm Hg and urine protein excretion less than 2.0 g/d were associated with the lowest risk for kidney disease progression. Angiotensin-converting enzyme inhibitors remained beneficial after adjustment for blood pressure and urine protein excretion (relative risk, 0.67 [95% CI, 0.53 to 0.84]). The increased risk for kidney progression at higher systolic blood pressure levels was greater in patients with urine protein excretion greater than 1.0 g/d (P< 0.006).” (A. S. Levey, Tufts– New England Med. Ctr., Boston)

An editorialist writes that this study adds to evidence in three areas: “First, proteinuria has earned a seat at the table of modifiable cardiovascular risk factors and should not be viewed as only a domain of nephrologists. Second, reducing proteinuria is an important factor for preserving renal function, not only in diabetic patients but also in nondiabetic patients with hypertension. Third, the findings add credence to the following reasonable, although not yet proved beneficial, approach: Perform dipstick urine testing periodically ... in all patients with hypertension. Measure spot urinary albumin–creatinine ratios in patients with positive dipstick test results. In patients with proteinuria, aim to reduce excretion levels to less than 1 to 2 g/d (that is, a spot urinary albumin–creatinine ratio 1). In patients with chronic renal disease and proteinuria, target systolic blood pressures of 110 to 130 mm Hg. Aim for lower levels within this range, when possible and if tolerated, in patients with protein excretion greater than 2 g/d.” (C. D. Mulrow, American College of Physicians, Philadelphia)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Aug. 20, 2003 Vol. 10, No. 161
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Aug. 20 issue of JAMA (www.jama.com; 2003; 290).

Pediatric Drug Labeling: Better information about pharmacokinetics, important dose changes, and improved safety have resulted from the pediatric clinical studies that were stimulated by the Food and Drug Administration Modernization Act, according to authors who looked at FDA’s requests for more information and manufacturers’ responses (pp. 905-11). “There were 53 studies for 33 drug products, 12 (23%) were evaluated for safety only; 23 (43%), safety and efficacy; and 18 (34%), pharmacokinetics and/or pharmacodynamics,” write the authors. “Significant new dosing and/or safety information was identified for 12 (36%) drugs. New dosing information was determined for 7 of these drugs.” (R. Roberts, robertsr@cder.fda.gov)

Prescribing for children using trial and error should end, says an editorialist (pp. 950-1): “Critics have noted that extending market exclusivity as the motivation for voluntary compliance can lead manufacturers to focus on drugs with large adult markets but only limited application in children. That approach also provides no incentive for pediatric studies of drugs with expired patents, and does not address the critical need for trials of drugs now predominantly used to treat relatively small numbers of children. Thus, although the exclusivity provisions have led to important information on some drugs, this approach has left large gaps....

“Additional tools are needed to minimize the use of medications not specifically approved for children [including a system for collecting information and FDA using its recently granted authority to require studies of drugs that might be used in children].... The era of prescribing for children by trial and error should come to an end.” (P. P. Budetti, U. Okla., Okla. City, peter-budetti@ouhsc.edu)

Risk Factors & Coronary Events: Claims that 50% or more of coronary events occur in people who have no major risk factors are not accurate, according to investigators who analyzed data from three prospective cohort studies that lasted from 21 to 30 years (pp. 891-7). Contrary to the 50% myth, fatal CHD events (n = 20,995) were preceded by at least one clinically elevated major risk factor (total cholesterol of at least 240 mg/dL, systolic blood pressure of at least 140 mm Hg, diastolic blood pressure of at least 90 mm Hg, cigarette smoking, diabetes) in 87% to 100% of the subsets of patients analyzed. Among patients who were 40–59 years old at baseline and who had fatal CHD, 87–94% had at least one major risk factor. In patients with nonfatal myocardial infarction, 92% of men and 87% of women had at least one pre-existing CHD risk factor. (P. Greenland, p-greenland@northwestern.edu)

A second article supports these findings (pp. 898-904). Based on data from 122,458 patients enrolled in 14 international trials, authors found, “Among patients with CHD, at least 1 of the 4 conventional risk factors [cigarette smoking, diabetes, hyperlipidemia, and hypertension] was present in 84.6% of women and 80.6% of men. In younger patients (men 55 years and women 65 years) and most patients presenting either with unstable angina or for percutaneous coronary intervention, only 10% to 15% of patients lacked any of the 4 conventional risk factors. This pattern was largely independent of sex, geographic region, trial entry criteria, or prior CHD.” (U. N. Khot, Ind. Heart Physicians, Beech Grove, Ind., khot@cvresearch.net)

C-reactive protein, lipoprotein(a), fibrinogen, and homocysteine should not yet be incorporated into clinical practice, concludes a writer who reviewed 373 studies (pp. 932-40). While these “emerging risk factors” are “associated with are associated with vascular disease risk,” the author concludes that “their optimal use in routine screening and risk stratification remains to be determined” and that “the focus of clinicians, policy makers, health care organizations, and patients must be on lowering the burden of proven, modifiable risk factors, including their upstream determinants (eg, obesity).” (S. S. Anand, McMaster U., Hamilton, Ontario, Canada; anands@mcmaster.ca)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Aug. 21, 2003 Vol. 10, No. 162
Providing news and information about medications and their proper use

>>>Second Agent Approved for Erectile Dysfunction
FDA on Tuesday approved vardenafil (Levitra; Bayer, GlaxoSmithKline) for treatment of men with erectile dysfunction. Marking the beginning of competition in the oral phosphodiesterase type 5 inhibitor category, vardenafil appears to be similar on most counts as the innovator agent, sildenafil. A third agent, tadalafil (Cialis, Lilly), is believed close to FDA approval.

Men with histories of diabetes or radical prostatectomies were included in pivotal trials of vardenafil, and GSK, which will distribute the product in the U.S., may emphasize this point in its promotions. Based on self-reporting by more than 2,000 men in the studies, vardenafil improved patients’ ability to achieve and maintain a penile erection adequate for intercourse. The most common adverse effects included headache, flushing, rhinitis, and indigestion. Dizziness was reported in about 2% of patients. A small number of patients taking vardenafil also reported abnormal vision.

Because of the possibility of hypotension, vardenafil is contraindicated in men taking intermittent or regularly scheduled nitrates and/or alpha-adrenergic antagonists. The drug should not be taken by men for whom sexual activity is inadvisable because of their underlying medical status (have had a myocardial infarction or stroke within the last 6 months, or have significantly low blood pressure, uncontrolled high blood pressure, unstable angina, severe liver impairment, end-stage renal disease requiring dialysis, or retinitis pigmentosa).

The recommended dose is 10 mg taken 1 hour before sexual activity. A higher dose of 20 mg is available for patients whose response to the 10 mg dose is not adequate. Two lower doses are used in patients taking interacting drugs, including those that inhibit the cytochrome P450 3A4 isoenzyme. A maximum single dose of 2.5 mg should be used in patients who are also taking the strongest 3A4 inhibitors (e.g., ritonavir, indinavir, ketoconazole, itraconazole), and those on ritonavir should not repeat the vardenafil dose for 72 hours. Patients on weaker 3A4 inhibitors such as erythromycin should take the 5 mg dose of vardenafil.

>>>NEJM Highlights
Source:
Aug. 21 issue of the New England Journal of Medicine (content.nejm.org; 2003; 349).

Angioplasty vs. Fibrinolysis for Coronary Reperfusion: Patients who are having myocardial infarction with ST-segment elevation should be transferred for primary angioplasty rather than undergo onsite fibrinolysis when the transfer can be completed in less than 2 hours, according to a study of 1,572 individuals (pp. 733-42). A total of 1,129 patients were first seen at referral hospitals, while 443 patients presented at invasive-treatment centers. Reinfarction occurred less often with angioplasty, and this enabled the researchers to identify significant differences in a composite endpoint of death, clinical evidence of reinfarction, or disabling stroke at 30 days. At referral hospitals, this endpoint was reached in 8.5% of angioplasty patients and 14.2% of fibrinolysis patients. At invasive-treatment centers, results were similar, with 6.7% and 12.3% of two respective groups reaching the composite endpoint. Transfers required less than 2 hours for 96% of patients who presented initially at referral hospitals. (H. R. Andersen, U. Hosp., Aarhus N, Denmark; henning.rud.andersen@iekf.au.dk)

Leukemic Cell Sensitization with G-CSF: Growth factors can be used to sensitize leukemic cells to the cytotoxic effects of chemotherapy, report authors of a study of 640 patients with acute myeloid leukemia (pp. 743-52). Patients who received induction chemotherapy plus lenograstim, a granulocyte colony stimulating factor, had higher rates of disease-free survival after a median follow-up of 55 months, compared with those who received only the induction therapy (42% vs. 33% at 4 years). G-CSF failed to improve outcomes in those with the most unfavorable prognosis, but patients with standard-risk AML had improved overall survival (45% vs. 35% at 4 years). (B. Löwenberg, Erasmus U., Rotterdam, the Netherlands; b.lowenberg@erasmusmc.nl)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Aug. 22, 2003 Vol. 10, No. 163
Providing news and information about medications and their proper use

>>>Cardiology Update
Source:
Aug. 6 issue of the Journal of the American College of Cardiology (www.cardiosource.com; 2003; 42).

I.V. Enoxaparin in ACS: To reduce the early risk of thrombotic complications in patients with acute coronary syndromes, an intravenous plus subcutaneous regimen of enoxaparin achieves therapeutic plasma levels more quickly than does subcutaneous-only doing (pp. 424-7). Coagulation markers were measured at nine points during the first 24 hours of IV/SQ dosing of 14 patients and SQ-only dosing of 11 patients. The authors report, “The IV+SQ therapy immediately resulted in therapeutic anti-Xa levels, which remained significantly higher for 6 h compared with SQ alone, without reaching excessively high levels. A rapid decrease of plasma prothrombin fragments 1+2 (F 1+2) levels was observed as soon as 5 min after the IV injection (33% lower; P = 0.007), and these levels remained lower up to 2 h after the start of treatment compared with SQ alone.... As the risk of thrombotic complications is greatest early after admission, the observed differences in antithrombotic effects may translate into a clinical benefit.” (N. R. Bijsterveld, Academic Med. Ctr., Amsterdam, The Netherlands)

Early Diabetic Cardiomyopathy: Despite subtle left ventricular dysfunction in diabetic patients without overt cardiac disease, the risk of ischemia appears low, according to a study of 41 individuals (pp. 446-53). Peak myocardial systolic velocity (Sm) and early diastolic velocity (Em) were measured, and mean Sm and Em values were compared between diabetic patients and controls and among different stages of dobutamine stress. The investigators found that Sm and Em increased from rest to peak dobutamine stress. Baseline Sm was significantly lower in patients with diabetes than in control patients, but values at low doses, before peak, and peak stress did not differ significantly between the groups. Em in the diabetic group was significantly lower than that of controls, but absolute and relative increases in Sm or Em from rest to peak stress did not differ significantly between the diabetic and control groups. Based on these findings, the authors conclude, “The normal response to stress suggests that ischemia due to small-vessel disease may not be important in early diabetic heart muscle disease.” (T. H. Marwick, U. Queensland, Brisbane, Australia)

>>>Infectious Disease Report
Source:
Aug. 15 issue of Clinical Infectious Diseases (www.journals.uchicago.edu/CID; 2003; 37).

PI-Induced Opiate Withdrawal: Lopinavir but not ritonavir induces methadone metabolism and can lead to a need for higher doses in opiate-dependent patients (pp. 476-82). Area under the serum methadone concentration– time curve was significantly reduced during treatment with the lopinavir/ritonavir combination but not ritonavir alone. Minimum serum methadone concentrations were lower, and oral clearance of the drug were higher during lopinavir/ritonavir treatment. The authors recommend clinical monitoring and in some patients, increased methadone doses when lopinavir is a part of HIV-infected, opiate-dependent patients’ regimen. (E. F. McCance-Katz, Med. Coll. of Va., Richmond)

Hypothyroidism & HIV Infection: Among 350 HIV-infected patients, 16% had some form of hypothyroidism, leading researchers to recommend screening of patients, particularly if they are men, have received stavudine, or have decreased CD4 cell counts (pp. 579-83). In this study, 2.6% of the entire patient group had overt hypothyroidism, 6.6% had subclinical hypothyroidism, and 6.8% had low free T4 concentrations. The prevalence of subclinical hypothyroidism was higher among men than among women. A case–control study compared 56 hypothyroid and 287 euthyroid patients, revealing the possible associations of stavudine exposure and low CD4 cell count with hypothyroidism. (S. Beltran, Hosp. and U. Ctr., Amiens, France)

>>>PNN NewsWatch
* FDA this week released a strategic plan, Protecting and Advancing America’s Health: A Strategic Action Plan for the 21st Century (http://www.fda.gov/bbs/topics/ NEWS/2003/NEW00934.html).

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Aug. 25, 2003 Vol. 10, No. 164
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
Aug. 23 issue of Lancet (www.thelancet.com; 2003; 362).

Acetylcysteine for Prevention of Nephropathy: Pretreatment with acetylcysteine adds to the renoprotective effects of hydration in patients with chronic renal insufficiency undergoing tests with contrast media, according to a meta-analysis of seven trials (pp. 598-603). The incidence of contrast-induced acute renal failure (defined as a 0.5 mg/dL rise in serum creatinine within 48 hours after contrast media administration) varied from 8% to 28% among the trials, which collectively included 805 patients. “Compared with periprocedural hydration alone, administration of acetylcysteine and hydration significantly reduced the relative risk of contrast nephropathy by 56% (0.435 [95% CI 0.215–0.879], p=0.02) in patients with chronic renal insufficiency,” the authors report. “Meta-regression revealed no significant relation between the relative risk of contrast nephropathy and the volume of radiocontrast media administered or the degree of chronic renal insufficiency before the procedure.” (R. Birck, U. Hosp., Mannheim, Germany; rainer.birck@med5.ma.uni-heidelberg.de)

An editorialist points out limitations of this analysis while supporting its overall conclusion (pp. 589-90): “Does a 0.5 mg/dL rise in serum creatinine at 48 h constitute acute renal failure? Acute renal failure is a poorly defined entity with over 30 different published biochemical definitions and widely different outcomes depending on the definitions used.... Avoiding even this subtle rise in serum creatinine appears to be useful, especially if the treatment is not harmful.
N-acetylcysteine given with intravenous fluids is non-toxic and inexpensive, and is an effective way to reduce the occurrence of contrast-induced acute renal failure.

“Unfortunately, the data provide little guidance as to who should receive
N-acetylcysteine. Although the studies reviewed by Birck and colleagues included only patients with chronic renal insufficiency, this entity is also ill-defined and given that mean serum creatinine was as low as 1.4 mg/dL (123.76 µmol/L) in some studies, it is likely that some patients had normal or near normal renal function. Patients with diabetes and those with underlying cardiovascular or hepatic disease are known to be at increased risk for contrast-induced acute renal failure, as are patients with sepsis and those receiving other nephrotoxic drugs. Given the low costs and good side-effect profile of N-acetylcysteine, it would seem prudent to give this drug with intravenous fluids to all patients with these risk factors who are receiving intravenous radiographic contrast media. At last we seem to have a drug to prevent, or at least reduce, the occurrence of one common form of acute renal failure.” (J. A. Kellum, U. Pittsburgh, Pittsburgh, Kellumja@ccm.upmc.edu)

>>>PNN JournalWatch
* Survival of Patients with Chronic-Phase Chronic Myeloid Leukaemia on Imatinib After Failure on Interferon Alfa, in Lancet, 2003; 362: 617–9. Reprints: www.thelancet.com; J. M. Goldman, Hammersmith Hosp., London, j.goldman@imperial.ac.uk

* Effect of Losartan on Sudden Cardiac Death in People with Diabetes: Data from the LIFE Study, in
Lancet, 2003; 362: 619–20. Reprints: www.thelancet.com; L. H. Lindholm, Umeå U. Hosp., Umeå, Sweden; larsh.lindholm@fammed.umu.se

* Problems with Sexual Function in People Attending London General Practitioners: Cross Sectional Study, in
BMJ, 2003; 327: 423 ff. Reprints: www.bmj.org; I. Nazareth, Royal Free and U. College Med. Sch., London; i.nazareth@pcps.ucl.ac.uk

* Shikonin, a Component of Chinese Herbal Medicine, Inhibits Chemokine Receptor Function and Suppresses Human Immunodeficiency Virus Type 1, in
Antimicrobial Agents & Chemotherapy, 2003; 47: 2810–6. Reprints: aac.asm.org; X. Chen, Natl. Cancer Inst.

* Inhibition of Human Immunodeficiency Virus by a New Class of Pyridine Oxide Derivatives, in
Antimicrobial Agents & Chemotherapy, 2003; 47: 2951–7. Reprints: aac.asm.org; M. Stevens, Rega Inst. for Med. Res., Katholieke Universiteit, Leuven, Belgium.

* Nonsteroidal Anti-inflammatory Drugs and the Risk of Parkinson Disease, in
Archives of Neurology, 2003; 60: 1059–64. Reprints: www.archneurol.com; H. Chen, hchen@hsph.harvard.edu

* A Reduced–Glycemic Load Diet in the Treatment of Adolescent Obesity, in
Archives of Pediatrics & Adolescent Medicine, 2003; 157: 773–9. Reprints: www.archpediatr.com; D. S. Ludwig, david.ludwig@tch.harvard.edu

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Aug. 26, 2003 Vol. 10, No. 165
Providing news and information about medications and their proper use

>>>Gastroenterology Update
Source:
Aug. Gastroenterology (www.gastro.org; 2003; 125).

Infections After IBD Surgery: Postoperative infectious complications occur more frequently when corticosteroids are used in patients with inflammatory bowel disease who are undergoing elective bowel surgery (pp. 320-6). In a retrospective cohort study of 159 such patients, 56 individuals received corticosteroids alone, 52 patients were given 6-mercaptopurine/azathioprine alone or with corticosteroids, and 51 patients received neither corticosteroids nor 6-mercaptopurine/azathioprine. The adjusted odds ratios were 3.69 and 5.54 for any and major infectious complications, respectively, among patients who received corticosteroids. Infectious complications were not significantly increased in patients who were given 6-mercaptopurine/azathioprine, with respective adjusted ORs of 1.68 and 1.20. (G. R. Lichtenstein, grl@mail.med.upenn.edu)

Soluble Aspirin & Colorectal Cancer: Use of daily soluble lysine acetylsalicylate (160 or 300 mg/day) significantly reduced the number of adenomas observed over a 1-year period among 238 patients with histories of colorectal adenomas (pp. 328-36). Reporting the initial data from a planned 4-year study, the authors write, “Among the 238 patients who completed the year 1 colonoscopy, at least one adenoma was observed in 38 patients of the 126 (30%) in the aspirin group and in 46 of the 112 (41%) in the placebo group; relative risk was 0.73 (95% confidence interval: 0.52–1.04; P= 0.08). At least one adenoma of more than 5 mm diameter was observed in 13 patients (10%) in the aspirin group and 26 (23%) in the placebo group (P= 0.01). The corresponding numbers for adenomas more than 10 mm in diameter were one (1%) and 7 (6%) (P= 0.05).” (S. Chaussade, Hôpital Cochin, Paris; apacc@club-internet.fr)

COX-2 Inhibitors & Colorectal Neoplasia: Rofecoxib, celecoxib, and nonselective NSAIDs appear to protect against colorectal neoplasia, according to authors who analyzed a government insurance database (pp. 404-12). In a nested case–control study, patients older than 65 years who underwent a diagnostic test or procedure for colorectal neoplasia between January and June 2001 were assessed, including 2,568 who were free of colorectal neoplasia, 730 patients who were diagnosed with colorectal adenoma, and 179 who were diagnosed with colorectal cancer. The group reports, “Exposures to rofecoxib ([odds ratio, 95% confidence interval], 0.67, 0.46–0.98) and nonselective nonsteroidal anti-inflammatory drugs (0.41, 0.21–0.83) reduced the risk of colorectal adenoma. Rofecoxib, celecoxib, and nonselective nonsteroidal anti-inflammatory drugs were all protective against both neoplasias (0.64, 0.45–0.91; 0.73, 0.54–0.99; and 0.47, 0.26–0.86, respectively).” (E. Rahme, Montreal Genl. Hosp., Montreal; elham.rahme@mcgill.ca)

Coxib Costs: While the use of gastrointestinal resources declines when patients are switched from nonselective NSAIDs to COX-2–specific inhibitors, overall costs are significantly less with NSAIDs (pp. 389-95). Three groups were compared: 2,246 patients who were switched from NSAIDs to a coxib, 25,989 individuals who began therapy with NSAIDs, and 2,125 patients who began therapy with a coxib. In the switcher group, the odds ratio for any GI resource use in the year after the switch was 14% lower than in the year before the switch. The reduced OR resulted from less cotherapy with GI medications. However, overall costs were only reduced by a mean of $19 after switching to coxibs. Adjusted ORs for GI resource use in the new-coxib and new-NSAID groups were about the same, but GI costs were significantly lower in the new-NSAID patients. The authors conclude, “Patients switching from chronic NSAID therapy to chronic coxib therapy had a slight decrease in the proportion using GI-related resources but not in GI costs. When NSAID/coxib drug costs were included, costs were significantly less with NSAIDs than with coxibs. The potential GI-related cost savings suggested in coxib clinical trials may not be fully realized in ‘real-world’ settings.” (L. Laine, llaine@usc.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Aug. 27, 2003 Vol. 10, No. 166
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Aug. 27 issue of JAMA (www.jama.com; 2003; 290).

Sertraline Treatment of Pediatric Depression: Sertraline is an effective and well-tolerated short-term treatment for children and adolescents with major depressive disorder, according to a study of 376 children and adolescents aged 6–17 years (pp. 1033-41). Flexible dosage (50–200 mg/day) of sertraline (n = 189) was compared with placebo tablets (n = 187) over a 10-week period in terms of total scores on the Children’s Depression Rating Scale–Revised Best Description of Child instrument and reported adverse events.

The authors report: “Sertraline-treated patients experienced statistically significantly greater improvement than placebo patients on the CDRS-R total score (mean change at week 10, –30.24 vs –25.83, respectively; P= .001; overall mean change, –22.84 vs –20.19, respectively; P= .007). Based on a 40% decrease in the adjusted CDRS-R total score at study end point, 69% of sertraline-treated patients compared with 59% of placebo patients were considered responders (P= .05). Sertraline treatment was generally well tolerated. Seventeen sertraline-treated patients (9%) and 5 placebo patients (3%) prematurely discontinued the study because of adverse events. Adverse events that occurred in at least 5% of sertraline-treated patients and with an incidence of at least twice that in placebo patients included diarrhea, vomiting, anorexia, and agitation.” (K. D. Wagner, U. Texas Medical Branch, Galveston; kwagner@utmb.edu)

Recalling problems with suicidal thinking and suicide attempts in children and adolescents taking the SSRI paroxetine (see PNN, June 20), an editorialist writes (pp. 1091-3): “Until this [suicide] issue is resolved, prudent practice in the treatment of depressive illnesses in children and adolescents must include careful attention to the decision to treat a child or adolescent with medication for MDD; clinical expertise with mental health assessment, consideration of varied treatment modes including cognitive behavioral or interpersonal psychotherapy, partnership with patients and their parents, and careful attention to symptom course, particularly emotional lability and the assessment of suicidal ideation in youth who are treated with antidepressant medications (specifically, SSRIs, and more particularly, paroxetine). Current evidence continues to support the use of SSRIs, particularly fluoxetine and sertraline, in the treatment of MDD in children and adolescents. Caution is indicated at this time regarding the use of paroxetine in children and adolescents with MDD, and a clinician would be ill-advised to begin treatment with paroxetine for a patient younger than 18 years with MDD. In patients who have been identified as having a robust response to paroxetine, it does not appear prudent to switch to another SSRI based on current data.” (C. K. Varley, cvarley@u.washington.edu)

Ultralow Estrogen Therapy in Older Women: Bone status was improved without apparent adverse effects among 167 older women who took 0.25 mg/day doses of micronized 17-beta-estradiol (pp. 1042-8). In the 3-year study, mean bone mineral density increased significantly for femoral neck (2.6%), hip (3.6%), spine (2.8%), and total body (1.2%) in participants taking low-dose estrogen, compared with placebo. “Estradiol, estrone, and sex hormone–binding globulin levels increased in the estrogen-treated group compared with placebo,” write the authors. “The adverse effect profile was similar; specifically, there were no statistically significant differences in breast tenderness, changes in endometrial thickness or pathological effects, or annual mammographic results between the 2 groups.... There were no reports of breast cancer during the study.” (K. M. Prestwood, U. Connecticut Health Center, Farmington)

Daily Antibiotic Prophylaxis in Sickle Cell Disease: Children with sickle cell disease who were covered by Medicaid in Washington State and Tennessee received inadequate prophylaxis against pneumococcal infections in 1995–99 (pp. 1057-61). While daily prophylaxis is advised, patients received prescriptions for a mean of 148.4 days of therapy per year. (C. M. Sox, U. Washington, Seattle)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Aug. 28, 2003 Vol. 10, No. 167
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Aug. 28 issue of the New England Journal of Medicine (content.nejm.org; 2003; 349).

HIV Treatment Interruptions: Structured treatment interruption is not a good idea for patients infected with multidrug-resistant HIV, according to a study of 270 patients (pp. 837-46). Some have proposed such drug holidays in patients with drug-resistant HIV based on the observation that treatment interruptions sometimes result in re-emergence of a more sensitive strain. In this study, patients with multidrug-resistant HIV and HIV RNA levels of more than 5,000 copies/mL were randomly assigned to a 4-month structured treatment interruption followed by a change in antiretroviral regimen or to an immediate change in regimen. While eight deaths occurred in each group, mortality or disease progression was significantly higher in the treatment-interruption group (22 of 138 patients, compared with 12 of 132 patients in the immediate-intervention group, a hazard ratio of 2.57). Participants in the treatment-interruption group also had persistently fewer CD4+ T-cells and showed no benefit in HIV viral load response or quality of life relative to those patients in the control group. (J. Lawrence, jlawrence@php.ucsf.edu)

After reviewing divergent results on structured treatment interruptions, a writer proposes this course of action for clinicians (pp. 827-8): “Partial or complete interruption of treatment may still have a role before the initiation of salvage therapy; perhaps the duration should be shorter than four months. Partial interruption of treatment involves stopping the drugs in which resistance has little influence on viral fitness while keeping those, such as lamivudine, that lead to less-fit resistant mutants. This interesting approach to treatment awaits clinical trials. Thus, for the time being, unless there are unbearable side effects, patients should continue treatment while awaiting salvage therapy. Maintaining the selection pressure may also reduce the virulence of the virus and therefore benefit the patient.” (B. Hirschel, Hôpital Cantonal Universitaire, Geneva)

Treatment of Immune Thrombocytopenic Purpura: Four days of high-dose dexamethasone is an effective treatment for patients with immune thrombocytopenic purpura, conclude authors who studied 125 patients (pp. 831-6). Patients had newly diagnosed immune thrombocytopenic purpura and a platelet count of less than 20,000/cu mm or a platelet count of less than 50,000/ cu mm and clinically significant bleeding. The authors report that 85% of patients responded to the steroid treatment in the short term, but about one half of patients relapsed within 6 months. Steroid treatment actually helped predict which patients might relapse, as 70% of those with platelet counts of less than 90,000/cu mm on day 10 had relapses within 6 months. The authors note, “Relapse within two months and a low platelet count at day 10 were associated with corticosteroid treatment failure and the need for other treatment. A prolonged remission might have been attainable with further courses of high-dose dexamethasone therapy in some of our patients who had no response to the initial course of dexamethasone therapy or who had a relapse.” (Y. Cheng, Chinese U., Hong Kong; gcheng@cuhk.edu.hk)

Treatment of Locally Advanced Bladder Cancer: Neoadjuvant chemotherapy combined with radical cystectomy improved survival among 307 patients with locally advanced bladder cancer, compared with cystectomy alone (pp. 859–66). Patients were at risk for metastases because of the presence of muscle-invasive bladder cancer (stage T2 to T4a). They were randomly assigned to radical cystectomy or three cycles of methotrexate, vinblastine, doxorubicin, and cisplatin followed by radical cystectomy. Over an 11-year period, median survival among surgical patients was 46 months, compared with 77 months among those who received chemotherapy plus surgery. “In both groups, improved survival was associated with the absence of residual cancer in the cystectomy specimen,” note the researchers. “Significantly more patients in the combination-therapy group had no residual disease than patients in the cystectomy group.” (Southwest Oncology Group, San Antonio)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.


PNN Pharmacotherapy Line
Aug. 29, 2003 Vol. 10, No. 168
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Sept. issue of Diabetes Care (care.diabetes.org; 2003; 26).

Intensive Insulin Regimens: Pump therapy should be considered when initiating intensive insulin regimens in patients with type 2 diabetes, conclude authors of a 132-patient study (pp. 2598–603). In a multicenter, open-label, randomized, parallel-group, 24-week study, patients randomly received continuous subcutaneous insulin infusion (using insulin aspart) or multiple daily injection therapy (bolus insulin aspart and basal NPH insulin). Glycosylated hemoglobin values declined similarly in the two groups (to 8.2% for CSII and 8.0% for MDI), and the CSII demonstrated a statistical trend toward lower blood glucose values at most time points measured, although the difference reached significance only for the measurements at 90 minutes after breakfast. The authors add, “A total of 93% of CSII-treated subjects preferred the pump to their previous injectable insulin regimen for reasons of convenience, flexibility, ease of use, and overall preference. Safety assessments were comparable for both treatment groups.” (P. Raskin, U. Texas Southwestern Med. Ctr., Dallas; praski@mednet.swmed.edu)

Antiatherogenic Effects of Pioglitazone: Two studies provide evidence of antiatherogenic effects of thiazolidinediones that are separate from any effect on blood glucose values.

In 136 Japanese type 2 diabetic patients, pioglitazone 30 mg/day exerted an antiatherogenic effect independent of its antidiabetic effect (pp. 2493-9). In a 3-month study, C-reactive protein and pulse wave velocity were significantly lower in treated versus placebo patients. Hyperglycemia, hyperinsulinemia, glycosylated hemoglobin, and adiponectin concentrations also improved relative to the control group. Importantly, antiatherogenic effects were just as marked in patients whose A1c levels fell by less than 1% as in those with greater reductions in this marker of glucose metabolism. (Y. Ogawa, Tokyo Med. and Dental U., Tokyo; ogawa.mmm@mri.tmd.ac.jp )

The levels of atherogenic dense LDL in 54 nondiabetic, hypertensive patients were significantly reduced by pioglitazone independent from the drug’s effects on fasting triglycerides and HDL cholesterol (pp. 2588-94). During 16 weeks of treatment, triglycerides, total, LDL, and HDL cholesterol were not changed significantly, but pioglitazone lowered dense LDLs by 22%. “The anti-atherogenic potential of pioglitazone may thus be greater than that expected from its effects on triglycerides, LDL, and HDL cholesterol alone,” the researchers conclude. (K. Winkler, Albert Ludwigs-U. Hugstetter, Freiburg, Germany; kwinkler@ukl.uni-freiburg.de)

Metformin for Primary Diabetes Prevention: For preventing diabetes, both lifestyle and metformin proved effective and cost-effective in analyses conducted from the perspectives of both a health system and society (pp. 2518-23). “As implemented in the [Diabetes Prevention Program] and from a societal perspective, the lifestyle and metformin interventions cost $24,400 and $34,500, respectively, per case of diabetes delayed or prevented and $51,600 and $99,200 per quality-adjusted life-year (QALY) gained,” write the authors. “As the interventions might be implemented in routine clinical practice and from a societal perspective, the lifestyle and metformin interventions cost $13,200 and $14,300, respectively, per case of diabetes delayed or prevented and $27,100 and $35,000 per QALY gained. From a health system perspective, costs per case of diabetes delayed or prevented and costs per QALY gained tended to be lower.” (Diabetes Prevention Program Group, George Washington U., Rockville, Md.; dppmail@biostat.bsc.gwu.edu)

>>>PNN NewsWatch
* Little progress has been made on the Medicare prescription drug benefit over the long Congressional summer break. Republicans appear split over differences in the House and Senate plans, and former House speaker Newt Gingrich has predicted the benefit will produce a catastrophic fiscal crisis as baby boomers retire, according to the New York Times and Wall Street Journal.

*
PNN will not be published on Monday, Sept. 1, Labor Day.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2003, Pharmacy Editorial & News Services, Inc. All rights reserved. Redistribution of PNN by recipients by any means, including print and electronic, is strictly prohibited. L. Michael Posey, Editor and Publisher (mposey@aol.com). Call 800/211-4222 to request missing copies of PNN.

PNN Pharmacotherapy Line
Sept. 2, 2003 Vol. 10, No. 169
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
Aug. 30 issue of Lancet (www.thelancet.com; 2003; 362).

Prognostic Implications of HAART Response: Patient CD4 cell count and viral load after 6 months of highly active antiretroviral therapy are better predictors than are those parameters at baseline in patients newly diagnosed with HIV infection, according to an analysis of 13 cohort studies (pp. 679-86). Among 9,323 adult treatment-naive patients who were followed for a collective 13,408 years, adjusted hazard ratios for progression to AIDS or death were greater for those with lower CD4 counts or higher viral loads at 6 months. “Baseline CD4 and HIV-1 RNA were not associated with progression after controlling for 6-month concentrations,” write the authors. “The probability of progression at 3 years ranged from 2.4% in the patients in the lowest-risk stratum to 83% in patients in the highest-risk stratum.”

The researchers add, “Every CD4 cell is important: at 6 months patients with fewer than 25 cells/µL are at a much higher risk of progression than patients with 25–49 cells/µL. By contrast with our previous analysis of prognostic factors at the time of starting HAART, we found that the relation between 6-month viral load and clinical progression is graded, suggesting that continued viral replication under HAART worsens prognosis in a dose-dependent fashion. It is nevertheless noteworthy that in patients with 200 or more CD4 cells at month 6, absolute differences in progression rates between viral load strata are small, unless viral load exceeds 100,000 copies.” (M. Egger, U. Bern, Bern, Switzerland; egger@ispm.unibe.ch)

>>>BMJ Highlights
Source:
Aug. 30 issue of BMJ (www.bmj.org; 2003; 327).

Bisphosphonates in Metastatic Cancer: Treatment with bisphosphonates should begin when bone metastases are diagnosed and should continue until the risk of skeletal morbidity is no longer clinical relevant, according to authors who reviewed 30 prior publications (pp. 469 ff). In studies that lasted at least 6 months, patients on bisphosphonates experienced significantly fewer fractures and bouts of hypercalcemia. They also required less radiotherapy, but bisphosphonates failed to significantly reduce the need for orthopedic surgery or the rate of spinal cord compressions.

While no trials directly compared oral with intravenous agents, the authors made these observations about route of administration and the optimal bisphosphonate regimen: “The pooled results of trials that used intravenous bisphosphonates were highly significant and mirror the primary analysis. In comparison, oral bisphosphonates showed a significant reduction in only vertebral and non-vertebral fractures, but numbers contributing to the analysis were small. Therefore, at present, most evidence supports the use of intravenous aminobisphosphonates.” (J. R. Ross, Royal Marsden Hosp., London; joy.ross@talk21.com)

>>>PNN JournalWatch
* Antiplatelet Therapy, in Circulation, 2003; 108: 45–7. Reprints: circ.ahajournals.org; R. A. Harrington.

* Chemotherapy Dose and Schedule in Adjuvant Treatment of Breast Cancer: Phoenix, Turkey, or Dodo?, in
Lancet, 2003; 362: 677–8. Reprints: J. Crown, St. Vincent's U. Hosp., Dublin, Ireland; John.Crown@ICORG.IE

* Considerations in the Management of Steroid-Dependent Crohn’s Disease, in
Gastroenterology, 2003; 327: 906–10. Reprints: www.gastro.org; L. Laine.

* American Gastroenterological Association Medical Position Statement: Osteoporosis in Hepatic Disorders and AGA Technical Review on Os