Dec 2004

PNN Annual File—2004

PNN Pharmacotherapy Line
Jan. 5, 2004 Vol. 11, No. 1
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Jan. 1 issue of the New England Journal of Medicine (content.nejm.org; 2004; 350).

Valacyclovir & Herpes Transmission: In 1,484 immunocompetent, heterosexual, monogamous, herpes-discordant couples, once-daily valacyclovir significantly reduced the risk of transmission of genital herpes simplex type 2 (pp. 11-20). In each couple, one partner had clinically symptomatic genital HSV-2, while the other was susceptible to HSV-2. Seropositive partners took valacyclovir 500 mg once daily or placebo for 8 months, and safe-sex practices were encouraged. Clinically symptomatic HSV-2 infection developed in 4 of 743 susceptible individuals whose seropositive partners were given valacyclovir, compared with 16 of 741 of those whose partners were given placebo, a significant risk reduction of 75%. In the valacyclovir group, 14 susceptible partners acquired HSV-2 (1.9%), compared with 27 (3.6%) of susceptible partners in the placebo group, also a significant 48% reduction in risk. Analysis of genital-swab samples showed that active treatment significantly reduced the percentage of days that seropositive partners were shedding virus (2.9% of days with valacyclovir, versus 10.8% of days with placebo). (L. Corey, lcorey@u.washington.edu.)

An editorialist discusses the possibility of using acyclovir rather than the more expensive valacyclovir and the broader, AIDS-related implications of protecting against herpes ulcers (pp. 67-8): “Generic acyclovir is inexpensive (therapy with 400-mg tablets given twice per day costs 20 cents per day, or about $73 per year), it is unlikely to induce resistance with prolonged use, and it is the safest of the antiviral drugs. The urgency of ... trials is enormous, because they promise to separate the complex issues of confounding sexual behavior from questions about whether HSV-2 really is causal in HIV-1 transmission. Millions could benefit if the use of acyclovir is proven to decrease the transmission of HIV-1 by preventing HSV-2 genital ulcers. The time for ethically designed interventional studies is now.” (C. S. Crumpacker, Beth Israel Deaconess Medical Center, Boston)

>>>PNN NewsWatch
* FDA and Roche are warning against use of oseltamivir in infants younger than 1 year. Based on deaths of young rats given large amounts of the flu drug, researchers believe it may preferentially penetrate immature blood-brain barriers.

* Merck has submitted an NDA for
etoricoxib (Arcoxia) for treating osteoarthritis, rheumatoid arthritis, chronic low back pain, acute pain, dysmenorrhea, acute gouty arthritis, and ankylosing spondylitis.

* FDA last week approved
Symbyax (fluoxetine plus olanzapine) for treatment of the depressive phase of bipolar disorder.

>>>PNN JournalWatch
* Recommended Childhood and Adolescent Immunization Schedule—United States, January–June 2004, in Pediatrics, 2004; 113: 142–3. Reprints: www.pediatrics.org; American Academy of Pediatrics Committee on Infectious Diseases.

* Acquired Immunodeficiency Syndrome and the Risk of Stroke, in
Stroke, 2004; 35: 196–203. Reprints: stroke.ahajournals.org; J. W. Cole, U. Maryland, Baltimore; jwc007@dnamail.com

* A Review of Natural-Rubber Latex Allergy in Health Care Workers, in
Clinical Infectious Diseases, 2004; 38: 252–6. Reprints: www.journals.uchicago.edu/ CID; P. M. Ranta, Med. College of Ga., Augusta.

* Clinical Stability in Human Immunodeficiency Virus–Infected Patients with Community-Acquired Pneumonia, in
Clinical Infectious Diseases, 2004; 38: 271–9. Reprints: www.journals.uchicago.edu/CID; P. Viale, U. Udine, Udine, Italy.

* What Is a “Mood Stabilizer”? An Evidence-Based Response, in
American Journal of Psychiatry, 2004; 161: 3–18. Reprints: ajp.psychiatryonline.org; M. S. Bauer.

* Maintenance Treatment of Insomnia: What Can We Learn From the Depression Literature?, in
American Journal of Psychiatry, 2004; 161: 19–24. Reprints: ajp.psychiatryonline.org; R. D. Jindal.

* Omega 3 Fatty Acids and Cardiovascular Disease—Fishing for a Natural Treatment, in
BMJ, 2004; 328: 30–5. Reprints: www.bmj.org; J. N. Din, U. Edinburgh, Edinburgh, U.K.; jehangirdin@hotmail.com

* Artesunate Combinations for Treatment of Malaria: Meta-analysis, in
Lancet, 2004; 363: 9–17. Reprints: www.thelancet.com; P. Garner, Liverpool Sch. of Tropical Med., Liverpool, U.K.; pgarner@liv.ac.uk)

* The New Medicare Prescription-Drug Legislation, in
New England Journal of Medicine, 2004; 350: 9–10. Reprints: content.nejm.org; D. E. Altman.

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 6, 2004 Vol. 11, No. 2
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Jan. 6 issue of the Annals of Internal Medicine (www.annals.org; 2004; 140).

Coffee Consumption & DM: Long-term coffee consumption significantly lowers patients’ risk of developing type 2 diabetes mellitus, according to data from the Nurses’ Health Study and Health Professionals’ Follow-up Study (pp. 1-8). Based on information provided by 41,934 men from 1986 to 1998 and 84,276 women from 1980 to 1998, the investigators found that caffeine was a necessary ingredient for this effect, “The multivariate relative risks for diabetes according to regular coffee consumption categories (0, <1, 1 to 3, 4 to 5, or 6 cups per day) in men were 1.00, 0.98, 0.93, 0.71, and 0.46 (95% CI, 0.26 to 0.82; P = 0.007 for trend), respectively. The corresponding multivariate relative risks in women were 1.00, 1.16, 0.99, 0.70, and 0.71 (CI, 0.56 to 0.89; P < 0.001 for trend), respectively. For decaffeinated coffee, the multivariate relative risks comparing persons who drank 4 cups or more per day with nondrinkers were 0.74 (CI, 0.48 to 1.12) for men and 0.85 (CI, 0.61 to 1.17) for women. Total caffeine intake from coffee and other sources was associated with a statistically significantly lower risk for diabetes in both men and women.”

In seeking to explain their findings, the authors note that tolerance develops after a few days to several acute effects of caffeine, including changes in blood pressure, heart rate, plasma renin activity, plasma catecholamines, or urinary catecholamines. This makes acute effects of caffeine on insulin sensitivity transient. Beneficial effects of caffeine maintained over time include increased basal energy expenditure, fat oxidation and glycogen mobilization in muscle, and stimulation of free fatty acid release in peripheral tissues, the group explains. (F. B. Hu, frank.hu@channing.harvard.edu)

Cardiac Risk Factors in Kidney Disease: Adults with chronic kidney disease have several changes in serum proteins that increase their risks for cardiovascular disease, note authors who analyzed data from the Third National Health and Nutrition Examination survey (pp. 9-17). Included in the data set was information from 12,547, 3,180, and 744 individuals with glomerular filtration rates in the normal, mildly impaired, and moderately impaired ranges, respectively. Levels of apolipoprotein A1 were decreased and levels of homocysteine, lipoprotein(a), fibrinogen, and C-reactive protein were increased in those with declining renal function. The researchers conclude that these “may be important underlying causes of an excess risk for cardiovascular disease among patients with chronic kidney disease.” (J. He, jhe@tulane.edu)

An editorialist finds these data interesting but of limited clinical relevance because of paucity of interventions that can affect these nontraditional risk factors (pp. 60-1). Instead, he writes, clinicians should focus on more important risk factors for cardiovascular disease (CVD), such as blood pressure: “My own hunch is that nontraditional risk factors have a modest causal role in the pathogenesis of CVD in the general population and a much greater role in patients with chronic kidney disease. I also suspect that we have substantially underestimated the effects of traditional risk factors. In particular, the strength of the relationship between blood pressure and CVD has probably been underestimated, in part because of enormous measurement error and in part because office blood pressure does not capture a potentially important dimension of blood pressure, namely, diurnal patterns. Sustained nocturnal blood pressure—a dimension rarely measured in observational studies—has emerged as a risk factor for CVD. Of interest, patients with chronic kidney disease have an extremely high prevalence of elevated nocturnal blood pressure. While high nocturnal blood pressure may represent an adaptive response to maintain glomerular filtration rate, it is likely that such blood pressure elevations also accelerate vascular damage....

“Aggressive management of traditional risk factors is a sensible, albeit largely unproven, strategy to prevent CVD in patients with chronic kidney disease.” (L. J. Appel, Johns Hopkins U., Baltimore; lappel@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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 7, 2004 Vol. 11, No. 3
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Jan. 7 issue of JAMA (www.jama.com; 2004; 291).

Prescribing Patterns After Study Publicity: Two studies and an editorial explore the impact of highly publicized clinical studies on national prescribing patterns.

Hormone-replacement therapy prescribing patterns changed quickly and dramatically following publication of the Women’s Health Initiative results in July 2002, according to the first study (pp. 47-53). Two databases were examined to determine national trends in hormone therapy use from January 1995 to July 2003: the National Prescription Audit and the National Disease and Therapeutic Index. Researchers found that annual hormone therapy prescriptions increased from 58 million in 1995 to 90 million in 1999, representing approximately 15 million women per year, then remained stable through June 2002. Adoption of new oral estrogen–progestin combinations, primarily Prempro, accounted for most of this growth. The authors write: “Following the publication of [WHI] trial results in July 2002, hormone therapy prescriptions declined in successive months. Relative to January–June 2002, prescriptions from January– June 2003 declined by 66 percent for Prempro and 33 percent for Premarin. Small increases were observed in vaginal formulations and in new prescriptions for low-dose Premarin. If prescription rates observed through July 2003 remain stable, a decline to 57 million prescriptions for 2003, similar to the rate in 1995, is projected.”

The same research group examines prescribing patterns for alpha-adrenergic antagonists following the ALLHAT-driven, spring 2000 changes in recommendations for their use as antihypertensives (pp. 54-62). Using the same two databases as in the above study, the researchers found steady increases in alpha-blocker new prescriptions, dispensed prescriptions, and physician drug use from 1996 through 1999. “There was a moderate reversal in these trends following ALLHAT early termination and subsequent publications in early 2000,” they write. “Between 1999 and 2002, new annual alpha-blocker prescription orders declined by 26 percent (from 5.15 million to 3.79 million), dispensed prescriptions by 22 percent (from 17.2 million to 13.4 million), and physician-reported drug use by 54 percent (from 2.26 million to 1.03 million). Other potential influences did not appear to have contributed significantly to this decline although cessation of alpha-blocker marketing may have hastened the decline.... Our findings are clearly consistent with ALLHAT early termination results having a significant impact on alpha-blocker use. Declining pharmaceutical industry promotion also may have contributed further to decreased alpha-blocker use. The lack of an abrupt and more pronounced decline in prescribing shortly after the ALLHAT results, however, suggests slow and potentially incomplete diffusion of information from this clinical trial. Combined with past work that questions the potency of clinical trial results on physician practice, our analysis suggests the need for additional strategies to augment the dissemination of results from clinical trials.” (R. S. Stafford, rstafford@stanford.edu)

An accompanying editorial is provocative and interesting (pp. 104-6): “In this context, a pointed question is already being asked. Were health care opinion leaders and the pharmaceutical industry locked into an alliance that accelerated the medicalization of menopause? Hormone therapy was indeed a heavily promoted and profitable product line. This is wonderful terrain for neo-Marxists and feminist deconstructionists, but the problem may be even deeper-seated.... Just as the incredibly wide uptake of the WHI results by the media turned patients into ‘evidence vectors,’ direct-to-consumer advertising gives a whole new meaning to the concept of mass medicalization. The ever-expanding role for therapy, particularly prescription drugs, is generally supported by at least some lines of evidence and embraced by millions of professionals and patients eager to avoid death, disease, dysfunction, disability, and distress. The current therapeutic culture, in short, has its roots in the religion of modernity: faith in science and redemption through technology.” (C. D. Naylor, david.naylor@utoronto.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 8, 2004 Vol. 11, No. 4
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Jan. 8 issue of the New England Journal of Medicine (content.nejm.org; 2004; 350).

Vasopressin in Cardiac Arrest: For treatment of out-of-hospital refractory cardiac arrest, vasopressin followed by epinephrine may be more effective than epinephrine alone, according to a study from the European Resuscitation Council Vasopressor during Cardiopulmonary Resuscitation Study Group (pp. 105-13). Among 1,196 patients who received two injections of either vasopressin 40 IU or epinephrine 1 mg, researchers found no significant differences in rates of survival to hospital admission for patients with ventricular fibrillation (46.2% for vasopressin and 43.0% for epinephrine) or pulseless electrical activity (33.7% and 30.5%, respectively). But significantly higher admission rates were recorded for patients in asystole (29.0% and 20.3%, respectively), and this group also had significantly higher rates of hospital discharge (4.7% and 1.5%, respectively).
The authors also report, “Among 732 patients in whom spontaneous circulation was not restored with the two injections of [vasopressin], additional treatment with epinephrine resulted in significant improvement in the rates of survival to hospital admission and hospital discharge in the vasopressin group, but not in the epinephrine group (hospital admission rate, 25.7 percent vs. 16.4 percent; P=0.002; hospital discharge rate, 6.2 percent vs. 1.7 percent; P=0.002).” (V. Wenzel, Leopold-Franzens U., Innsbruck, Austria; volker.wenzel@uibk.ac.at)

An editorialist suggests that clinicians consider immediately incorporating vasopressin into resuscitation protocols (pp. 179-81): “Major changes in the guidelines for resuscitation are adopted at international conferences of experts on cardiopulmonary resuscitation and emergency cardiac care, but such conferences are generally held only at intervals of four to five years. Because of the size and power of the study by Wenzel et al., the dismal rate of resuscitation among patients with asystolic cardiac arrest, and the apparent absence of any added risk of injury to patients who may be treated according to the new therapeutic sequences, practitioners should perhaps be encouraged to incorporate the use of vasopressin into their resuscitation protocols immediately. The best approach to optimizing survival as soon as possible would be to have the appropriate committees of the American Heart Association and the American College of Cardiology convene in order to issue an interim guideline incorporating these important new therapeutic advances.” (K. M. McIntyre, Harvard Med. Sch., Boston)

Low-Dose ASA in Polycythemia Vera: Thrombotic complications can be safely prevented in patients with polycythemia vera by daily use of low-dose aspirin, according to a study of 518 patients (pp. 114-24). Study subjects, who had no clear indications for aspirin treatment and no contraindications to such therapy, were randomized to receive aspirin 100 mg daily or placebo. The risk of the combined end point of nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, or death from cardiovascular causes was reduced by a significant 60% with aspirin therapy. All-cause and cardiovascular mortality were not significantly reduced, and only a statistical trend was demonstrated for reduced risk of a combined end point of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes (p = .09). Risk of major bleeding episodes was increased by 62% with aspirin therapy, but the difference did not reach significance. (R. Landolfi, Università Cattolica, Rome, Italy; atrlandolfi@rm.unicatt.it)

An editorialist differs, citing problems in management of study patients (pp. 99-101): “[These] patients were heavily pretreated with chemotherapy to normalize the platelet count, and the results may therefore not be generally applicable. Moreover, many of the patients should have been excluded, since their hematocrits were above the acceptable level. Thus, one can conclude only that low-dose aspirin is safe and effective in polycythemia vera when the platelet count is normal.” (J. Spivak, Johns Hopkins U., Baltimore)

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 9, 2004 Vol. 11, No. 5
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Jan. Pharmacotherapy (www.accp.org; 2004; 24).

Carbapenem Pharmacodynamics: Based on a 10,000-subject Monte Carlo simulation, investigators explore possible pharmacodynamic breakpoints for meropenem and imipenem treatment of Enterobacteriaceae, Acinetobacter baumannii, and Pseudomonas aeruginosa infections (pp. 8-15). The simulation varied total body clearance, volume of distribution, and minimum inhibitory concentrations (MICs) of the organisms, while drug doses were held constant at 500 mg every 6 hours. The percentage of the dosing interval that serum drug concentrations exceeded bacterial MICs were significantly greater for meropenem used for treatment of Enterobacteriaceae and P. aeruginosa, while imipenem achieved higher exposure to A. baumannii. The simulation showed that both drugs covered most organisms during 30% and 50% of the dosing interval under most conditions, but meropenem achieved 100% coverage more frequently than did imipenem. “Further study of the benefits of achieving this pharmacodynamic breakpoint with a higher probability of attaining targets is necessary,” the group concludes. (D. P. Nicolau, Hartford Hosp., Hartford, Conn.; dnicola@harthosp.org)

Intranasal Drug Interaction: Patients with allergic rhinitis who are treated with intranasal fluticasone may have decreased absorption of intranasally administered hydromorphone, according to a study of 12 patients (pp. 26-32). The subjects, all of whom had allergic rhinitis, received three treatments in crossover fashion: intravenous hydromorphone; intranasal hydromorphone; and intranasal hydromorphone after 6 days of intranasal fluticasone. Several pharmacokinetic parameters were decreased slightly but not significantly when fluticasone therapy preceded hydromorphone administration, and the time to peak serum concentration was significantly delayed by the rhinitis therapy (15 versus 30 minutes). (G. A. Davis, gadavi00@email.uky.edu)

Treatment Adequacy with Antidepressants: A retrospective analysis of patients in a managed-care organization reveals that those newly started on extended-release venlafaxine are more likely to achieve adequate doses of that agent within 84 and 180 days, compared with patients newly started on fluoxetine (pp. 33-40). The study included 11,298 patients who began treatment with one of the agents in 2000 and early 2001 and a subset of 7,430 patients who continued on one of the drugs through this period. Patients whose drug doses were within 10% of target daily doses (75–150 mg for venlafaxine XR and 20 mg for fluoxetine) were considered to be treated adequately. The adjusted odds ratios for achieving treatment adequacy were 3.05 and 3.57 at 84 and 180 days, respectively, for venlafaxine XR, compared with fluoxetine. Unadjusted adequacy rates were for venlafaxine XR and fluoxetine were 79% and 57%, respectively, at 84 days, and 77% and 52%, respectively, at 180 days. The authors conclude, “Treatment adequacy as a proxy for optimal treatment may be an important factor to consider when selecting an antidepressant drug.” (K. S. Yu-Isenberg, Prescription Solutions, Costa Mesa, Calif.; yu.isenberg@sbcglobal.net)

Nonhormonal Treatments for Hot Flashes: Clonidine, venlafaxine, paroxetine, fluoxetine, and gabapentin are possible nonhormonal treatments for women experiencing hot flashes, conclude authors of a review article (pp. 79-83). For women unable or unwilling to take hormonal agents for treatment of hot flashes, oral and transdermal clonidine are moderately effective, and comparative studies indicate that venlafaxine, paroxetine, and gabapentin are even more effective than clonidine for reducing the frequency and severity of symptoms. Fluoxetine’s effects may be more modest, although comparative trials have not been conducted. (B. L. Sicat, Va. Commonwealth U., Richmond)

Other Review Articles: Also reviewed in this issue are daptomycin (pp. 41-57); oritavancin and tigecycline (pp. 58-68); inhaled nitrite (“poppers&rdquoWinking abuse (pp. 69-78); and carvedilol for portal hypertension (pp. 94-104).

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.
PNN Pharmacotherapy Line
Jan. 12, 2004 Vol. 11, No. 6
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
Jan. 10 issue of Lancet (www.thelancet.com; 2004; 363).

Molecular Genetics of the SARS Virus: As concern re-emerges along with four cases of severe acute respiratory syndrome in China, an analysis of the molecular genetics of strains of the SARS coronavirus isolated during last season’s outbreak shows that most cases in Hong Kong were related to a single index case (pp. 99-104). “Most of the Hong Kong viruses (139/142), including those from a large outbreak in an apartment block, clustered closely together with the isolate from a single index case (HKU-33) who came from Guangdong to Hong Kong in late February,” the researchers write. “Three other isolates were genetically distinct from HKU-33 in Hong Kong during February, but none of these contributed substantially to the subsequent local outbreak. Viruses identified in Guangdong and Beijing were genetically more diverse.... The molecular epidemiological evidence suggests that most SARS-CoV from the outbreak in Hong Kong, as well as the viruses from Canada, Vietnam, and Singapore, are genetically closely linked. Three viruses found in Hong Kong in February were phylogenetically distinct from the major cluster, which suggests that several introductions of the virus had occurred, but that only one was associated with the subsequent outbreak in Hong Kong, which in turn spread globally.” (F. C. Leung, U. Hong Kong, Hong Kong; fcleung@hkucc.hku.hk)

>>>BMJ Highlights
Source:
Jan. 10 issue of BMJ (www.bmj.org; 2004; 328).

Mortality & Low-Tar Cigarettes: The amount of tar in cigarettes makes little difference to deaths from lung cancer, according to results from the Cancer Prevention Study II (pp. 72 ff). Released on the 40th anniversary of the 1963 U.S. Surgeon’s General report on health effects of tobacco, this article grouped 364,239 men and 576,535 women, aged 30 years or older, according to their smoking history [never smoked, former smokers, smokers of very low tar (7 mg tar/cigarette or less) filter, low tar (8–14 mg) filter, high tar (22 mg or more) nonfilter brands, and medium tar conventional filter brands (15–21 mg)]. “Irrespective of the tar level of their current brand, all current smokers had a far greater risk of lung cancer than people who had stopped smoking or had never smoked,” the investigators report. The increases in lung cancer risk among those who smoked medium, low, and very low tar cigarettes were similar, and the risks were even higher among patients who smoked nonfiltered, high tar cigarettes.

“Addicted smokers who switch from a higher to lower tar cigarette can maintain their nicotine intake by blocking ventilation holes, increasing the puff volume or the time during which the smoke is retained in the lungs, and smoking more cigarettes,” concludes the study group. “As a result, the actual dose of toxicants to the smoker may be much higher than is predicted by machine measured yields. Changes in inhalation patterns induced by lower tar cigarettes may increase the surface area of the lung exposed to carcinogens in smoke and thus result in greater deposition of submicron sized particles deeper into the airways.” (J. E. Harris, jeharris@partners.org)

>>>PNN JournalWatch
* Review of Prevalence Data in, and Evaluation of Methods for Cross Cultural Adaptation of, UK Surveys on Tobacco and Alcohol in Ethnic Minority Groups, in BMJ, 2004; 328: 76 ff. Reprints: www.bmj.org; R. Bhopal, U. Edinburgh, Edinburgh, U.K.; Raj.Bhopal@ed.ac.uk

* Tobacco Control in the Wake of the 1998 Master Settlement Agreement, special report released early on Web site of the
New England Journal of Medicine, 2004; 350: 293–301. Reprints: content.nejm.org; S. A. Schroeder.

* Supervised Injecting Centres, in
BMJ, 2004; 328: 100–2. Reprints: www.bmj.org; N. M. .J Wright, North East Leeds Primary Care Trust, Leeds; n.wright@leeds.ac.uk

* Can Angiotensin II Type 2 Receptors Have Deleterious Effects in Cardiovascular Disease?: Implications for Therapeutic Blockade of the Renin–Angiotensin System, in
Circulation, 2004; 109: 8–13. Reprints: circ.ahajournals.org; B. I. Lévy.

* Vitamin D Intake Is Inversely Associated with Rheumatoid Arthritis: Results from the Iowa Women’s Health Study, in
Arthritis & Rheumatism, 2004; 50: 72–7. Reprints: www.rheumatology.org; K. G. Saag, U. Alabama, Birmingham.

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.
PNN Pharmacotherapy Line
Jan. 13, 2004 Vol. 11, No. 7
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Jan. 12 issue of Archives of Internal Medicine (www.archinternmed.com; 2004; 164).

Weight Loss: Nondieting, overweight individuals can lose weight and fat by walking 30 minutes every day, according to a study of 120 individuals (pp. 31-9). Patients were encouraged in the 8-month trial to maintain their normal dietary intake and weights. They were randomly assigned to control, high amount/vigorous intensity, low amount/vigorous intensity, or low amount/moderate intensity exercise groups. The authors found “a significant ... dose-response relationship between amount of exercise and amount of weight loss and fat mass loss,” with changes in weight and fat mass for the four respective groups of +1.0 and +0.4, –2.9 and –4.8, –0.9 and –2.0, and –0.6 and –2.5 kg. (C. A. Slentz, Cris.Slentz@duke.edu)

Statins Plus Aspirin for Secondary CVD Prevention: “More widespread and appropriate combined use of statins and aspirin in secondary prevention of cardiovascular disease will avoid large numbers of premature deaths,” conclude authors who analyzed relevant trials and performed meta-analyses of pravastatin and aspirin (pp. 40-4). “Individual trials and all meta-analyses demonstrated similar additive benefits of pravastatin and aspirin on cardiovascular disease,” the group writes. “In meta-analysis, the relative risk reductions for fatal or nonfatal myocardial infarction were 31% for pravastatin plus aspirin vs aspirin alone and 26% for pravastatin plus aspirin vs pravastatin alone. For ischemic stroke, the corresponding relative risk reductions were 29% and 31%. For the composite end point of coronary heart disease death, nonfatal myocardial infarction, coronary artery bypass graft, percutaneous transluminal coronary angioplasty, or ischemic stroke, the relative risk reductions were 24% and 13%. All relative risk reductions were statistically significant.” (C. H. Hennekens, U. Miami, Boca Raton, Fla.; PROFCHHMD@prodigy.net)

HIV Postexposure Prophylaxis: For men seeking HIV postexposure prophylaxis after receptive anal intercourse, provision of medications could avert future HIV-related medical care costs, according to a retrospective cost-utility analysis (pp. 46-54). “The overall cost-utility ratio was $14,449 per [quality-adjusted life-year] saved,” reports the group. “The average cost of the PEP regimen was $1222, and the total cost of the program was $450,970. The PEP program prevented an estimated 1.26 HIV infections, saved 11.74 QALYs, and averted $281,323 in future HIV-related medical care costs.” (S. D. Pinkerton, Ctr. for AIDS Intervention Research, Milwaukee)

Medication Use in AF: Anticoagulation remains underused in patients with atrial fibrillation, especially in the oldest patients, and amiodarone has replaced quinidine as the most commonly used sinus rhythm medication, according to an analysis of data from the National Ambulatory Medical Care Survey (pp. 55-60). Declining use of digoxin dropped the use of rate control medications from 72% of physician office visits in 1991–92 to 56% in 1999–2000. Beta-blocker and calcium-channel blocker use was unchanged. The authors note, “Although there was no change in overall sinus rhythm medication use over time, amiodarone hydrochloride use increased from 0.2% to 6.4% (P<.001 for trend), while quinidine use decreased from 5.0% to 0.0% (P = .01 for trend). Oral anticoagulant use increased (28% to 41%, P = .01 for trend), with the greatest increase in patients aged 80 years and older (14% to 48%, P<.001 for trend). Despite this, only 46.5% of patients at high risk for stroke were taking anticoagulants in 1999–2000.” (M. C. Fang, mfang@medicine.ucsf.edu)

Problems with Warfarin After HIT: Because of the risk of venous limb gangrene and skin necrosis, warfarin must be introduced at modest doses in patients with heparin-induced thrombocytopenia after platelet recovery (pp. 66-70). Cases of six such patients are presented to illustrate problems with unopposed warfarin and the need for caution during transition from direct thrombin inhibitors. (L. Rice, Baylor Coll. of Med., Houston; lrice@bcm.tmc.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 14, 2004 Vol. 11, No. 8
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Jan. 14 issue of JAMA (www.jama.com; 2004; 291).

H. pylori Eradication & Gastric Cancer: The need for eradication of Helicobacter pylori for preventing gastric cancer has been controversial for several years. A new study sheds light on the patient populations that may benefit from this intervention, indicating that those with no precancerous lesions are most likely to require eradication therapy (pp. 187-94). Among 1,630 healthy carriers of H. pylori infection from Fujian Province, China, 988 participants had no precancerous lesions (gastric atrophy, intestinal metaplasia, or gastric dysplasia) on study entry in July 1994. Patients randomly received a 2-week course of omeprazole 20 mg, amoxicillin and clavulanate potassium 750 mg, and metronidazole 400 mg, all twice daily, or placebo.

Study results showed, “Among the 18 new cases of gastric cancers that developed, no overall reduction was observed in participants who received
H pylori eradication treatment (n = 7) compared with those who did not (n = 11) (P = .33). In a subgroup of patients with no precancerous lesions on presentation, no patient developed gastric cancer during a follow-up of 7.5 years after H pylori eradication treatment compared with those who received placebo (0 vs 6; P = .02). Smoking (hazard ratio [HR], 6.2; 95% confidence interval [CI], 2.3–16.5; P < .001) and older age (HR, 1.10; 95% CI, 1.05–1.15; P < .001) were independent risk factors for the development of gastric cancer in this cohort.” (B. C-Y. Wong, U. Hong Kong, Hong Kong, China; bcywong@hku.hk)

An editorialist agrees with the authors that more study is needed before public health officials change current recommendations (pp. 244-5): “The report by Wong et al provides the first experimental evidence in humans that
H pylori infection causes cancer. If the subgroup analysis is correct, then H pylori may be considered as the preeminent cause of gastric adenocarcinoma. The question of whom to treat, however, remains unanswered. Those in public health are unlikely to be convinced by this study to start the development of H pylori screening programs. It is encouraging that the authors plan to follow up their patients further. With careful follow-up over time, this cohort could reveal an increasing wealth of information. Other trials currently under way, as well as additional cost-effectiveness studies, will supplement these findings. Thus, in 5 to 10 years, the answers to many of these issues may be clear. In the meantime, many patients will come to their physicians asking for screening and myriad others previously diagnosed as having H pylori infection will request treatment. Until more outcomes are available, individual clinicians will continue to do what we have for the past decade: use the very best informed judgment and hope for the best.” (J. Parsonnet, parsonnet@stanford.edu)

Cardiovascular Effects of Metabolife: Patients should avoid dietary supplements containing ephedra and caffeine, conclude authors who measured in 15 healthy volunteers (nine men, six women) the electrocardiographic and hemodynamic effects of a Metabolife 356 (pp. 216-21). After a single dose of the dietary supplement, which contained 19 ingredients including ephedra 12 mg and caffeine 40 mg, the authors found, “Individuals receiving the [dietary supplement] had a longer maximal QTc interval (mean [SD], 419.4 [11.8] vs 396.1 [15.7] milliseconds; P<.001) and higher SBP (mean [SD], 123.5 [10.98] vs 118.93 [9.62] mm Hg; P = .009) compared with placebo. Participants who received the [dietary supplement] were more likely to experience a QTc interval increase of at least 30 milliseconds vs placebo (8 individuals [53.3%] vs 1 individual [6.7%]; relative risk, 2.67 [95% confidence interval, 1.40– 5.10]). There were no significant sex-related differences.” The authors, five pharmacists and a physician, conclude, “Since the actual ingredient or ingredients in Metabolife 356 responsible for these findings are not known, patients should be instructed to avoid this and similar dietary supplements until more information is known about their safety.” (C. M. White, Hartford Hosp., Hartford, Conn.; cmwhite@harthosp.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 15, 2004 Vol. 11, No. 9
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Jan. 15 issue of the New England Journal of Medicine (content.nejm.org; 2004; 350).

Abciximab in Elective PCI: Use of abciximab was associated with no added clinical benefit in patients at low to intermediate risk who underwent elective percutaneous coronary intervention after pretreatment with a high loading dose of clopidogrel 600 mg before the procedure (pp. 232-8). Among 2,159 patients with coronary artery disease who also received preprocedure aspirin, heparin plus placebo or heparin plus an abciximab bolus and infusion were administered during and following PCI. Four percent of patients in each group reached a primary end point of death, myocardial infarction, or urgent target-vessel revascularization within 30 days after randomization, the authors report, adding, “Most adverse events were myocardial infarctions: the incidence was 4 percent (40 patients) in the abciximab group and 4 percent (41 patients) in the placebo group (P=0.91). Twelve patients (1 percent) in the abciximab group and eight patients (1 percent) in the placebo group had major bleeding complications (P=0.37). Profound thrombocytopenia occurred in 10 patients (1 percent) in the abciximab group but in none in the placebo group (P=0.002).” (A. Kastrati, Deutsches Herzzentrum, Munich, Germany; kastrati@dhm.mhn.de)

Commenting on this study, editorialists assess the cost of glycoprotein IIb/IIIa inhibitors ($600 to $1,800 per infusion) and explain that two thirds of patients in the U.S. are high risk (pp. 277-80). They conclude: “In patients undergoing percutaneous coronary intervention (as well as those with acute coronary syndromes), the decision regarding which antiplatelet agent or agents to administer should be based on clinical and angiographic variables. Patients who are believed to be at low risk for an ischemic complication should receive only aspirin and clopidogrel. In such patients, a glycoprotein IIb/IIIa inhibitor, although more potent, does not provide additional benefit. This is good news for both patients and hospitals: patients can receive treatment with an oral antiplatelet regimen that is associated with a lower risk of bleeding, and hospitals can dispense a therapy that is much less expensive. In contrast, high-risk patients should receive all three agents.” (R. A. Lange, U. Tex. Southwestern Med. Ctr., Dallas)

Drug-Eluting Stent: A slow-release, polymer-based, paclitaxel-eluting stent was safe and reduced the rates of clinical and angiographic restenosis at 9 months among 1,314 patients who received a stent in a single, previously untreated coronary-artery stenosis (pp. 221-31). Compared with a bare-metal stent, the new model reduced the need for target-lesion revascularization by 73% and the rate of angiographic restenosis by 70% during the 9-month study. (G. W. Stone, Cardiovascular Res. Found., New York City; gstone@crf.org)

In discussing this new and improved drug-eluting stent, an editorialist provides an evaluation applicable to me-too drug products (pp. 211-2): “Me-too products do not mean that imitation has replaced innovation in health care. Developing a product takes decades; the product that reaches the market first is the one that won the race, not necessarily a reflection of who had the original or best idea. Even if products yield similar outcomes, the concepts behind them might be quite different. Drug-eluting stents might share a delivery technology, but their embedded drugs will ultimately determine their efficacy. The pressure on the manufacturers of the third and fourth entrants into the drug-eluting–stent marketplace to come up with a product that really improves outcomes or lowers cost will be tremendous. As a clinician and health care manager, I can’t wait.” (T. H. Lee, Harvard Med. Sch., Boston)

Tapeworms & Seizures: Albendazole/dexamethasone treatment of 120 patients with neurocysticercosis (CNS infection with Taenia solium larvae) for 10 days reduced the number of seizures by 46% over a 30-month period (pp. 249-58). (H. H. Garcia, Instituto de Ciencias Neurologicas, Lima, Peru, athgarcia@jhsph.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 16, 2004 Vol. 11, No. 10
Providing news and information about medications and their proper use

>>>Stroke Highlights
Source:
Jan. issue of Stroke (stroke.ahajournals.org; 2004; 35).

Aspirin Doses in Cerebrovascular Disease: Use of enteric-coated and low-dose aspirin is questioned by a study showing normal platelet function in substantial proportions of 129 patients with cerebrovascular disease (pp. 175 ff). A platelet function analyzer, the PFA-100, was used in the study, which included patients whose only antiplatelet agent was aspirin. Overall, 32% of patients were taking an enteric-coated aspirin product, and 32% were on low doses of aspirin (162 mg/day). The authors report, “For the entire cohort, 37% of patients had normal PFA-100 results, indicating normal platelet function. For the patients taking low-dose aspirin, 56% had normal PFAs compared with 28% of those taking 325 mg/d of aspirin, while 65% of patients taking enteric-coated aspirin had normal PFAs compared with 25% taking an uncoated preparation (P<0.01 for both comparisons). Similar results were obtained if PFA results were analyzed using mean closure times (low-dose aspirin, 183 sec; high-dose aspirin, 233 sec; enteric-coated, 173 sec; uncoated, 235 sec; P<0.01 for comparisons). Older patients and women were less likely to have a therapeutic response to aspirin, independent of aspirin dose or formulation.” The group concludes, “If these results correlate with clinical events, they have broad implications in determining how aspirin is used and monitored.” (M. J. Alberts, m-alberts@northwestern.edu)

Perindopril & Stroke Risk: In the Perindopril Protection Against Recurrent Stroke Study (PROGRESS), hypotensive therapy was effective for stroke prevention in patients with histories of cerebrovascular events, including those whose prior events were hemorrhagic in origin (pp. 116 ff). The study included 6,105 people, and they were assigned to placebo or perindopril and, unless they had contraindications, the diuretic indapamide. Relative risks for any stroke during a mean of 3.9 years of follow-up were reduced by 26% among patients with prior ischemic strokes and by 49% among those who had had intracerebral hemorrhages. Absolute rates of ischemic and hemorrhagic stroke were reduced by the ACE inhibitor from 10% to 8% and from 2% to 1%, respectively. (J. Chalmers, U. Sydney, Newtown, Sydney, Australia; progress@iih.usyd.edu.au)

>>>PNN NewsWatch
* Oxaliplatin (Eloxatin, Sanofi-Synthelabo) has been approved by FDA for first-line treatment of advanced colorectal cancer in combination with 5-fluorouracil and leucovorin. Oxaliplatin was originally approved in Aug. 2002 for second-line treatment of patients with metastatic carcinoma of the colon or rectum. Patients with advanced colorectal cancer treated with this regimen as first-line chemotherapy had a statistically significant improvement of nearly 5 months in median survival time compared with patients treated with a standard treatment of irinotecan in combination with 5-FU/LV.

* FDA has approved
quetiapine (Seroquel, AstraZeneca) for treatment of acute mania associated with bipolar disorder.

* NACDS and Express Scripts will work together in creating a national
Medicare discount card, the parties announced yesterday. Working through Pharmacy Care Alliance, the two organizations will seek CMS approval for a discount card, which they said would be “a consumer friendly product that delivers real value.” The cards were authorized by the new Medicare prescription drug benefit law; NACDS, along with NCPA and APhA, had in the past successfully fought establishment of such Medicare discount drug cards.

* Rep. Chris John (D–La.) has introduced the
Pharmacy Education Aid Act (HR 3591), which would provide loans and scholarships for pharmacy school students willing to provide care in underserved communities, and establishes a loan repayment plan for prospective pharmacy school faculty. The bill’s intent is to address the nation’s pharmacist shortage.

*
PNN will not be published on Mon., Jan. 19, 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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 20, 2004 Vol. 11, No. 11
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
Jan. 17 issue of Lancet (www.thelancet.com; 2004; 363).

I.V. Steroids & Guillain-Barré Syndrome: Use of intravenous methylprednisolone in combination with intravenous immunoglobulin merits further study in patients with Guillain-Barré syndrome, according to investigators who studied 225 individuals (pp. 192-6). Patients in the study had been treated with IVIg 0.4 g/kg/day that was begun within 14 days after the onset of weakness and continued for 5 days. Within 48 hours after the first dose of IVIg, the patients randomly began either i.v. methylprednisolone 500 mg/day or placebo for 5 days. The authors found, “We analysed 225 patients. GBS disability scores increased by one grade or more in 68% (76 of 112) of patients in the methylprednisolone group and in 56% (63 of 113) of controls (odds ratio [OR] 1.68, 95% CI 0.97–2.88; p=0.06). After adjustment for age and degree of disability at entry, treatment OR was 1.89 (95% CI 1.07–3.35; p=0.03). Side-effects did not differ greatly between groups.” Based on the importance of age as a prognostic factor and the limited adverse effects of methylprednisolone, the authors conclude that the combination treatment “warrants further investigation.” (R. van Koningsveld, Erasmus Med. Ctr., Rotterdam, the Netherlands; r.vankoningsveld@erasmusmc.nl)

Interleukin 6 & Meningococcal Septic Shock: Interleukin 6 and its downstream mediators are potential therapeutic targets for treating the myocardial depression that occurs in meningococcal disease, according to researchers who studied gene-expression patterns in blood cells (pp. 203-9). “We identified 174 significantly upregulated genes in meningococcus-infected blood: six encoded proteins that were of the predicted size and had characteristics of a myocardial depressant factor,” the group writes. “Of these, interleukin 6 caused significant myocardial depression in vitro. Removal of interleukin 6 from serum samples of patients with meningococcaemia and from supernatants of inflammatory cells stimulated by meningococci in vitro abolished the negative inotropic activity. Furthermore, concentrations in serum of interleukin 6 strongly predicted degree of myocardial dysfunction and severity of disease in children with meningococcal septic shock.” (N. Pathan, St Mary’s Hosp., London; n.pathan@imperial.ac.uk)

>>>Neurology Highlights
Source:
Jan. issue of Archives of Neurology (www.archneurol.com; 2004; 61).

Antioxidant Vitamins & AD: Elderly persons who take individual vitamin E and C supplements together may reduce their risk of Alzheimer disease, a study reports (pp. 82-8). Researchers assessed the prevalence of dementia and AD in 4,740 elderly residents of Cache County, Utah, identifying 200 cases of AD (prevalent cases) between 1995 and 1997, and 104 new cases (incident cases) of AD during follow-up. The researchers found the greatest reduction in both prevalence and incidence of AD in participants who used individual vitamin E and C supplements in combination, with or without an additional multivitamin. “Use of vitamin E and C supplements in combination reduced AD prevalence [by about 78%] and incidence [by about 64%],” the authors write. (P. P. Zandi, Johns Hopkins U., Baltimore)

>>>PNN JournalWatch
* The Role of Long-Acting Bronchodilators in the Management of Stable COPD, in Chest, 2004; 125: 249–59. Reprints: www.chestjournal.org; D. P. Tashkin, DTashkin@mednet.ucla.edu

* Syringe Distribution to Injection Drug Users for Prevention of HIV Infection: Opinions and Practices of Health Care Providers in New York City, in
Clinical Infectious Diseases, 2004; 38: 438–41. Reprints: www.journals.uchicago.edu/ CID; P. O. Coffin, N. Y. Acad. of Med.

* Clinical Cardiac Tolerability of Trastuzumab, in
Journal of Clinical Oncology, 2004; 22: 322–9. Reprints: www.jco.org; E. A. Perez, perez.edith@mayo.edu

* Relationship Between Deep Venous Thrombosis and the Postthrombotic Syndrome, in
Archives of Internal Medicine, 2004; 164: 17–26. Reprints: www.archinternmed.com; S. R. Kahn, McGill U., Montreal, Quebec, Canada; susan.kahn@mcgill.ca

* Sex Ratios in Healthcare Occupations: Population Based Study, in
BMJ, 2004; 328: 141–2. Reprints: www.bmj.org; V. J. Grant, U. Auckland, Auckland 1, New Zealand; vj.grant@auckland.ac.nz

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 21, 2004 Vol. 11, No. 12
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Jan. 21 issue of JAMA (www.jama.com; 2004; 291).

Ranolazine & Angina: A new pharmacologic option could change the landscape somewhat for patients with chronic angina who experience episodes despite revascularization and antianginal medications, according to a study of the investigational agent ranolazine (pp. 309-16). The drug, a fatty acid oxidation inhibitor that drives metabolism toward glucose oxidation, decreases myocardial oxygen demand by enabling the patient to generate more ATP from each oxygen molecule.

Among 823 such patients who were admitted to the Combination Assessment of Ranolazine In Stable Angina (CARISA) trial, twice-daily placebo or ranolazine 750 or 1,000 mg was administered while patients continued therapy with antianginal medications such as atenolol, amlodipine, or diltiazem. Treadmill exercise tests were administered during peak and trough ranolazine levels periods after 2, 6 (trough only), and 12 weeks of treatment.

The authors found, “Trough exercise duration increased by 115.6 seconds from baseline in both ranolazine groups (pooled) vs 91.7 seconds in the placebo group (P = .01). The times to angina and to electrocardiographic ischemia also increased in the ranolazine groups, at peak more than at trough. The increases did not depend on changes in blood pressure, heart rate, or background antianginal therapy and persisted throughout 12 weeks. Ranolazine reduced angina attacks and nitroglycerin use by about 1 per week vs placebo (P<.02). Survival of 750 patients taking ranolazine during the CARISA trial or its associated long-term open-label study was 98.4% in the first year and 95.9% in the second year.” (B. R. Chaitman, St. Louis University, St. Louis; chaitman@slu.edu)

An editorialist explains the impact ranolazine could have in patients for whom invasive interventions, such as percutaneous coronary interventions and coronary artery bypass grafts, are difficult (pp. 365-7): “The decision is rarely if ever whether to perform revascularization or administer medical therapy, but rather whether to perform PCI and administer medical therapy or to administer medical therapy alone. Furthermore, many patients cannot undergo successful percutaneous or surgical revascularization due to anatomic conditions such as severe distal vessel disease, small-branch vessel disease, or other factors. The therapeutic options for such patients include transmyocardial revascularization, which remains unproved; enhanced external counterpulsation, which requires a long course of therapy and is poorly understood; and angiogenesis, which remains an experimental, unproved approach. Thus, the availability of another effective and apparently safe antianginal medication such as ranolazine is particularly important for such patients with angina who are not candidates for revascularization. Use of ranolazine most likely will influence the frequency and timing with which PCI and CABG are performed in the far greater number of patients with angina who are suitable for revascularization procedures.” (P. Berger, Duke U., Durham, N.C.)

Memantine Plus Donepezil for AD: Memantine, added to stable doses of donepezil in patients with moderate or severe Alzheimer’s disease, significantly improved outcomes such as cognition, activities of daily living, global outcome, and behavior (pp. 317-24). The 404 patients in the study had scores of 5–14 on the Mini-Mental State Examination. While continuing stable doses of donepezil, memantine therapy was begun in randomly selected patients at doses of 5 mg/day, and these were titrated up to 20 mg/day. After 24 weeks, scores were significantly improved with memantine, compared with placebo, on several instruments: the Severe Impairment Battery, AD Cooperative Study–Activities of Daily Living Inventory, and the Clinician's Interview-Based Impression of Change Plus Caregiver Input. Treatment discontinuations because of adverse effects were higher with placebo than memantine (12.4% versus 7.4%). (P. N. Tariot, pierre_tariot@urmc.rochester.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 22, 2004 Vol. 11, No. 13
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Jan. 22 issue of the New England Journal of Medicine (content.nejm.org; 2004; 350).

Cisplatin & NSCLC: Among 1,867 patients who had undergone completely resected non–small-cell lung cancer, three or four rounds of cisplatin-based adjuvant chemotherapy improved survival significantly, compared with the observation (pp. 351-60). A total of 36.5% of patients had stage I disease, 24.2% stage II, and 39.3% stage III. They were randomly assigned to observation or cisplatin in doses of 80–120 mg/sq m plus vindesine, vinblastine, vinorelbine, and/or etoposide. Postoperative radiotherapy was provided to patients with certain levels of positive nodes, and this treatment was provided to the observation group immediately and to the cisplatin group after completion of chemotherapy.

Five-year survival rates were 44.5% in patients who received cisplatin and 40.4% of observation patients (hazard ratio for survival, 0.86), a significant difference. Disease-free survival rates at 5 years were also significantly higher among the cisplatin patients (39.4% versus 34.3%, HR, 0.83). Adverse effects associated with chemotherapy were associated with deaths of 7 patients (0.8%). (International Adjuvant Lung Cancer Trial Secretariat, Institut Gustave-Roussy, Villejuif, France)

An editorialist concludes that adjuvant chemotherapy for lung cancer represents “a new standard of care” (pp. 404-5): “The finding in the IALT that cisplatin-based adjuvant therapy confers an absolute increase in survival of 4.1 percent among patients with resected non–small-cell lung cancer is consistent with the benefit achieved with the use of adjuvant therapy for other cancers and represents a new standard of care, but not necessarily the only standard of care. For individual patients, the potential benefits of adjuvant chemotherapy must be balanced against the risks and the inherent and understandable preferences of physicians and patients. Only a continued commitment to well-designed, adequately powered clinical trials will allow us to gather the data necessary to make evidence-based decisions. Given the advances in cancer treatment and the increasing demand on limited resources, integration of the IALT findings into clinical practice is a task that should ultimately yield rich rewards.” (R. H. Blum, Beth Israel Med. Ctr., New York City)

In a review article on multidisciplinary management of lung cancer, authors provide a table that summarizes management approaches to this condition (pp. 379-92). They summarize the growing importance of targeted therapies in treating patients with lung cancer: “Future directions for treatment are heavily weighted toward targeted therapies—namely, those aimed at molecular abnormalities involved in the pathogenesis of lung cancer—rather than traditional cytotoxic agents.... Cellular targets abound, with the epithelial growth factor receptor the best studied. The first compound against this receptor, gefitinib, has recently been approved for use on the basis of moderate tumor responses, as well as improvements in the quality of life. Unfortunately, no additional benefit was seen when gefitinib was combined with standard therapy. Other compounds, such as those that target protein kinase C, vascular endothelial growth factor, cyclooxygenase-2, and farnesyl transferase, are being tested. Many of the available data are suboptimal; meta-analyses are used frequently instead of adequately powered, randomized, controlled trials. Since little further progress is expected with the use of traditional cytotoxic agents, new agents and approaches must be evaluated if we are to advance therapy for lung cancer.” (D. S. Ettinger, Johns Hopkins U., Baltimore; ettinda@jhmi.edu)

Universal Access to Health Care: The new Dirigo Health Reform Act, a law intended to provide universal access to citizens of Maine within 5 years, is described (pp. 330-2). “Dirigo Health represents an attempt to link comprehensive health system reform with an effort to achieve universality,” the authors note, adding that success will depend on collaborative efforts of involved parties. (T. Riley, Governor’s Office, Augusta, Maine)

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 23, 2004 Vol. 11, No. 14
Providing news and information about medications and their proper use

>>>FDA Educating Consumers About OTC Pain Meds
FDA yesterday launched a national education campaign to provide advice on the safe use of nonprescription analgesic products.

“Pain relievers and fever reducers are safe drugs when used as directed, but they can cause serious problems when used by people with certain conditions or those who are taking specific medicines,” FDA Commissioner Mark B. McClellan MD, PhD, was quoted as saying in a news release. “We want to remind consumers who take these products that it’s important to follow current dosing and label directions carefully.”

FDA’s nationwide campaign focuses on the OTC pain and fever reducers that contain acetaminophen and NSAIDs. “Read labels carefully, be sure you are getting the proper dose, and check with your doctor or pharmacist to be sure that you can use these drugs safely,” said McClellan.

To minimize the risks of an accidental overdose, FDA says consumers should avoid taking multiple medications that contain the same active ingredient at the same time. Acetaminophen, an active ingredient in more than 600 OTC and prescription products, is safe and effective when used correctly, but taking too much can lead to liver damage, and even death. The risk for liver damage may be increased in consumers who drink three or more alcoholic beverages per day while using medicines containing acetaminophen.

FDA is warning consumers about the gastrointestinal dangers of NSAIDs. These products can cause stomach bleeding with an increased risk in consumers who are over 60, are taking prescription blood thinners, are taking steroids, or have a history of stomach bleeding. NSAIDS may also increase the risk of reversible kidney problems in consumers with preexisting kidney disease, or who are taking a diuretic.

FDA’s consumer educational campaign will include: (1) an OTC pain reliever brochure to be distributed in pharmacies, and by health care providers, (2) a newspaper article to be distributed to 10,000 community papers across the country, (3) a reprint of “Use Caution With Pain Relievers”, an FDA Consumer magazine article that will be distributed at national health care conferences and available for reprinting in health publications, and (4) two print public service ads that will be sent to approximately 100 major magazines. All of these materials are available on the Web at http:// www.fda.gov/cder/drug/analgesics/default.htm.

>>>Pediatrics Report
Source:
Jan. issue of Pediatrics (www.pediatrics.org; 2004; 113).

CPOE & Med Errors:
Medication prescribing errors and rule violations were almost completely eliminated after a computerized physician order entry system was implemented in a pediatric critical care unit, and adverse drug events were significantly reduced in frequency (pp. 59-63). For 514 patients admitted to the 20-bed unit, the authors found, “A total of 13,828 medication orders were reviewed. Before implementation, potential ADEs occurred at a rate of 2.2 per 100 orders, MPEs at a rate of 30.1 per 100 orders, and RVs at a rate of 6.8 per 100 orders. After implementation, the rate of potential ADEs was reduced to 1.3 per 100 orders, MPEs to 0.2 per 100 orders, and RVs to 0.1 per 100 orders. The overall error reduction was 95.9%. Potential ADEs were reduced by 40.9%, and MPEs and RVs were reduced by 99.4% and 97.9%, respectively.” (A. L. Potts, Vanderbilt Children’s Hosp., Nashville)

Antibiotic Treatment Through Tympanostomy Tubes: In a study of 599 infants and children, topical ciprofloxacin 0.3%/dexamethasone 0.1% otic suspension proved superior to topical ofloxacin 0.3% otic solution for treatment of acute otitis media with otorrhea through tympanostomy tubes (e40–e46). Improved with combination therapy were clinical cure (90% versus 78%), microbiologic success (92% versus 81.8%) at the test-of-cure visit, treatment failures (4.4% versus 14.1%), median time to cessation of otorrhea (4 days versus 6 days). The treatments were equally safe and well tolerated, and no differences in speech or hearing abilities were observed. (P. S. Roland, U. Texas Southwestern Med. Ctr., Dallas)

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 26, 2004 Vol. 11, No. 15
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Jan. 24 issue of BMJ (www.bmj.org; 2004; 328).

Estimating Adverse Event Rates in Hospitals: For epidemiologic studies of adverse events in hospitals, prospective methods that follow patients through the course of stays should be preferred for risk-reduction programs and for determining the causes and consequences of AEs, according to a study that also assessed retrospective (chart reviews) and cross-sectional methods (all data gathered in 1 day; pp. 199 ff). The proportions of known and preventable AEs detected by each method were calculated for 778 patients in 7 hospitals in southwestern France.

The authors report, “The prospective and retrospective methods identified similar numbers of medical and surgical cases (70% and 66% of the total, respectively) but the prospective method identified more preventable cases (64% and 40%, respectively), had good reliability for identification (kappa = 0.83), represented an acceptable workload, and had higher face validity. The cross sectional method showed a large number of false positives and identified none of the most serious adverse events. None of the methods was appropriate for obstetrics.” (P. Michel, Hôpital Xavier Arnozan, Pessac, France; philippe.michel@ccecqa.asso.fr)

Hypertension Follow-up: Contact with treated hypertensive patients at 6 months is about as effective as follow-up every 3 months, according to a study of 609 patients in Ontario (pp. 204 ff). “As expected, patients in the six month group had significantly fewer visits, but patients in both groups visited their doctor more frequently than their assigned interval,” note the investigators. “Mean blood pressure was similar in the groups, as was control of hypertension. Patient satisfaction and adherence to treatment were similar in the groups. About 20% of patients in each group had blood pressures that were out of control during the study.” (R. Birtwhistle, Queen’s U., Kingston, Ontario, Canada; birtwhis@post.queensu.ca)

>>>Lancet Report
Source:
Jan. 24 issue of Lancet (www.thelancet.com; 2004; 363).

Double Doses of Inhaled Steroids in Asthma: For treating asthma exacerbations, the widely recommended practice of doubling the inhaled corticosteroid dose is of little benefit, conclude authors of a 390-patient study (pp. 271-5). Participants monitored their morning peak flows and asthma symptoms for 12 months. When deterioration occurred, they added a placebo or steroid inhaler to their regular steroid inhaler for 14 days. About one half of patients required the second inhaler during the study, and oral prednisolone was required by 11% and 12% of those in the active and placebo groups, respectively, not a significant difference. “Our findings provide little support for the recommendation that patients taking an inhaled corticosteroid should double the dose when asthma control is deteriorating,” the group concludes. “Whether a larger increase in inhaled corticosteroid dose would be effective needs to be established.” (T. W. Harrison, Nottingham City Hosp., Nottingham, U.K.; tharris2@ncht.trent.nhs.uk)

>>>PNN JournalWatch
* Bringing Reality to Drug-Eluting Stents, in Circulation, 2004; 109: 140–2. Reprints:circ.ahajournals.org; D. P. Faxon

* Contribution of Hepatic Cytochrome P450 3A4 Metabolic Activity to the Phenomenon of Clopidogrel Resistance, in
Circulation, 2004; 109: 166–71. Reprints:circ.ahajournals.org; W. C. Lau, weiclau@umich.edu

* Optimal Designs for Michaelis-Menten Kinetic Studies, in
Statistics in Medicine, 2004; 23: 477–91. Reprints: www3.inter science.wiley.com

* Comparison of Outcomes in Cancer Patients Treated Within and Outside Clinical Trials: Conceptual Framework and Structured Review, in
Lancet, 2004; 363: 263–70. Reprints: www.thelancet.com; S. Joffe, steven_joffe@dfci.harvard.edu

* Using an Electrocautery Strategy or Recombinant Follicle Stimulating Hormone To Induce Ovulation in Polycystic Ovary Syndrome, in
BMJ, 2004; 328: 192 ff. Reprints: www.bmj.org; N, Bayram, Academic Med. Ctr., Amsterdam, the Netherlands; n.bayram@amc.uva.nl

* Safety and Tolerability of Tegaserod in Irritable Bowel Syndrome Management, in
Journal of the American Pharmacists Association, 2004; 44: 41–51. Reprints: www.japha.org; R. R. Berardi, rberardi@umich.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 27, 2004 Vol. 11, No. 16
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Jan. 26 issue of Archives of Internal Medicine (www.archinternmed.com; 2004; 164).

Statins & Fractures: Attempting to sort divergent evidence about whether use of statins is linked to fewer fractures, authors used meta-analysis to combine data from observational and cardiovascular studies (pp. 146-52). Their conclusion is that the use of these agents provides “a consistent and clinically meaningful but nonsignificant reduction in hip and vertebral fractures in 4 prospective observational studies of older women,” one that is not seen in women taking nonstatin lipid-lowering agents. They add, “When these results were quantitatively combined with other studies of statin use and fracture, we observed a significant reduction in hip and nonspine fracture risk among statin users. These findings build on the recent reports that statins increase bone formation in rodents and suggest that statins may be useful agents for osteoporosis. Clinical trials are needed to test the ability of potent statins to prevent fracture.” (D. C. Bauer, dbauer@psg.ucsf.edu)

Statins & Cognition: Beginning what the Wall Street Journal yesterday said could be a year of “a statin backlash,” researchers write about the growing body of evidence that these drugs interfere with patients’ cognition (pp. 153-62): “There are reasons to think both favorable and adverse effects of statins and low cholesterol on cognition may pertain; the balance of these factors requires further elucidation. A substantial body of literature links low cholesterol level to aggressive behavior; statin randomized trials have not supported a connection, but they have not been designed to address this issue. A limited number of reports suggest a connection between reduced cholesterol level and reduced serotonin level, but more information is needed with serotonin measures that are practical for clinical use. Whether lipophilic and hydrophilic statins differ in their impact should be assessed.” (B. A. Golomb, U. Calif.–San Diego Sch. of Med., La Jolla)

The NIH-funded trial described in this
Archives article, the UCSD Statin Study, is underway, with results due out this spring, according to an article in yesterday’s Wall Street Journal. “A number of critics believe drug companies have vastly understated side effects caused by statins—particularly muscle pains and memory problems,” wrote reporter Tara Parker–Pope. “If, as expected, the research shows a higher rate of cognitive side effects than previously reported, doctors may finally start paying closer attention to the aches and pains of patients who use the drugs.”

Pain Control in Hospitalized Patients: Significant pain was observed among patients viewed as being at low risk, report researchers who studied 5,584 hospitalized individuals (pp. 175-80). Based on a follow-up telephone survey, the authors found, “Of the study patients, 59% had pain (28% reported severe, 19% moderate, and 12% mild pain). Among patients with common diagnoses, those with sickle cell crisis were the most likely and those with syncope were the least likely to report significant pain (90% and 34%, respectively). Patient characteristics significantly associated with increased pain included DRG (diagnosis related group) weight (odds ratio [OR], 1.19), Charlson Index score (OR, 1.03), age older than 65 years (OR, 0.65), female sex (OR, 1.17), and education level higher than high school (OR, 1.31). Pain was reported by 28% of patients without high-risk characteristics for pain; and 82.2% of patients were satisfied, 11.1% somewhat satisfied, and 6.7% dissatisfied with their pain treatment.”

The group concludes, “Although most patients thought that their pain was adequately controlled, 18% of patients with pain (10% of all patients) reported that their pain was inadequately controlled. Although patient characteristics were associated with pain or dissatisfaction with pain control, they were weak predictors and significant pain was common even in populations at the lowest-risk for pain.... ” (C. T. Whelan, cwhelan@uchicago.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 28, 2004 Vol. 11, No. 17
Providing news and information about medications and their proper use

>>>Neurology Highlights
Source:
Jan. 27 Neurology (www.neurology.org; 2004; 62).

AEDs & Male Fertility: Several antiepileptic drugs—carbamazepine, oxcarbazepine, and valproate—are associated with reduced semen quality and other abnormalities that could affect male fertility, according to an evaluation of 60 men with epilepsy and 41 control men (pp. 247-53). In the subjects, reproductive hormone levels were measured, semen quality was analyzed, ultrasonography of the testicles was performed, and testicular volume was calculated. The researchers found significantly depressed serum dehydroepiandrosterone sulfate concentrations in men taking carbamazepine and elevated levels of serum androstenedione with valproate. Morphologically abnormal sperm were significantly more common in men treated with carbamazepine, oxcarbazepine, and valproate, sperm motility was reduced significantly by carbamazepine and valproate, low sperm concentrations were observed with carbamazepine, and the frequency of any sperm abnormality was elevated with valproate. Men taking valproate also had smaller testicular volumes, compared with control patients. (J. I. T. Isojärvi, U. Oulu, Oulu, Finland; jouko.isojarvi@oulu.fi)

Remember to Eat Your Fish: In 1,613 subjects aged 45–70 years, consumptions of marine omega-3 polyunsaturated fatty acids (PUFA) and/or fatty fish was associated with a decreased risk of hypercholesterolemia and cognitive dysfunction (pp. 275-80). The risk of impaired overall cognitive function and speed was inversely related to PUFA consumption, with per-standard-deviation risks lowered by 19% and 28%, respectively. Fatty fish consumption showed similar results. “Higher dietary cholesterol intake was significantly associated with an increased risk of impaired memory and flexibility (per SD increase: [odds ratio] = 1.27, 95% CI 1.02 to 1.57 and OR = 1.26, 95% CI 1.01 to 1.57),” the authors added. “Per SD increase in saturated fat intake, the risk of impaired memory, speed, and flexibility was also increased, although not significantly.” (S. Kalmijn, U. Med. Ctr., Utrecht, the Netherlands; s.kalmijn@jc.azu.nl)

Valproic Acid for Pain in Polyneuropathy:
In a brief communication, researchers report that valproic acid failed to relieve pain any more effectively than did placebo among 31 patients with polyneuropathy (pp. 285-8). During two treatment phases of 4 weeks each, valproic acid 1,500 mg daily and placebo were similar in terms of ratings of total pain and in individual pain ratings. (M. Otto, Odense U. Hosp., Odense, Denmark; maritotto@dadlnet.dk)

>>>PNN NewsWatch
* FDA and the United States Customs and Border Protection (CBP) agency announced yesterday that their second series of import blitz examinations found 1,728 unapproved drugs, including foreign versions of FDA-approved drugs, recalled drugs, drugs requiring special storage conditions, drugs requiring close physician monitoring, and drugs containing addictive controlled substances. In an FDA news release, the agency said that these findings provide additional evidence of the serious risks posed by the illegal importation of prescription drugs. Conducted in Nov. 2003, these findings support those of a prior blitz in July and Aug. 2003. Detailed lists of the medications found are available on the FDA Web site (www.fda.gov) along with photographs of a Serevent Diskus product that had been previously recalled in the U.S.

* If patients ask for the
“wine pill,” they’re probably looking for a new dietary supplement that contains stabilized red wine extract. The distributor, Resveratrol Partners, says that Longevinex is an airtight capsule produced in an oxygen-free environment and stabilized with antioxidants (www.longevinex.com).

* Natriuretic peptide agonists, such as Scios’s Natrecor (nesiritide), and calcium sensitizers, including Orion’s Simdax (levosimendan), are highlighted in a new Decision Resources’ study on
acute heart failure. American researchers are enthusiastic about the former agents, the report notes, while Europeans support use of the latter group of drugs. (www.decisionresources.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 29, 2004 Vol. 11, No. 18
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Jan. 29 issue of the New England Journal of Medicine (content.nejm.org; 2004; 350).

Strontium Ranelate & Osteoporosis: An orally active drug currently in Phase II trials, strontium ranelate, produced “early and sustained reductions in the risk of vertebral fractures” in a placebo-controlled study of 1,649 postmenopausal women with osteoporosis and at least one previous vertebral fracture (pp. 459-68). “New vertebral fractures occurred in fewer patients in the strontium ranelate group than in the placebo group, with a risk reduction of 49 percent in the first year of treatment and 41 percent during the three-year study period (relative risk, 0.59; 95 percent confidence interval, 0.48 to 0.73),” report the authors. “Strontium ranelate increased bone mineral density at month 36 by 14.4 percent at the lumbar spine and 8.3 percent at the femoral neck (P < 0.001 for both comparisons). There were no significant differences between the groups in the incidence of serious adverse events.”(P. J. Meunier, Edouard Herriot Hosp., Lyons, France; pierre.meunier@laennec.univ-lyon1.fr)

Commenting on this study, an editorialist notes that strontium has a long history of use in osteoporosis therapy owing to its bone-seeking properties (pp. 504-6): “The current trial establishes the efficacy of strontium ranelate, a familiar element relaunched as a new compound, in reducing the risk of vertebral fractures and its role in the armamentarium of therapies for osteoporosis. New forms of technology and insights pertaining to the determinants of bone quality will be invaluable in the long-term monitoring of the safety and efficacy of this new compound, as well as of others, and will elucidate the mechanisms behind its molecular effects on bone.” (Ghada El-Hajj Fuleihan, American U. Med. Ctr., Beirut, Lebanon)

Testosterone-Replacement Therapy: In a review of testosterone-replacement therapy and monitoring parameters, authors assess the evidence on the hormone’s potential risks (pp. 482-92). In addition to common adverse effects such as testicular atrophy or infertility, testosterone therapy can more rarely produce cardiovascular disease, lipid alterations, erythrocytosis, fluid retention, benign prostatic hyperplasia, sleep apnea, gynecomastia, and acne or oily skin. Skin reactions are common (66%) with patch therapy, but gels produce these in only 5% of men, and they are rare with injectable therapy. Hepatotoxicity has been observed but mainly with oral agents that are not often used in the U.S. Any link between testosterone and prostate cancer is controversial, but the authors recommend long-term monitoring for it in men who use testosterone therapy. (A. Morgentaler, amorgent@caregroup.harvard.edu)

Mental Health Maze: “The [mental health] system is in shambles,” concluded a commission appointed by President Bush to conduct a comprehensive review of the care of people with mental illness. In a Health Policy Report article, an author explores options for America given this poor state of affairs (pp. 507-14): “An alternative approach, given the breadth of the recommendations [of the commission], would have been the creation of a department-wide or an interdepartmental task force chaired by Secretary Thompson or one of Bush’s trusted White House lieutenants. At the least, development of the Substance Abuse and Mental Health Services Administration’s implementation plan bears close watching, given the agency’s modest reach within the vast department, much less across the government. In any event, the mental health care movement has recognized the value of the exercise and is mobilizing its assets. Much like the Carter commission before it, the Bush commission has provided a report that will be the clarion call for this and future administrations to pursue dramatic improvements in the mental health care delivery system—a system that, as Bush envisioned in his charge, should enable people with serious mental illness to ‘live, work, learn, and participate fully in their communities.’” (J. K. Iglehart)

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 30, 2004 Vol. 11, No. 19
Providing news and information about medications and their proper use

>>>JAPhA Highlights
Source:
Jan/Feb issue of the Journal of the American Pharmacists Assoc. (www.japha.org; 2004; 44).

PBM ‘Spread’: Substantial and widely varying differences were found in a pilot study of the “spread” between what pharmacy benefit managers charge payers and what they pay pharmacies for medications (pp. 15-21). The authors compared drug ingredient costs billed for 129 prescriptions to two employer-payers by PBMs and what PBMs paid to six independent community pharmacies for those same prescriptions. The mean (± SD) difference was $12.29 ± 27.93 per prescription, indicating that the PBMs charged the employers that much more than they paid the pharmacies. “The mean spreads for brand name and generic medications were significantly different from one another, with mean (± SD) spreads of $4.65 ± 10.47 and $23.45 ± 39.47 per prescription, respectively,” write the authors. “The two PBMs differed significantly in their spreads for brand name drugs ($3.20 ± 2.85 and $5.93 ± 14.12), but the spreads for generic products did not achieve statistical significance in absolute dollars ($10.83 ± 13.58 and $31.74 ± 48.11) because of their greater variation (as reflected in the larger standard deviations). However, the percentage difference for generic products differed significantly.” (R. I. Garis, rgaris@creighton.edu)

An editorialist responds that PBM spread is “a reasonable, rational, realistic business practice” (pp. 10-1). After criticizing the limited nature of the pilot study, Terry Latanich, formerly of Medco Health Solutions, notes, “Retail spread is not a one-way street. In some instances a PBM may be required by a bid specification or competitive pressure to offer a plan sponsor a deeper discount (i.e., a ‘negative spread&rsquoWinking for the retail network than it has been able to negotiate. The PBM is at financial risk if it cannot negotiate a discount with pharmacies equivalent to its guarantee.”

Patient Counseling: State regulations, how busy a pharmacy is, and age of the pharmacist are significant factors in determining whether pharmacists offer counseling to patients in community pharmacies, according to a study conducted in eight states (pp. 22-9). Trained shoppers posing as patients presented three new prescriptions in each of 306 pharmacies and recorded what information and education they were offered. “About 63% of the shoppers were given oral drug information (mean = 2.3 items),” the article notes. “Shoppers with a younger responsible pharmacist were more likely than other shoppers to receive risk information, a higher number of informational items, and assessment of understanding. While pharmacy type was unrelated to counseling, busyness reduced the odds of any pharmacist talk, oral information-giving, and assessment of understanding. Counseling practices varied significantly according to the intensity of a state’s counseling regulation, with frequency of any information provision climbing from 40% to 94% as states’ counseling regulations increased in intensity. More intensive regulations also increased the likelihood of any pharmacist talk, any provision of risk information, any assessment of shopper understanding, and amount of oral information given.” (B. L. Svarstad, blsvarstad@pharmacy.wisc.edu)

Dietary Supplement Resources: Drug information centers are overlooked sources of information about dietary supplements, according to a survey of 116 centers (pp. 36-40). Despite respondents’ belief that centers were well equipped with references about dietary supplements, few requests for information about dietary supplements were received, and most requests came from consumers than from the health professionals who generally contacted the centers. (C. E. McQueen, mcqueenc@umkc.edu)

Review Articles: Topics reviewed in this issue include:
* Tegaserod (R. R. Berardi, rberardi@umich.edu)
* Tyrosine kinase (erbB) receptor inhibitors (O. Hamid, Oday.Hamid@pfizer.com)
* Dietary supplements used for weight loss (T. L. Lenz, tlenz@creighton.edu)
* Adverse effect monitoring (C. J. Hermansen-Kobulnicky, cjhkobul@uwyo.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 2, 2004 Vol. 11, No. 20
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Jan. 31 issue of BMJ (www.bmj.org; 2004; 328).

HAART: In treatment-experienced patients with HIV, protease inhibitor-based regimens are superior to those based on the nonnucleoside reverse transcriptase inhibitors nevirapine and delavirdine, according to a systematic review and meta-analysis (pp. 249 ff). Analyzing data from 14 trials that included 6,785 patients, the authors found, “Most patients had been exposed to [a nucleoside reverse transcriptase inhibitor] and had advanced immunodeficiency at baseline; 1096 progressed to AIDS or died. Seven trials assessed protease inhibitors based triple regimens and seven assessed NNRTI based triple regimens (nevirapine or delavirdine). Triple therapy was more effective than dual therapy. The effect was pronounced for protease inhibitor based regimens (odds ratio 0.49, 95% confidence interval 0.41 to 0.58) but non-significant for NNRTI based regimens (0.90, 0.71 to 1.15). Indirect comparison of the two regimens gave an odds ratio of 0.54 (0.49 to 0.73) in favour of protease inhibitor based treatments. Increases in CD4 cell counts were smaller and suppression of viral replication less with NNRTI based regimens.” (Y. Yazdanpanah, Faculté de Médecine de Lille, Tourcoing, France; yyazdan@yahoo.com)

An editorial adds these thoughts about this review (pp. 253 ff): “The WHO has recently launched its 3 by 5 motto of providing anti-HIV therapy to 3 million people by the end of 2005. Hopefully, the therapy will be state of the art, but some may receive inferior regimens of 1–2 nucleosides, increasing the number of patients with resistance to these drugs. It will be critical to start randomised controlled trials with clinical outcomes to establish a rational order of utilisation of the available anti-HIV drugs in this situation. Hopefully, the WHO or other organisations will ensure that this critical knowledge is generated. Yazdanpanah and coworkers provide a strong rationale that this is important.” (J. D. Lundgren, Hvidovre U. Hosp., Hvidovre, Denmark; jdl@cphiv.dk)

>>>Lancet Report
Source:
Jan. 31 issue of Lancet (www.thelancet.com; 2004; 363).

X-Ray Exposure & Cancer Risk: The risk of cancer from diagnostic X-ray exposure is low but variable among industrialized countries, a study shows (pp. 345-51). In the U.K., of the cumulative risk of cancer was attributable to such exposure was lowest, about 0.6%; in 13 other developed countries, the risk ranged up to 1.8%; but the risk in Japan was more than 3%. “The possibility that we have overestimated the risks cannot be ruled out, but it seems unlikely that we have underestimated them substantially,” conclude the authors. (A. B. de González, U. Oxford, Oxford, U.K.; amy.berrington@cancer.org.uk)

>>>PNN JournalWatch
* Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes, in Diabetes Care, 2004; 27: 596–601. Reprints: www.carediabetesjournals.org.

* Management of Diabetes and Hyperglycemia in Hospitals, in
Diabetes Care, 2004; 27: 553–91. Reprints: www.carediabetesjournals.org; S. Clement.

* Lowering the Cut Point for Impaired Fasting Glucose: Where Is the Evidence? Where Is the Logic?, in
Diabetes Care, 2004; 27: 592–5. Reprints: www.carediabetesjournals.org; D. L. Schriger.

* Issues in Pharmacokinetics and Pharmacodynamics of Anti-Infective Agents: Kill Curves versus MIC, in
Antimicrobial Agents & Chemotherapy, 2004; 48: 369–77. Reprints: aac.asm.org; M. Mueller.

* Definition of Metabolic Syndrome: Report of the National Heart, Lung, and Blood Institute/American Heart Association Conference on Scientific Issues Related to Definition, in
Circulation, 2004; 109: 433–8. Reprints: circ.ahajournals.org; S. M. Grundy.

* How Do Institutional Review Boards Apply the Federal Risk and Benefit Standards for Pediatric Research?, in
JAMA, 2004; 291: 476–82. Reprints: www.jama.com; D. Wendler, dwendler@nih.gov

* Care of the Dying Adolescent: Special Considerations, in
Pediatrics, 2004; 113: 381–8. Reprints: www.pediatrics.org; D. R. Freyer.

* Gastroesophageal Reflux: A Critical Review of Its Role in Preterm Infants, in
Pediatrics, 2004; 113: e128–e132. Reprints: www.pediatrics.org; C. F. Poets.

* Long-Term Lithium Therapy for Bipolar Disorder: Systematic Review and Meta-Analysis of Randomized Controlled Trials, in
American Journal of Psychiatry, 2004; 161: 217–22. Reprints: ajp.psychiatryonline.org; J. R. Geddes.

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 3, 2004 Vol. 11, No. 21
Providing news and information about medications and their proper use

>>>Tiotropium Approved
FDA has approved for U.S. marketing tiotropium bromide (Spiriva HandiHaler, Boehringer Ingelheim). The inhaled anticholinergic medication is approved for long-term, once-daily maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease. The product will be available to pharmacies by midyear and will be copromoted by Pfizer.

Boehringer Ingelheim notes in a news release that tiotropium is the first inhaled treatment to provide significant and sustained improvements in lung function with once-daily dosing. It works by targeting the primary reversible component of COPD—constriction of the airways. Tiotropium provides significant improvements in key measures of lung function and represents a major advance in the treatment of all stages of COPD, and the bronchodilator is expected to become a first-line maintenance treatment for patients with mild to severe COPD.
In clinical trials, tiotropium demonstrated significant, sustained bronchodilation. In trials, tiotropium demonstrated significant improvements in lung function over ipratropium bromide, a current first-line therapy for COPD, which were maintained over 1 year. In addition, in 1-year, placebo-controlled studies, patients treated with tiotropium required fewer doses of rescue medications.

The most common adverse reaction patients reported in tiotropium clinical trials was dry mouth, which was usually mild and often resolved during treatment. Constipation and increased heart rate have been reported infrequently in patients receiving tiotropium. As an anticholinergic drug, tiotropium must be used with caution in patients with glaucoma and prostatic hyperplasia.

>>>Internal Medicine Report
Source:
Feb. 3 issue of the Annals of Internal Medicine (www.annals.org; 2004; 140).

Aspirin & Colorectal Cancer: Aspirin use is associated with decreased risk for colorectal adenoma, but the greatest protective effects may require doses higher than those used for cardiovascular protection, according to an analysis of data from the Nurses’ Health Study (pp. 157-66). Data on self-reported aspirin use were combined with results of endoscopy of the lower gastrointestinal tract for 27,077 women. The authors found, “Women who regularly used aspirin (2 standard aspirin tablets/wk) had a multivariate relative risk for adenoma of 0.75 (95% CI, 0.66 to 0.84) compared with nonregular users. Compared with women who denied any aspirin use, the multivariate relative risks for adenoma were 0.80 (CI, 0.70 to 0.93) for women who used 0.5 to 1.5 standard tablets per week, 0.74 (CI, 0.62 to 0.88) for those who used 2 to 5 tablets per week, 0.72 (CI, 0.61 to 0.85) for those who used 6 to 14 tablets per week, and 0.49 (CI, 0.36 to 0.65) for those who used more than 14 tablets per week (P < 0.001 for trend). Similar dose–response relationships were found among regular short-term users (5 years; P < 0.001) and long-term users (>5 years; P < 0.001). In contrast, after adjustments were made for dose, increasing duration of aspirin use did not confer greater risk reduction (P > 0.2).” These findings led the authors to conclude that “a more thorough evaluation of the risks and benefits of routine aspirin use at doses not previously considered” is needed. (A. T. Chan, Mass. Genl. Hosp., Boston)

LMWHs for PE: Fixed doses of low molecular weight heparins are as safe and effective as dose-adjusted unfractionated heparin for initial treatment of nonmassive pulmonary embolism, conclude authors who conducted a meta-analysis of 12 trials involving 1,951 patients (pp. 175-83). LMWHs generally performed better than did heparin, with slightly greater measures of effectiveness (prevention of recurrent symptomatic venous thromboembolism; similar results in those presenting initially with symptomatic versus nonsymptomatic PE) and somewhat reduced rates of major bleeding complications (1.2% versus 2.1%). However, differences did not reach statistical significance. (J. W. Eikelboom, Royal Perth Hosp., Perth, Australia; john.eikelboom@health.wa.gov.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 4, 2004 Vol. 11, No. 22
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Feb. 4 issue of JAMA (www.jama.com; 2004; 291).

Vitamin Therapy & Homocysteine: Moderate reduction in total homocysteine concentrations with high-dose vitamin therapy had no effect on vascular outcomes, according to a study of 3,680 adults with nondisabling cerebral infarction (pp. 565-75). Patients received either a high-dose (pyridoxine 25 mg, cobalamin 0.4 mg , and folic acid 2.5 mg) or low-dose (pyridoxine 200 mcg, cobalamin 6 mcg, and folic acid 20 mcg) vitamin formulation, and investigators monitored recurrent cerebral infarction (primary outcome) and coronary heart disease events and death (secondary outcomes).

The researchers report that the mean reduction in total homocysteine was 2 µmol/L greater in the high-dose group than in the low-dose group, but the chances of any event over 2 years was statistically equivalent, 18.0% in the high-dose group and 18.6% among low-dose patients. “The risk of ischemic stroke within 2 years was 9.2% for the high-dose and 8.8% for the low-dose groups (risk ratio, 1.0; 95% CI, 0.8–1.3) (P = .80 by log-rank test of the primary hypothesis of difference in ischemic stroke between treatment groups),” write the researchers. “There was a persistent and graded association between baseline total homocysteine level and outcomes. A 3-µmol/L lower total homocysteine level was associated with a 10% lower risk of stroke (P = .05), a 26% lower risk of CHD events (P<.001), and a 16% lower risk of death (P = .001) in the low-dose group and a nonsignificantly lower risk in the high-dose group by 2% for stroke, 7% for CHD events, and 7% for death.”

Despite the statistical similarities, the authors note encouraging trends in the data, “The consistent findings of an association of total homocysteine with vascular risk suggests that further exploration of the hypothesis is warranted and longer trials in different populations with elevated total homocysteine may be necessary.” (E. G. Sides, Wake Forest U., Winston-Salem, N.C.; esides@wfubmc.edu)

Reviewing this study along with another one on the role of antiphospholipid antibodies in stroke prevention (pp. 576-84), an editorialist offers this advice about vitamin therapy (pp. 621-2): “How should clinicians integrate this information into daily practice? The results are clearly negative from the intention-to-treat basis, and, thus, most clinical trialists would reject the idea of a causal role for total homocysteine in the etiology of cerebrovascular disease and stroke. However, a closer look at the data suggests that the link may be plausible. One interpretation is that the effect of elevated total homocysteine on cerebral vessels is different than on coronary arteries, where much larger treatment effects have been demonstrated. This seems possible, given the Kaplan–Meier curves for stroke, coronary events, and death ... in the article by Toole et al. Here, no indication of differential stroke rates existed for the 2 treatment groups, but some effect of the high-dose regimen for preventing coronary events and death is evident.” (D. F. Hanley, Johns Hopkins Med. Inst., Baltimore; dhanley@jhmi.edu)

Ethics of CAM Research: Research on complementary and alternative medicine should adhere to the same ethical requirements for all clinical research, argue authors who call into question “the legitimacy of providing CAM and conventional therapies that have been demonstrated to be effective only by virtue of the placebo effect” (pp. 599-604). The authors conclude, “The standards of evidence-based medicine, developed over the years to understand and evaluate conventional medical therapies, apply equally to CAM. The arguments that placebo-controlled [randomized controlled trials] are not appropriate for evaluating most CAM treatments lack merit. Although the use of placebo-controlled trials raises ethical concerns when proven effective treatment exists for the condition under investigation, they are ethically justified, provided that stringent criteria for protecting research subjects are satisfied.” (S. E. Straus, sstraus@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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 5, 2004 Vol. 11, No. 23
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Feb. 5 issue of the New England Journal of Medicine (content.nejm.org; 2004; 350).

Eculizumab & Paroxysmal Nocturnal Hemoglobinuria:
An antibody against terminal complement protein C5, eculizumab, has beneficial effects in patients with paroxysmal nocturnal hemoglobinuria, conclude researchers who studied use of the agent in 11 transfusion-dependent patients (pp. 552-9). Eculizumab 600 mg was infused every week for 4 weeks, followed 1 week later by a 900-mg dose and then by 900 mg every other week through week 12. Based on decreased mean lactate dehydrogenase levels, increased percentage of PNH type III erythrocytes, decreased need for transfusions, fewer episodes of hemoglobinuria, and better results on quality of life instruments, the authors conclude, “Eculizumab was safe and well tolerated during this open-label pilot study. The adverse events reported by patients were similar in type and frequency to those reported with either eculizumab or placebo in other controlled trials. All patients are currently participating in a one-year extension study in which the drug continues to be well tolerated.” (P. Hillmen, Leeds Genl. Infirm., Leeds, U.K.; peter.hillmen@panp-tr.northy.nhs.uk)

Fatty Acids & CF: Tissue specimens from 38 patients with cystic fibrosis show the same alterations in long-chain fatty acid defects as do CF-knockout mice (pp. 560-9). The study compared fatty acid composition of nasal- and rectal-biopsy specimens obtained from CF patients with those from a variety of other patient types. “The ratio of arachidonic to docosahexaenoic acid was increased in mucosal and submucosal nasal-biopsy specimens (P<0.001) and rectal-biopsy specimens (P=0.009) from subjects with cystic fibrosis and pancreatic sufficiency and subjects with cystic fibrosis and pancreatic insufficiency, as compared with values in healthy control subjects,” the researchers report. “In nasal tissue, this change reflected an increase in arachidonic acid levels and a decrease in docosahexaenoic acid levels. In cells from nasal mucosa, the ratio of arachidonic to docosahexaenoic acid was increased in subjects with cystic fibrosis (P < 0.001), as compared with healthy controls, with values in obligate heterozygotes intermediate between these two groups (P < 0.001). The ratio was not increased in subjects with inflammatory bowel disease. Subjects with asthma and those with upper respiratory tract infection had values intermediate between those in subjects with cystic fibrosis and those in healthy control subjects.” (S. D. Freedman, sfreedma@caregroup.harvard.edu)

An editorialist notes that while these “long-chain essential fatty acids and their eicosanoids have ... a profound influence on membrane receptor function, transmembrane signaling mechanisms, phospholipase activation, calcium release, ion channels, and gene expression,” normalization of fatty acid levels will be a challenge (pp. 605-7). “We know that the fatty acid profile of different tissues may not be reflected in the plasma, or even in the phospholipids of red-cell membranes,” the writer explains. “Until we understand the defective fatty acid metabolism in cystic fibrosis and how these abnormalities may interfere with [the cystic fibrosis transmembrane conductance regulator gene] function, specific treatment, especially with pharmacologic amounts of these acids, should be approached with great caution.” (B. Strandvik, Göteborg University, Göteborg, Sweden)

Big Pharma & Medicaid: “States may proceed with caution along ... new roads to pharmaceutical cost containment” in Medicaid programs, conclude authors who analyze the complicated U.S. Supreme Court decision in the Pharmaceutical Research and Manufacturers of America v. Walsh case (pp. 608-13). “The bottom line seems to be that states will be permitted to try out drug-discount programs, but only if states work within certain boundaries and respect the role of the federal government in the joint governance of Medicaid,” write the authors, specifically noting acceptability of prior authorization and preferred-drug lists. (T. A. Brennan, Brigham and Women’s Hosp., Boston; tabrennan@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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 6, 2004 Vol. 11, No. 24
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Feb. issue of Diabetes Care (care.diabetesjournals.org; 2004; 27).

DASH & Diabetes: Use of the Dietary Approaches to Stop Hypertension (DASH) dietary pattern enhances insulin actions even beyond those produced by comprehensive nonpharmacologic interventions (pp. 340-7). Participants received either advice only (Group A), weight loss, reduced sodium intake, increased physical activity, and moderate alcohol intake (Group B), or all of the Group B interventions plus the DASH dietary pattern (Group C). Insulin sensitivity improved significantly only in Group C, the authors report, adding, “Both intervention groups decreased total calories, percentage of calories from fat, and sodium intake to similar levels, with similar amounts of energy expenditure and weight loss.... Group B did have a significant decrease in fasting insulin and glucose, but the changes in insulin sensitivity did not reach statistical significance when compared with control subjects.” (J. D. Ard, U. Alabama, Birmingham; jamy.ard@uab.edu)

Very-Low-Calorie Diets in Children: Ketogenic very-low-calorie diets, used in 20 teenagers with type 2 diabetes, were effective in a short-term trial for improving blood glucose and body mass and enabling patients to discontinue insulin and other hypoglycemic therapies (pp. 348-53). Charts of the children (mean age, 14.5 years) were reviewed during periods of use of the ketogenic VLCD and for 2 years thereafter. The authors report, “Before starting the diet, 11 of 20 patients were treated with insulin and 6 with metformin. Mean daily blood glucose values fell from 8.9 ± 1.1 to 5.5 ± 0.38 mmol/l (P < 0.0001) in the first 3 days of the VLCD, allowing insulin and oral agents to be discontinued in all but one subject. BMI fell from 43.5 ± 1.8 to 39.3 ± 1.8 kg/m2 (P < 0.0001) and HbA1c dropped from 8.8 ± 0.6 to 7.4 ± 0.6% (P < 0.005) as the diet was continued for a mean of 60 ± 8 days (range 4–130 days), and none required resumption of antidiabetic medications. Sustained decreases in BMI and insulin requirements were observed in patients remaining on the VLCD for at least 6 weeks when compared with those of the control group.”(S. M. Willi, willis@musc.edu)

Antioxidant Vitamin Intake & DM: The risk for development of type 2 diabetes can be reduced by increased intake of dietary antioxidant vitamins, according to a study of 2,285 men and 2,019 women aged 40–69 years who were free of diabetes at baseline in 1967–72 (pp. 362-6). Prior-year food consumption was recorded at baseline, including consumption of vitamin C, four tocopherols, four tocotrienols, and six carotenoids. Comparing patients who never developed diabetes with the 164 men and 219 women who did, the authors found, “Vitamin E intake was significantly associated with a reduced risk of type 2 diabetes. The relative risk (RR) of type 2 diabetes between the extreme quartiles of the intake was 0.69 (95% CI 0.51–0.94, P for trend = 0.003). Intakes of alpha-tocopherol, gamma-tocopherol, delta-tocopherol, and beta-tocotrienol were inversely related to a risk of type 2 diabetes. Among single carotenoids, beta-cryptoxanthin intake was significantly associated with a reduced risk of type 2 diabetes (RR 0.58, 95% CI 0.44–0.78, P < 0.001). No association was evident between intake of vitamin C and type 2 diabetes risk.” (J. Montonen, National Public Health Inst., Helsinki, Finland; jukka.montonen@ktl.fi)

Out-of-Pocket Medication Costs: A national survey of 875 adults with diabetes shows that many have trouble paying out-of-pocket medication costs associated with their hypoglycemic therapies (pp. 384-91). “A total of 19% of respondents reported cutting back on medication use in the prior year due to cost, 11% reported cutting back on their diabetes medications, and 7% reported cutting back on their diabetes medications at least once per month,” the authors write. “Moreover, 28% reported forgoing food or other essentials to pay medication costs, 14% increased their credit card debt, and 10% borrowed money from family or friends to pay for their prescriptions.” (J. D. Piette, jpiette@umich.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 9, 2004 Vol. 11, No. 25
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
Feb. 7 issue of Lancet (www.thelancet.com; 2004; 363).

Rosiglitazone & Antiretroviral Lipoatrophy: Prevention of antiretroviral-associated lipoatrophy is necessary through use of less toxic agents, conclude authors who found that 48 weeks of rosiglitazone therapy had no effect on the condition (pp. 429-38). Among 108 HIV-infected lipoatrophic adults on antiretroviral therapy, rosiglitazone 4 mg or placebo was administered twice daily. After 48 weeks, the authors found, “Limb fat increased by 0.14 kg in the rosiglitazone group and 0.18 kg in the placebo group (mean difference –0.04 kg [95%CI –0.29 to 0.21]; p=0.74 by t test), with three participants (one on rosiglitazone and two controls), lost to follow-up. Rosiglitazone had no significant benefit on any other measure of lipodystrophy, despite large relative increases in plasma adiponectin (4.2 mmol/L [102%]; p < 0.0001) and in three markers of insulin sensitivity (p = 0.01 to 0.02). Six participants ceased study drug in each group, four participants (three on rosiglitazone and one control) for related adverse events. The main adverse effects, which seem to be almost unique to this population, were asymptomatic hypertriglyceridaemia (mean relative increase 0.9 mmol/L at week 48; p=0.04) and hypercholesterolaemia (1.5 mmol/L; p = 0.001).” (A. Carr, St. Vincent’s Hosp., Sydney; acarr@stvincents.com.au)

Magnesium for Acute Stroke: Administration of magnesium within 12 hours of the onset of acute stroke had no effect on the risks of mortality or disability, according to investigators in the Intravenous Magnesium Efficacy in Stroke (IMAGES) study (pp. 439-45). Magnesium therapy included doses of 16 mmol over 15 minutes and then 65 mmol over 24 hours. Among 2,386 patients in the placebo-controlled trial, the odds ratio for death or disability at day 90 was a nonsignificant 0.95. In fact, slightly higher mortality among patients given magnesium nearly reached significance (OR, 1.18; P = .098). Even though the investigators had expected greater benefits to emerge among patients with cortical strokes, subgroup analysis showed that significant benefits of magnesium were evident only in patients with noncortical strokes. (K. R. Lees, Gardiner Inst., Western Infirm., Glasgow; k.r.lees@clinmed.gla.ac.uk)

HRT After Breast Cancer: The risk of hormone-replacement therapy in women who have had breast cancer is “unacceptable,” according to researchers who conducted the Hormonal replacement therapy After Breast cancer—Is It Safe? (HABITS) trial (pp. 453-5). “After a median follow-up of 2.1 years [in 434 women], 26 women in the HRT group and seven in the non-HRT group had a new breast-cancer event,” write the authors. “All women with an event in the HRT group and two of those in the non-HRT group were exposed to HRT and most women had their event when on treatment. We decided that these findings indicated an unacceptable risk for women exposed to HRT in the HABITS trial, and the trial was terminated on Dec 17, 2003.” (L. Holmberg, U. Hosp., Uppsala, Sweden; lars.holmberg@lul.se)

>>>PNN JournalWatch
* Effect of Alcohol Consumption on Diabetes Mellitus: A Systematic Review, in Annals of Internal Medicine, 2004; 140: 211–9. Reprints: www.annals.org; A.A. Howard, Montefiore Med. Ctr., Bronx, N.Y.; ahoward@montefiore.org

* Effectiveness of Opportunistic Brief Interventions for Problem Drinking in a General Hospital Setting: Systematic Review, in
BMJ, 2004; 328: 318 ff. Reprints: www.bmj.org; M. J. Emmen, Amsterdam Inst. for Addiction Research, Amsterdam, the Netherlands; emmen@aiar.nl

* Assessment of Dependence and Motivation to Stop Smoking, in
BMJ, 2004; 328: 338–9. Reprints: www.bmj.org; R. West, University College, London.

* Acute Heart Failure Complicating Acute Coronary Syndromes: A Deadly Intersection, in
Circulation, 2004; 109: 440–2. Reprints: circ.ahajournals.org; E. J. Velazquez.

* Pharmacologic Treatment of Bronchiolitis in Infants and Children: A Systematic Review, in
Archives of Pediatric Adolescent Medicine, 2004; 158: 127–37. Reprints: archpedi.ama-assn.org; V. J. King.

* Heart Failure with Preserved Left Ventricular Systolic Function: Epidemiology, Clinical Characteristics, and Prognosis, in
Journal of the American College of Cardiology, 2004; 43: 317–27. Reprints: www.cardiosource.com; J. McMurray, mailto:j.mcmurray@bio.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 10, 2004 Vol. 11, No. 26
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Feb. 9 issue of Archives of Internal Medicine (www.archinternmed.com; 2004; 164).

Obesity Pandemic: Authors issue a call for action by physicians to address the growing pandemics of obesity and sedentary lifestyles (pp. 249-58). At each patient visit, the patient’s weight and height should be measured and the body mass index determined. For patients with BMIs of 25 kg/sq m or more, the waist circumference should be measured. For patients with BMIs of 25–29.9 kg/sq m and waist circumferences of less than 40 inches for men and 35 inches for women, physical activity should be prescribed, the authors state. Patients with higher BMIs or BMIs in the above range but with larger waist circumferences, physical activity should be prescribed, and the a referral should be made to a nutritionist for weight loss.

Weight-loss medications should be considered for patients with BMIs of 30 kg/sq m or more or 27 kg/sq m with comorbidities. In addition, sibutramine, orlistat, or phentermine are possible therapies if overweight and obese patients do not lose 10–15 pounds in 3–6 months.

“As citizens, clinicians can also provide an important voice in the community for changes that will promote healthy weight, increased physical activity, and disease prevention,” conclude the authors. “Let us not be like Pogo, ‘confronted with insurmountable opportunities.’ Instead, let us seize the opportunities that patient visits afford us and lead the way to stemming the pandemics of obesity and physical inactivity.” (J. E. Manson, jmanson@rics.bwh.harvard.edu)

Treating Opioid Dependence in Primary Care: The increasing medicalization of heroin and opioid dependence is explored in a review article that advocates increased attention and care by primary care physicians (pp. 277-88): “In addition to improved access, shifting the treatment of opioid addiction into physicians’ offices has the potential to enhance health care provision. Intravenous drug users are less likely to be offered and to receive appropriate HIV treatment than other HIV-infected patients. The requirements for medical care of HIV-infected drug users have increased with the use of antiretroviral therapies. Moreover, creating linkages between primary care and addiction medicine should improve the receipt of preventive care by these individuals. Without this improved access, there is increased reliance on emergency services. Primary care–based opioid treatment might therefore improve access to comprehensive medical care for these vulnerable patients.

“With the passage of the Drug Abuse Treatment Act of 2000, buprenorphine has become available to treat opioid addiction in a physician’s office without requiring participation in [opioid treatment programs]. Primary care physicians interested in treating opioid-dependent patients can qualify by submitting a notification of intent to the Substance Abuse and Mental Health Services Administration, which will then provide a waiver.” (M. J. Krantz, Denver Health, Denver; mkrantz@dhha.org)

Geriatric Medication Prescribing: Analyzing data for office-based physicians in the National Ambulatory Medical Care Survey and from hospital outpatient departments in the National Hospital Ambulatory Medical Care Survey, researchers find that little improved in prescribing for elderly Americans between 1995 and 2000 (pp. 305-12). “In 1995 and 2000, at least 1 drug considered inappropriate by the Beers expert panel was prescribed at 7.8% of ambulatory care visits by elderly patients,” the authors write. “At least 1 drug classified as never or rarely appropriate by the Zhan expert panel was prescribed at 3.7% and 3.8% of these visits in 1995 and 2000, respectively. Pain relievers and central nervous system drugs were a large share of the problem. The odds of potentially inappropriate prescribing were higher for visits with multiple drugs and double for female visits. The latter was due to more prescribing of potentially inappropriate pain relievers and central nervous system drugs.” Older women are particularly at risk for medication-related prescribing problems, the group notes. (M. R. Goulding, mgoulding@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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 11, 2004 Vol. 11, No. 27
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Feb. 11 issue of JAMA (www.jama.com; 2004; 291).

Patients’ Dialysis Preferences: Patients newly begun on peritoneal dialysis rate their care higher than those started on hemodialysis, according to a survey of 736 patients (pp. 697-703). Completing a questionnaire an average of 7 weeks after beginning dialysis, the “patients receiving peritoneal dialysis were much more likely than those receiving hemodialysis to give excellent ratings of dialysis care overall (85% vs 56%, respectively; relative probability, 1.46 [95% confidence interval, 1.31-1.57]) and significantly more likely to give excellent ratings for each specific aspect of care rated,” the authors reported. “The 3 items with the greatest differences were in the domain of information provided (average of information items: peritoneal dialysis [69% excellent] vs hemodialysis [30% excellent]). The smallest differences were in ratings of accuracy of information from the nephrologist, response to pain, amount of fluid removed, and staff availability in an emergency.”

The group concludes, “Our results that peritoneal dialysis patients rate their care more highly than hemodialysis patients suggest that nephrologists and primary care physicians should give greater consideration to peritoneal dialysis when patients are eligible for either modality, especially in light of no clear superiority in survival. More thorough information about choice of modality prior to the start of renal replacement therapy may lead more patients to choose peritoneal dialysis and lead to better patient satisfaction.” (H. R. Rubin, Johns Hopkins U., Baltimore; hrubin@jhmi.edu)

>>>Chest Highlights
Source:
Feb. issue of Chest (www.chestjournal.org; 2004; 125).

Potassium Sources:
Postoperative consumption of potassium-rich foods is as effective as medications in maintaining serum potassium levels in patients who have undergone cardiac surgery, according to results of a 38-patient trial (pp. 404-9). Serum potassium concentrations were not significantly different between patients assigned to diet versus potassium chloride supplements, but length of hospital stay was significantly shorter in the diet group (5.0 versus 6.3 days). Some 79% of patients preferred the diet method. (W. Norris, wnorris@u.washington.edu)

Nebulized Opioids in COPD: Use of nebulized opioids should be discouraged in patients with chronic obstructive pulmonary disorders, conclude authors who reviewed relevant literature, an assessment consistent with the recently published Global Initiative for Lung Disease guidelines, which state that opioids are contraindicated in COPD management because of potential respiratory depression and worsening hypercapnia (pp. 691-4). “Currently, the evidence in the literature is lacking regarding placebo-controlled studies to support nebulized morphine for the relief of dyspnea in patients with COPD,” write the authors. “The studies reviewed varied considerably in the dose, opioid used, administration schedule, and methodology. One study found improved exercise capacity in 11 patients not reproducible in a larger sample, and another study found benefit in 54 terminal patients. All other studies found no benefit.” (P. A. Foral, pforal@creighton.edu)

Treatment of Pulmonary Hypertension: Inhaled nitric oxide, iloprost aerosol, and oral sildenafil all significantly improved pulmonary hemodynamics in 10 consecutive patients with primary pulmonary hypertension (pp. 580-6). The researchers report, “iNO, iloprost aerosol, and sildenafil caused a significant fall of mean pulmonary artery pressure and pulmonary vascular resistance (PVR) [p < 0.05]. Correspondingly, cardiac output and mixed venous saturation increased slightly in all groups. Systemic arterial pressure and vascular resistance were mainly unaltered. Using a PVR reduction of 20% to define a significant response, 7 of 10 patients were responders to iloprost aerosol, whereas 4 of 10 patients responded to iNO and oral sildenafil.”(H. H. Leuchte, Ludwig-Maximilians-University Munich, Munich, Germany; hleuchte@helios.med.uni-muenchen.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 12, 2004 Vol. 11, No. 28
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Feb. 12 issue of the New England Journal of Medicine (content.nejm.org; 2004: 350).

B-Type Natriuretic Peptide: Two articles and an editorial explore the clinical utility of B-type natriuretic peptide levels.

In a study of 452 patients who presented to an emergency department with acute dyspnea, rapid measurement of B-type natriuretic peptide improved evaluation and treatment of patients with acute dyspnea and thereby reduced time to discharge and total cost of treatment (pp. 647-54). Significantly fewer patients screened for peptide levels required hospitalization (75%, compared with 85% of patients who were assessed using standard procedures) or intensive care (15% of peptide patients, compared with 24% of normally screened individuals). (C. Mueller, Universitätsklinik, Basel, Switzerland; chmueller@uhbs.ch)

Natriuretic peptide levels were useful as early predictors of risk for death and cardiovascular events, report authors of a community-based study of 3,346 persons without heart failure (pp. 655-63). “During a mean follow-up of 5.2 years, 119 participants died and 79 had a first cardiovascular event,” the authors report. “After adjustment for cardiovascular risk factors, each increment of 1 SD in log B-type natriuretic peptide levels was associated with a 27 percent increase in the risk of death (P = 0.009), a 28 percent increase in the risk of a first cardiovascular event (P = 0.03), a 77 percent increase in the risk of heart failure (P < 0.001), a 66 percent increase in the risk of atrial fibrillation (P < 0.001), and a 53 percent increase in the risk of stroke or transient ischemic attack (P = 0.002).” The researchers conclude, “The prognostic information provided by plasma natriuretic peptide levels is incremental to that provided by traditional cardiovascular risk factors. Although echocardiography may provide more specific information regarding cardiac structure, its high cost makes it an impractical screening tool in asymptomatic persons. Furthermore, measurement of plasma natriuretic peptide levels and echocardiography may be complementary tests in some circumstances, because peptide levels may be a marker of elevated filling pressures, which may otherwise be detectable only with invasive tests.” (T. J. Wang, Framingham Heart Study, Framingham, Mass., vasan@fram.nhlbi.nih.gov)

Editorialists ponder whether B-type natriuretic peptide is becoming “a marker for all seasons” (pp. 718-20): “It is tempting to use new biomarkers to elucidate pathophysiological processes in our patients, as if we have been given a new powerful microscope to see into the body. However, to say that B-type natriuretic peptide reflects subclinical or overt hemodynamic stress does not necessarily make us any wiser about how to care for patients. We need to remember that clinical disease is the product of uncompensated perturbations in the dynamic equilibrium between risk factors and the body’s defense and repair mechanisms. Looking at B-type natriuretic peptide in isolation may thus be akin to seeing smoke trailing out of the window of a house without having any notion of what is on fire, where that fire is, or how it can best be extinguished.” (D. B. Mark, Duke U. Med. Ctr., Durham, N.C.)

Mitochondrial Activity & Type 2 DM: “Insulin resistance in the skeletal muscle of insulin-resistant offspring of patients with type 2 diabetes is associated with dysregulation of intramyocellular fatty acid metabolism, possibly because of an inherited defect in mitochondrial oxidative phosphorylation,” report researchers who studied 14 insulin-resistant and 12 insulin-sensitive control subjects (pp. 664-71). Insulin-stimulated rate of glucose uptake by muscle was some 60% lower in the insulin-resistant subjects than in the insulin-sensitive control subjects. Intramyocellular lipid content was increased by approximately 80%, most likely because of mitochondrial dysfunction, as mitochondrial phosphorylation was 30% lower in insulin-resistant subjects but no other significant, relevant metabolic and serum chemistry differences could be identified between control and test patients. (G. I. Shulman, gerald.shulman@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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 13, 2004 Vol. 11, No. 29
Providing news and information about medications and their proper use

>>>FDA Approves Cetuximab
FDA yesterday approved cetuximab (Erbitux, ImClone; Bristol-Myers Squibb) for treatment of advanced metastatic colorectal cancer. Cetuximab is the first monoclonal antibody approved to treat this type of cancer and is indicated as a combination treatment to be given intravenously with irinotecan or alone if patients cannot tolerate irinotecan.

Cetuximab was approved under FDA’s accelerated approval program. Although treatment with cetuximab has not been shown to extend patients’ lives, it was shown to shrink tumors in some patients and delay tumor growth, especially when used as a combination treatment.

Genetically engineered version cetuximab works by targeting epidermal growth factor receptor on the surface of cancer cells, interfering with their growth. For patients with tumors that express EGFR and who no longer responded to treatment with irinotecan alone or in combination with other chemotherapy drugs, the combination treatment of cetuximab and irinotecan shrank tumors in 22.9% of patients and delayed tumor growth by approximately 4.1 months. For patients who received cetuximab alone, the tumor response rate was 10.8% and tumor growth was delayed by 1.5 months.

The efficacy and safety of cetuximab alone or in combination with irinotecan were studied in a randomized, controlled trial with 329 patients and also in combination with irinotecan in 138 patients in which all patients received both drugs. Cetuximab was further evaluated as a single agent in a third clinical trial with 57 patients. Safety data from an additional 111 patients treated only with cetuximab was also evaluated. All of the trials included patients with EGFR-expressing metastatic colorectal cancer, whose disease had progressed after receiving irinotecan.

Two studies involving approximately 2,000 patients are underway to assess the clinical benefits of cetuximab. These studies are specifically examining the ability of cetuximab to stop the progression of colorectal cancer and to extend patient survival.

Cetuximab can cause serious adverse effects, usually during the administration of the first treatment, including difficulty breathing and low blood pressure. Interstitial lung disease has been reported infrequently, but the relationship between ILD and the drug is not clear. Other more common adverse effects of cetuximab treatment include acne-like rash, dry skin, tiredness or weakness, fever, constipation, and abdominal pain.

>>>PNN NewsWatch
* Generics sales are expected to reach more than $60 billion by 2007, according to “Combating Generic: Pharmaceutical Brand Defense,” a recent report from Cutting Edge Information. Strategies for dealing with competition, trends, profiles of generics companies, and ideas on managing product life cycles and planning portfolios are included in the 164-page report (919/433-0219; www.PharmaGenerics.com)

*
Cost of prescription drugs is a common point of discussion between patients and physicians, according to a recent Wall Street Journal Online/Harris Interactive Health-Care Poll. Two in five adults (43%) had discussed with their doctors the pros and cons of different prescription drugs. More than one half of these people also had discussed costs to them of different drugs their doctors might prescribe, often leading to lower-cost choices. One in seven adults (14%) indicated their physicians prescribed one drug rather than another because it was less expensive for them under managed care plans’ tiered formularies.

* In a recent survey conducted by Weiss Ratings, 42% of 1,834 consumers blamed
pharmaceutical companies' excessive profits for high prescription drug costs. Another 23.3% cited expensive marketing, bringing the total number of respondents holding drug companies responsible for soaring prescription drug costs to nearly two thirds. Some 19.3% cited high research costs, while 10.5% chose the high costs of lawsuits for defective drugs. (www.WeissRatings.com)

*
PNN will not be published on Mon., Feb. 16, 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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 17, 2004 Vol. 11, No. 30
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
Lancet article released early online (www.thelancet.com; 2004; 363).

Procalcitonin Levels as Indicators of Need for Antibiotics: Based on observed elevations in serum calcitonin precursor concentrations in patients with bacterial infections, clinicians tested whether unnecessary antibiotic use could be avoided in patients with suspected lower respiratory tract infections (published online Feb. 10). The 243 patients in the study were randomly assigned to standard care or procalcitonin-guided treatment (antibiotic use discouraged at lower serum procalcitonin concentrations and encouraged at higher levels). The adjusted relative risk of antibiotic exposure was 0.49 in the procalcitonin group, indicating a significant reduction in exposure to antibiotics. Favorable outcomes occurred in 97% of patients in each group. Final diagnoses of the patients included pneumonia (36%), acute exacerbation of chronic obstructive pulmonary disorder (25%), acute bronchitis (24%), asthma (5%), and other respiratory conditions (10%). (M. Christ-Crain)

>>>BMJ Highlights
Source:
Feb. 14 issue of BMJ (www.bmj.org; 2004; 328).

Individualizing HRT Prescribing Decisions: The decision to prescribe hormone-replacement therapy should be tailored to the individual woman and not based on population-based approaches, according to a clinical decision analysis of a hypothetical U.K. population (pp. 371 ff). Measuring gain or loss in quality adjusted life-years, the authors found, “Women free of menopausal symptoms showed a net harm from HRT use, which increased for increasing baseline risk of breast cancer. Those with a baseline risk of 1.2% would expect a loss in QALYs of 0.4 months (–0.03 QALYs, 95% credibility interval –0.05 to –0.01). The main analysis showed HRT to be on average beneficial in women with symptoms, with benefit decreasing with increasing baseline risk of breast cancer. The results were sensitive to the assumed value of quality of life with menopausal symptoms, therefore a contour plot was developed to show the probability of net harm for a range of different values and baseline risks.” (K. R Abrams, U. Leicester, Leicester, U.K.; keith.abrams@le.ac.uk)

Cardiac Risk & Statins: Under the National Health Service in the U.K., statins are prescribed only for patients with a 3% or greater annual chance of developing coronary artery disease, and patients with lower risks cannot receive the medications even if they wish to pay for them out-of-pocket (pp. 400-2). The ethics of this situation are explored, and the authors conclude, “The debate concerning access to statins is a parable for the future of the NHS. Under current guidelines many people are being denied not only effective treatment but also the choice of obtaining that treatment though their own expense within the NHS (in itself paradoxical given the current emphasis of government on promoting patient choice).... We suggest that unless patients who are excluded from effective treatment (because of rationing) are offered the option of obtaining this treatment privately, it is this inequity that will threaten the future of the NHS.” (N. Raithatha, Health Centre, U. East Anglia, Norwich, U.K.; N.Raithatha@uea.ac.uk)

>>>PNN JournalWatch
* Epoetin Alfa: Clinical Evolution of a Pleiotropic Cytokine, in Archives of Internal Medicine, 2004; 164: 262–76. Reprints: www.archinternmed.com; D. H. Henry, Penn. Hosp., Philadelphia.

* Pathophysiology and Management of Patients with Chest Pain and Normal Coronary Arteriograms (Cardiac Syndrome X) , in
Circulation, 2004; 109: 568–72. Reprints: circ.ahajournals.org; J. C. Kaski.

* Alzheimer Disease Risk and Genetic Variation in ACE: A Meta-analysis, in
Neurology, 2004; 62: 363–8. Reprints: www.neurology.org; J.S. Elkins, elkinsj@itsa.ucsf.edu

* Enfuvirtide, a New Fusion Inhibitor for Therapy of Human Immunodeficiency Virus Infection, in
Pharmacotherapy, 2004; 24: 198–211. Reprints: www.accp.com; H. Hardy.

* Aripiprazole, a Novel Atypical Antipsychotic Drug, in
Pharmacotherapy, 2004; 24: 212–28. Reprints: www.accp.com; T. R. Argo.

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 18, 2004 Vol. 11, No. 31
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Feb. 18 issue of JAMA (www.jama.com; 2004; 291).

Antibiotics & Breast Cancer: Use of antibiotics was associated with an increased risk of incident and fatal breast cancer in a study of 2,266 women with primary, invasive breast cancer and 7,953 randomly selected control subjects (pp. 827-35). The study, conducted among members of a nonprofit health plan between 1993 and 2001, relied on computerized pharmacy records to identify antibiotic use since 1977. The authors found odds ratios for breast cancer of 1.45 to 2.07 among women as antibiotic use rose: “Increasing cumulative days of antibiotic use were associated with increased risk of incident breast cancer, adjusted for age and length of enrollment.... Increased risk was observed in all antibiotic classes studied and in a subanalysis having breast cancer fatality as the outcome. Among women with the highest levels of tetracycline or macrolide use, risk of breast cancer was not elevated in those using these antibiotics exclusively for acne or rosacea (indications that could be risk factors for breast cancer due to altered hormone levels), compared with those using them exclusively for respiratory tract infections, adjusted for age and length of enrollment (odds ratio, 0.91; 95% confidence interval, 0.44–1.87).” (S. R. Heckbert, heckbert@u.washington.edu)

Editorialists attempt to explain the meaning of this potential link between antibiotics and breast cancer (pp. 880-1): “As is often true for reports of new associations, this study provides many (or more) questions than answers. Is the observed link between use of antibiotics and risk of breast cancer confounded by unmeasured factors? Is the effect due to use of antibiotics or to the indications for antibiotics? Does the link suggest caution in the use of antibiotics or suggest that infections at distant sites might promote inflammation localized to the breast? And, whether antibiotics are markers of inflammation or are themselves contributors to carcinogenesis, is use of antibiotics a risk factor for cancers at other sites? Time and further scrutiny will tell. While more research is needed, this study raises the possibility that long-term use of antibiotics may have harmful consequences, especially for patients for whom other therapeutic options are available.” (R. B. Ness, repro@pitt.edu)

Varicella Vaccine Effectiveness: The effectiveness of varicella vaccine may begin to decline as early as 1 year after immunization, according to a study of the impact of time since vaccination and age at vaccination (pp. 851-5). In a case–control comparison conducted from March 1997 through June 2003, 339 children who developed chickenpox were compared with 678 matched controls. “Although the adjusted overall effectiveness of the vaccine was 87% (95% confidence interval, 81%–91%; P<.001), there was a substantial difference in the vaccine's effectiveness in the first year after vaccination (97%) and in years 2 to 8 after vaccination (84%, P = .003),” report the authors. “The vaccine’s effectiveness in year 1 was substantially lower if the vaccine was administered at younger than 15 months (73%) than if it was administered at 15 months or older (99%, P = .01), although the difference in effectiveness overall for children immunized at younger than 15 months was not statistically significantly different than for those immunized at 15 months or older (81% vs 88%, P = .17). Most cases of chickenpox in vaccinees were mild.” (E. D. Shapiro, Eugene.Shapiro@Yale.edu)

Peer Review & Grants: Commenting on a study of outcomes of grant applications for clinical versus laboratory research (pp. 836-43), an editorialist writes (pp. 882-3): “Clinical research, when properly applied, will save money and improve care. The reward of doubling the NIH budget will be realized only through clinical applications of its discoveries within a better delivery system. However, this will not occur unless a substantial proportion of that budget is spent on clinical research.... Through coordinated efforts, the medical community can help transform the clinical researcher from an endangered to an emerging species.” (R. Snyderman, snyde001@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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 19, 2004 Vol. 11, No. 32
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Feb. 19 issue of the New England Journal of Medicine (content.nejm.org; 2004; 350).

Alendronate Versus Calcitriol for Bone-Loss Prevention: Overall, alendronate was superior to calcitriol for preventing bone loss among 149 patients during the first year after they underwent cardiac transplantation (pp. 767-76). Beginning an average of 21 days after transplantation, patients randomly received either alendronate 10 mg/day or calcitriol 0.5 mcg/day, and bone mineral density in the two groups was compared with reference values from 27 untreated cardiac transplant recipients.

The authors report, “The degree of bone loss and the rates of fracture did not differ significantly between the intervention groups. Calcitriol was associated with a higher risk of hypercalciuria. Alendronate-treated patients sustained less bone loss at the spine than those in the reference group, and both intervention groups sustained less bone loss at the hip than the reference group. The requirement for monitoring the serum and urinary calcium levels in calcitriol-treated patients makes alendronate more attractive for the prevention of bone loss early after cardiac transplantation.” (E. Shane, Columbia U., New York City)

In an accompanying Perspectives article, an author argues that minimizing the use of medications that produce bone loss is equally important as bone-preserving therapy (pp. 751-4): “Shane et al. report a nonsignificant trend toward fewer fractures in the treatment groups; the study, however, was limited both by its small size and by the lack of randomized controls, so this observation is of unclear import. Although one may speculate that combination treatment with calcitriol and a bisphosphonate might confer an additive skeletal benefit, it is important to conduct further studies in order to assess this possibility. Ultimately, post-transplantation immunosuppressive protocols that minimize the use of glucocorticoids, calcineurin inhibitors, and other medications that have adverse effects on the skeleton will go a long way toward reducing the prevalence of fractures after cardiac transplantation.” (R. Lindsay, Helen Hayes Hosp., West Haverstraw, N.Y.)

New Medicare Drug Benefit: Describing the new Medicare prescription-drug law as “a pure power play,” journal editor John K. Iglehart provides a blow-by-blow description of how the bill emerged last year and passed during a long night of political wrangling (pp. 826-33). He concludes, “The story is that the Medicare law will certainly help many beneficiaries pay for their prescription drugs, but the process of securing that coverage, gaps and all, will pose new challenges for the elderly. And there will be other effects as well. The measure will add to a federal deficit that is already soaring. The administration has estimated in its new 2005 budget that the cost of the drug-benefit program will be $530 billion over a 10-year period — about one third more than the [Congressional Budget Office] estimated about two months ago. CBO director Douglas Holtz-Eakin has testified that its ‘cost would exceed $1 trillion and could approach $2 trillion during the following decade.’ Nevertheless, Republicans determined to break the long hold that Democrats have maintained on Medicare as a political asset seem to have achieved that goal by winning enactment of a drug benefit. Democrats who have pledged to expose the law’s shortcomings will have a difficult time of it in this election year, since the drug benefit does not take effect until 2006 and federal budget deficits have had little resonance in the minds of voters.”

Two members of Congress add their divergent assessments of the new law (pp. 747-51). Democrat Sen. Edward M. Kennedy (Mass.) assails the law—even though he supported earlier versions of the legislation—as “wrong for senior citizens, wrong for Medicare, and wrong for the country.” Republican Bill Thomas (Calif.) retorts that the bill “delivers on the promise to provide the best health care to our greatest generation [the baby boomers]” and “does more to cut drug prices than any other action ever taken by Congress.”

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 20, 2004 Vol. 11, No. 33
Providing news and information about medications and their proper use

>>>Circulation Highlights
Source: Feb. 17 Circulation (circ.ahajournals.org; 2004; 109).

Metabolic Syndrome in Women: Numerous articles in this issue detail results of the Women’s Ischemia Syndrome Evaluation (WISE) study. In addition to the two articles highlighted here, proceedings of an October 2002 conference on “Women’s Ischemic Syndrome Evaluation” are provided in the print and online editions of the journal (pp. 805-7, e44-6, e47-9, e50-2, e53-5, e56-8, e59-61, e62-3). The conference covered the need for improved diagnosis of ischemia and coronary artery disease in women; explored strategies for improved translation of promising research results into clinical practice; and assessed opportunities for effective educational strategies for at-risk women.

All the components of the metabolic syndrome must be addressed in treating women at risk for CAD events, not just overweight and obesity, according to a study of 780 women in the WISE study (pp. 706-13). “Prevalence of significant angiographic coronary artery disease (CAD; 50% stenosis) and 3-year risk of [cardiovascular disease] were compared by BMI and metabolic status,” the authors write. “The metabolic syndrome and BMI were strongly associated, but only metabolic syndrome was associated with significant CAD. Similarly, unit increases in BMI (normal to overweight to obese) were not associated with 3-year risk of death (adjusted hazard ratio [HR] 0.92, 95% CI 0.59 to 1.51) or major adverse cardiovascular event (MACE: death, nonfatal myocardial infarction, stroke, congestive heart failure; adjusted HR 0.95, 95% CI 0.71 to 1.27), whereas metabolic status (normal to metabolic syndrome to diabetes) conferred an approximate 2-fold adjusted risk of death (HR 2.01, 95% CI 1.26 to 3.20) and MACE (HR 1.88, 95% CI 1.38 to 2.57).” (K. E. Kip, kipk@edc.pitt.edu)

A second WISE report shows that metabolic syndrome was associated with increased cardiovascular disease risks only when the patients had significant angiographic CAD (pp. 714-21). In 755 women, the researchers found, “Compared with women with normal metabolic status, women with the metabolic syndrome had a significantly lower 4-year survival rate (94.3% versus 97.8%, P=0.03) and event-free survival from major adverse cardiovascular events (death, nonfatal myocardial infarction, stroke, or congestive heart failure; 87.8% versus 93.5%, P=0.003). When the subjects were stratified by the presence or absence of angiographically significant CAD at study entry, in women with angiographically significant CAD, the metabolic syndrome resulted in significantly higher risk of cardiovascular events than in women with normal metabolic status (hazard ratio 4.93, 95% CI 1.02 to 23.76; P=0.05), whereas it did not result in increased 4-year cardiovascular risk in women without angiographically significant CAD (hazard ratio 1.41, 95% CI 0.32 to 6.32; P=0.65).” (S. E. Reis, MD, U. Pittsburgh Med. Ctr., Pittsburgh; reisse@msx.upmc.edu)

Combination Therapy in ACS: Use of multiple medications in patients with acute coronary syndromes is supported in a study of 1,358 consecutive patients (pp. 745-9). Using only therapies that are supported by evidence as effective for ACS or other comorbidities present in these patients, the authors assessed outcomes at 6 months: “The odds ratio for death for all indicated medications used (appropriateness level IV) versus none of the indicated medications used (appropriateness level 0) was 0.10 (95% CI, 0.03 to 0.42; P<0.0001); similarly, odds ratio for appropriateness level III versus level 0 was 0.17 (95% CI, 0.04 to 0.75; P=0.0018), odds ratio for appropriateness level II versus level 0 was 0.18 (95% CI, 0.04 to 0.77; P=0.01), and odds ratio for appropriateness level I versus level 0 was 0.36 (95% CI, 0.08 to 1.75; P=0.20).” The group concludes, “[Use of combination evidence-based medical therapies], most of which are generic and inexpensive today, seem to offer a marked survival advantage compared with patients in whom such therapies are omitted.” (D. Mukherjee, dmukherj@umich.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 23, 2004 Vol. 11, No. 34
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Feb. 21 issue of BMJ (www.bmj.org; 2004; 328).

ASA-Induced Asthma: Review of the data in 21 published articles indicates that the prevalence of aspirin-induced symptoms in patients with asthma may be higher than previously appreciated (pp. 434 ff). When adults and children were tested using oral provocation doses, 21% and 5%, respectively, showed evidence of asthma, the authors found. Nonprescription NSAIDs were often cross-reactive, with rates of 98% for ibuprofen, 100% for naproxen, and 93% for diclofenac, but these patients were rarely cross-reactive to acetaminophen (7%). Overall, only 2% of asthmatic patients were sensitive to both aspirin and acetaminophen.

“The continuing recommendation of [acetaminophen] as the analgesic and antipyretic of first choice for patients with asthma seems warranted given the relatively low incidence of sensitivity,” the authors note. “The new generation of COX-2 specific analgesics may also be safer than NSAIDs and aspirin in asthmatic patients, but further experience with these compounds is required. Based on this conclusion, we have simplified guidelines for the use of analgesics in asthmatic patients. Where history neither supports nor excludes aspirin induced asthma, and aspirin or NSAIDs are clinically indicated, formal provocation testing is warranted, but because of the risk of severe bronchoconstriction this must be conducted by specialised staff with facilities for emergency resuscitation.” (C. Jenkins, Royal Prince Alfred Hosp., Camperdown, Australia; crj@med.usyd.edu.au)

>>>Lancet Report
Source:
Feb. 21 issue of Lancet (www.thelancet.com; 2004; 363).

Renal Carcinoma Vaccine: Renal tumor cell vaccine should be considered in patients after nephrectomy for renal-cell carcinoma for lesions larger than 2.5 cm in diameter, according to researchers who studied 379 patients (pp. 594-9). After follow-up every 6 months for a minimum of 4.5 years, the authors found, “At 5-year and 70-month follow-up, the hazard ratios for tumour progression were 1.58 (95% CI 1.05–2.37) and 1.59 (1.07–2.36), respectively, in favour of the vaccine group (p=0.0204, log-rank test). 5-year and 70-month progression-free survival rates were 77.4% and 72%, respectively, in the vaccine group and 67.8% and 59.3%, respectively, in the control group. The vaccine was well tolerated, with only 12 adverse events associated with the treatment.” (D. Jocham, Lübeck Med. Sch., Lübeck, Germany; Prof.Jocham.MUL@t-online.de)

Editorialists note the importance of this paper, “The trial infrastructure and aTL results of Jocham and colleagues contribute towards the goal of specific anticancer immunotherapy. The key milestone is the suggestion of a fixed point—a non-toxic vaccine with a biological clinically relevant effect in T2-3N0 renal cancer--around which innovations can be built. Such a milestone can serve as a concrete step towards making adjuvant treatment of renal cancer a routine and effective intervention.” (M. Fishman, H. Lee Moffitt Cancer Ctr. & Research Inst., Tampa; FishmaMN@moffitt.usf.edu)

>>>PNN JournalWatch
* Training for Patients in a Randomised Controlled Trial of Self Management of Warfarin Treatment, in BMJ, 2004; 328: 437–8. Reprints: www.bmj.org; E. Murray, U. Birmingham, Birmingham; e.t.murray@bham.ac.uk

* Nicotine Replacement Therapy, in
BMJ, 2004; 328: 454–6. Reprints: www.bmj.org; A. Molyneux, City Hosp., Nottingham, U.K.

* Diarrhoea in Children: An Interface Between Developing and Developed Countries, in
Lancet, 2004; 363: 641–53. Reprints: www.thelancet.com; N. Thapar, Royal London Hosp., London, U.K.; thaparn@doctors.org.uk

* Management of Overactive Bladder, in
New England Journal of Medicine, 2004; 350: 786–99. Reprints: content.nejm.org; J. G. Ouslander, Wesley Woods Ctr. of Emory U., Atlanta; jouslan@emory.edu

* Acute Chemical Emergencies, in
New England Journal of Medicine, 2004; 350: 800–8. Reprints: content.nejm.org; S. N. Kales, Occupational and Environmental Health, Cambridge, Mass.; skales@challiance.org

* Improved Refill Persistence with Fluticasone Propionate and Salmeterol in a Single Inhaler Compared with Other Controller Therapies, in
Journal of Allergy and Clinical Immunology, 2004; 113: 245–51. Reprints: S. W. Stoloff, Carson City, Nev.

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 24, 2004 Vol. 11, No. 35
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Feb. 23 issue of Archives of Internal Medicine (www.archinternmed.com; 2004; 164).

HRT & Asthma: Use of postmenopausal hormone-replacement therapy contributes to newly diagnosed cases of asthma but does not affect development of chronic obstructive pulmonary disease, according to data from the Nurses’ Health Study (pp. 379-86). Participants were asked biennially about HRT use beginning in 1976, and new diagnoses of asthma or COPD were recorded from 1988 to 1996. The authors found, “During 546,259 person-years of follow-up, current use of estrogen alone was associated with an increased rate of asthma (multivariate rate ratio, 2.29; 95% confidence interval [CI], 1.59–3.29) compared with those who never used hormones. Current users of estrogen plus progestin had a similarly increased rate of newly diagnosed asthma. Rate ratios increased with certainty of diagnosis of asthma. In contrast, rates of newly diagnosed COPD were the same among hormone users and nonusers (multivariate rate ratio, 1.05; 95% CI, 0.80–1.37).” (R. G. Barr, rgb9@columbia.edu)

DTC Pharmaceutical Advertising: Physicians and consumers have largely negative views of direct-to-consumer pharmaceutical advertising, according to mail and telephone surveys (pp. 427-32). Among 523 Colorado physicians, 261 national physicians, and 500 Colorado households, the authors found these perceptions: “Most physicians tended to view DTC advertisements negatively, indicating that such advertisements rarely provide enough information on cost (98.7%), alternative treatment options (94.9%), or adverse effects (54.8%). Most also believed that DTC advertisements affected interactions with patients by lengthening clinical encounters (55.9%), leading to patient requests for specific medications (80.7%), and changing patient expectations of physicians’ prescribing practices (67.0%). Only 29.0% of public respondents agreed that DTC advertising is a positive trend in health care and 28.6% indicated that advertisements make them better informed about medical problems; fewer indicated that advertisements motivated them to seek care (10.5%) or led them to request specific medications from their physicians (13.3%).” The researchers conclude, “While these advertisements may be influencing only a few consumers, it seems that the impact on physicians and their interactions with patients may be significant.” (A. R. Robinson, Denver; arobinson@health1.org)

Dietary Fiber & Heart Disease: The more fruits and cereals people eat, the lower their chances of developing coronary heart disease, according to an analysis of data from 10 prospective cohort studies from the U.S. and Europe (pp. 370-6). During 6 to 10 years of follow-up in 91,058 men and 245,186 women, each 10-gram increase in daily total dietary fiber produced a 14% decrease in risk of all coronary events and a 27% drop in risk of coronary death. “These results provide strong confirmation of the results of previously published cohort studies, and they are supported by numerous experimental studies that demonstrate a wide range of possible biological mechanisms through which fiber may reduce the risk of CHD,” conclude the authors. “Therefore, the recommendations to consume a diet that includes an abundance of fiber-rich foods to prevent CHD are based on a wealth of consistent scientific evidence.” (M. A. Pereira, pereira@epi.umn.edu)

>>>PNN NewsWatch
* Universal influenza vaccination is on the agenda for debate at today’s meeting of the CDC’s Advisory Committee on Immunization Practices. According to today’s Atlanta Journal-Constitution, experts believe that “herd vaccination” of every American every year could substantially reduce the country’s 36,000 deaths and 114,000 hospitalizations that influenza causes annually.

*
Combinatorial chemistry has not produced the results the pharmaceutical industry expected and may even be impeding the discovery of useful new drugs, according to a page 1 article in today’s Wall Street Journal.

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 25, 2004 Vol. 11, No. 36
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Feb. 25 issue of JAMA (www.jama.com; 2004; 291).

Reteplase + Abciximab for MI: In 253 patients with ST-segment elevation myocardial infarction who were undergoing percutaneous coronary interventions, the addition of reteplase to abciximab therapy did not further reduce final infarct size (pp. 947-54). The patients presented within 12 hours of the onset of symptoms at 13 community hospitals without catheterization facilities or 5 hospitals with catheterization facilities. They randomly received open-label abciximab alone (0.25 mg/kg bolus, 0.125 mcg/kg/min infusion [maximum 10 mcg/min for 12 hours]) or a combination of half-dose reteplase (two 5-unit boluses given 30 minutes apart) plus abciximab in the above standard dose. Final infarct size of the left ventricle was 13.0% in the combination group and 11.5% in the abciximab-alone group, not a significant difference. Other measures also did not reach significance, including a composite endpoint of death, recurrent MI, or stroke within 6 months (6.4% and 4.7% of patients in the combination and abciximab groups, respectively) and major bleeding complications (5.6% and 1.6% of patients in the combination and abciximab groups, respectively). (A. Kastrati, Deutsches Herzzentrum, München, Germany; kastrati@dhm.mhn.de)

The “plateau” in mortality reduction by fibrinolytic therapy is the focus of an editorialist commenting on this study (pp. 1000-2): “For the physician treating patients with MI, primary PCI remains the reference standard for acute reperfusion therapy. The strategy of pharmacologic pretreatment before PCI remains unproven and cannot yet be recommended routinely. If long delays are unavoidable before reperfusion can be achieved by primary PCI, however, clinical judgment may compel a facilitated PCI approach, particularly for high-risk patients. Under those circumstances, the results of this randomized comparison between different regimens suggest that abciximab alone is at least as effective, with less bleeding risk, than the combination of [glycoprotein] IIb/IIIa blockade and reduced-dose fibrinolysis. The results of ongoing pivotal clinical trials should help to provide more definitive insights into how best to facilitate PCI during acute MI.” (A. M. Lincoff, Cleveland Clinic Foundation, Cleveland, Ohio; lincofa@ccf.org)

Incorporating Home BP Measurements into Care: Less intensive drug treatment regimens can be used when therapy is based on home measurements of blood pressure rather than in-office readings, according to a study of 400 patients in Belgium and Ireland (pp. 955-64). In the 1-year blinded trial, antihypertensive treatments were adjusted in patients with diastolic BP of 95 mm Hg or more based on either self-measured DBP at home (average of six readings per day) or the average of three readings at the physician’s office. After a median follow-up of 350 days, the authors found, “More home BP than office BP patients had stopped antihypertensive drug treatment (25.6% vs 11.3%; P < .001) with no significant difference in the proportions of patients progressing to multiple-drug treatment (38.7% vs 45.1%; P = .14). The final office, home, and 24-hour ambulatory BP measurements were higher (P < .001) in the home BP group than in the office BP group. The mean baseline-adjusted systolic/diastolic differences between the home and office BP groups averaged 6.8/3.5 mm Hg, 4.9/2.9 mm Hg, and 4.9/2.9 mm Hg, respectively.” (J. A. Staessen, Campus Gasthuisberg, Leuven, Belgium; jan.staessen@med.kuleuven.ac.be)

Topiramate for Migraine Prevention: The antiepileptic agent topiramate reduced migraine occurrence in 468 patients in an 18-week trial, with benefits evident during the first month of therapy in those treated with 100 or 200 mg of the drug (pp. 965-73). Compared with placebo, topiramate produced significantly greater responder rates and significantly reduced numbers of migraine days and use of rescue medications. Adverse effects included paresthesia, fatigue, and nausea. (J. L. Brandes, Nashville Neuroscience Group, Nashville, Tenn.; jbrandes@nashvilleneuroscience.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 26, 2004 Vol. 11, No. 37
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Feb. 26 issue of the New England Journal of Medicine (content.nejm.org; 2004; 350).

Infliximab as Maintenance Therapy in Crohn’s Disease: Responses to infliximab were sustained over a 54-week period in a study of 306 adult patients with Crohn’s disease and one or more draining abdominal or perianal fistulas of at least 3 months’ duration (pp. 876-85). “Patients received 5 mg of infliximab per kilogram of body weight intravenously on weeks 0, 2, and 6,” the authors write. “A total of 195 patients who had a response at weeks 10 and 14 and 87 patients who had no response were then randomly assigned to receive placebo or 5 mg of infliximab per kilogram every eight weeks and to be followed to week 54.” Compared with placebo maintenance doses, infliximab therapy produced significantly longer time to loss of response (more than 40 weeks versus 14 weeks) and significantly higher percentages of patients with complete absence of draining fistulas (36% versus 19%). (B. E. Sands, Mass. Genl. Hosp., Boston)

An editorialist questions whether the cost and especially the safety profile of infliximab are consistent with the need for lifelong maintenance therapy in patients fistulizing Crohn’s disease (pp. 934-6): “By oath, physicians must abide to the
primum non nocere principle. Hence, they will inevitably face the dilemma of deciding what is best for a patient with Crohn’s disease who has had lifelong disabling fistulas and is considering infliximab therapy. In practice, if traditional approaches have failed, the decision comes down to a matter of how much risk the physician and the patient are willing to accept, given the often remarkable healing effects of infliximab and the possibility, currently remote, that malignant or autoimmune disease will develop. For now, most will opt for infliximab and take their chances as long as the drug continues to provide tangible clinical benefits. Meanwhile, new knowledge should emerge on the fistula-healing power of other biologic agents with less immunosuppressive activity or none, combination therapies, thalidomide, probiotics, or even a trip to the Dead Sea for a good dose of hyperbaric oxygen.” (C. Fiocchi, Case Western Reserve U., Cleveland)

Inactivated Intranasal Flu Vaccine & Bell’s Palsy: An inactivated intranasal influenza vaccine that is no longer in clinical use is linked to 46 cases of Bell’s palsy that occurred in Switzerland after marketing of the product (pp. 896-903). A matched case–control study and case-series analysis from the German-speaking regions of that country identified 773 patients with Bell’s palsy. From the 412 patients who could be evaluated, 250 patients were enrolled and matched with 722 control patients, while the remaining 162 patients had no controls. The authors report, “In the case–control study, we found that 68 patients with Bell’s palsy (27.2 percent) and 8 controls (1.1 percent) had received the intranasal vaccine (P < 0.001). In contrast to parenteral vaccines, the intranasal vaccine significantly increased the risk of Bell’s palsy (adjusted odds ratio, 84.0; 95 percent confidence interval, 20.1 to 351.9). Even according to conservative assumptions, the relative risk of Bell’s palsy was estimated to be 19 times the risk in the controls, corresponding to 13 excess cases per 10,000 vaccinees within 1 to 91 days after vaccination. In the case-series analysis, the period of highest risk was 31 to 60 days after vaccination.” The researchers conclude, “As with the experience with the rotavirus vaccine and intussusception, the risk of Bell’s palsy found after licensure of the intranasal influenza vaccine could not have been detected beforehand, given the sample size in the prelicensure trials. These experiences may reinforce the arguments both for larger prelicensure safety trials and for enhanced postlicensure surveillance.”(M. Mutsch, Inst. of Social and Preventive Med., Zurich, Switzerland; muetsch@ifspm.unizh.ch)

In accompanying Perspectives article, an author surmises that these cases might be the result of reactivation of either varicella-zoster virus (similar to the Ramsay Hunt syndrome) or herpesvirus infection (pp. 860-1; R. B. Couch, 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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 27, 2004 Vol. 11, No. 38
Providing news and information about medications and their proper use

>>>Infectious Disease Report
Source:
Mar. 1 issue of Clinical Infectious Diseases (www.journals.uchicago.edu/CID; 2004; 38).

Inactivated Influenza Virus Vaccines in Children: “Killed influenza vaccines in children are safe, immunogenic, effective, and potentially cost-saving,” writes an author of a review article (pp. 678-88). “In years with sufficient disease rates for study, killed-virus vaccines have shown efficacy for the prevention of influenza ranging from 31% to 91% in healthy children (in 5 separate studies) and in subjects with asthma (in 1 study) ranging in age from 6 months to 15 years. In 2 separate studies, killed-virus vaccines prevented 32%–36% of cases of acute otitis media during the influenza season in children aged 13 years who attended day care centers. Economic analyses conclude that vaccinating children against influenza is cost-saving. On the basis of this review, future studies with killed-virus influenza vaccines might include additional studies of their efficacy against influenza virus infection and the effect on hospitalization due to influenza-associated diseases, such as pneumonia, croup, and other complications in children.” (F. L. Ruben, Aventis Pasteur, Swiftwater, Penn.; red.ruben@aventis.com)

As the country contemplates the possibility of universal vaccination against influenza (see PNN, Feb. 24), an editorialist assesses the implications of the above article and the difficulties with getting flu vaccine to every child on an annual basis (pp. 689-91): “The message to the public needs to be clear: influenza vaccination is safe and effective and should be offered to anyone aged 6 months who wishes to reduce his or her chances of becoming ill from influenza. For healthy children aged 5 years, either inactivated or live-attenuated intranasal vaccine may be given. Increasing the number of children who receive influenza vaccine may have benefits beyond protection of the individual child. Children are important in the transmission of influenza virus within households and communities, and increasing influenza vaccine coverage among children may interrupt transmission and attenuate community epidemics. These strategies will be particularly important when history repeats itself and the next severe influenza season rolls around.” (K. M. Neuzil, kneuzil@u.washington.edu)

Zidovudine–Valproate Interaction: Severe anemia developed in a 42-year-old man with HIV infection and a history of complex partial seizures after valproic acid was added to a stable antiretroviral regimen of zidovudine, lamivudine, and abacavir (e38–e40). The patient’s area under the concentration– time curve for zidovudine increased by 80% following addition of valproic acid, leading the researchers to surmise: “The inhibition of zidovudine glucuronidation by valproic acid and the resultant zidovudine hematologic toxicity is the proposed mechanism of the interaction.” They conclude, “Clinicians should be aware of the potential for this interaction and monitor complete blood counts closely when valproic acid and zidovudine are coadministered. Alternatively, nucleoside analogues that do not undergo glucuronidation and/or do not cause significant hematologic toxicity (e.g., stavudine, tenofovir, and abacavir) can be substituted for zidovudine in regimens for patients receiving concomitant valproic acid.” (T. Antoniou, St. Michael’s Hosp., Toronto, Ontario, Canada;
tantoniou@smh.toronto.on.ca)

>>>PNN NewsWatch
* The GlucoWatch G2 Biographer (Cygnus) and the continuous glucose monitoring system (Medtronic MiniMed) fail to reliably detect hypoglycemia in children and adolescents with type 1 diabetes, according to The Diabetes Research in Children Network (DirecNet) Study Group, writing in the March issue of Diabetes Care (care.diabetesjournals.org; 2004; 27: 722-6). An editorialist maintains that such findings “call for greater realism in our expectations” concerning such devices (pp. 834-6; D. C. Klonoff, klonoff@itsa.ucsf.edu), adding, “Performance [of new real-time continuous glucose monitors] in the hypoglycemic range will need to be closely scrutinized, especially if their manufacturers should propose to market them as stand-alone monitors.”

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 1, 2004 Vol. 11, No. 39
Providing news and information about medications and their proper use

>>>Bevacizumab Approved for Colorectal Cancer
FDA has approved bevacizumab (Avastin, Genentech), the first angiogenesis inhibitor to reach the U.S. market, as first-line treatment for patients with metastatic colorectal cancer. In a randomized, double-blind clinical trial of more than 800 patients with metastatic colorectal cancer, the monoclonal antibody was shown to extend patients’ lives by about 5 months when given in a combination treatment along standard chemotherapy drugs for colon cancer (the “Saltz regimen” of irinotecan, leucovorin, and 5-fluorouracil), compared with ILF alone.

With the new drug, the mean time before tumors started regrowing or new tumors appeared was 4 months longer than in patients receiving IFL alone. The overall response rate to bevacizumab treatment was 45%, compared with 35% for controls.

Serious but uncommon adverse effects of bevacizumab include gastrointestinal perforation generally requiring surgery and sometimes leading to intra-abdominal infections, impaired wound healing, and bleeding from the lungs or internally. More common adverse effects are hypertension, tiredness, blood clots, diarrhea, decreased white blood cells, headache, appetite loss, and mouth sores.

>>>Lancet Report
Source:
Feb. 28 issue of Lancet (www.thelancet.com; 2004; 363).

Combination RA Treatment: Etanercept 25 mg subcutaneously twice weekly plus methotrexate 20 mg orally once weekly reduced disease activity, improved functional disability, and retarded radiographic progression of rheumatoid arthritis in comparison with either drug alone, according to a 682-patient study (pp. 675-81). Based on findings of the 24-week study, the authors conclude, “Concurrent initiation and use of the combination of etanercept and methotrexate brings us closer to the goals of antirheumatic treatment, specifically the achievement of clinical remission and repair of structural damage.” (L. Klareskog, Karolinska Hosp., Stockholm, Sweden; Lars.Klareskog@medks.ki.se)

>>>BMJ Highlights
Source:
Feb. 28 issue of BMJ (www.bmj.org; 2004; 328).

Low-Dose Ramipril: Cardiovascular and renal outcomes were unaffected in 4,912 patients with type 2 diabetes who received either ramipril 1.25 mg/day or placebo in a multiyear trial (pp. 495 ff). Cardiovascular death, nonfatal myocardial infarction, stroke, heart failure leading to hospital admission, and end-stage renal failure occurred with similar frequency among those in the low-dose ramipril and placebo groups. Systolic and diastolic blood pressures and renal parameters (microalbuminuria, proteinuria) improved with ramipril but not significantly so. (M. Marre, Hôpital Bichat-Claude Bernard, Paris; michel.marre@bch.ap-hop-paris.fr)

>>>PNN JournalWatch
* "Drink Plenty of Fluids": A Systematic Review of Evidence for This Recommendation in Acute Respiratory Infections, in BMJ, 2004; 328: 499–500. Reprints: www.bmj.org; M. P. B. Guppy, U. Queensland, Herston, Queensland, Australia.

* Variant Creutzfeldt–Jakob Disease and the Acquired and Transmissible Spongiform Encephalopathies, in
Clinical Infectious Diseases, 2004; 38: 697–704. Reprints: www.journals.uchicago.edu/CID; C. E. Beisel; NIH; Bethesda, Md.

* Early Bactericidal Activity of Moxifloxacin in Treatment of Pulmonary Tuberculosis: A Prospective, Randomized Study, in
Antimicrobial Agents and Chemotherapy, 2004; 48: 780–2. Reprints: aac.asm.org; M, W. R. Pletz, City Hosp. Emil von Behring/Chest Hosp, Heckeshorn, Berlin.

* Aspirin Resistance Is Associated With a High Incidence of Myonecrosis After Non-Urgent Percutaneous Coronary Intervention Despite Clopidogrel Pretreatment, in
Journal of the American College of Cardiology, 2004; 43 (expedited online publication). Reprints: www.cardiosource.com; W-H Chen, U. Hong Kong, Hong Kong, China.

* Low-Carbohydrate–High-Protein Diets: Is There a Place for Them in Clinical Cardiology?, in
Journal of the American College of Cardiology, 2004; 43: 725–30. Reprints: www.cardiosource.com; C. T. Kappagoda, ctkappagoda@ucdavis.edu

* Delaying the Onset of Type 2 Diabetes Mellitus in Patients with Prediabetes, in
Pharmacotherapy, 2004; 24: 362–71. Reprints: www.accp.com; B. K. Irons, brian.irons@ttuhsc.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 2, 2004 Vol. 11, No. 40
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Mar. 2 issue of the Annals of Internal Medicine (www.annals.org; 2004; 140).

Genotyping Guidance for Treatment of Chronic Hepatitis C: Viral genotypes can be used to guide the choice of antiviral agents in treatment of chronic hepatitis C, according to a study of 1,311 patients treated with peginterferon-2a 180 mcg/week plus ribavirin in either low (800 mg/ day) or standard weight-based doses (1,000 or 1,200 mg/day) for 24 or 48 weeks (pp. 346-55). The authors conclude, “Patients with HCV genotype 1 require treatment for 48 weeks and a standard dose of ribavirin; those with HCV genotypes 2 or 3 seem to be adequately treated with a low dose of ribavirin for 24 weeks.” They explain, “Sustained virologic response rates for peginterferon-2a and standard-dose ribavirin for 48 weeks were 63% (CI, 59% to 68%) overall and 52% (CI, 46% to 58%) in patients with HCV genotype 1. In patients with HCV genotypes 2 or 3, the sustained virologic response rates in the 4 treatment groups were not statistically significantly different.” (S. J. Hadziyannis, Henry Dunant Hosp., Athens, Greece; hadziyannis@ath.forthnet.gr)

In a related review article (pp. 370-81), an author explores patient-related factors that can explain failure to respond to interferon-based hepatitis C treatments, including previous relapse or nonresponse to treatment, the presence of cirrhosis, African American ethnicity, older age, contraindications to treatment, and obesity. The potential use in such patients of pegylated interferons is explored. (S. Zeuzem, Saarland U. Hosp., Homburg/Saar, Germany; Zeuzem@uniklinik-saarland.de)

Infectious Disease & Antibacterial Handwashes in the Home: In a primarily Hispanic, northern Manhattan neighborhood, the use of antibacterial products for general cleaning, laundry, and handwashing had no effect on the frequency of infectious disease symptoms, compared with nonantibacterial products (pp. 321-9). The 228 households, all of which included at least one preschool-age child, were randomly assigned to use blinded products for household chores and hygiene. After 48 weeks of observation, the investigators found, “Symptoms were primarily respiratory: During 26.2% (717 of 2736) of household-months, 23.3% (640 of 2737) of household-months, and 10.2% (278 of 2737) of household-months, one or more members of the household had a runny nose, cough, or sore throat, respectively. Fever was present during 11% (301 of 2737) of household-months, vomiting was present in 2.2% (61 of 2737), diarrhea was present in 2.5% (69 of 2737), and boils or conjunctivitis were present in 0.77% (21 of 2737). Differences between intervention and control groups were not significant for any symptoms (all unadjusted and adjusted relative risks included 1.0) or for numbers of symptoms (overall incidence density ratio, 0.96 [95% CI, 0.82 to 1.12]).” (E. Larson, ELL23@Columbia.edu)

>>>PNN NewsWatch
* Illegal diversion and abuse of prescription drugs is the target of a coordinated strategy announced yesterday by the Bush Administration. The President’s National Drug Control Strategy outlines the extent of prescription drug abuse in the United States and new federal programs designed to address the problem. Nonmedical use of narcotic pain relievers, tranquilizers, stimulants, and sedatives ranks second (behind marijuana) as a category of illicit drug abuse among adults and youth, federal officials said, adding that emergency room visits for narcotic analgesic abuse have increased 163% since 1995. Federal initiatives will include more education and training for physicians, increasing state Prescription Monitoring Programs to detect suspicious prescriptions and patients who are “doctor shopping,” and prosecution of Internet pharmacies that provide controlled substances illegally.

*
Increasing use by pregnant women of OTC medications—such as pseudoephedrine, acetaminophen, and ibuprofen—is discussed in today’s Wall Street Journal. An article explains that little information is available for most nonprescription medications about their use during pregnancy, making the standard advice of “ask your doctor” of little value.

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 3, 2004 Vol. 11, No. 41
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Mar. 3 issue of JAMA (www.jama.com; 2004; 291).

Intensive Lipid Lowering with Atorvastatin: In the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial at 34 community and tertiary care centers, progression of coronary atherosclerosis was reduced more with intensive atorvastatin therapy (80 mg daily) than with moderate (40 mg daily) doses of pravastatin (pp. 1071-80). Based on intravascular ultrasound examinations at baseline and after 18 months of treatment in 502 patients, the authors found, “Baseline low-density lipoprotein cholesterol level (mean, 150.2 mg/dL [3.89 mmol/L] in both treatment groups) was reduced to 110 mg/dL (2.85 mmol/L) in the pravastatin group and to 79 mg/dL (2.05 mmol/L) in the atorvastatin group (P < .001). C-reactive protein decreased 5.2% with pravastatin and 36.4% with atorvastatin (P < .001). The primary end point (percentage change in atheroma volume) showed a significantly lower progression rate in the atorvastatin (intensive) group (P = .02). Similar differences between groups were observed for secondary efficacy parameters, including change in total atheroma volume (P = .02), change in percentage atheroma volume (P < .001), and change in atheroma volume in the most severely diseased 10-mm vessel subsegment (P < .01). For the primary end point, progression of coronary atherosclerosis occurred in the pravastatin group (2.7%; 95% confidence interval [CI], 0.2% to 4.7%; P = .001) compared with baseline. Progression did not occur in the atorvastatin group (–0.4%; CI –2.4% to 1.5%; P = .98) compared with baseline.” (S. E. Nissen, Cleveland Clinic Foundation, Cleveland, Ohio; nissens@ccf.org)

An editorialist ponders how far clinicians should go with this evidence on aggressive lipid lowering (pp. 1132-4): “Is this reasoning compelling enough to change clinical practice without the need for a clinical outcome trial...? A policy to use the highest statin doses as standard therapy has implications for cost and potential adverse effects. The vast majority of clinical and research experience is with conventional statin doses, which have provided a deservedly positive view of statin therapy. To put maximal statin therapy, such as with 80 mg of atorvastatin or 40 mg of rosuvastatin, on the same footing of clinical confidence requires results from large long-term clinical trials. Fortunately, several large trials comparing intensive with conventional statin therapy are near completion and results are expected soon.

“Until the results of these studies are available, it is prudent to treat any high-risk patient, as defined by national guidelines, with a statin at an intensity appropriate to achieve the recommended goals for LDL-C. In addition, with this focus on LDL-C reduction, clinicians must not lose sight of the need to manage other established cardiovascular disease risk factors including hypertension and atherogenic dyslipidemia....” (F. M. Sacks, fsacks@hsph.harvard.edu)

Suicidal Ideation Among the Elderly: Primary care interventions—including drug therapy with serotonin selective reuptake inhibitors—can reduce the rates of suicidal ideation among older patients, according to a study of 598 community-dwelling individuals diagnosed with depression (pp. 1081-91). During 12 months of therapy, the 60–74-year-old patients randomly received either care management (citalopram or other antidepressants or interpersonal psychotherapy in those declining medication therapy) or usual care. “At 4 months, in the intervention group, raw rates of suicidal ideation declined 12.9% points (29.4% to 16.5%) compared with 3.0% points (20.1% to 17.1% in usual care [P = .01]),” the researchers report. “Among patients reporting suicidal ideation, resolution of ideation was faster among intervention patients (P = .03); differences peaked at 8 months (70.7% vs 43.9% resolution; P = .005). Intervention patients had a more favorable course of depression in both degree and speed of symptom reduction.... The effects on depression were not significant among patients with minor depression unless suicidal ideation was present.” (C. F. Reynolds III, U. Pittsburgh, Pittsburgh; ReynoldsCF@msx.upmc.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 4, 2004 Vol. 11, No. 42
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Mar. 4 issue of the New England Journal of Medicine (content.nejm.org; 2004; 350).

Treatment of Lupus Nephritis: Short-term intravenous cyclophosphamide followed by maintenance mycophenolate mofetil or azathioprine was more efficacious and safer than long-term therapy with intravenous cyclophosphamide, according to a study of 59 patients with proliferative lupus nephritis (pp. 971-80). Patients randomly received either quarterly intravenous injections of cyclophosphamide 0.5–1.0 g/sq m, oral azathioprine 1–3 mg/kg/day, or oral mycophenolate mofetil 500–3,000 mg/day for 1–3 years. “The 72-month event-free survival rate for the composite end point of death or chronic renal failure was higher in the mycophenolate mofetil and azathioprine groups than in the cyclophosphamide group (P = 0.05 and P = 0.009, respectively),” report the researchers. “The rate of relapse-free survival was higher in the mycophenolate mofetil group than in the cyclophosphamide group (P = 0.02). The incidence of hospitalization, amenorrhea, infections, nausea, and vomiting was significantly lower in the mycophenolate mofetil and azathioprine groups than in the cyclophosphamide group.” (G. Contreras, gcontrer@med.miami.edu)

Editorialists cite several factors that limit the application of these findings to the general population of patients in the U.S. with proliferative lupus nephritis, including racial and ethnic distribution of patients and the lower-than-usual dose of cyclophosphamide in the study (pp. 1044-6). They comment: “The argument for the superior efficacy of azathioprine and mycophenolate mofetil for lupus nephritis emerged only when the authors combined the outcomes of patient survival and renal survival. Moreover, there were no significant differences among the treatment groups in renal survival—a fact that modulates to some degree the authors’ claim that azathioprine and mycophenolate mofetil are superior to cyclophosphamide.... The most reliable take-home message of the study by Contreras et al. is that azathioprine and mycophenolate mofetil are good options for maintenance therapy in patients with proliferative lupus nephritis. Nonetheless, there is clearly a need for further studies, with longer follow-up, conducted in a more broadly representative population of patients....” (J. E. Balow, NIH, Bethesda, Md.)

HRT & Colorectal Cancer: On the heels of this week’s announcement of termination of the estrogen-only arm of the Women’s Health Initiative, data from that trial show a decreased risk but more aggressive nature of colorectal cancer among postmenopausal women while they were taking estrogen plus progestin (pp. 991-1004). The women on dual hormone-replacement therapy had an intact uterus, while those only on estrogens had had hysterectomies. Conjugated equine estrogens 0.625 mg/day plus medroxyprogesterone acetate 2.5 mg/day or placebo, administered to 16,608 women, produced these results: “There were 43 invasive colorectal cancers in the hormone group and 72 in the placebo group (hazard ratio, 0.56; 95 percent confidence interval, 0.38 to 0.81; P = 0.003). The invasive colorectal cancers in the hormone group were similar in histologic features and grade to those in the placebo group but with a greater number of positive lymph nodes (mean ± SD, 3.2 ± 4.1 vs. 0.8 ± 1.7; P = 0.002) and were more advanced (regional or metastatic disease, 76.2 percent vs. 48.5 percent; P = 0.004). In exploratory analyses, women in the hormone group with antecedent vaginal bleeding had colorectal cancers with a greater number of positive nodes than women in the hormone group who did not have vaginal bleeding (3.8 ± 4.3 vs. 0.7 ± 1.5 nodes, P = 0.006).” Because of the more advanced stages of cancers in the HRT group, the authors recommend “wider implementation of bowel screening among postmenopausal women who are using hormone therapy” and conclude that current data do not support use of HRT for lowering risk of colorectal cancer. (R. T. Chlebowski, Harbor–UCLA Res. and Ed. Inst., Torrance, Calif.; rchlebowski@rei.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 5, 2004 Vol. 11, No. 43
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Mar. Pharmacotherapy (www.accp.com; 2004; 24).

Once-Daily Zidovudine: Once-daily administration of zidovudine was less effective than twice-daily doses of the drug in an open-label study of 32 antiretroviral-naive patients with HIV infection (pp. 307-21). Patients received either zidovudine 600 mg every 24 hours or 300 mg every 12 hours for 13 days. While HIV-1 RNA levels were similar between the groups at baseline, a trend toward lower mean reduction in RNA levels was evident by day 14 in the once-daily group, and viral load reduction tended to be slower in the patients taking doses every 24 hours, compared with the 12-hourly group. No differences were observed in safety or tolerability. (P. J. Ruane, Tower ID Med. Assoc., Los Angeles; peter_ ruane@towerid.com)

Darbepoetin Dosing: In both epoetin alfa–naive and –experienced patients, a starting dosage of darbepoetin alfa 200 mcg every 2 weeks is reasonable, conclude researchers who assessed retrospectively the experiences of 330 anemic patients with nonmyeloid malignancies and developed an algorithm based on their data (pp. 313-23). In an effort to confirm the optimal starting dose for darbepoetin, the authors considered hematologic values, patient variables such as weight, and the drug’s usage data. They found, “The proportion of patients receiving a red blood cell transfusion in the darbepoetin alfa treatment phase was low (15% in each group). No variation in transfusion rates was observed across weight categories in patients who received a fixed dosage of darbepoetin alfa. Darbepoetin alfa was well tolerated. A detailed usage algorithm was validated by these results and is being used in ... three US Oncology–affiliated practices.” (W. A. Thames, Southwest Regional Cancer Ctr., Houston; william.thames@usoncology.com)

Computerized Treatment Suggestions: Would the combination of computer-based interventions tied to a sophisticated physician order entry system improved prescribing patterns and outcomes in 712 patients with hypertension? No, according to a study conducted in an academic primary care internal medicine practice (pp. 324-37). Evidence-based suggestions were displayed on computer terminals for physicians while they were writing outpatient orders and pharmacists while prescriptions were being dispensed. Considering whether physicians, pharmacists, both, or neither took action based on the computerized information, the researchers found, “Compliance with suggestions was poor, with treatment suggestions implemented in 25% of patients for whom suggestions were displayed only to pharmacists, 29% of those for whom suggestions were displayed only to physicians, and 35% of the group for whom both physicians and pharmacists received suggestions (p = 0.13 [compared with the patient group for whom no alerts were issued]).” No statistically significant or clinically relevant differences were identified in generic health-related quality of life, symptom and adverse effect profiles, number of emergency department visits and hospitalizations, blood pressure measurements, charges, or drug therapy adherence. (M. D. Murray, Regenstrief Inst., Indianapolis; mmurray@regenstrief.org)

Symptoms & HRQOL in Hypertension: For patients with hypertension, health-related quality of life is affected by symptoms more than by patient characteristics, blood pressure, or drug-related factors, conclude authors of a survey and chart review of 125 patients (pp. 344-50). Using scores on the Physical and Mental Component Summaries of the Short Form 36, the investigators made these observations, “Higher symptom counts and symptom distress scores were strongly associated with lower HRQOL scores in multivariate models, with standardized coefficients from –0.62 to –0.41. These were greater in magnitude than any other predictor, including demographic information (age, sex, race, educational level, income), disease variables (blood pressure, years of hypertension), and drug treatment (number of antihypertensive drugs and duration of regimen).” (S. R. Erickson, serick@umich.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 8, 2004 Vol. 11, No. 44
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
Mar. 6 issue of Lancet (www.thelancet.com; 2004; 363).

Angiogenesis After MI: Intracoronary infusion of peripheral blood stem cells mobilized by granulocyte colony-stimulating factor provided apparent angiogenesis in 27 patients undergoing stent placement after myocardial infarction (pp. 751-6). However, an increase in the restenosis rate prompted investigators to terminate the study early. Patients received either G-CSF followed by PBSC infusion, G-CSF alone, or neither. Exercise capacity, myocardial infusion, and systolic function at 6 months were all significantly improved in patients who received PBSC infusions, compared with baseline. At the point the study was stopped, five of seven cell-infusion patients and two of three G-CSF patients had had in-stent restenosis. The investigators conclude, “Despite the favourable effects on cardiac function, however, our data warrant a more cautious approach to stem-cell therapy, in view of the possible aggravation of restenosis.” (H-S Kim, Seoul Natl. U. Hosp., Seoul, Korea; hyosoo@snu.ac.kr)

Statins for Cerebrovascular Disease: Simvastatin 40 mg daily reduced the rate of ischemic but not hemorrhagic strokes and appeared beneficial in patients with pre-existing cerebrovascular disease but no evidence of coronary disease (pp. 757-67). Among more than 20,000 patients in the Heart Protection Study, 3,280 adults had cerebrovascular disease. Compared with placebo, simvastatin therapy reduced the first-event stroke rate by 25% (4.3% and 5.7% of the respective groups), the percentage of patients with transient ischemic attacks (2.0% and 2.4%), and the number of individuals requiring carotid endarterectomy or angioplasty (0.4% and 0.8%). Reductions in stroke rates were the results of fewer ischemic strokes and became significant by the end of the second year of treatment; the frequency of hemorrhagic strokes was unchanged. “Given that stroke is one of the major causes of mortality and major morbidity worldwide, these findings indicate that statin therapy should now be considered routinely for all patients at high risk of stroke, irrespective of their initial cholesterol concentrations or the presence of coronary disease,” conclude the authors. (Heart Protection Study, Radcliffe Infirmary, Oxford, U.K.; hps@ctsu.ox.ac.uk)

tPA Treatment of Early Stroke: Prompt administration of recombinant tissue plasminogen activator is important in patients with early stroke, according to authors who combined data from six trials in an effort to define the optimal timeframe for thrombolysis (pp. 768-74). Odds of a favorable 3-month outcome decreased as the time between symptom onset and rt-PA administration increased: 2.8 for 0–90 minutes, 1.6 for 91–180 minutes, 1.4 for 181–270 minutes, and 1.2 (not significant) for 271–360 minutes. “An acute stroke intervention team can increase the speed and quality of assessment given to a stroke patient before treatment and after arrival in an emergency department,” note the authors. “We urge setting a target of 1 h from time of presentation to intravenous treatment for patients with acute ischaemic stroke. This goal could be a challenge for many institutions and might need reorganisation of resources, but it can be achieved.” (J. R. Marler, marlerj@ninds.nih.gov)

>>>PNN JournalWatch
* Retraction of an Interpretation [regarding MMR vaccine], in Lancet, 2004; 363: 750. Reprints: www.thelancet.com; S. H. Murch, Royal Free Med. Sch., London; s.murch@rfc.ucl.ac.uk

* Use of Lithium and the Risk of Injurious Motor Vehicle Crash in Elderly Adults: Case-Control Study Nested Within a Cohort, in
BMJ, 2004; 328: 558–9. Reprints: www.bmj.org; S. Suissa, McGill U., West Montreal, Quebec; samy.suissa@clinepi.mcgill.ca

* Lower Risk for Tardive Dyskinesia Associated With Second-Generation Antipsychotics: A Systematic Review of 1-Year Studies, in
American Journal of Psychiatry, 2004; 161: 414–25. Reprints: ajp.psychiatryonline.org; C. U. Correll.

* Mania During Treatment of Chronic Hepatitis C with Pegylated Interferon and Ribavirin, in
American Journal of Psychiatry, 2004; 161: 429–35. Reprints: ajp.psychiatryonline.org; C. U. Onyike.

* Teen Home Pregnancy Test Takers: More Worried or More Wishful?, in
Pediatrics, 2004; 113: 581–4. Reprints: www.pediatrics.org; L. Kelly, U. Colorado, 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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 9, 2004 Vol. 11, No. 45
Providing news and information about medications and their proper use

>>>NEJM Report
Source:
Article and editorial released early on New England Journal of Medicine Web site (content.nejm.org; 2004; 350).

Intensive Statin Therapy: In a comparison of pravastatin 40 mg/day and atorvastatin 80 mg/day, patients with recent acute coronary syndromes did significantly better on the more intensive regimen. Median LDL cholesterol levels were 95 mg/dL and 62 mg/dL in the two respective groups, and the percentages of patients reaching a composite endpoint of all-cause death, myocardial infarction, documented unstable angina requiring hospitalization, revascularization, and/or stroke were 26.3% and 22.4%, respectively. Based on these findings in 4,162 patients, the authors conclude, “The National Cholesterol Education Program and European guidelines currently recommend that the goal of treatment in patients with established coronary artery disease should be an LDL cholesterol level of less than 100 mg per deciliter. Although our data provide support for the use of this approach, given the substantially lower LDL cholesterol levels achieved in the group given 80 mg of atorvastatin daily..., our results suggest that after an acute coronary syndrome, the target LDL cholesterol level may be lower than that recommended in the current guidelines.” (C. P. Cannon, Brigham and Women’s Hosp., Boston; cpcannon@partners.org.)

An editorialist predicts that intensive statin therapy will produce a “sea change in cardiovascular prevention”: “The proportional reduction in major clinical outcomes that results from aggressive statin therapy is of the same order of magnitude as that seen when statins were compared with placebo in controlled trials. Intensive therapy with statins, monitored by means of measurements of LDL cholesterol or biologic markers of inflammation, is likely to result in even greater steps toward actualizing the full benefit of this remarkable class of medicines.” (E. J. Topol, Cleveland Clinic Foundation, Cleveland; topole@ccf.org)

>>>Internal Medicine Report
Source:
Mar. 8 issue of Archives of Internal Medicine (www.archinternmed.com; 2004; 164).

Sildenafil Use in HF: Sildenafil can be safely used to treat erectile dysfunction in men who also have heart failure in NYHA classes II and III, according to a 35-patient, 12-week, placebo-controlled, crossover trial (pp. 514-20). Patients in the study had chronic ED and no myocardial ischemia or use of nitrates. Their ambulatory blood pressure was measured in a clinic for 4 hours following a single 50-mg dose of sildenafil, and quality of life and depressive symptoms were assessed using the Minnesota Living With Heart Failure Questionnaire, the Beck Depression Index, and the Center for Epidemiological Studies–Depression Scale. “Sildenafil caused a mean ± SEM asymptomatic decrease in blood pressure of 6 ± 3 mm Hg, and no patient experienced symptomatic hypotension or other significant adverse effects,” the authors report. “Sildenafil improved the International Index for Erectile Function (P<.001) and both sets of depression scores. The Living With Heart Failure Questionnaire index also improved with sildenafil (P = .02).” Assuming the patients have adequate physical fitness for sexual activity and no other contraindications for sildenafil use, the drug provides an alternative to “invasive solutions of the past,” the authors conclude. (S. L. Archer, U. Alberta, Edmonton, Alberta, Canada; sarcher@cha.ab.ca)

ADEs Following Institutional Transfers: Medication changes during transfers between acute-care institutions and long-term care facilities are a common cause of adverse drug events, according to a study of four nursing homes and two academic hospitals (pp. 545-50). An average of 3.1 and 1.4 medication changes were made during each hospital and nursing home admission, respectively. ADEs attributable to the medication change occurred during 20% of 71 bidirectional transfers. Most medication changes were made in the hospitals, but most ADEs occurred in the nursing homes. (K. Boockvar, Mt. Sinai Sch. of Med., New York City; kenneth.boockvar@mssm.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 10, 2004 Vol. 11, No. 46
Providing news and information about medications and their proper use

>>>Cinacalcet Approved for Hyperparathyroidism
The first oral calcimimetic agent, cinacalcet hydrochloride (Sensipar, Amgen) has been approved for marketing in the U.S. by FDA. It is indicated for treatment of secondary hyperparathyroidism in chronic kidney disease patients on dialysis and treatment of hypercalcemia in patients with parathyroid carcinoma.

Occurring in nearly all of more than 300,000 U.S. dialysis patients, secondary HPT produces abnormal calcium and phosphorus levels, and these can lead to calcium deposition at various body sites, producing serious consequences such as bone disease, bone pain and fractures, and vascular and soft tissue calcifications that can produce cardiovascular morbidity.

In three 6-month clinical trials of more than 1,100 patients with chronic kidney disease receiving dialysis, 40% of cinacalcet patients and 5% of placebo patients receiving standard of care achieved parathyroid hormone levels of 250 pg/mL or less in the primary efficacy analysis. Secondary efficacy parameters also improved in patients treated with cinacalcet, including lowering of calcium– phosphorus ion product, calcium, and phosphorus levels. Reductions in PTH and the calcium–phosphorus product were maintained during up to 12 months of treatment.

The most commonly reported adverse effects were nausea and vomiting, which occurred in 31% and 27%, respectively, of cinacalcet-treated patients, compared with 19% and 15%, respectively, of patients who received placebo. Treatment of patients with chronic kidney disease with cinacalcet was associated with development of low serum calcium levels in a significant number of patients. Frequent monitoring of patients’ calcium levels is therefore recommended in the cinacalcet labeling, and treatment should not be initiated if patients’ initial calcium level is less than 8.4 mg/dL.

>>>JAMA Highlights
Source:
Mar. 10 issue of JAMA (www.jama.com; 2004; 291).

Fever in Early Infancy: Pediatricians performed well in recognizing and treating bacteremia and bacterial meningitis in 3,066 infants aged 3 months or younger who presented with fever over a 3-year period at the offices of 573 practitioners in a pediatric research network (pp. 1203-12). Even though the clinicians followed current guidelines in just 42% of cases, they treated 61 of 63 cases of bacteremia/bacterial meningitis with antibiotics at the first visit. In fact, individualized clinical judgment was just as accurate as current guidelines and a model developed for this study, and use of the latter two approaches would have resulted in more hospitalizations and laboratory tests. “The findings suggest that if close follow-up care is attainable, the management of selected cases by experienced clinicians using clinical judgment may be more appropriate than strict adherence to published recommendations, with the potential benefit of reducing considerable costs and iatrogenic morbidity,” the authors conclude. “While guidelines have an important role in ensuring the quality of care for many clinical issues, their performance in complex clinical situations, such as the management of febrile illnesses, should be analyzed to evaluate whether the guidelines actually optimize care.” (R. H. Pantell, pantell@itsa.ucsf.edu)

Coffee & DM: Coffee consumption was inversely related with risks of developing type 2 diabetes mellitus in a study conducted in 6,974 Finnish men and 7,655 Finnish women without history of stroke, coronary artery disease, or DM at baseline in 1982 (pp. 1213-9). Hazard ratios declined in both sexes as coffee consumption increased, reaching 0.21 for women and 0.45 for men who drank 10 cups daily. The relationship held when patients were stratified by age, smoking status, weight, alcohol consumption, and use of filtered and nonfiltered coffee. The authors note that several coffee constituents have effects on glucose regulation, possibly explaining the otherwise intriguing relationship (e.g., chlorogenic acid affects glucose-6-phosphatase, polyphenols affect alpha-glucosidase, caffeine affects insulin secretion). (J. Tuomilehto, National Public Health Inst., Helsinki, Finland; jaakko.tuomilehto@ktl.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 11, 2004 Vol. 11, No. 47
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Mar. 11 issue of the New England Journal of Medicine (content.nejm.org; 2004; 350).

Exemestane in Breast Cancer: Replacing tamoxifen with exemestane about halfway through 5 years of postsurgical adjuvant treatment produced superior results in 4,742 postmenopausal women with primary, estrogen-receptor–positive breast cancer (pp. 1081-92). After 2–3 years of tamoxifen therapy, women in the trial were randomly assigned to continue tamoxifen therapy or be switched to exemestane. Assessing disease-free survival as a primary endpoint, the authors found, “After a median follow-up of 30.6 months, 449 first events (local or metastatic recurrence, contralateral breast cancer, or death) were reported—183 in the exemestane group and 266 in the tamoxifen group. The unadjusted hazard ratio in the exemestane group as compared with the tamoxifen group was 0.68 (95 percent confidence interval, 0.56 to 0.82; P < 0.001 by the log-rank test), representing a 32 percent reduction in risk and corresponding to an absolute benefit in terms of disease-free survival of 4.7 percent (95 percent confidence interval, 2.6 to 6.8) at three years after randomization. Overall survival was not significantly different in the two groups, with 93 deaths occurring in the exemestane group and 106 in the tamoxifen group. Severe toxic effects of exemestane were rare. Contralateral breast cancer occurred in 20 patients in the tamoxifen group and 9 in the exemestane group (P = 0.04).”

The researchers conclude, “Our results add to the evidence that the sequential use of aromatase inactivators and tamoxifen provides additional options for improving adjuvant endocrine therapy for postmenopausal women with hormone-responsive primary breast cancer. Our results indicate that five years of tamoxifen monotherapy after surgery may be suboptimal for postmenopausal patients with estrogen-receptor–positive breast cancer and suggest that clinicians should consider switching patients to exemestane between two and three years after the start of tamoxifen therapy.” (R. C. Coombes, Imperial College, Hammersmith Hosp., London)

Noting that the above study was, like others before it, terminated early because of positive results, an editorialist discusses the quandary this creates in determining how long therapy should be administered (pp. 1140-2). For the present, the writer advises, “Considering these three important trials, what should clinicians do? Many more years will be required to fine-tune the risk–benefit assessment of adjuvant aromatase inhibitors, but the use of these agents should be discussed with patients who are suitable candidates, and they should be informed about the limitations of the current data. In my opinion, women whose risk of recurrence is high are reasonable candidates for the inclusion of an aromatase inhibitor in plans for adjuvant treatment, whereas women with a low risk of recurrence might give more weight to long-term safety and be better served by tamoxifen therapy.”(M. J. Piccart-Gebhart, Jules Bordet Inst., Brussels, Belgium)

CGRP Antagonist Treatment of Migraine: An investigational antagonist of the calcitonin gene–related peptide (CGRP) was effective in treating 126 patients with migraine in a placebo-controlled, proof of concept trial (pp. 1104-10). CGRP may play a causative role in migraine, and BIBN 4096 B is a highly specific and potent nonpeptide CGRP-receptor antagonist. Over a period of 10 minutes, patients received placebo or one of six doses of BIBN 4096 BS. With the investigational agent, the authors explain, “significant superiority over placebo was ... observed with respect to most secondary end points: the pain-free rate at 2 hours; the rate of sustained response over a period of 24 hours; the rate of recurrence of headache; improvement in nausea, photophobia, phonophobia, and functional capacity; and the time to meaningful relief.” Overall, 60% of patients receiving active drug responded, with the best response (66%) noted with the 2.5 mg dose. (J. Olesen, Glostrup Hosp., Copenhagen, Denmark; jeol@glostruphosp.kbhamt.dk)

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 12, 2004 Vol. 11, No. 48
Providing news and information about medications and their proper use

>>>Chest Highlights
Source:
Mar. issue of Chest (www.chestjournal.org; 2004; 125).

Bleeding with UFH or LWMH in Renal Dysfunction: Major bleeding episodes are increased with both unfractionated heparin and the low-molecular-weight heparin enoxaparin when these agents are used in full doses in patients with renal dysfunction, according to a retrospective 620-patient analysis (pp. 856-63). Major and minor bleeding rates were calculated for all patients with renal insufficiency (estimated glomerular filtration rates less than 60 mL/min) who were hospitalized over a 13-month period. The authors found, “Major bleeding rates were 26.3 per 1,000 person-days for UFH and 20.7 per 1,000 person-days for enoxaparin. Major bleeding complications were similarly increased for both UFH and enoxaparin therapy across categories of worsening renal insufficiency. Patients with severe renal insufficiency while receiving enoxaparin had a 154% excess incidence of minor bleeding compared to those receiving UFH (incidence ratio, 2.54; 95% confidence interval, 1.01 to 6.36). Worsening renal insufficiency, female gender, and prolonged duration of anticoagulation therapy emerged as the main determinants for bleeding complications.” Based on these findings, the researchers recommend caution when anticoagulation therapy is used in patients with renal insufficiency. (C. A. Manthous, Bridgeport Hosp., Bridgeport, Conn.; pcmant@bpthosp.org)

Asthma Treatment Preferences: Patients with asthma have particular preferences for their medication therapy, and they are willing to pay more to have their preferred products, according a survey of 298 adult Swedish patients (pp. 916-23). A conjoint analysis indicated that patients perceived the most important aspect of therapy to be the number of symptom-free days they enjoyed, and 40% of patients reported having 15 or fewer SFDs per month. Patients were dissatisfied with the current treatments: 85% preferred another agent or product, and 78% of preferred treatments were not covered by current treatment guidelines. “A total of 148 patients (50%) preferred a combination inhaler to separate inhalers, and 233 patients (78%) preferred a reliever that is both rapid and long acting,” write the authors. “The most preferred treatment was a combination inhaler for maintenance and reliever use. On average, the patients were willing to pay an additional 328 Swedish krona [US $36] per month for the change to the preferred treatment.” (G. Johansson, Uppsala U., Uppsala, Sweden; gunnar.johansson@lul.se)

Differing Patterns of Vascular Dysfunction: The types of vascular dysfunction produced by smoking, uncontrolled hypertension, and type 2 diabetes mellitus have similarities but also important differences, according to a study of 100 patients (pp. 823-30). Endothelium-dependent, nitric oxide flow-mediated vasodilatation was impaired in all three groups, compared with control patients. Smokers had a normal endothelium-independent function induced by glyceryl trinitrate (an NO donor), but patients with DM and HTN had impaired endothelium-independent responses. (H. Moreno, State U. Campinas, São Paulo, Brazil; hmoreno@uol.com.br)

>>>Infectious Disease Report
Source:
Mar. 15 issue of Clinical Infectious Diseases (www.journals.uchicago.edu/CID; 2004; 38).

Amphetamines & HIV: Increasing use of the recreational drug crystal methamphetamine presents new challenges to clinicians managing patients with HIV infections, write authors of a review article (pp. 890-4). In addition to increasing unsafe sex practices, methamphetamine abuse can also produce several medical (hypertension, hyperthermia, rhabdomyolysis, stroke) and psychiatric (paranoia, auditory hallucinations, occasional violent behavior) morbidities. Amphetamine withdrawal can also produce depression. One patient died after taking methamphetamine with HIV medications, and two fatalities involved combining HIV medications with another drug of abuse in the amphetamine group, ecstasy. (A. Urbina, N. Y. Med. Coll., 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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 15, 2004 Vol. 11, No. 49
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Mar. 13 issue of BMJ (www.bmj.org; 2004; 328).

End-of-Life Care in the U.S.: In American hospitals with strong reputations for high quality care in managing chronic illness, striking variations were observed in end-of-life care, according to an analysis of health care resource use (pp. 607 ff). Focusing on 77 hospitals named in 2001 as “best hospitals” for cardiac and pulmonary disorders, cancer, and geriatrics services by US News and World Report, investigators report, “Extensive variation in each measure existed among the 77 hospital cohorts. Days in hospital per decedent ranged from 9.4 to 27.1 (interquartile range 11.6–16.1); days in intensive care units ranged from 1.6 to 9.5 (2.6–4.5); number of physician visits ranged from 17.6 to 76.2 (25.5–39.5); percentage of patients seeing 10 or more physicians ranged from 16.9% to 58.5% (29.4–43.4%); and hospice enrolment ranged from 10.8% to 43.8% (22.0–32.0%). The percentage of deaths occurring in hospital ranged from 15.9% to 55.6% (35.4–43.1%), and the percentage of deaths associated with a stay in intensive care ranged from 8.4% to 36.8% (20.2–27.1%).” (J. E. Wennberg, john.wennberg@ Dartmouth.edu)

An editorialist attempts to identify reasons and rationales for such variations in hospitals on both sides of the Atlantic Ocean (pp. 610 ff): “Perhaps the most important lesson arising from the study is that if real change in the way health systems function is to occur then far greater attention must be given to the way clinicians operate and manage resources throughout the care pathway. Improving the micromanagement of chronic illness through integrated care pathways and ‘whole systems’ thinking demands that health and social care services work together with and in the interests of patients. We have struggled with these issues for decades with limited effect. In contrast to some other European countries, Britain is still some way from reaching the promised land of integrated care. Wennberg and colleagues provide some critical insights into why.” (D. J. Hunter, U. Durham, Stockton on Tees, U.K.; d.j.hunter@durham.ac.uk)

Intrathecal Antitetanus Ig: The intrathecal route may be preferred over intramuscular injection for patients being treated with antitetanus immunoglobulin, according to a 120-patient study (pp. 615 ff). Those treated for tetanus intrathecally had lower durations of spasms, shorter hospital stays, and required fewer days of respiratory assistance, compared with those treated i.m. (D. B. Miranda-Filho, Recife, Brazil; demofilho@uol.com.br)

>>>PNN JournalWatch
* Relative Rates of Non-Pneumonic SARS Coronavirus Infection and SARS Coronavirus Pneumonia, in Lancet, 2004; 363: 841–5. Reprints: www.thelancet.com; K-y Yuen, Queen Mary Hosp., Hong Kong; kyyuen@hkucc.hku.hk

* Hepatitis B Virus Infection—Natural History and Clinical Consequences, in
New England Journal of Medicine, 2004; 350: 1118–29. Reprints: content. nejm.org; A. M. Prince, New York Blood Ctr., New York City; aprince@nybloodcenter.org

*
Rickettsia parkeri: A Newly Recognized Cause of Spotted Fever Rickettsiosis in the United States, in Clinical Infectious Diseases, 2004; 38: 805–11. Reprints: www.journals.uchicago.edu/ CID; C. D. Paddock, cpaddock@cdc.gov

* Clinical Relevance of Bacteriostatic versus Bactericidal Mechanisms of Action in the Treatment of Gram-Positive Bacterial Infections, in
Clinical Infectious Diseases, 2004; 38: 864–70. Reprints: www.journals.uchicago.edu/ CID; G. A. Pankey, Ochsner Clinic Foundation, New Orleans; gpankey@ochsner.org

* Primary Prevention of Sudden Cardiac Death: The Time of Your Life, in
Circulation, 2004; 109: 1073–5. Reprints: circ.ahajournals.org; E. N. Prystowsky.

* Dental Disease, Coronary Heart Disease and Stroke, and Inflammatory Markers: What Are the Associations, and What Do They Mean?, in
Circulation, 2004; 109: 1076–8. Reprints: circ.ahajournals.org; G. D.O. Lowe.

* Acute Asthma in Adults: A Review, in
Chest, 2004; 125: 1081–102. Reprints: www.chestjournal.org; G. J. Rodrigo, Hosp. Central de las Fuerzas Armadas, Montevideo, Uruguay; gurodrig@adinet.com.uy

* New Drugs of 2003, in
Journal of the American Pharmacists Association, 2004; 44: 168–210. Reprints: www.japha.org; D. A. Hussar, d.hussar@usip.edu

* New OTC Drugs and Devices 2003: A Selective Review, in
Journal of the American Pharmacists Association, 2004; 44: 211–25. Reprints: www.japha.org; N. G. Popovich, nickp@uic.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 16, 2004 Vol. 11, No. 50
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Mar. 16 issue of the Annals of Internal Medicine (www.annals.org; 2004; 140).

Nicotine-Replacement Therapy: A study of 299 smokers found that after 6 months, those who used a nicotine nasal spray and those who used a skin patch quit at about the same rate—12% percent of those using the spray and 15% of those using the patch (pp. 426-33). However, smokers who were highly dependent on nicotine, obese, and nonwhite achieved higher abstinence rates with the spray, while low to moderately nicotine dependent, nonobese, and white smokers achieved higher abstinence rates with the patch. Thus, ethnicity, weight, and level of nicotine dependence may help identify smokers who will do well with one form of nicotine replacement therapy or another. These findings require confirmation in larger studies. (C. Lerman, U. Penn. Transdisciplinary Tobacco Use Research Ctr., Philadelphia)

Mupirocin Prophylaxis: Routine culture for Staphylococcus aureus nasal carriage on hospital admission and mupirocin application failed to reduce nosocomial infections, report authors of a study of 1,602 carriers (pp. 419-25). At four hospitals, nonsurgical patients were routinely cultured, and carriers of S. aureus randomly received either mupirocin 2% nasal ointment or placebo. “The mupirocin and placebo groups did not statistically differ in the rates of nosocomial S. aureus infections (mupirocin, 2.6%; placebo, 2.8%; risk difference, 0.2 percentage point [95% CI, –1.5 to 1.9 percentage points]), mortality (mupirocin, 3.0%; placebo, 2.8%; risk difference, –0.2 percentage point [CI, –1.9 to 1.5 percentage points]), or duration of hospitalization (median for both, 8 days),” report the authors. “However, time to nosocomial S. aureus infection was decreased in the mupirocin group from 12 to 25 days (P > 0.2). A total of 77% of S. aureus nosocomial infections were endogenous.” (H. F. L. Wertheim, Erasmus Med. Ctr., Rotterdam, the Netherlands; h.wertheim@erasmusmc.nl)

Editorialists call for new approaches in limiting the nosocomial spread of
S. aureus (pp. 484-5): “ How should we interpret the results of Wertheim and colleagues’ study in the context of previous research on intranasal mupirocin? Previous studies indicate that the only patients who are likely to benefit are those with S. aureus nasal colonization. The evidence from this study convinces us that general inpatient populations, even if screened and selected for colonization, do not benefit from this intervention. Whether mupirocin, perhaps in a repetitive dosing regimen, would be effective for selected, nonsurgical patients with identifiable risk factors in addition to colonization remains to be seen. In the meantime, we need to test other approaches and new strategies to prevent nosocomial S. aureus infections.” (H. F. Chambers III, San Francisco General Hosp., San Francisco)

Disclosure of Medical Errors: A study of how people react to descriptions of a patient and a medical mistake found that full disclosure of the error improved patients’ trust and satisfaction with their physicians but did not necessarily affect their feelings about seeking legal advice (pp. 409-18). Researchers studied responses of 958 adults who returned a survey containing a scenario that described a medical error and asked the subject to state whether he or she would seek legal advice. Each participant received one of eight scenarios, which differed in the type of error, its severity, and the completeness of error disclosure. Full disclosure neither increased nor decreased the likelihood that a patient would agree that they would seek legal advice. (K. M. Mazor, Meyers Primary Care Inst., Worcester, Mass.)

Editorialists agree with this study’s conclusions, noting that a poorly done apology “can make things worse” (pp. 482-4): “This study indicates the potential value to be gained if lawyers, physicians, and patients talk together about these difficult issues. While discussion may not solve the ‘malpractice crisis,’ it may shed some light on the enormous potential power of a few well-chosen, well-delivered, and well-timed words.” (D. N. Frenkel, U. Penn. Law School, Philadelphia; dfrenkel@law.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 17, 2004 Vol. 11, No. 51
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Mar. 17 issue of JAMA (www.jama.com; 2004; 291).

Transdermal Patient-Controlled Analgesia: Use of a transdermal patch to deliver fentanyl was found to be equivalent to morphine delivered by an intravenous pump for controlling pain following surgery in a study 636 adult patients (pp. 1333-41). The fentanyl patch was an investigational patient-controlled iontophoretic transdermal system, and it was compared with a standard intravenous morphine patient-controlled pump. During the first 72 hours after surgery, the authors found, “Ratings of good or excellent after 24 hours of treatment for the method of pain control were given by 73.7% of patients (233/316) who used transdermal fentanyl PCA and 76.9% of patients (246/320) who used intravenous morphine PCA; treatment difference was –3.2% (95% confidence interval, –9.9% to 3.5%; P = .36). Early patient discontinuations (25.9% fentanyl vs 25.0% morphine; P = .78) and last pain intensity scores (32.7 fentanyl vs 31.1 morphine on the [visual analogue scale]; P = .45) were not different between the 2 treatments. With continued treatment for up to 48 or 72 hours, more than 80% of patient assessments in each treatment group were good or excellent. The incidence of opioid-related adverse events was similar between the groups.” (E. R. Viscusi, Thomas Jefferson U., Philadelphia; eugene.viscusi@jefferson.edu)

Prehospital Fluid Therapy for Hypotension and Brain Injury: Administered before arrival at the hospital, hypertonic saline solutions produced outcomes similar to those of conventional fluids in 226 patients with hypotension and severe traumatic brain injury (pp. 1350-7). Control patients received 250 mL of Ringer’s lactate solution, and neurologic function of those individuals was compared with that of intervention patients, who were given a rapid intravenous infusion of 250 mL of 7.5% sodium chloride injection. Proportions of patients surviving to hospital discharge and to 6 months were similar in the two groups (55% for hypertonic saline at both time points, and 50% and 47%, respectively, for Ringer’s lactate). Neurologic outcomes and the fraction of good outcome survivors were likewise not significantly different. (D. J. Cooper, Alfred Hosp., Melbourne, Victoria, Australia; j.cooper@alfred.org.au)

An editorialist agrees that these data do not bode well for hypertonic saline (HTS) therapy but encourages further research (pp. 1382-4): “The strategy of initial HTS followed by standard fluid resuscitation practices does not appear to substantially improve long-term neurological outcome for patients with severe blunt head injury and posttraumatic hypotension. However, it would be premature to abandon prehospital research with HTS. To build on the work of Cooper et al and others, future studies should be larger in size and should evaluate ‘pure’ HTS-based or HTS-dextran–based strategies, with the goal of determining if a larger or more prolonged effect on [intracranial pressure] and cerebral perfusion pressure can be achieved with an attendant improvement in neurological outcome, and if the small difference in survival noted in the current study can be established as a real treatment effect rather than a random fluctuation of small numbers. Until then, routine use of HTS for resuscitation of patients with hypotension and traumatic brain injury should be reconsidered.” (R. J. Lewis, Harbor–U. Calif. Los Angeles Med. Ctr., Torrance, Calif; roger@emedharbor.edu)

Discharge Planning for HF: Comprehensive discharge planning combined with postdischarge support can significantly lower readmission rates and may improve outcomes in patients with congestive heart failure, conclude authors of a meta-analysis of 18 studies (pp. 1358-67). A statistical trend toward lower all-cause mortality and significant improvements in quality of life scores were identified, and the interventions can be delivered at no increase in health care costs, the authors note. In fact, cost savings perhaps can be realized as a result of the averted medical costs associated with improved care. (C. O. Phillips, Brigham and Women’s Hosp., Boston;chr_phi@yahoo.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 18, 2004 Vol. 11, No. 52
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Mar. 18 issue of New England Journal of Medicine (content.nejm.org; 2004; 350).

Long-term Alendronate Therapy: Alendronate is safe and effective when used for 10 years, conclude investigators in a study of 247 women (pp. 1189-99). Randomized grouping and blinding were maintained throughout four phases of the study, which included placebo arms and used drug doses of 5, 10, and 20 mg daily. The authors report, “Treatment with 10 mg of alendronate daily for 10 years produced mean increases in bone mineral density of 13.7 percent at the lumbar spine (95 percent confidence interval, 12.0 to 15.5 percent), 10.3 percent at the trochanter (95 percent confidence interval, 8.1 to 12.4 percent), 5.4 percent at the femoral neck (95 percent confidence interval, 3.5 to 7.4 percent), and 6.7 percent at the total proximal femur (95 percent confidence interval, 4.4 to 9.1 percent) as compared with base-line values; smaller gains occurred in the group given 5 mg daily. The discontinuation of alendronate resulted in a gradual loss of effect, as measured by bone density and biochemical markers of bone remodeling. Safety data, including fractures and stature, did not suggest that prolonged treatment resulted in any loss of benefit.” (H. G. Bone, Michigan Bone and Mineral Clinic, Detroit)

Despite this evidence, the author of a perspective article questions how much is really known about appropriate duration of alendronate therapy (pp. 1172-4): “Does a decrease in bone mineral density after the discontinuation of alendronate therapy, which is likely to reflect a decrease in mineralization rather than a decrease in bone mass, imply an increase in the risk of fracture? Could alendronate treatment be stopped after 10 or more years with persistent protection against fractures? Better data regarding the relative risk of fracture associated with continued treatment as compared with the discontinuation of treatment will be required for good clinical decision making.” (G. J. Strewler, Harvard Med. Sch., Boston)

Chemotherapy & Pancreatic Cancer: Adjuvant fluorouracil was beneficial but adjuvant chemoradiotherapy deleterious in a trial conducted in 289 patients with resected pancreatic ductal adenocarcinoma (pp. 1200-10). Four patient groups were studied: observation only, chemoradiotherapy (20 Gy over a 2-week period plus fluorouracil), fluorouracil only, and both chemotherapy and radiotherapy. After a median follow-up of 47 months, 82% of the patients had died. “The estimated five-year survival rate was 10 percent among patients assigned to receive chemoradiotherapy and 20 percent among patients who did not receive chemoradiotherapy (P=0.05),” write the authors. “The five-year survival rate was 21 percent among patients who received chemotherapy and 8 percent among patients who did not receive chemotherapy (P=0.009). The benefit of chemotherapy persisted after adjustment for major prognostic factors.” The researchers conclude that standard care for patients with resectable pancreatic cancer “should consist of curative surgery followed by adjuvant systemic chemotherapy.” (J. P. Neoptolemos, Liverpool U., Liverpool, U.K.)

The outlook is improving for patients with pancreatic cancer, notes an editorialist (pp. 1249-51): “As ... studies [such as this one] evolve, promising new therapies will certainly make their way into adjuvant-therapy trials. In the future, decisions about adjuvant therapy will probably be influenced by improved methods for the assessment of the risk of recurrence, by the availability of more accurate surgical staging methods, and by the application of molecular diagnostic techniques. Many remain hopeful that advances in systemic and locoregional therapies, along with improvements in risk assessment and early detection of pancreatic cancer, will result in an optimism heretofore not seen among patients and physicians concerned with this disease.” (M. A. Choti, Johns Hopkins Hosp., Baltimore; mchoti@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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 19, 2004 Vol. 11, No. 53
Providing news and information about medications and their proper use

>>>Kidney Disease Update
Source:
Mar. issue of the American Journal of Kidney Diseases (www.ajkd.org; 2004; 43).

LMWHs & Renal Failure: Anticoagulant effects of fixed doses of low molecular weight heparins are unpredictable in patients with advanced chronic kidney disease, according to a systematic case review (pp. 531-7). At a U.K. hospital during July 2002 through March 2003, 10 patients had an adverse incident while on LMWHs. The authors write, “Five patients were on maintenance hemodialysis therapy, and 1 patient was on continuous ambulatory peritoneal dialysis therapy. Three patients had calculated creatinine clearances of 5, 11, and 33 mL/min (0.08, 0.18, and 0.55 mL/s), and 1 patient had an estimated glomerular filtration rate of 12 mL/min. Age range was 45 to 89 years. Indications for anticoagulation were suspected pulmonary embolism (1 patient), acute coronary syndrome (7 patients), severe nephrotic syndrome (1 patient), and postoperative venous thromboembolic prophylaxis (1 patient). Three patients also were administered aspirin; 1 patient, clopidogrel; and 3 patients, aspirin and clopidogrel. LMWHs used were enoxaparin (6 patients), tinzaparin (3 patients), and dalteparin sodium (1 patient). Bleeding sources were retroperitoneal (1 patient), spontaneous soft tissue (3 patients), gastrointestinal (2 patients), dialysis catheter and cannula sites (2 patients), hemorrhagic pericardial effusion (1 patient), and intracranial (1 patient). Activated partial thromboplastin time was prolonged in 7 of 10 patients, with no other identifiable cause found. Three patients died despite aggressive resuscitation, including packed red blood cell infusions and protamine sulfate administration.... The approximate incidence of major hemorrhagic events in patients with chronic kidney disease of 7.8%.” (G. N. Wood, Hope Hosp., Salford, U.K.; grahame.wood@srht.nhs.uk)

>>>Pediatrics Highlights
Source:
Mar. issue of Pediatrics (www.pediatrics.org; 2004; 113).

Breakthrough Chickenpox:
Adding further evidence to the need for booster doses of varicella vaccine, an outbreak of chickenpox is reported in a highly vaccinated population at an Oregon school (pp. 455-9). Among 422 children, 218 had no prior history of chickenpox, and 211 (97%) of them were vaccinated. Despite this, the authors report, 21 cases of chickenpox occurred in 9 of 16 classrooms. “In these 9 classrooms, 18 of 152 (12%) vaccinated students developed chickenpox, compared with 3 of 7 (43%) unvaccinated students,” note the authors. “Vaccine effectiveness was 72% (95% confidence interval: 3%–87%). Students vaccinated >5 years before the outbreak were 6.7 times (95% confidence interval: 2.2–22.9) as likely to develop breakthrough disease as those vaccinated 5 years before the outbreak (15 of 65 [23%] vs 3 of 87 [3%]).” The investigators conclude, “Students vaccinated >5 years before the outbreak were at risk for breakthrough disease. Booster vaccination may deserve additional consideration.” (B. D. Tugwell, CDC, Atlanta)

Pneumococcal Infections After Vaccine Introduction: At eight U.S. children’s hospitals, the number of invasive pneumococcal infections decreased by more than 75% among young children after introduction of the 7-valent pneumococcal conjugate vaccine (pp. 443-9). Data for 1994–2002 were collected by prospective surveillance of all invasive pneumococcal infections in children. Focusing specifically on infants and children aged 24 months or younger, the authors found, “When compared with the mean of the years 1994 to 2000, the annual number of invasive pneumococcal infections for children 24 months of age declined 58% in 2001 and 66% in 2002. If only the serogroups in the PCV7 are considered, the number of cases in children 24 months old declined 63% and 77% in 2001 and 2002, respectively.... The proportion of all isolates nonsusceptible to penicillin increased yearly from 1994 to 2000, reached a plateau in 2001 at 45%, and declined to 33% in 2002. Decrease in nonsusceptibility to penicillin occurred entirely in the isolates with penicillin minimum inhibitory concentration 2 µg/mL.” (S. L. Kaplan, Baylor Coll. of Med., 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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 22, 2004 Vol. 11, No. 54
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
Mar. 20 issue of Lancet (www.thelancet.com; 2004; 363).

Nicotinamide for DM Prevention: Nicotinamide, useful in animal studies for preventing type 1 diabetes, failed to have a significant impact in a study of 552 people with first-degree family histories of the disease (pp. 925-31). Participants received either placebo or nicotinamide 1.2 g/sq m for 5 years. The authors report, “Of 159 participants who developed diabetes in the course of the trial, 82 were taking nicotinamide and 77 were on placebo. The unadjusted hazard ratio for development of diabetes was 1.07 (95% CI 0.78-1.45; p = 0.69), and the hazard ratio adjusted for age-at-entry, baseline glucose tolerance, and number of islet autoantibodies detected was 1.01 (0.73–1.38; p = 0.97). Of 168 (30.4%) participants who withdrew from the trial, 83 were on placebo. The number of serious adverse events did not differ between treatment groups. Nicotinamide treatment did not affect growth in children or first-phase insulin secretion.” (E. A. M. Gale, Southmead Hosp., Bristol, U.K.; edwin.gale@bristol.ac.uk)

>>>BMJ Highlights
Source:
Mar. 20 issue of BMJ (www.bmj.org; 2004; 328).

Sepsis Treatment:
In patients with sepsis, addition of an aminoglycoside to beta-lactam treatment should be discouraged, conclude authors of a meta-analysis of 64 trials (pp. 668 ff). Based on the experiences of 7,586 patients included in the studies, the authors find no difference in fatality rates but an increased risk of adverse events with aminoglycosides: “Clinical failure was more common with combination treatment overall (0.87, 0.78 to 0.97) and among studies comparing different beta-lactams (0.76, 0.68 to 0.86). There was no advantage to combination therapy among patients with Gram negative infections (1835 patients) or Pseudomonas aeruginosa infections (426 patients). There was no difference in the rate of development of resistance. Nephrotoxicity was significantly more common with combination therapy (0.36, 0.28 to 0.47).” (M. Paul, Rabin Med. Ctr., Petah-Tikva, Israel; mica@zahav.net.il)

Training of Journal Peer Reviewers: Short-term training packages had little impact on the quality of critiques received from peer reviewers of BMJ studies (pp. 673 ff). Some 609 reviewers either attended a training workshop or completed a self-taught training package on what editors want from reviewers and how to critique clinical trials, and their later performances were compared with those of a control group. “Both intervention groups identified significantly more major errors after training than did the control group (3.14 and 2.96 v 2.13; P < 0.001), and this remained significant after the reviewers’ performance at baseline assessment was taken into account,” the authors explain. “The evidence for benefit of training was no longer apparent on further testing six months after the interventions. Training had no impact on the time taken to review the papers but was associated with an increased likelihood of recommending rejection (92% and 84% v 76%; P = 0.002).” (S. Schroter; sschroter@bmj.com)

>>>PNN JournalWatch
* Interventions for the Prevention of Falls in Older Adults: Systematic Review and Meta-Analysis of Randomised Clinical Trials, in BMJ, 2004; 328: 680 ff. Reprints: www.bmj.org; J. T. Chang, johnchang@mednet.ucla.edu

* Pain: Moving from Symptom Control Toward Mechanism-Specific Pharmacologic Management, in
Annals of Internal Medicine, 2004; 140: 441–51. Reprints: www.annals.org; C. J. Woolf, Harvard Med. Sch., Charlestown, Mass.; cwoolf@partners.org

* Screening for Hepatitis C Virus Infection: A Review of the Evidence for the U.S. Preventive Services Task Force, in
Annals of Internal Medicine, 2004; 140: 465–79. Reprints: www.annals.org; reprints available from the Agency for Healthcare Research and Quality Web site, www.preventiveservices.ahrq.gov

* Acquired and Inherited Lipodystrophies, in
New England Journal of Medicine, 2004; 350: 1220–34. Reprints: con tent.nejm.org; A. Garg, U. Texas Southwestern Med. Ctr., Dallas; abhimanyu.garg@utsouthwestern.edu

* Inhibitors of Protein Kinase Signaling Pathways: Emerging Therapies for Cardiovascular Disease, in
Circulation, 2004; 109: 1196–205. Reprints: circ.ahajournals.org; T. Force, Tufts-New England Med. Ctr., Boston; tforce@tufts-nemc.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 23, 2004 Vol. 11, No. 55
Providing news and information about medications and their proper use

>>>FDA Broadens Warning About Antidepressants
The risk of suicidal thoughts and actions is increased in both adults and children taking newer antidepressants, especially in the first stages of treatment, FDA said yesterday. In its broadest and strongest statement about this emerging problem, the federal agency added that it is asking manufacturers of 10 antidepressants (bupropion, citalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, escitalopram, and venlafaxine) to include stronger cautions and warnings about the need to monitor patients for the worsening of depression and the emergence of suicidal ideation, regardless of the cause of such worsening.

FDA has been closely reviewing the results of antidepressant studies in children after an initial report on studies with paroxetine (see PNN, June 20, 2003) and subsequent reports on studies of other drugs (see PNN, Sept. 9, 2003; Oct. 28, 2003) appeared to suggest an increased risk of suicidal thoughts and actions in the children given antidepressants. FDA has initiated a full review of these reported behaviors by experts in such evaluation. However, whether antidepressants contribute to the emergence of suicidal thinking and behavior is unclear. The agency is advising clinicians, patients, families, and caregivers of adults and children that they should closely monitor all patients being placed on therapy with these drugs for worsening depression and suicidal thinking, which can occur during the early period of treatment. The agency is also advising that these patients be observed for certain behaviors that are known to be associated with these drugs, such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania, and that physicians be particularly vigilant in patients who may have bipolar disorder.

>>>Internal Medicine Report
Source:
Mar. 22 issue of Archives of Internal Medicine (www.archinternmed.com; 2004; 164).

Lowered Anticoagulation Intensity: Decreased INR treatment targets for oral anticoagulation can decrease complications among patients requiring aggressive warfarin therapy, conclude authors of a study of 4,597 patients (pp. 668-73). Indications for warfarin therapy in the study were histories of mechanical heart valve placement, atrial fibrillation, or cerebral ischemia. Target INRs initially were 4.0 for heart valve patients and 3.5 for the other conditions. But target intensities were lowered to 3.5 and 3.0, respectively, halfway through the study. “Higher target treatments were given to 2341 patients (2863 patient-years) and lower target treatments to 2256 patients (2260 patient-years),” write the authors. “After introduction of the lower target ranges, the overall incidence rate of major untoward events declined from 5.7 (95% confidence interval [CI], 4.9-6.7) to 3.6 (95% CI, 2.8-4.4) per 100 patient-years. The incidence of major bleeding fell from 3.6 (95% CI, 2.9-4.4) to 2.7 (95% CI, 2.1-3.5) and the incidence of major thromboembolism from 2.0 (95% CI, 1.5-2.5) to 0.8 (95% CI, 0.5-1.3) per 100 patient-years.” (F. R. Rosendaal, Leiden U. Med. Ctr., Leiden, the Netherlands; F.R.Rosendaal@lumc.nl)

Editorialists agree with lower INR targets but note the need for anticoagulation expertise (which could be provided by experienced pharmacists; pp. 588-90): “It is likely that a single therapeutic range for coumarins will not be optimal for all indications. However, a moderate-intensity INR (2.0–3.0) is effective for most indications. The possible exceptions are acute myocardial infarction, in which a higher INR range is likely to be superior, and primary prevention of myocardial infarction in high-risk patients, in which a lower INR range is effective....
“Defining an appropriate range is an important step in improving patient management, but it is only the first of 2 steps. The second is ensuring that the targeted range is achieved. In general, our success in achieving this second goal has been poor; it is better when the INR is controlled by experienced personnel in anticoagulant clinics and by using computer-assisted dosage adjustment.” (J. Hirsh, Henderson Res. Ctr., Hamilton, Ontario, Canada)


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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 24, 2004 Vol. 11, No. 56
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Mar. 24 issue of JAMA (www.jama.com; 2004; 291).

Hysterectomy vs. Medication for Uterine Bleeding: Premenopausal women with abnormal uterine bleeding and who were dissatisfied with medroxyprogesterone treatment did better following hysterectomy than with expanded medical treatments, report investigators who studied 63 patients (pp. 1447-55). The women, aged 30 to 50 years, had abnormal uterine bleeding for a median of 4 years before study entry. They randomly underwent hysterectomy (with type and route chosen by the gynecologist) or received expanded treatment with estrogen and/or progesterone and/or a prostaglandin synthetase inhibitor. Using the Mental Component Summary (MCS) of the 36-Item Short-Form Health Survey to assess patient responses, the authors report, “At 6 months, women in the hysterectomy group had greater improvement in MCS scores than women in the medicine group (8 vs 2, P = .04). They also had greater improvement in symptom resolution (75 vs 29, P < .001), symptom satisfaction (44 vs 7, P < .001), interference with sex (41 vs 22, P = .003), sexual desire (21 vs 3, P = .01), health distress (33 vs 13, P = .009), sleep problems (13 vs 1, P = .03), overall health (12 vs 2, P = .006), and satisfaction with health (31 vs 14, P = .01). By the end of the study, 17 (53%) of the women in the medicine group had requested and received hysterectomy, and these women reported improvements in quality-of-life outcomes during the 2 years that were similar to those reported by women randomized to the hysterectomy group. Women who continued medical treatment also reported some improvements (P < .001 for within-group change in many outcomes), with the result that most differences between randomized groups at the end of the study were no longer statistically significant in the intention-to-treat analysis.” (M. Kuppermann, kuppermannm@obgyn.ucsf.edu)

Hormonal Intrauterine System vs. Hysterectomy for Menorrhagia: A levonorgestrel-releasing intrauterine system was preferred over hysterectomy for improvement of health-related quality of life in 232 women with menorrhagia, and it provided these benefits at lower costs (pp. 1456-63). The device is approved in many countries for both contraception and treatment of bleeding, but its only FDA-approved indication is for contraception. At five Finnish university hospitals, the women—who had been randomly assigned to receive hysterectomy or the LNG-IUS—were followed for 5 years, with the authors finding, “The 2 groups did not differ substantially in terms of HRQL or psychosocial well-being. Although 50 (42%) of the women assigned to the LNG-IUS group eventually underwent hysterectomy, the discounted direct and indirect costs in the LNG-IUS group ($2817 [95% confidence interval, $2222–$3530] per participant) remained substantially lower than in the hysterectomy group ($4660 [95% confidence interval, $4014–$5180]). Satisfaction with treatment was similar in both groups.” (R. Hurskainen, Helsinki U. Hosp., HUS, Finland; ritva.hurskainen@stakes.fi)

Evaluating Gynecologic Surgeries: Commenting on the above two studies, editorialists address the difficulties of conducting high-quality randomized controlled trials when the interventions are as different as taking a medication and having major surgery (pp. 1503-4): “In essence, [the clinical dilemma these studies pose] is the familiar conundrum of whether the glass is half-empty or half-full. Does it mean that surgery will likely be necessary eventually anyway, so perhaps better sooner than later, sparing the woman continued symptoms? Or does it mean that there is a 50% chance of avoiding hysterectomy and these odds are worth taking to avoid a major operation? Inevitably, different patients and different physicians will give different answers to this question. Additional rigorous RCTs with longer follow-up are needed to determine whether these (or other) more conservative treatments are more efficacious and cost-effective in the long run than hysterectomy. The results of such studies will be important for counseling patients and formulating decisions about surgical options for gynecological treatment.” (R. M. Pitkin, La Quinta, Calif.; r.pitkin@earthlink.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 25, 2004 Vol. 11, No. 57
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Mar. 25 issue of the New England Journal of Medicine (content.nejm.org; 2004; 350).

Treatment of Aggressive Lymphoma: Intensive therapy with stem-cell support was more effective than a standard CHOP regimen in treating 197 adolescents and adults with disseminated aggressive lymphoma (pp. 1287-95). Intensive therapy consisted of two courses of the following (CEEP) 15 days apart: cyclophosphamide 1,200 mg/sq m intravenously on day 1, epirubicin 100 mg/sq m i.v. on day 1, vindesine 3 mg/sq m i.v. on day 1, and prednisone 80 mg/sq m orally or i.v. on days 1 through 5. Granulocyte–macrophage colony-stimulating factor 5 mcg/sq m was administered i.v. or subcutaneously on day 5 of each course, and intrathecal methotrexate 15 mg and methylprednisolone 20 mg were given routinely on day 2 of each CEEP course.

Compared with standard doses of cyclophosphamide, doxorubicin, vincristine, and prednisone, the intensive option produced these results: “Overall, 78 percent of the patients completed the assigned treatment; the median follow-up was four years. The estimated event-free survival rate (± SD) at five years was significantly higher among patients who received high-dose therapy than among patients who received CHOP (55 ± 5 percent vs. 37 ± 5 percent, P = 0.037). Among patients with a high intermediate risk of death, according to the age-adjusted International Prognostic Index, the five-year survival rate was significantly higher after high-dose therapy than after CHOP (74 ± 6 percent vs. 44 ± 7 percent, P = 0.001).” (N. Milpied, CHU, Nantes, France; noel.milpied@chu-nantes.fr)

In a Perspectives article, an author points out the difficulty of determining just what these results mean to clinicians treating patients with aggressive lymphoma (pp. 1277-8): “As Milpied et al. themselves point out, in determining how to act on their results, we must remember that CHOP is no longer the gold standard for the treatment of the most common of the aggressive lymphomas, diffuse large-B-cell lymphoma. The combination of anti-CD20 (rituximab) and CHOP has been shown to be superior to CHOP alone in both older and younger patients with non-Hodgkin’s lymphoma; chemoimmunotherapy is becoming the order of the day. Shortening the interval between cycles of CHOP by a week (from 21 days to 14 days) is also finding favor. What result would have been obtained had Milpied et al. compared CHOP plus rituximab administered every 14 days with myeloablative therapy? Is myeloablative therapy appropriate for the substantial proportion of patients who present in later life with coexisting conditions?

“The answers to these questions notwithstanding, this critique does not devalue the relevance of the data presented by Milpied et al. These investigators have shown that considerable intensification of treatment is feasible for most patients with aggressive lymphoma of low-to-intermediate risk and that the fraction of patients who are cured may well be increased.” (T. A. Lister, St. Bartholomew’s Hosp., London)

Long-term Outcomes After Dexamethasone Treatment of Premature Infants: Early postnatal dexamethasone therapy is associated with a variety of adverse consequences in children surviving to school age, according to an analysis of 262 children born with severe respiratory distress syndrome requiring mechanical ventilation (pp. 1304-13). A total of 159 children who survived to school age, and 146 of these were analyzed. Compared with 74 children in the placebo group, the 72 children treated with dexamethasone (initiated within 12 hours of birth) had significantly shorter heights; smaller head circumferences; poorer motor skills, motor coordination, and visual–motor integration; lower full IQ scores, verbal IQ scores, and performance IQ scores. “Routine systemic dexamethasone should not be used postnatally to prevent or treat chronic lung disease of prematurity,” conclude the authors. (T. F. Yeh, China Medical U., Taichung, Taiwan, master@mail.cmu.edu.tw)

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 26, 2004 Vol. 11, No. 58
Providing news and information about medications and their proper use

>>>JAPhA Highlights
Source:
Mar/Apr issue of the Journal of the American Pharmacists Association (www.japha.org; 2004; 44).

Drug Interaction Compendia: Four major compendia fail to agree on what constitutes a serious drug interaction and consequently a new, more consensus-oriented system is needed for assessing the potential for interactions, according to two studies (pp. 136-41 and 142-51).

Among 406 drug–drug interactions identified by one of the four compendia as having the greatest clinical importance, only 9 (2.2%) were listed in all four references, the authors report. “In fact, the majority of interactions were listed in only one compendium (291 DDIs, 71.7%), despite these interactions being considered of greatest clinical relevance by at least one compendium,” the group adds. “A concerted effort to identify DDIs of the highest clinical importance is needed to design effective strategies to avoid and manage them.”

Based on these disconcerting findings, the authors sought to develop a list of clinically important DDIs likely to be encountered in community and ambulatory pharmacy. A panel of two physicians, two clinical pharmacists, and an interactions expert systematically rated DDIs and used a modified Delphi technique to reach consensus about the most important interactions. Their final list contains 25 DDIs. “These interactions represent a subset of all interactions that have been noted by drug interaction compendia as being of high severity or major importance,” write the authors. “We encourage pharmacists to take steps to prevent patients from receiving these interacting medications and computer software vendors to focus interaction alerts on these and similarly important DDIs.” (D. C. Malone, malone@pharmacy.arizona.edu)

In an accompanying editorial, a writer proposes eight strategies to optimize the use of technology in minimizing patients’ exposure to serious DDIs: Share electronic information among pharmacies and physicians, individualize DDI warnings, define and eliminate trivial DDIs, promptly apply new findings about DDIs, eliminate inappropriate class-specific warnings, provide optional links to additional information, propose therapeutic alternatives that avoid the DDI, and make serious DDIs more difficult to override. “Harm resulting from DDIs will never be fully extinguished,” writes the editorialist. “The solutions proposed above are not exhaustive, and some are easier to deploy than others. However, each holds some promise to aid us in our efforts to minimize injuries and deaths from DDIs. The stakes are high, but there is ample room for improvement. Surely we can do better than we have thus far.” (D. N. Juurlink, Sunnybrook and Women’s College Health Sciences Ctr., Toronto, Ontario, Canada; dnj@ices.on.ca)

Pharmacy-Based Osteoporosis Screenings: Two articles describe results of pharmacy-based osteoporosis screenings.

At 22 Ukrop’s Super Market pharmacies in Richmond, the APhA Foundation’s Project ImPACT: Osteoporosis screened 532 self-paying patients for decreased bone mineral density (pp. 152-60). Two thirds of those screened were at high or moderate risk for osteoporosis, and 78% of patients indicated they had no prior knowledge of their relative risks. More than one third sought medical care as a result of the screenings, and one fourth of patients were initiated on osteoporosis therapy. As a result of the benefits of such a program, a regional health plan is paying participating pharmacies for screenings and collaborative community health management services provided to its members. (J-V Goode, jrgoode@vcu.edu)

Feedback was positive from 140 women whose BMD was measured at six community pharmacies (pp. 161-7). At 3 months after the screening, 11% reported they had improved exercise habits, and 30% had increased their calcium and vitamin D intake. While screenings were provided for free under a research grant, 41% of participants indicated a willingness to pay $20 or more for BMD screenings. The authors calculate that a pharmacy could recoup analyzer cost in only 24 to 35 screening days. (J. Cerulli, cerullij@acp.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 29, 2004 Vol. 11, No. 59
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
Mar. 27 issue of Lancet (www.thelancet.com; 2004; 363).

Reducing Alcohol Consumption: Commenting on a report, Alcohol Harm Reduction Strategy For England, released last week by the U.K. Prime Minister’s Strategy Unit, editors of Lancet called for coordinated action on the ill effects of the overuse of alcohol: “Primary-care services ... are best placed to identify and manage alcohol-related problems. We agree with the charity Alcohol Concern that those in primary-care settings need to be further trained to ask about drinking habits and to provide relevant information. But training and educational materials cost money, on which the Government’s strategy fails to provide details. Dr Clare Gerada, speaking for the Royal College of General Practitioners, said ‘the RCGP is concerned it [the Government’s strategy] will not make a significant impact without the resources necessary to fund change.’ A coordinated funded strategy on alcohol involving primary-care providers is needed, which is what we do not yet have. Targeting binge or chronic drinkers is a start, but cannot be done without support from properly funded relevant health professionals.”

>>>APhA2004 Highlights
* At APhA2004 in Seattle, APhA, the National Association of Boards of Pharmacy, and several other organizations announced plans to begin voluntary certification of pharmacies that compound medications. The effort will initially focus on those pharmacies that provide sterile compounding services.

* APhA’s
Pain Management Partnership with Purdue Pharma provides resources for pharmacists, colleges of pharmacy, and pharmacy students with the goal of addressing issues of appropriate pain management and prescription drug abuse. In addition to live programming and print informational and CE articles, the Partnership provides an Online Pain Management Library for pharmacists at www.pharmacist.com.

* Pharmacists are making a dramatic difference in the
care of patients with diabetes, according to data from the APhA Foundation’s Patient Self-Management Program. Initial results released at a news conference highlighted clinical and humanistic improvements documented among the first 300 patients in the practice-based research project.

>>>PNN JournalWatch
* Clinical Considerations in Premenopausal Osteoporosis, in Archives of Internal Medicine, 2004; 164: 603–14. Reprints: www.archinternmed.com; M. L. Gourlay, margaret_gourlay@med.unc.edu

* Acupuncture for Chronic Headache in Primary Care: Large, Pragmatic, Randomised Trial, in
BMJ, 2004; 328: 744 ff. Reprints: www.bmj.org; A. J. Vickers, Memorial Sloan-Kettering Cancer Ctr., 1275 York Ave., New York City; vickersa@mskcc.org

* Cost Effectiveness Analysis of a Randomised Trial of Acupuncture for Chronic Headache in Primary Care, in
BMJ, 2004; 328: 747 ff. Reprints: www.bmj.org; D. Wonderling, London Sch. of Hygiene and Tropical Med., London; David.Wonderling@lshtm.ac.uk

* Human Metapneumovirus: A New Player Among Respiratory Viruses, in
Clinical Infectious Diseases, 2004; 38: 983–90. Reprints: www.journals.uchicago.edu/CID; M-È Hamelin, Laval U., Quebec City, Canada.

* Daptomycin: Another Novel Agent for Treating Infections Due to Drug-Resistant Gram-Positive Pathogens, in
Clinical Infectious Diseases, 2004; 38: 994– 1000. Reprints: www.journals.uchicago.edu/CID; C. F. Carpenter, William Beaumont Hosp., Royal Oak, Mich.

* Risk of Metabolic Abnormalities in Patients Infected with HIV Receiving Antiretroviral Therapy that Contains Lopinavir-Ritonavir, in
Clinical Infectious Diseases, 2004; 38: 1017–23. Reprints: www.journals.uchicago.edu/CID; E. Martínez, Hosp. Clínic, Barcelona, Spain; esteban@fundsoriano.es.

* Cognitive Side Effects of Antiepileptic Drugs in Children, in
Neurology, 2004; 164: 872–7. Reprints: www.neurology.org; D. W. Loring, dwl7@georgetown.edu

* Rosiglitazone Facilitates Angiogenic Progenitor Cell Differentiation Toward Endothelial Lineage: A New Paradigm in Glitazone Pleiotropy, in
Circulation, 2004; 109: 1392–400. Reprints: circ.ahajournals.org; S. Verma, Toronto General Hosp., Toronto; Subodh.Verma@sympatico.ca

* Atorvastatin Does Not Affect the Antiplatelet Potency of Clopidogrel When It Is Administered Concomitantly for 5 Weeks in Patients with Acute Coronary Syndromes, in
Circulation, 2004; 109: 1335–8. Reprints: circ.ahajournals.org; A. D. Tselepis, U. Ioannina, Ioannina, Greece; atselep@cc.uoi.gr

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 30, 2004 Vol. 11, No. 60
Providing news and information about medications and their proper use

>>>Infectious Disease Update
Source:
Apr. 1 issue of Clinical Infectious Diseases (www.journals.uchicago.edu/CID; 2004; 38).

Oral Treatment of Typhoid Fever: A 5-day course of oral azithromycin proved to be an effective treatment for uncomplicated typhoid fever in children and adolescents, according to a study of 149 such patients (pp. 951-7). Study subjects received either oral azithromycin 20 mg/kg/day (maximum dose, 1,000 mg/day) or intravenous ceftriaxone 75 mg/day (maximum dose, 2.5 g/day) daily for 5 days. The authors found, “Cure was achieved in 30 (94%) of 32 patients in the azithromycin group and in 35 (97%) of 36 patients in the ceftriaxone group (P = NS). Mean time to clearance of bacteremia was longer in the azithromycin group than in the ceftriaxone group. No patient who received azithromycin had a relapse, compared with 6 patients who received ceftriaxone.” (R. W. Frenck, Jr., U.S. Naval Med. Res. Unit, FrenckR@namru3.org)

Adverse Effects of Intranasal Influenza Vaccine: Facial paralysis and other adverse effects that led to the market withdrawal of a Swiss intranasal influenza vaccine are described (pp. 974-80). Among 1,600 working-age adults vaccinated in 2000, 97% chose the intranasal formulation over an injectable vaccine. “The incidence of influenza-like symptoms and side effects was 13% and 36%” with the injectable and intranasal products, respectively, the authors noted. “Individuals who chose the intranasal vaccine were more likely to report side effects ([odds ratio], 3.23; 95% CI, 1.29–8.08). Facial paralysis was observed in 11 patients and was the most severe adverse event associated with the intranasal influenza vaccine.” (M. Battegay, U. Hosp., Basel, Switzerland; mbattegay@uhbs.ch)

Infectious Disease Consultants in Hospitals: Pharmacies in 250 of 502 (50%) responding hospitals had antimicrobial restriction policies in place that required involvement of infectious disease consultants, according to a survey of members of the Infectious Diseases Society of America Emerging Infections Network (pp. 934-8). “Moreover, 89% agreed that infectious diseases consultants need to be directly involved in the approval process,” investigators report. “At hospitals with control policies, commonly restricted agents included lipid formulations of amphotericin B, carbapenems, fluoroquinolones, piperacillin–tazobactam, and vancomycin. Only 46 EIN members (18%) reported remuneration of infectious diseases consultants for participation in the approval process.” (L. J. Strausbaugh, VA Med. Ctr., Portland, Oreg.; strausba@ohsu.edu)

An editorialist comments on the value of the infectious diseases physician (pp. 939-42): “The ... IDP is the key person or a valuable resource for implementing most, if not all, of ... strategies for minimizing the impact of resistance.... This is true because there are several groups of stakeholders [prescribers; patients; health care administrators; institutional thought leaders; pharmacists, nurses, and laboratory personnel; and professional societies and the government] that must be included in efforts to deal with resistance in the health care setting.” (J. E. McGowan, Jr., Emory U., Atlanta; jmcgowa@sph.emory.edu)

>>>APhA2004 Highlights
* American Pharmacists Month is being launched by APhA in October 2004, President-elect Dan Herbert told the 6,400 attendees in Seattle on Sunday. The new month-long observance, replacing National Pharmacy Week, was described as an exponential increase in APhA opportunities to promote activities and convey messages about the pharmacist’s role in improving medication use and advancing patient care.

* More than 300 patients with diabetes are receiving care through employer–pharmacist partnerships as part of the APhA Foundation’s
Patient Self-Management Program. At sites in Georgia, North Carolina, and Wisconsin, the number of patients with A1c levels less than 7% has increased by 26% in the first year of the effort. Pharmacists see patients periodically to assess care, educate them about diabetes, identify unmet needs, and provide flu vaccines, monitoring, and other needed services.

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 31, 2004 Vol. 11, No. 61
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Apr. issue of Diabetes Care (care.diabetesjournals.org; 2004; 27).

Simvastatin & Atherosclerosis: In a study of 21 patients with type 2 diabetes and triglyceride levels of 400 mg/dL or less, simvastatin significantly reduced the concentration of modified lipoprotein components of circulating immune complexes (mLDL-ICs), an effect the investigators write is likely “to have a beneficial impact in the inflammatory reaction associated with atherosclerosis” (pp. 908-13). The patients, who were taking no lipid-lowering medications or CYP 3A4 inhibitors before the study, were begun on exercise regimen and lipid-lowering diet for 2 weeks. They then began 6 months’ treatment with simvastatin 20 mg/day. Compared with baseline, levels of mLDL-ICs declined significantly during simvastatin therapy and returned to near-baseline levels after drug treatment ended. (M. F. Lopes-Virella, virellam@musc.edu)

Vitamin Therapy, Haptoglobin Type, & Atherosclerosis: Antioxidant vitamin therapy may be of cardiovascular benefit in postmenopausal women who are homozygous for the haptoglobin 1 allele and detrimental for women homozygous for the Hp 2 gene, report authors of the Women’s Angiographic Vitamin and Estrogen (WAVE) trial (pp. 925-30). The prospective angiographic study of vitamins C and E with or without hormone replacement therapy included 299 women whose annualized change in minimum luminal diameter was monitored. The authors report, “We found a significant benefit on the change in MLD with vitamin therapy as compared with placebo in Hp 1-1 subjects (0.079 ± 0.040 mm, P = 0.049). This benefit was more marked in diabetic subjects (0.149 ± 0.064 mm, P = 0.021). On the other hand, there was a trend toward a more rapid decrease in MLD with vitamin therapy in Hp 2-2 subjects, which was more marked in diabetic subjects (0.128 ± 0.057 mm, P = 0.027). HRT had no effect on these outcomes.” (A. P. Levy, Technion-Israel Inst. of Technology, Haifa, Israel; alevy@tx.technion.ac.il)

Triglyceride-to-HDL Ratios & Cardiovascular Risk: In patients with prolonged times to heart rate recovery after exercise testing, elevated triglyceride-to-HDL cholesterol ratios indicate an increased risk of death, conclude researchers who conducted the 4,963-patient Lipid Research Clinics Prevalence Study (pp. 936-41). “As a continuous variable, an increase in 1 SD of triglyceride-to-HDL cholesterol ratio was associated with a greater likelihood of an abnormal HRR, even after adjusting for [more than] 20 covariates (adjusted OR 1.16, 95% CI 1.07–1.25; P < 0.001). During 12 years of follow-up, there were 284 deaths. In age- and sex-adjusted analysis, participants with an abnormal HRR and high triglyceride-to-HDL cholesterol ratio had significantly higher mortality than those with a normal HRR and high triglyceride-to-HDL cholesterol ratio (hazard ratio = 1.49, 95% CI 1.08–2.04; P = 0.015).” (M. S. Lauer, Cleveland Clinic Found., Cleveland; lauerm@ccf.org)

>>>APhA2004 Update
With attendance topping 6,500, APhA2004 ended yesterday in Seattle. In addition to the incoming address of President Daniel A. Herbert (“You’ve Just Got to Believe&rdquoWinking, the closing hours of the meeting saw approval of policy statements on these topics by the Association’s House of Delegates:

* Use of automation and technology in pharmacy practice as long as pharmacists maintain oversight of such systems, with the specific language that “APhA recommends that pharmacists and other pharmacy personnel implement policies and procedures addressing the use of technology and automation to ensure safety, accuracy, security, data integrity, and patient confidentiality.”

* Protection of the integrity of the medication supply through use of appropriate technology, tracking mechanisms, business practices, and other initiatives.

* Support of certification of pharmacy technicians by the Pharmacy Technician Certification Board, pharmacists’ responsibilities to provide guidance and training to technicians, and state regulation of technicians through registration or licensure.


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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 1, 2004 Vol. 11, No. 62
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Apr. 1 issue of the New England Journal of Medicine (content.nejm.org; 2004; 350).

Counterfeit Drugs: A Perspectives articles details the problem of counterfeit drugs and discusses potential solutions, including track-and-trace technology (pp. 1384-6): “Perhaps the most important element in ensuring a safe drug supply will be the attachment of radio-frequency identification tags containing a unique electronic serial number (the electronic product code, or EPC) to every bottle of drugs intended for sale in the United States. Each EPC will be irreversibly written by the manufacturer and will be associated with drug-specific information that will be kept in a secure data base. Thus, the EPC should permit the tracking and tracing of the item from the point of manufacture to the point of dispensing (providing an unimpeachable pedigree) and be virtually impossible to counterfeit. EPCs will also allow for easier inventory control, recalling of products, and assurance that patients get the right prescriptions; eventually, it may enable patients to determine precisely where their drugs have been and the environmental conditions in which they have been stored from manufacture to final purchase. Although it may be 2007 before these tags are in common use for drugs, they are currently in commercial use on consumer products such as jeans and perfume and are being tested on pharmaceutical products.”(P. M. Rudolf, FDA, Rockville, Md.)

CRP as CHD Predictor: The value of C-reactive protein as a predictor of coronary heart disease is modest and perhaps overstated by those who advocate its inclusion in routine monitoring panels as a marker of “inflammatory underpinnings of atherothrombosis,” according to investigators who studied 2,459 patients with CHD and 3,969 control patients without CHD (pp. 1387-97). Focusing on baseline measurements for these two groups and paired-sample measurements taken 12 years apart from 379 of the patients, the authors found, “After adjustment for base-line values for established risk factors, the odds ratio for coronary heart disease was 1.45 (95 percent confidence interval, 1.25 to 1.68) in a comparison of participants in the top third of the group with respect to base-line C-reactive protein values with those in the bottom third, and similar overall findings were observed in an updated meta-analysis involving a total of 7068 patients with coronary heart disease. By comparison, the odds ratios in [our] Reykjavik Study for coronary heart disease were somewhat weaker for the erythrocyte sedimentation rate (1.30; 95 percent confidence interval, 1.13 to 1.51) and the von Willebrand factor concentration (1.11; 95 percent confidence interval, 0.97 to 1.27) but generally stronger for established risk factors, such as an increased total cholesterol concentration (2.35; 95 percent confidence interval, 2.03 to 2.74) and cigarette smoking (1.87; 95 percent confidence interval, 1.62 to 2.16).” (J. Danesh, U. Cambridge, Cambridge, U.K.)

Cancer Immunotherapy: The use of immunotherapy—vaccine therapy and cell-transfer therapy—in treatment of cancer is reviewed (pp. 1461-3): “A variety of problems, however, have plagued the translation of results obtained in animal models into effective immune-based treatments of cancer in humans; the study by Yu et al. [in the journal Nature Immunology] is not exempt from these problems. The authors focus mainly on immunization strategies that can prevent the establishment and outgrowth of a transplanted tumor, but effecting the regression of established, invasive, vascularized cancers is more difficult, since the three requirements must be met and there are currently no immunization strategies capable of meeting them. And although the genetic tweak engineered by Yu et al. is sufficient to trigger an effective host response to a tumor bearing the H-2d alloantigen, this strong antigen is an unrealistic surrogate for human cancer antigens. Most human cancer antigens are normal, nonmutated differentiation molecules or nonmutated proteins found only in tumor or germ cells; the human immune system seems to be more tolerant of these antigens than the mouse system is of alloantigen.” (S. A. Rosenberg, Natl. Cancer Inst., 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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 2, 2004 Vol. 11, No. 63
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
Apr. 7 of the Journal of the American College of Cardiology (www.cardiosource.com; 2004; 43).

Sildenafil in Primary Pulmonary Hypertension: In 22 patients with primary pulmonary hypertension, sildenafil significantly improved exercise tolerance, cardiac index, and quality of life (pp. 1149-53). In this randomized, double-blind, crossover trial, patients took placebo or sildenafil in doses of 25–100 mg (based on weight) three times daily for 6 weeks. The authors found, “Exercise time increased by 44% from 475 ± 168 s at the end of placebo phase to 686 ± 224 s at the end of sildenafil phase (p < 0.0001). With sildenafil, cardiac index improved from 2.80 ± 0.9 l/m2 to 3.45 ± 1.1 l/m2 (p < 0.0001), whereas pulmonary artery systolic pressure decreased insignificantly from 105.23 ± 17.82 mm Hg to 98.50 ± 24.38 mm Hg. There was significant improvement in the dyspnea and fatigue components of the QOL questionnaire. During the placebo phase, one patient died and another had syncope. There were no serious side effects with sildenafil.” (B. K. S. Sastry, CARE Hosp., Nampally, Hyderabad AP, India; bkssastry@hotmail.com)

Rhythm Control in AF: Beta-blockers proved to be the most effective agents for rhythm control in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study of 2,027 patients (pp. 1201-8). During a mean of 3.5 years of follow-up, the investigators determined, “Initial treatment included a beta-adrenergic blocker (beta-blocker) alone in 24%, a calcium channel blocker alone in 17%, digoxin alone in 16%, a beta-blocker and digoxin in 14%, or a calcium channel blocker and digoxin in 14% of patients. Overall rate control was achieved in 70% of patients given beta-blockers as the first drug (with or without digoxin), 54% with calcium channel blockers (with or without digoxin), and 58% with digoxin alone. Adequate overall rate control was achieved in 58% of patients with the first drug or combination. Multivariate analysis revealed an association between first drug class and several clinical variables. There were more changes to beta-blockers than to the other two-drug classes (p < 0.0001).” (B. Olshansky, brian-olshansky@uiowa.edu)

Azimilide in AF: The antiarrhythmic agent azimilide was safe and effective for atrial fibrillation therapy in 3,381 patients with depressed left ventricular function after a myocardial infarction (pp. 1211-6). In this placebo-controlled, double-blind study, azimilide 100 mg was administered and all-cause mortality was monitored. Only 93 patients had AF at baseline, and the condition was detected in an additional 27 patients during routine monitoring during the first post-MI year. “Patients with AF at baseline had a higher mortality than those without AF (p = 0.0006),” report the authors. “Among AF patients, there was no difference in mortality between AZ patients and placebo patients (p = 0.82). Fewer AZ patients developed AF than placebo patients (p = 0.04). More AZ patients than placebo patients converted to sinus rhythm, but this difference did not achieve statistical significance (p = 0.076). Over one-year follow-up, more AZ patients were in sinus rhythm than placebo patients (p = 0.04).” (C. M. Pratt, Baylor Coll. of Med., Houston; cpratt@bcm.tmc.edu)

>>>Circulation Highlights
Source:
Mar. 27 Circulation (circ.ahajournals.org; 2004; 109)

Clopidogrel Pretreatment for Carotid Endarterectomy: The risk of postoperative thromboembolism can be safely reduced in patients undergoing carotid endarterectomy, report authors of a study of 100 patients (pp. 1476-81). Study subjects, all of whom were taking aspirin 150 mg/day, randomly received placebo or clopidogrel 75 mg the night before surgery. “Clopidogrel produced a small (8.8%) but significant reduction in the platelet response to ADP (P<0.05) while conferring a 10-fold reduction in the relative risk of those patients having >20 emboli in the postoperative period.... There was no increase in bleeding complications or blood transfusions.” (A. R. Naylor, U. Leicester, Leicester, U.K.; arnaylor@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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.


PNN Pharmacotherapy Line
Apr. 5, 2004 Vol. 11, No. 64
Providing news and information about medications and their proper use

>>>Telithromycin Approved
FDA has approved telithromycin tablets (Ketek, Aventis) for treatment of acute exacerbation of chronic bronchitis; acute bacterial sinusitis; and mild to moderate community-acquired pneumonia, including those infections caused by multidrug resistant Streptococcus pneumoniae, in patients age 18 and older. Telithromycin—the first in a new class of antibiotics known as the ketolides—was specifically designed to treat community-acquired respiratory tract infections (RTIs).

Approximately one third of S
. pneumoniae, the most common pathogen causing RTIs, are resistant to commonly used first-line antibiotics, Aventis noted in a news release. By acting through a different mechanism of action, telithromycin selectively targets common respiratory pathogens, including resistant strains, without significant effects on bacteria not normally involved in RTIs. Because the chemical structure and mechanism of action of ketolides are sufficiently different from those of macrolides, cross-resistance is not expected to occur.
More than seven million patients have used telithromycin since it was first introduced in major European, Latin American, and Asian markets. Clinical trials have found equivalence between 5- or 7-day, once-daily, 800-mg telithromycin regimens and standard 10-day treatments with clarithromycin 500 mg twice daily. The most commonly reported adverse effects of telithromycin have been nausea, headache, dizziness, vomiting, and diarrhea.

>>>BMJ Highlights
Source:
Apr. 3 issue of BMJ (www.bmj.org; 2004; 328).

Short-Course Amoxicillin for Childhood Pneumonia: Among 2,188 children with nonsevere pneumonia, 3 days of oral amoxicillin was just as effective as 5 day’s treatment with the drug (pp. 791 ff). The children, ages 2 to 59 months, received doses of 31–54 mg/kg/day in three divided doses. “The clinical cure rates with three days and five days of treatment were 89.5% and 89.9%, respectively (absolute difference 0.4 [95% confidence interval –2.1 to 3.0]),” report the researchers. “Adherence to treatment regimen was 94% and 85% for three day and five day treatments, respectively. Loss to follow up was 5.4% by day 5. There were no deaths, 41 hospitalisations, and 36 minor adverse reactions. There were 225 (10.3%) clinical failures and 106 (5.3%) relapses, and rates were similar in both treatments. At enrolment, 513 (23.4%) children tested positive for respiratory syncytial virus, and Streptococcus pneumoniae and Haemophilus influenzae were isolated from the nasopharynx in 878 (40.4%) and 496 (22.8%) children, respectively. Clinical failure was associated with isolation of respiratory syncytial virus (adjusted odds ratio 1.95 [95% confidence interval 1.0 to 3.8]), excess respiratory rate of > 10 breaths/minute (2.89 [1.83 to 4.55]), and non-adherence with treatment at day 5 (11.57 [7.4 to 18.0]).” (S. Awasthi, King George’s Med. U., Lucknow, India; sawasthi@sancharnet.in)

>>>PNN JournalWatch
* Responsiveness to a Pandemic Alert: Use of Reverse Genetics for Rapid Development of Influenza Vaccines, in Lancet, 2004; 363: 1099–103. Reprints: www.thelancet.com; R. Webby, St. Jude Children’s Res. Hosp., Memphis; richard.webby@stjude.org

* Changing Requirements for Evaluation of Pharmacologic Agents, in
Pediatrics, 2004; 113: 1128–32. Reprints: www.pediatrics.org; R. W. Chesney, U. Tenn., Memphis.

* Management of Bipolar Disorder During Pregnancy and the Postpartum Period, in
American Journal of Psychiatry, 2004; 161: 608–20. Reprints: ajp.psychiatryonline.org; K. A. Yonkers.

* Antihistamines and Driving Ability: Evidence from On-the-Road Driving Studies During Normal Traffic, in
Annals of Allergy, Asthma, & Immunology, 2004; 92: 294–304. Reprints: allergy. edoc.com; J. C. Verster.

* P Glycoprotein in Human Immunodeficiency Virus Type 1 Infection and Therapy, in
Antimicrobial Agents & Chemotherapy, 2004; 48: 1073–81. Reprints: aac.asm.org/current.shtml; S. U. C. Sankatsing.

* New Antimicrobial Agents Approved by the U. S. Food and Drug Administration in 2003 and New Indications for Previously Approved Agents, in
Antimicrobial Agents & Chemotherapy, 2004; 48: 1438–9. Reprints: aac.asm.org/current.shtml

* Meta-Analysis of the Effect of Diabetes on Restenosis Rates Among Patients Receiving Coronary Angioplasty Stenting, in
Diabetes Care, 2004; 27: 990–4. Reprints: www.diabetes.org; B. Zinman, Mt. Sinai Hosp., Toronto; zinman@mshri.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 6, 2004 Vol. 11, No. 65
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Apr. 6 issue of the Annals of Internal Medicine (www.annals.org; 2004; 140).

PPI Therapy as GERD Test: Patient response to short-term treatment of gastrointestinal symptoms with proton-pump inhibitors does not provide a reliable diagnosis of gastroesophageal reflux disease, according to a meta-analysis of 15 studies (pp. 518-27). The investigators chose trials with 1- to 4-week trials of normal- or high-dose PPIs in patients who also had objective measures of GERD, such as 24-hour pH monitoring, endoscopy findings, or symptom questionnaires. They found: “With 24-hour pH monitoring as the reference standard, the positive likelihood ratio ranged from 1.63 to 1.87, and combined estimates of sensitivity and specificity were 0.78 (95% CI, 0.66 to 0.86) and 0.54 (CI, 0.44 to 0.65), respectively. These values were lower with the other reference standards.”

Assessing the implications of these findings, the authors conclude: “Given these results, is it reasonable to offer a trial of a PPI in patients suspected of having GERD? Although there may be diagnostic uncertainty, many patients will respond to an empirical trial of a PPI, suggesting that a PPI trial might be reasonable in patients without alarm symptoms or other suspected complications of GERD.

“On the other hand, the decision to begin with a PPI has long-term economic and clinical implications because responding patients will probably continue treatment even though a diagnosis has not been clearly established. Until better methods are available to establish a confident diagnosis, the empirical treatment approach (and selection of the dose and type of acid-suppressing agents) should be individualized on the basis of the clinical setting, the response to therapy, and judicious diagnostic testing.” (M. E. Numans, U. Med. Ctr., Utrecht, the Netherlands; m.e.numans@med.uu.nl)

Vitamin C Pharmacokinetics: The role of vitamin C in cancer treatment should be re-evaluated, according to researchers who found far higher plasma and urine concentrations after intravenous administration of the substance than after oral dosing (pp. 533-7). In 17 healthy, hospitalized volunteers, oral and i.v. vitamin C was administered in doses ranging from 0.015 to 1.25 grams, and plasma concentrations were projected for a dose range of 1 to 100 grams.

“Peak plasma vitamin C concentrations were higher after administration of intravenous doses than after administration of oral doses (P < 0.001), and the difference increased according to dose,” the authors write. “Vitamin C at a dose of 1.25 g administered orally produced mean (± SD) peak plasma concentrations of 134.8 ± 20.6 µmol/L compared with 885 ± 201.2 µmol/L for intravenous administration. For the maximum tolerated oral dose of 3 g every 4 hours, pharmacokinetic modeling predicted peak plasma vitamin C concentrations of 220 µmol/L and 13,400 µmol/L for a 50-g intravenous dose. Peak predicted urine concentrations of vitamin C from intravenous administration were 140-fold higher than those from maximum oral doses.” (M. Levine, NIH, Bethesda, Md.)

West Nile Virus: New drugs and a vaccine are in development to combat the mosquito-borne West Nile virus, according to results of an NIH conference on the flavivirus (pp. 545-53). “No therapeutic intervention has shown consistent clinical efficacy in West Nile virus disease,” the conference concluded. “Several approaches, including interferon-2b and immunoglobulin with high titer against West Nile virus, offer promise based on animal models and limited clinical experience. New drugs with in vitro activity are being investigated, and a vaccine is being developed....

“A total of 34 [antiviral] compounds have been screened, and thus far 6 compounds have been identified that have in vitro activity against West Nile virus with minimal toxicity: 2-thio-6 azauridine, mycophenolic acid, 6-azauridine triacetate, cyclopentycytosine, pyrazofurin, and 6-azauridine. These compounds are inhibitors of cellular enzymes that are involved in nucleotide synthesis.” (J. Gea-Banacloche, banacloj@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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 7, 2004 Vol. 11, No. 66
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Apr. 7 issue of JAMA (www.jama.com; 2004; 291).

Home-Based Depression Treatment: A community-integrated, home-based treatment for depression significantly reduced depressive symptoms and improved health status in chronically medically ill older adults with minor depression and dysthymia, report authors of a 138-patient study (pp. 1569-77). The Program to Encourage Active, Rewarding Lives for Seniors (PEARLS) intervention involved problem-solving treatment, social and physical activation, and potential recommendations to patients’ physicians regarding antidepressant medications. Comparing PEARLS patients with those managed with usual care for 12 months, the authors found, “Patients receiving the PEARLS intervention were more likely to have at least a 50% reduction in depressive symptoms (43% vs 15%; odds ratio [OR], 5.21; 95% confidence interval [CI], 2.01– 13.49), to achieve complete remission from depression (36% vs 12%; OR, 4.96; 95% CI, 1.79– 13.72), and to have greater health-related quality-of-life improvements in functional well-being (P = .001) and emotional well-being (P = .048).” (P. Ciechanowski, pavelcie@u.washington.edu)

An editorialist notes the social and economic challenges of treating depression and other mental illnesses in America’s growing older population (pp. 1626-8): “There are numerous barriers to the delivery of mental health care for older adults, even for traditional services, let alone for innovative methods such as on-site care managers or home-based programs. Among these barriers are disparities in Medicare reimbursement for depression and other mental illnesses compared with ‘physical’ disorders. The current system can only be described as discriminatory and, in many cases, results in prohibitive costs for elders. To turn the implications of studies such as ... PEARLS into reality for older adults will require the application of their results, and concomitant demonstrations of favorable cost-benefit analyses, to the changing of social policy and health care payment and delivery systems. The well-being of an aging society demands meeting these challenges.” (J. M. Lyness, Jeffrey_Lyness@urmc.rochester.edu)

Nitric Oxide Therapy for Acute Lung Injury: In a study of 385 patients with moderately severe acute lung injury, nitric oxide therapy produced short-term improvements in oxygenation but had no substantial impact on the duration of ventilatory support or mortality (pp. 1603-9). Patients admitted to the study did not have lung injury caused by sepsis, and they were excluded if they had significant nonpulmonary organ dysfunction at randomization. The number of days patients were alive and off assisted breathing was similar in patients assigned to placebo (nitrogen gas) or inhaled NO (means of 10.6 versus 10.7 days, respectively), the authors report. “This lack of effect on clinical outcomes was seen despite a statistically significant increase in Pao2 that resolved by 48 hours. Mortality was similar between groups (20% placebo vs 23% nitric oxide; P = .54).” (R. P. Dellinger, Robert Wood Johnson Med. Sch.–UMDNJ, Camden, N.J.; Dellinger-Phil@cooperhealth.edu)

After noting that NO therapy is important in situations where the objective is to reduce pulmonary arterial pressure and improve right ventricular function rather than improve ventilation-perfusion mismatching, editorialists advise (pp. 1629-31): “Current cumulative evidence from clinical trials suggests that nitric oxide has no place in the routine therapy of patients with [acute lung injury or acute respiratory distress syndrome]. Consequently, this expensive intervention cannot be recommended as standard care for these patients. However, in severe cases of ARDS for which refractory hypoxemia or pulmonary hypertension are major clinical problems, short-term physiological improvements may be crucial for patient survival. In these limited situations, nitric oxide may have a role as ‘salvage’ therapy, as a component of a multimodal approach that includes other strategies such as high-frequency oscillation or prone positioning.” (J. T. Granton, Toronto Genl. Hosp., Toronto; john.granton@uhn.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 8, 2004 Vol. 11, No. 67
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Apr. 8 issue of the New England Journal of Medicine (content.nejm.org; 2004; 350).

Intensive Statin Therapy: In a comparison of pravastatin 40 mg/day and atorvastatin 80 mg/day released last month on the NEJM Web site (see PNN, Mar. 9), patients with recent acute coronary syndromes did significantly better on the more intensive regimen (pp. 1495-504). Median LDL cholesterol levels were 95 mg/dL and 62 mg/dL in the two respective groups, and the percentages of patients reaching a composite endpoint of all-cause death, myocardial infarction, documented unstable angina requiring hospitalization, revascularization, and/or stroke were 26.3% and 22.4%, respectively. Based on these findings in 4,162 patients, the authors conclude, “The National Cholesterol Education Program and European guidelines currently recommend that the goal of treatment in patients with established coronary artery disease should be an LDL cholesterol level of less than 100 mg per deciliter. Although our data provide support for the use of this approach, given the substantially lower LDL cholesterol levels achieved in the group given 80 mg of atorvastatin daily..., our results suggest that after an acute coronary syndrome, the target LDL cholesterol level may be lower than that recommended in the current guidelines.” (C. P. Cannon, Brigham and Women’s Hosp., Boston; cpcannon@partners.org.)

An editorialist predicts that intensive statin therapy will produce a “sea change in cardiovascular prevention” (pp. 1562-4): “The proportional reduction in major clinical outcomes that results from aggressive statin therapy is of the same order of magnitude as that seen when statins were compared with placebo in controlled trials. Intensive therapy with statins, monitored by means of measurements of LDL cholesterol or biologic markers of inflammation, is likely to result in even greater steps toward actualizing the full benefit of this remarkable class of medicines.” (E. J. Topol, Cleveland Clinic Foundation, Cleveland; topole@ccf.org)

Drug for Raising HDL: In a single-blind study of 19 patients with low HDL cholesterol levels, an investigational drug produced remarkable improvements in HDL and LDL levels, and effects were increased further when the drug was administered with a statin (pp. 1505-15). Torcetrapib, a potent inhibitor of cholesteryl ester transfer protein, was administered for 4 weeks in daily doses of 120 mg to the patients following a 4-week placebo period. Nine of the patients also took atorvastatin 20 mg daily during active treatment. HDL cholesterol levels climbed by 46% and 61% with torcetrapib alone and that agent plus atorvastatin, respectively. Among six patients who did not receive atorvastatin, an additional 4 weeks of torcetrapib in doses of 120 mg twice daily had HDL cholesterol that were increased by 106%. Torcetrapib also significantly increased mean particle size of HDL and LDL, the authors noted. (M. E. Brousseau, margaret.brousseau@tufts.edu)

Cinacalcet Treatment: Results of the pivotal clinical trial of cinacalcet, recently approved for marketing in the U.S. for treatment of secondary hyperparathyroidism in chronic kidney disease patients on dialysis and treatment of hypercalcemia in patients with parathyroid carcinoma (see PNN, Mar. 10), are presented (pp. 1516-25). Once-daily doses were titrated from 30 mg to 180 mg to achieve parathyroid hormone levels of 250 pg/mL or less. At 14 weeks, 43% and 5% of cinacalcet- and placebo-treated patients had reached this endpoint. (G. A. Block, Denver Nephrologists, Denver; gablock@denverneph.net)

OTC Emergency Contraception: Editorialists maintain that FDA’s recent decision to delay a decision on the Rx-to-OTC switch of levonorgestrel for emergency contraception was “influenced by political considerations” (pp. 1561-2). The writers reject any need for proof of age for those purchasing Plan B or for keeping the product behind pharmacy counters or in the direct view of the pharmacist. Arguing that OTC availability of emergency contraception makes good medical sense, they urge FDA to move ahead swiftly with approval. (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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 9, 2004 Vol. 11, No. 68
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Apr. Pharmacotherapy (www.accp.com; 2004; 24).

Core Clinical Pharmacy Services: Five core clinical pharmacy services could be offered throughout U.S. hospitals with minimal increases in pharmacist staffing, according to an analysis of 1998 data (pp. 427-40). Providing 14 services to 100% of inpatients by 2020 would require an increase of 37,814 FTEs in pharmacist staffing levels, and the 1998 level in hospitals was only 45,734 pharmacist FTEs, with just 17,325 of these FTEs were devoted to clinical pharmacy services. However, the authors explain, focusing on core services (drug information, adverse drug reaction management, drug protocol management, medical rounds, and admission drug histories) could be accomplished with a national increase of 14,508 pharmacist FTEs.

“The average U.S. hospital (based on an average daily census of 108.97 ± 169.45 patients) would need to add a maximum of 3.32 pharmacist FTEs to provide these core clinical services,” the research group notes. “Using this evidence-based approach, the five selected core clinical pharmacy services could be provided with only modest increases in clinical pharmacist staffing.”

The feasibility of implementing the above scenario is assessed in a second article by the same authors (pp. 441-52). Projecting a net increase in pharmacists of 139,929 between 2000 and 2020 (a 71% increase in supply) and citing a current increase of 100,000 pharmacy technicians between 1996 and 2002, the investigators write, “It is feasible, based on manpower, marketplace factors, and pharmacy leadership, to implement a core set of clinical pharmacy services for patients in U.S. hospitals by 2020.” (C. A. B. Bond, cab.bond@ttuhsc.edu)

Grapefruit Juice & Itraconazole: Systemic availability of itraconazole is moderately increased by repeated administration of grapefruit juice, according to a study conducted in 20 healthy adult volunteers (pp. 460-7). The 10 men and 10 women consumed grapefruit juice or bottled water three times daily for 2 days before taking a single dose of a hydroxypropyl-beta-cyclodextrin formulation of itraconazole that enhances the drug’s gastric solubility. Areas under the serum concentration–time curve were significantly increased during concomitant administration, and apparent oral clearance of itraconazole dropped by 14%. The authors note that the observed changes are “consistent with grapefruit juice inhibition of intestinal cytochrome P450 3A4.” (P. O. Gubbins, U. Arkansas, gubbinspaulo@uams.edu)

CSF Costs in Patients at Risk for Neutropenia: Prophylactic use of colony-stimulating factors is supported by a cost–benefit analysis of 26 patients at risk for severe neutropenia secondary to cancer chemotherapy (pp. 488-94). A cost-minimization model that included some direct costs “showed cost neutrality ... when the risk of hospitalization for febrile neutropenia was approximately 23%.” The authors add, “Including previously excluded direct costs and indirect costs ranging from $1000–5000 attributable to severe neutropenia ... lowered the risk threshold [for cost neutrality] to between 22% and 18%.” (L. E. Cosler, Albany College of Pharmacy, coslerl@acp.edu)

HRT Discontinuation & WHI Publicity: Highly publicized, negative outcomes data can quickly affect pharmacotherapy prescribing decisions, according to a study of hormone-replacement therapy discontinuations after release of data from the Women’s Health Initiative (pp. 495-9). A retrospective chart review in a university family medicine clinic identified 98 postmenopausal women with intact uteri who were receiving HRT around the time the data were released in July 2002. A time-to-event analysis showed that women were significantly more likely to have HRT stopped after the WHI data were released than beforehand. In a subset of 85 women who were taking HRT in July 2001, discontinuation of HRT occurred in 8% of women during the year preceding the 2002 WHI publicity and in 38% of women within 6 months afterwards. Of the post-WHI discontinuations, 80% occurred within 3 months of the release of data. (J. J. Saseen, joseph.saseen@uchsc.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 12, 2004 Vol. 11, No. 69
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Apr. 10 issue of BMJ (www.bmj.org; 2004; 328).

Antidepressants in Pediatrics: Because of deficiencies in clinical trial methods and biased reporting of results, antidepressant drugs cannot confidently be recommended as a treatment option for childhood depression, argue authors of a clinical review article (pp. 879-83). Six clinical studies were included in the analysis, all of them randomized, placebo-controlled trials. “The trials consistently found large improvements in placebo groups, with statistically significant additional benefits for active drug on some measures only,” the group writes. “These results make a major benefit from newer antidepressants unlikely, but a small benefit remains possible. Randomised controlled trials usually underestimate the serious adverse effects of drugs. The fact that serious adverse effects with newer antidepressants are common enough to be detected in randomised controlled trials raises serious concerns about their potential for harm. The magnitude of benefit is unlikely to be sufficient to justify risking those harms, so confidently recommending these drugs as a treatment option, let alone as first line treatment, would be inappropriate.” (J. N. Jureidini, Women’s and Children’s Hosp., North Adelaide, Australia; jureidinij@wch.sa.gov.au)

Corticosteroid Injections for Osteoarthritis of Knees: Intra-articular corticosteroid injections provide short- and long-term improvement in symptoms of osteoarthritis of the knee, conclude authors of a meta-analysis (pp. 869 ff). Combining data from 10 studies that met selection criteria, the authors found, “The pooled relative risk for improvement in symptoms of osteoarthritis of the knee at 16–24 weeks after intra-articular corticosteroid injections was 2.09 (95% confidence interval 1.2 to 3.7) and the number needed to treat was 4.4. The pooled relative risk for improvement up to two weeks after injections was 1.66 (1.37 to 2.0). The numbers needed to treat to get one improvement in the statistically significant studies was 1.3 to 3.5 patients.”(B. Arroll, U. Auckland, Auckland, New Zealand; b.arroll@auckland.ac.nz)

>>>Lancet Report
Source:
Apr. 10 issue of Lancet (www.thelancet.com; 2004; 363).

Heart Disease with Pergolide for PD:
Restrictive valvular heart disease was found in 33% of 78 patients taking pergolide, compared with none of 18 control patients (pp. 1179-83). “Significant correlation was noted between cumulative doses of pergolide and tenting areas of the mitral valves (r = 0.412, p = 0.017),” the researchers report. “Mean systolic pulmonary artery pressures were 39.3 mm Hg (range 25–71) in the high-dose group versus 38.5 mm Hg (20– 65) in the low-dose group (p = 0.76) and 31 mm Hg (25–40) in controls (p = 0.02 vs all patients given pergolide). In six patients, pergolide treatment was stopped because of restrictive valvular heart disease, in two of whom regression of disease was shown.” (G. Van Camp, Free U. Brussels, Brussels, Belgium; guy.vancamp@az.vub.ac.be)

>>>PNN JournalWatch
* Workplace Expansion, Long-Term Sickness Absence, and Hospital Admission, in Lancet, 2004; 363: 1193–7. Reprints: www.thelancet.com; H. Westerlund, National Inst. for Psychosocial Med., Falköping, Sweden; hugo.westerlund@ipm.ki.se

* Commonly Used Types of Postmenopausal Estrogen for Treatment of Hot Flashes: Scientific Review, in
JAMA, 2004; 291: 1610–20. Reprints: www.jama.com; H. D. Nelson, Oregon Health and Science U., Portland; nelsonh@ohsu.edu

* Targeted Anticytokine Therapy in Patients with Chronic Heart Failure: Results of the Randomized Etanercept Worldwide Evaluation (RENEWAL), in
Circulation, 2004; 109: 1594–602. Reprints: circ.ahajournals.org; D. L. Mann.

* A Walnut Diet Improves Endothelial Function in Hypercholesterolemic Subjects: A Randomized Crossover Trial , in
Circulation, 2004; 109: 1609–14. Reprints: circ.ahajournals.org; E. Ros.

* Co-occurrence of 12-Month Alcohol and Drug Use Disorders and Personality Disorders in the United States, in
Archives of General Psychiatry, 2004; 61: 361–8. Reprints: archpsyc.ama-assn.org; B. F. Grant, bgrant@willco.niaaa.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 13, 2004 Vol. 11, No. 70
Providing news and information about medications and their proper use

>>>Internal Medicine Update
Source: Apr. 12 issue of Archives of Internal Medicine (www.archinternmed.com; 2004; 164).

CPOE & Prescribing Errors: Pharmacists are a necessary element in safe prescribing patterns, even after computerized medication order entry systems are implemented, according to a study in a 700-bed academic medical center in Chicago (pp. 785-92). Medication orders that contained prescribing errors from 1 week in early 2002 were later classified and rated as to the likelihood of CPOE preventing the mistake. “A total of 1111 prescribing errors were identified (62.4 errors per 1000 medication orders), most occurring on admission (64%),” the authors report. “Of these, 30.8% were rated clinically significant and were most frequently related to anti-infective medication orders, incorrect dose, and medication knowledge deficiency. Of all verified prescribing errors, 64.4% were rated as likely to be prevented with CPOE (including 43% of the potentially harmful errors), 13.2% unlikely to be prevented with CPOE, and 22.4% possibly prevented with CPOE depending on specific CPOE system characteristics.”

The researchers conclude, “While CPOE systems could improve practitioner prescribing, design and implementation of a CPOE system should focus on errors with the greatest potential for patient harm. Pharmacist involvement, in addition to a CPOE system with advanced clinical decision support, is vital for achieving maximum medication safety.” (A. Bobb, Northwestern Mem. Hosp., Chicago; abobb@nmh.org)

Niacin Therapy: Extended-release niacin offers a preferred dosing and adverse effects profile in treating patients with lipid disorders, according to a review article (pp. 697-705). “Niacin is currently available in 3 formulations (immediate release, extended release, and long acting), which differ significantly with respect to their safety and efficacy profiles,” writes the author. “Immediate-release niacin is generally taken 3 times a day and is associated with adverse flushing, gastrointestinal symptoms, and elevations in blood glucose levels. Long-acting niacin can be taken once daily and is associated with significantly reduced flushing, but its metabolism increases the risk of hepatotoxic effects. Extended-release niacin, also given once daily, has an absorption rate intermediate between the other formulations and is associated with fewer flushing and gastrointestinal symptoms without increasing hepatotoxic risk.”(J. McKenney, Natl. Clinical Research, Richmond; jmckenney@ncrinc.net)

Treatment of Hypertension: Reduction in the number of daily doses should be a first-line approach in patients who are not adherent to antihypertensive medications, according to a systematic review of 38 studies of 15,519 patients (pp. 709-20). “Simplifying dosing regimens increased adherence in 7 of 9 studies, with a relative increase in adherence of 8% to 19.6%,” the reviewers found. “Motivational strategies were partly successful in 10 of 24 studies with generally small increases in adherence up to a maximum of 23%. Complex interventions comparing more than 1 technique increased adherence in 8 of 18 studies, ranging from 5% to a maximum of 41%. Patient education alone seemed largely unsuccessful.” (K. Schroeder, U. Bristol, Bristol, U.K.; k.schroeder@bristol.ac.uk)

Stroke & Low-Dose OCs: Any relationship between use of low-dose oral contraceptives and stroke is “tenuous at best and perhaps nonexistent,” conclude authors who evaluated data from 4 cohort and 16 case–control studies (pp. 741-7). Case–control studies showed a significantly increased odds ratio (2.13; 95% CI, 1.59–2.86), but only thrombotic strokes occurred more often (OR, 2.74; 95% CI, 2.24–3.35). Further, the cohort studies (considered the most powerful of observational methods) showed no effect (OR, 0.95; 95% CI, 0.51–1.78). “If such an association exists, it has probably been exaggerated, particularly in women younger than 35 years who are normotensive and do not smoke,” add the authors. (W-S Chan, Sunnybrook and Women’s College Health Sci. Ctr., Toronto; wee-shian.chan@sw.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 14, 2004 Vol. 11, No. 71
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Apr. 14 issue of JAMA (www.jama.com; 2004; 291).

More on ERT from WHI: Estrogen-replacement therapy provides no overall benefit for chronic disease prevention in postmenopausal women with previous hysterectomy but does appear to increase the risk of stroke and decrease the risk of hip fracture, according to analysis of estrogen-only data from the Women’s Health Initiative (pp. 1701-12). In 10,739 postmenopausal women with hysterectomy, conjugated equine estrogen 0.625 mg daily was tested for its effects on major disease incidence rates. Based on data for the major clinical outcomes available through February 29, 2004 (when the trial was terminated early), the researchers found that with an average of 6.8 years of follow-up, CEE had no significant effect on reducing the risk of coronary artery disease (376 cases) but did cause a significant 39% increase (in risk of stroke (276 cases). CEE significantly reduced the risk of hip fracture (39% reduction, 102 cases), was associated with a nonsignificant reduction in risk of breast cancer (218 cases), and had no significant effect on risk of pulmonary embolism (85 cases) or colorectal cancer (119 cases).

Corresponding results for composite outcomes were a significant increase (12%) in the risk of total cardiovascular disease, and a significantly decreased risk (30%) of total fractures, but no significant effect on total cancer, total mortality, and a global index . For the outcomes significantly affected by CEE, there was an absolute excess risk of 12 additional strokes per 10,000 person-years and an absolute risk reduction of 6 fewer hip fractures per 10,000 person-years. The estimated excess risk for all monitored events in the global index was a nonsignificant 2 events per 10,000 person-years.

“Based on these findings, women and their health care professionals now have usable risk estimates for the benefits and harms of CEE alone,” the researchers write. “Women considering taking CEE should be counseled about an increased risk of stroke but can be reassured about no excess risk of heart disease or breast cancer for at least 6.8 years of use. At present, these data demonstrate no overall benefit of CEE for chronic disease prevention in postmenopausal women and thus argue against its use in this setting. Overall, these data support the current U.S. Food and Drug Administration recommendations for postmenopausal women to use CEE only for menopausal symptoms at the smallest effective dose for the shortest possible time.” (WHI Clinical Coordinating Center, Fred Hutchinson Cancer Res. Ctr., Seattle)

Editorialists favor estrogen only over estrogen–progestin for treatment of menopausal symptoms (pp. 1769-71). For prevention of chronic disease, they offer this advice: “In the absence of evidence for an overall net benefit of postmenopausal treatment with estrogen alone, and with the evidence that estrogen plus progestin is harmful, neither therapy should be used for preventing disease. Although it is possible that other forms or doses of hormones could be more beneficial, this must be demonstrated in disease–end point trials before any hormone regimen can be recommended for disease prevention. Fortunately, there are other good approaches to preventing [coronary artery disease] and fractures for which trials have found benefits to outweigh harms.” (S. B. Hulley, UCSF)

>>>PNN NewsWatch
* On the first anniversary of the implementation of the Health Insurance Portability Accountability Act, Cutting Edge Information (www.PharmaSalesManagement.com) notes that pharmaceutical companies report up to a 25% drop in physician access for sales representatives as a result of overall caution associated with the regulations.

* Among the approaches being developed to combat
pharmaceutical counterfeiting are tablet and capsule fingerprinting, use of holograms and color-shifting ink, barcodes printed directly onto the tablets and capsules themselves, and use of radiofrequency identification, Associated Press reports.

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 15, 2004 Vol. 11, No. 72
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Apr. 15 issue of the New England Journal of Medicine (content.nejm.org; 2004; 350).

Genomic Approaches to Leukemias: Two articles, an editorial, and a perspectives article detail how analysis of multiple genes—a genomic approach to the discovery of biomarkers—is changing the way researchers approach trials of therapies for leukemias.

Gene-expression profiling improves the molecular classification of acute myeloid leukemia, conclude authors who used complementary-DNA microarrays to determine the levels of gene expression in peripheral-blood or bone marrow samples from 116 adults with the disease (pp. 1605-16). “Unsupervised analysis identified new molecular subtypes of AML, including two prognostically relevant subgroups in AML with a normal karyotype,” the researchers write. “Using the supervised learning algorithm, we constructed an optimal 133-gene clinical-outcome predictor, which accurately predicted overall survival among patients in the independent validation group (P = 0.006), including the subgroup of patients with AML with a normal karyotype (P = 0.046). In multivariate analysis, the gene-expression predictor was a strong independent prognostic factor (odds ratio, 8.8; 95 percent confidence interval, 2.6 to 29.3; P < 0.001).” (J. R. Pollack, pollack1@stanford.edu)

Similar results come from a study of 285 patients with AML, with investigators concluding that “gene-expression profiling allows a comprehensive classification of AML that includes previously identified genetically defined subgroups and a novel cluster with an adverse prognosis” (pp. 1617-28). In identifying 16 groups of patients with similar genetic clusters, the researchers found, “Clustering was driven by the presence of chromosomal lesions (e.g., t(8;21), t(15;17), and inv(16)), particular genetic mutations (
CEBPA), and abnormal oncogene expression (EVI1). We identified several novel clusters, some consisting of specimens with normal karyotypes. A unique cluster with a distinctive gene-expression signature included cases of AML with a poor treatment outcome.” (P. J. M. Valk, Erasmus U. Med. Ctr., Rotterdam, the Netherlands; p.valk@erasmusmc.nl)

Editorialists provide this broader perspective on gene profiling (pp. 1676-8): “Gene-expression profiling has already yielded considerable insights into other hematologic cancers, such as diffuse large-B-cell lymphoma, and solid tumors, such as breast carcinoma. The studies of AML by Valk et al. and Bullinger et al. set the scene for investigations that will use this technique to answer fundamental questions concerning the biology of AML and its response to therapy. We anticipate further insights in cases of AML with no known molecular markers. Moreover, these types of studies will inform us about associations between genetic lesions that predict a poor outcome and mechanisms of drug resistance. Although the results of gene-expression profiling may predict the outcome of various cancers, clinically significant increases in overall cure rates are unlikely to be achieved through improvements in risk stratification alone. For this reason, a more ambitious aim of gene-expression profiling should be to characterize the hierarchy of leukemic stem cells and determine the differences between leukemic stem cells and their normal counterparts. This undertaking is fundamental to the development of treatments that can eliminate the neoplastic clone at its source, rather than target the nonclonogenic progeny that constitute the bulk of the tumor burden.” (D. Grimwade, King’s and St. Thomas’ Sch. of Med., London)

Glucocorticoid Therapy in Critically Ill Patients: Unnecessary glucocorticoid therapy could be avoided by measuring serum free cortisol concentrations in critically ill patients, according to a study of 66 such patients and 33 healthy volunteers (pp. 1629-38). In the study, 36 critically ill patients were hypoproteinemic, and their free cortisol levels were in the same range as 30 critically ill patients with near-normal serum albumin concentrations. Cortisol levels in both patient groups were several times higher than among control subjects. (B. M. Arafah, U. Hosp., Cleveland; bxa@po.cwru.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 16, 2004 Vol. 11, No. 73
Providing news and information about medications and their proper use

>>>Pediatrics Highlights
Source:
Apr. issue of Pediatrics (www.pediatrics.org; 2004; 113).

ADHD Treatment: Benefits of 14 months of intensive intervention diminished over the next 10 months in 540 children with attention-deficit/hyperactivity disorder (pp. 754-61). In the Multimodal Treatment Study of ADHD (MTA), continuing medication use made difficult the assessment of the comparative long-term benefits of medication management, behavior-modification therapy, the combination of those two strategies, and usual care. The MTA medication strategy continued to be significantly superior to behavioral therapy and usual care for ADHD and oppositional-defiant symptoms at 24 months, but the differences were smaller than at the end of the intervention phase at 14 months. The medication-management and combination therapy groups were taking significantly higher mean doses of methylphenidate, leading the authors to surmise that drug therapy was mediating the “persisting superiority” of medication-based interventions. (MTA Cooperative Group)

Antibiotic Therapy for Tonsillitis: Compared with oral penicillins, oral cephalosporins provide significantly lower bacteriologic and clinical failure rates in children with group A beta-hemolytic streptococcal tonsillopharyngitis, according to a meta-analysis of 35 trials involving 7,125 patients (pp. 866-72). The authors find, “The overall summary odds ratio (OR) for the bacteriologic cure rate significantly favored cephalosporins compared with penicillin (OR: 3.02; 95% confidence interval [CI]: 2.49–3.67, with the individual cephalosporins [cephalexin, cefadroxil, cefuroxime, cefpodoxime, cefprozil, cefixime, ceftibuten, and cefdinir] showing superior bacteriologic cure rates). The overall summary OR for clinical cure rate was 2.33 (95% CI: 1.84–2.97), significantly favoring the same individual cephalosporins. There was a trend for diminishing bacterial cure with penicillin over time, comparing the trials published in the 1970s, 1980s, and 1990s. Sensitivity analyses for bacterial cure significantly favored cephalosporin treatment over penicillin treatment when trials were grouped as double-blind (OR: 2.31; 95% CI: 1.39–3.85), high-quality (OR: 2.50; 95% CI: 1.85–3.36) trials with well-defined clinical status (OR: 2.12; 95% CI: 1.54–2.90), with detailed compliance monitoring (OR: 2.85; 95% CI: 2.33–3.47), with GABHS serotyping (OR: 3.10; 95% CI: 2.42–3.98), with carriers eliminated (OR: 2.51; 95% CI: 1.55–4.08), and with test of cure 3 to 14 days posttreatment (OR: 3.53; 95% CI: 2.75–4.54). Analysis of comparative bacteriologic cure rates for the 3 generations of cephalosporins did not show a difference.” (J. R. Casey, U. Rochester, Rochester)

Online TPN Calculator: Errors were reduced through use of a low-cost online system for total parenteral nutrition order entry in a newborn intensive-care unit (pp. 748-53). Comparing the time periods before (control), immediately after the TPN calculator was developed (intervention 1), and 2 years later (intervention 2), the researchers recorded these results: “During the control period, an average of 10.8 errors were detected per 100 TPN orders compared with 4.2 per 100 orders in the first intervention period (61% reduction of error rate) and 1.2 per 100 orders after 2 years and some redesign of TPN Calculator (89% reduction of error rate). We found a reduction in the following types of problems (intervention 1; intervention 2): calculation errors (100%; 100%), osmolality outside the allowed range (88%; 91%), and other knowledge problems (84%; 100%). There was a 35% increase in the number of incomplete forms in the first intervention period and a 100% reduction in the second.” (C. U. Lehmann, Johns Hopkins U., Baltimore)

Emesis & Activated Charcoal: About 1 in 5 children who were given activated charcoal in a pediatric emergency department vomited, and the rate was higher among those with histories of vomiting or nasogastric tube administration (pp. 806-10). In the 275-patient study, the median time to vomiting was 10 minutes among the 56 children who vomited. Age greater than 12 years was an additional risk factor that approached but did not reach significance. (K. C. Osterhoudt, Children’s Hosp., 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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 19, 2004 Vol. 11, No. 74
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
Apr. 17 issue of Lancet (www.thelancet.com; 2004; 363).

2NN Study Compares NNRTIs: First-line treatment of HIV infection with three-drug regimens that included either nevirapine or efavirenz (but not both) are appropriate based on results of the 2NN study (pp. 1253-63). In this comparison of nonnucleoside reverse-transcriptase inhibitors, 1,216 patients took nevirapine 400 mg once daily, nevirapine 200 mg twice daily, efavirenz 600 mg once daily, or nevirapine 400 mg and efavirenz 800 mg once daily, plus stavudine and lamivudine, for 48 weeks. “There were no significant differences among the study groups in the proportions with plasma HIV-1 RNA concentrations below 50 copies per mL at week 48 (p = 0.193) or the increases in CD4-positive cells (p = 0.800),” the authors report. “Nevirapine plus efavirenz was associated with the highest frequency of clinical adverse events, and nevirapine once daily with significantly more hepatobiliary laboratory toxicities than efavirenz. Of 25 observed deaths, two were attributed to nevirapine.” (J. M. A. Lange, U. Amsterdam, Amsterdam, the Netherlands; j.lange@amc.uva.nl)

An editorialist makes these predictions about HIV therapy (pp. 1248-50):“What does the future hold? It could include: once-daily therapy (there are about ten such drugs), co-formulations (there are three dual combinations of nucleoside-analogue reverse-transcriptase inhibitors in developed countries, and four combinations of nucleoside and non-nucleoside-analogue inhibitors in the developing world), and antiretroviral therapy on the basis of potency and patients’ co-morbidity and preference rather than on drug class itself. Studies of antiretroviral therapy in previously untreated adults will ideally be placebo-controlled, include active collection of all known related adverse events and their effect on adherence, report on resistance, and primary comparisons will be made after at least 2 years. Then we will be able to translate clinical trial results more confidently to routine care of patients.” (A. Carr, St. Vincent’s Hosp., Sydney; acarr@stvincents.com.au)

Alcohol & Gout: While a new study confirms that alcohol intake is associated with risk of gout, the type of beverage consumed made a surprising difference (pp. 1277-81). In this study of 47,150 participants who were followed for 12 years, 730 cases of gout were identified. Increasing levels of alcohol intake were associated with increased risks of gout, with risk elevated by 2.5 times among men who drank more than 50 grams of alcohol per day. “Beer consumption showed the strongest independent association with the risk of gout (multivariate [relative risk] per 12-oz serving per day 1.49; 95% CI 1.32–1.70),” the authors noted. “Consumption of spirits was also significantly associated with gout (multivariate RR per drink or shot per day 1.15; 95% CI 1.04–1.28); however, wine consumption was not (multivariate RR per 4-oz serving per day 1.04; 95% CI 0.88–1.22).” (H. K. Choi, Mass. Genl. Hosp., Boston; hchoi@partners.org)

>>>PNN JournalWatch
* Pertussis Vaccination in Infancy and Asthma or Allergy in Later Childhood: Birth Cohort Study, in BMJ, 2004; 328: 925–6. Reprints: www.bmj.org; A. Maitra, Royal Hosp. for Children, Bristol, U.K.; dramaitra@yahoo.co.uk

* Treatment of Anxiety and Depressive Disorders in Patients with Cardiovascular Disease, in
BMJ, 2004; 328: 939–43. Reprints: www.bmj.org; S. J. C. Davies, Psychopharmacology Unit, Dorothy Hodgkin Building, Bristol, U.K.; simon.davies@bristol.ac.uk

* Regenerative Capacity of the Myocardium: Implications for Treatment of Heart Failure, in
Lancet, 2004; 363: 1306–13. Reprints: www.thelancet.com; R. von Harsdorf, Humboldt-Universität, Berlin, Germany; ruediger.harsdorf@charite.de

* Keeping Your Patient with Heart Failure Safe: A Review of Potentially Dangerous Medications, in
Archives of Internal Medicine, 2004; 164: 709–20. Reprints: www.archinternmed.com; C. M. Amabile, Maricopa Integrated Health System, Phoenix; celene.amabile@hcs.maricopa.gov

* Management of Cirrhosis and Ascites, in
New England Journal of Medicine, 2004; 350: 1646–54. Reprints: content.nejm.org; P. Ginès, Hosp. Clinic, Barcelona, Spain; gines@medicina.ub.es

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 20, 2004 Vol. 11, No. 75
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Apr. 20 issue of the Annals of Internal Medicine (www.annals.org; 2004; 140).

Lipid Control in Type 2 DM: The Clinical Efficacy Assessment Subcommittee of the American College of Physicians provides these guidelines for management of dyslipidemia, particularly hypercholesterolemia, in people with type 2 diabetes mellitus (pp. 644-9; V. Snow, vincenza@acponline.org):

1—Lipid-lowering therapy should be used for secondary prevention of cardiovascular mortality and morbidity for all patients (both men and women) with known coronary artery disease and type 2 diabetes.

2—Statins should be used for primary prevention against macrovascular complications in patients (both men and women) with type 2 diabetes and other cardiovascular risk factors.

3—Once lipid-lowering therapy is initiated, patients with type 2 diabetes mellitus should be taking at least moderate doses of a statin.

4—For those patients with type 2 diabetes who are taking statins, routine monitoring of liver function tests or muscle enzymes is not recommended except in specific circumstances.

In a background paper prepared for the ACP subcommittee, authors who assessed the published literature through Sept. 2002 make these observations about their meta-analysis of six primary-prevention studies (pp. 650-8): “Lipid-lowering medications reduced risks for cardiovascular outcomes (relative risk, 0.78 [95% CI, 0.67 to 0.89]; absolute risk reduction, 0.03 [CI, 0.01 to 0.04] in 4.3 years of treatment); 1 major cardiovascular event was prevented by treating 34 to 35 patients. Meta-analysis of 8 studies of secondary prevention showed a similar relative risk (0.76 [CI, 0.59 to 0.93]) but more than twice the absolute risk reduction (0.07 [CI, 0.03 to 0.12] in 4.9 years of treatment) and a number needed to treat for benefit of 13 to 14. Most studies compared a lipid-lowering drug with placebo but did not evaluate the effect of reaching specific cholesterol levels. The benefit of lipid lowering with a fixed dose of a statin appeared to be similar regardless of starting cholesterol levels.” (S. Vijan, svijan@umich.edu)

Alcohol Intake & Colorectal Cancer: The rate of colorectal cancer was modestly elevated with the highest rate of alcohol intake in an analysis of 489,979 patients from North America and Europe (pp. 603-13). Pooling data from eight cohort studies in five countries, the investigators identified 4,687 cases of colorectal cancer during 6 to 16 years of follow-up. They note: “Increased risk for colorectal cancer was limited to persons with an alcohol intake of 30 g/d or greater (approximately 2 drinks/d), a consumption level reported by 4% of women and 13% of men. Compared with nondrinkers, the pooled multivariate relative risks were 1.16 (95% CI, 0.99 to 1.36) for persons who consumed 30 to less than 45 g/d and 1.41 (CI, 1.16 to 1.72) for those who consumed 45 g/d or greater. No significant heterogeneity by study or sex was observed. The association was evident for cancer of the proximal colon, distal colon, and rectum. No clear difference in relative risks was found among specific alcoholic beverages.” (E. Cho, eunyoung.cho@channing.harvard.edu)

Severity of SARS: Little evidence of subclinical or mild cases of the coronavirus associated with severe acute respiratory syndrome was found in a study of 910 patients who presented during last year’s outbreak in Hong Kong and were managed without hospitalization (pp. 614-9). Only six of these patients had serologic evidence of SARS, and five of those patients had normal chest radiographs. Four had symptoms such as myalgia, chills, coughing, and feeling feverish, the authors report. (T. H. Rainer, Chinese U. of Hong Kong, Shatin, Hong Kong; rainer1091@cuhk.edu.hk)

d-Dimers for VT Diagnosis: For excluding pulmonary embolism or deep-vein thrombosis, a negative result on a quantitative rapid ELISA test of d-dimers is as useful as a normal lung scan or negative duplex ultrasonography finding, conclude authors of a systematic review (pp. 589-602; P. D. Stein, Saint Joseph Mercy-Oakland, Pontiac, Mich.; steinp@trinity-health.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 21, 2004 Vol. 11, No. 76
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Apr. 21 issue of JAMA (www.jama.com; 2004; 291).

Cost, Evidence, & Hypertension: Savings of $1.2 billion nationally would be possible if clinicians more closely adhered to evidence-based recommendations for treatment of hypertension, according to an analysis conducted from the perspective of a health plan (pp. 1850-6). Using data on 133,624 patients treated for hypertension in 2001 and enrolled in a large state pharmaceutical assistance program for the elderly, the authors found, “The patients studied filled more than 2.05 million prescriptions for antihypertensive medications in 2001, at an annual program cost of $48.5 million ($363 per patient). We identified 815,316 prescriptions (40%) for which an alternative regimen appeared more appropriate according to evidence-based recommendations. Such changes would have reduced the costs to payers in 2001 by $11.6 million (nearly a quarter of program spending on antihypertensive medications), as well as being more clinically appropriate overall. Replacement of calcium channel blockers resulted in the largest potential savings. Use of pricing limits similar to those in the Medicaid program would have resulted in even larger potential savings of $20.5 million (42% of program costs).” (M. A. Fischer, Brigham and Women’s Hosp., Boston; mfischer@partners.org)

Lipid-Lowering Therapy for High-Risk Elderly Patients: In a paradoxical relationship, the fraction of older patients prescribed statins for lipid lowering declines as risk increases, according to a retrospective cohort study of 1.4 million Ontario residents aged 66 years or older (pp. 1864-70). Among 396,077 patients with histories of cardiovascular disease or diabetes while undergoing medical treatment and who were alive on April 1, 1998, the investigators determined that “Only 75,617 patients (19.1%) in this secondary prevention cohort were prescribed statins. In patients 66 to 74 years old, the adjusted probabilities of statin prescription were 37.7%, 26.7%, and 23.4% in the categories of low, intermediate, and high baseline risk, respectively. The likelihood of statin prescription was 6.4% lower (adjusted odds ratio, 0.94; 95% confidence interval, 0.93-0.95) for each year of increase in age and each 1% increase in predicted 3-year mortality risk. The influence of age also interacted synergistically with baseline risk on the prescription of statins (P < .001).”

“Given the importance of baseline risk in determining the impact of therapy in the population, the treatment-risk paradox implies that the survival benefits of statin therapy may never be fully realized until physicians appropriately attune their prescribing behaviors to the risk profiles of their patients,” conclude the authors. (D. A. Alter, Inst. for Clinical Evaluative Sci., Toronto; david.alter@ices.on.ca)

Treating Depression & Dependence: Patients with depression and comorbid substance-abuse disorders require therapy for the addiction in addition to antidepressant medication, according to a meta-analysis of 14 clinical trials of 848 patients (pp. 1887-96). Effect sizes were measured using the standardized difference between means on the Hamilton Depression Scale. “Antidepressant medication exerts a modest beneficial effect for patients with combined depressive- and substance-use disorders,” report the researchers. “It is not a stand-alone treatment, and concurrent therapy directly targeting the addiction is also indicated. More research is needed to understand variations in the strength of the effect, but the data suggest that care be exercised in the diagnosis of depression–either by observing depression to persist during at least a brief period of abstinence or through efforts by clinical history to screen out substance-related depressive symptoms.”

“Antidepressant treatment may have a limited impact on alcohol or other drug use, and attention is needed in the treatment plan to specific psychosocial or pharmacologic interventions targeting addiction itself,” the authors conclude. “At the same time, this should not detract from the importance of treating depression, given growing evidence of its adverse prognostic implications in a variety of health domains.” (E. V. Nunes, nunesed@pi.cpmc.columbia.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 22, 2004 Vol. 11, No. 77
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Apr. 22 issue of the New England Journal of Medicine (content.nejm.org; 2004; 350).

Postsurgical Chemotherapy for Lung Cancer: The combination of uracil–tegafur (UFT) may represent a new standard of care in the postsurgical management of patients with resected stage I lung adenocarcinoma, based on results of a 979-patient study (pp. 1713-21). Tegafur is a prodrug that is converted by the liver to 5-fluorouracil, and the combination is administered in a molar ratio of 4:1 (uracil:tegafur). Uracil acts as a competitive inhibitor of 5-FU catabolism.

Patients were randomly assigned to receive postsurgical oral UFT (tegafur 250 mg/sq m) for 2 years or no treatment. The authors report, “The median duration of follow-up for surviving patients was 73 months. The difference in overall survival between the two groups was statistically significant in favor of the uracil– tegafur group (P = 0.04 by a stratified log-rank test). Grade 3 toxic effects occurred in 10 of the 482 patients (2 percent) who actually received uracil–tegafur.... Treatment with uracil–tegafur tended to improve the survival rate among patients with a tumor that was 2 to 3 cm in diameter and provided a definitive survival benefit for patients with a tumor that was more than 3 cm in diameter.” (Y. Ichinose, Natl. Kyushu Cancer Ctr., Notame, Minami-ku, Fukuoka, Japan; yichinos@nk-cc.go.jp)

Commenting on this study, an editorialist notes (pp. 1777-9): “A few potent inhibitors of dihydropyrimidine dehydrogenase (e.g., eniluracil) have been examined in combination with fluorouracil in clinical trials for the treatment of tumor types other than non–small-cell lung cancer, but the effects of the newer fluoropyrimidines that inhibit dihydropyrimidine dehydrogenase, such as S-1, a recently developed combination of tegafur, 5-chloro-2,4-dihydroxypyridine (a dihydropyrimidine dehydrogenase inhibitor), and oxonic acid (which is thought to decrease the incidence of diarrhea, a common toxic effect of fluoropyrimidines), have yet to be studied. If adjuvant chemotherapy with uracil–tegafur improves survival among patients with adenocarcinoma of the lung, as several studies now suggest, the effect of S-1 on survival may be even greater.” (R. B. Diasio, U. Alabama, Birmingham)

Epinephrine Doses in Pediatric Cardiac Arrest: High-dose epinephrine therapy provides no advantage over and may be worse than standard doses in children in cardiac arrest, conclude authors of a study of 68 children with average ages of 62–74 months (pp. 1722-30). High-dose (0.1 mg/kg) or standard-dose epinephrine (0.01 mg/kg) was administered as rescue therapy in hospital wards, intensive care units, or emergency departments. “The rate of survival at 24 hours was lower in the group assigned to a high dose of epinephrine as rescue therapy than in the group assigned to a standard dose: 1 of the 34 patients in the high-dose group survived for 24 hours, as compared with 7 of the 34 patients in the standard-dose group (unadjusted odds ratio for death with the high dose, 8.6; 97.5 percent confidence interval, 1.0 to 397.0; P=0.05),” write the authors. “After adjustment by multiple logistic-regression analysis for differences in the groups at the time of arrest, the high-dose group tended to have a lower 24-hour survival rate (odds ratio for death, 7.9; 97.5 percent confidence interval, 0.9 to 72.5; P = 0.08).” (R. A. Berg, rberg@peds.arizona.edu)

Physician Supply: After analyzing the ebb and flow of the supply of physicians in the U.S., a writer calls for more frequent assessments of this supply and less emphasis on projections that go 20 years into the future (pp. 1780-7): “The drawback of [the short-term] approach is the length of training to become a physician and thus the long lag in time between the implementation of policy interventions and any resultant changes in the number of physicians. Increasing the frequency of assessments of the physician workforce will not necessarily lead to a more effective and rational workforce policy, something that seems likely to remain a critical, but elusive, goal for the profession and for the larger society.” (D. Blumenthal)

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 23, 2004 Vol. 11, No. 78
Providing news and information about medications and their proper use

>>>Chest Highlights
Source:
Apr. issue of Chest (www.chestjournal.org; 2004; 125).

Dobutamine for Advanced CHF: In a study of 30 patients with end-stage congestive heart failure, long-term intermittent dobutamine infusion combined with amiodarone plus conventional drugs improved survival (pp. 1198-204). Patients who could be weaned from dobutamine therapy after a first 72-hour infusion randomly received intravenous infusions of placebo (group 1) or dobutamine 10 mcg/kg/min (group 2) for 8 hours every 14 days.

The investigators found: “Kaplan–Meier survival analysis showed a 60% reduction in the risk of death from any cause in the group treated with the combination of dobutamine and amiodarone, compared with the group treated with placebo and amiodarone (hazard ratio, 0.403; 95% confidence interval, 0.164 to 0.992; p = 0.048). The 1-year and 2-year survival rates were 69% and 44%, respectively, in the dobutamine-treated group, vs 28% and 21%, respectively, in the placebo-treated group (p < 0.05 for both comparisons). Median survival times were 574 and 144 days, respectively, for groups 2 and 1. At 6 months, the New York Heart Association functional class was significantly improved in the patients who survived from both groups.” (J. N. Nanas, U. Athens Sch. of Med., Athens, Greece; jnanas@ath.forthnet.gr)

Medication-Associated Sleep Apnea: Use of antihypertensive or antidepressant medications—especially in combination— increases the likelihood of obstructive sleep apnea, according to an analysis of prescription medications for 212,972 patients (pp. 1279-85). “The prevalence rates of OSA were 0.8%, 2.8%, and 3.2% for men and 0.4%, 1.4%, and 1.8% for women aged 20 to 39 years, 40 to 59 years, and 60 years, respectively,” the authors report. “Compared to groups of corresponding age and gender who had not received prescriptions for either hypertension or depression, the highest [prevalence odds ratios] were found in patients receiving medications from both categories: 18.30 (95% CI, 10.69 to 25.66), 5.72 (95% CI, 4.10 to 6.70), and 4.47 (95% CI, 2.45 to 7.01) for men, and 17.43 (95% CI, 9.54 to 28.67), 7.29 (95% CI, 5.20 to 9.29), and 2.72 (95% CI, 1.48 to 4.73) for women.” (R. J. Farney, LDS Hosp., Salt Lake City; rjfmd@msn.com)

Add-On Therapy in Atopic Asthma: Repeated dosing with the mediator antagonists fexofenadine and montelukast improved symptoms after provocation, other surrogate inflammatory markers, and diary outcomes in 18 patients with atopic asthma who were being treated with inhaled corticosteroids (pp. 1372-7). Using adenosine monophosphate bronchial challenge as their primary outcome, the authors found that the drugs improved patients’ responses to provocative concentrations of AMP that caused a 20% fall in expiratory flow, produced spontaneous recovery after AMP challenges, and significantly suppressed levels of exhaled nitric oxide. Only montelukast significantly reduced patients’ peripheral eosinophil counts. “Morning and evening peak expiratory flow were significantly higher (p < 0.05), and the frequency of salbutamol rescue was significantly reduced (p < 0.05) with [fexofenadine] and [montelukast] compared to [placebo],” the authors report. (B. J. Lipworth, Ninewells Hosp. and Med. Sch., U. Dundee, Dundee, Scotland, U.K.; b.j.lipworth@dundee.ac.uk)

Omalizumab Responses in Allergic Asthma: “Patients who benefit most when omalizumab is administered as add-on therapy are those receiving high doses of [beclomethasone], those with a history of frequent emergency asthma treatment, and those with poor lung function,” conclude authors who studied 1,070 subjects with allergic asthma whose symptoms persisted despite moderate or high doses of the steroid (pp. 1378-86). Comparing omalizumab with placebo, the researchers determined that treatment should continue for a minimum of 12 weeks, as only 61% of responders had done so at 4 weeks, compared with 87% at 12 weeks. (J. Bousquet, Hôpital Arnaud de Villeneuve, Montpellier, France; jean.bousquet@wanadoo.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 26, 2004 Vol. 11, No. 79
Providing news and information about medications and their proper use

>>>Apomorphine Approved for ‘Off’ Parkinsonian Periods
FDA last week approved apomorphine (Apokyn—Bertek) for treatment of patients with Parkinson’s disease during episodes of hypomobility. The injectable agent is the first medication approved for use during these “off” periods of PD, and it has been designated an orphan product.

Hypomobility is more common after patients have been treated for PD for 3–5 years. The drug is expected to benefit about 10% of advanced (stage IV) PD patients who are unresponsive to standard medications.
The effectiveness of apomorphine for this indication was established in three randomized, controlled trials of patients who had either end-of-dose or spontaneous hypomobility. On average, patients participating in these trials had had PD for 11.3 years and were being treated with l-dopa and at least one other agent, usually an oral dopamine agonist.

Apomorphine, administered only by subcutaneous injection, must be taken with an antiemetic drug because, when taken alone, it causes severe nausea and vomiting. It must not be taken with ondansetron and other 5-HT3 antagonists because these combinations can result in hypotension and loss of consciousness.

Apomorphine’s labeling includes specific warnings about low blood pressure, fainting, hallucinations, and excessive sleepiness. The most common adverse events observed in controlled trials were yawning, dyskinesias, nausea and vomiting, sedation or sleepiness, dizziness, runny nose, hallucinations, edema, chest pain, increased sweating, flushing, and pallor.

>>>Lancet Report
Source:
Apr. 24 issue of Lancet (www.thelancet.com; 2004; 363).

SSRIs & Childhood Depression: Addition of unpublished data tilts the balance in treating childhood depression toward risks of all SSRIs except fluoxetine, concludes a research group that performed a meta-analysis (pp. 1341-5). “Data for two published trials suggest that fluoxetine has a favourable risk-benefit profile, and unpublished data lend support to this finding,” write the authors. “Published results from one trial of paroxetine and two trials of sertraline suggest equivocal or weak positive risk-benefit profiles. However, in both cases, addition of unpublished data indicates that risks outweigh benefits. Data from unpublished trials of citalopram and venlafaxine show unfavourable risk-benefit profiles.” (C. Whittington, U. Coll., London; c.whittington@ucl.ac.uk)

In an editorial written by the
Lancet editors, blame for such selective reporting is placed on the pharmaceutical industry and medical researchers (p. 1335): “Meta-analysis of published data supports an increasing number of clinical decisions and guidelines, which in turn dictate the use of vast levels of health-care resources. This process is made entirely redundant if its results are so easily manipulated by those with potentially massive financial gains. The global sales of the GlaxoSmithKline SSRI paroxetine, for example, amounted to US$4·97 billion last year alone. Moreover, the utility of organisations such as the National Institute for Clinical Excellence (NICE) is significantly undermined in circumstances where they are only able to access data on health-care products that are seen as advantageous to the products’ manufacturers.”

>>>PNN JournalWatch
* Reduced Incidence of Admissions for Myocardial Infarction Associated with Public Smoking Ban: Before and After Study, in BMJ, 2004; 328: 977–80. Reprints: www.bmj.org; S. Glantz; glantz@medicine.ucsf.edu

* Systematic Review of Topical Capsaicin for the Treatment of Chronic Pain, in
BMJ, 2004; 328: 991 ff. Reprints: www.bmj.org; R. A. Moore, U. Oxford, Headington, Oxford, U.K.; andrew.moore@pru.ox.ac.uk

* Combination Therapy in Ischemic Stroke: Synergistic Neuroprotective Effects of Memantine and Clenbuterol, in
Stroke, 2004; 35: 1197 ff. Reprints: stroke.ahajournals.org; C. Culmsee, Ludwig-Maximilians-Universität, München, Germany; ccuph@cup.uni-muenchen.de

* Trends in Antimicrobial Drug Development: Implications for the Future, in
Clinical Infectious Diseases, 2004; 38: 1279–86. Reprints: www.journals.uchicago.edu/CID; B. Spellberg, UCLA.

* Are Antimicrobial-Impregnated Catheters Effective? Don't Throw Out the Baby with the Bathwater, in
Clinical Infectious Diseases, 2004; 38: 1279–86. Reprints: www.journals.uchicago.edu/CID; D. J. Maki, U. Wisconsin, Madison.

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 27, 2004 Vol. 11, No. 80
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Apr. 26 issue of Archives of Internal Medicine (www.archinternmed.com; 2004; 164).

Concomitant ASA–Ibuprofen Use: Ibuprofen did not interfere with the cardioprotective effects of aspirin in a retrospective analysis of pharmacy and clinical records at a VA facility (pp. 852-6). Testing the clinical importance of in vitro studies showing a potential ibuprofen interference of aspirin’s inhibition of cyclooxygenase, investigators calculated the rate of myocardial infarction among patients who received outpatient prescriptions for aspirin and ibuprofen in 1990–2000. They found, “Some 3859 patients received both aspirin and ibuprofen, for a total of 52,139 patient-months of medication use. This group experienced 138 infarctions. The 10,239 patients receiving aspirin only, for a total of 156,417 patient-months of use, experienced 684 infarctions. The rate ratio of having an infarction was 0.61 (95% confidence interval, 0.50–0.73) (P < .001), favoring the group that took aspirin and ibuprofen simultaneously. An analysis of diabetic patients found a rate ratio of 0.48 (95% confidence interval, 0.34–0.66) (P < .001). An examination of patients who spent time in both groups at different times resulted in a rate ratio of infarction during combined use of 0.70 (95% confidence interval, 0.59–0.83) (P < .001).” (K. C. Goldberg, VA Med. Ctr., Durham, N.C.)

Seasonal Cholesterol Variations: Seasonal changes in plasma volume appear to result in considerable seasonal variation in patients’ serum cholesterol values, especially among women and those with hypercholesterolemia, report authors of a longitudinal study of 517 healthy volunteers (pp. 863-70). “Amplitude of seasonal variation was 3.9 mg/dL (0.10 mmol/L) in men, with a peak in December, and 5.4 mg/dL (0.14 mmol/L) in women, with a peak in January,” the investigators report. “Overall, 22% more participants had total cholesterol levels of 240 mg/dL or greater (6.22 mmol/L) in the winter than in the summer.” (I. S. Ockene, Ira.Ockene@umassmed.edu)

Bone and Lipid Effects of Raloxifene vs. Estrogen: Conjugated equine estrogen 0.625 mg daily has more marked effects on bone density and turnover than does raloxifene 60 or 150 mg daily, and the agents produce different adverse effect and lipid profiles, according to a study of 619 postmenopausal women with prior hysterectomy (pp. 871-9). The authors note: “Compared with baseline, bone density in the lumbar spine progressively declined by 2.0% in the placebo group (P <.05), was stable in the 2 raloxifene groups, and increased 4.6% in the subjects receiving CEE (P <.001). Effects in both raloxifene groups were different from those observed in the CEE and placebo groups (P <.001). Bone density in the total hip showed similar results.... Each of the active treatments caused comparable depression of low-density lipoprotein cholesterol below placebo levels (P <.001 at most time points). Raloxifene did not affect high-density lipoprotein cholesterol, whereas CEE increased it by 13.4% compared with placebo at 3 years (P <.001). Triglyceride concentrations increased 24.6% in the CEE group at 3 years (P <.003), a significantly greater change than in the raloxifene groups, which were 4.9% and 8.0% above baseline (P ≤ .002) but not different from placebo. Urinary incontinence was reported in 11 women receiving CEE, but in only 1 or 2 in each of the other groups (P ≤ .01 compared with the other groups).” (I. R. Reid, U. Auckland, Auckland, New Zealand; i.reid@auckland.ac.nz)

Warfarin & ICH Mortality: Careful control of international normalized ratios during warfarin therapy can control not only the rate of intracerebral hemorrhage but also its severity, conclude authors of a 7-year prospective study of 435 consecutive patients (pp. 880-4). Among 102 patients taking warfarin at the time of ICH, 3-month mortality was 52.0%, compared with 25.8% among those not warfarin. While 68% of warfarin-related hemorrhages occurred at INRs of 3.0 or less, increasing INR values were strongly associated with increased risk of death. (S. M. Greenberg, sgreenberg@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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 28, 2004 Vol. 11, No. 81
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Apr. 28 issue of JAMA (www.jama.com; 2004; 291).

Vaptans for HF: Clinical results were promising in the first reported trial of a new class of vasopressin antagonists for management of systemic congestion in patients with chronic heart failure (pp. 1963-71). A total of 319 patients with left ventricular ejection fraction of less than 40% and hospitalized for heart failure with persistent signs and symptoms of systemic congestion despite standard therapy received standard therapy, including diuretics, plus placebo or oral tolvaptan 30, 60, or 90 mg/day. “Median (interquartile range) body weight at 24 hours after randomization decreased by –1.80 (–3.85 to –0.50), –2.10 (–3.10 to –0.85), –2.05 (–2.80 to –0.60), and –0.60 (–1.60 to 0.00) kg in the groups receiving tolvaptan 30, 60, and 90 mg/d, and placebo, respectively (P.008 for all tolvaptan groups vs placebo),” reports the research group. “The decrease in body weight with tolvaptan was not associated with changes in heart rate or blood pressure, nor did it result in hypokalemia or worsening renal function. There were no differences in worsening heart failure at 60 days between the tolvaptan and placebo groups (P = .88 for trend). In post hoc analysis, 60-day mortality was lower in tolvaptan-treated patients with renal dysfunction or severe systemic congestion.” (M. Gheorghiade, m-gheorghiade@northwestern.edu)

Editorialists evaluate the promise of the “vaptans” (pp. 2107-8): “Tolvaptan is one of a new class of drugs and addresses important problems in acute heart failure, eg, hyponatremia, water retention, and renal dysfunction. The study by Gheorghiade et al ... raises important regulatory issues. The question arises as to what should be measured to demonstrate efficacy in clinical trials of such new therapy for the treatment of acute or decompensated heart failure.... Some demonstration of physiologic improvement, such as weight loss and correction of hyponatremia, is necessary but should be coupled to some index of improvement in clinical outcome. Heart failure researchers are still struggling to identify a measure of improved clinical outcome in the setting of acute heart failure that is objective, quantitative, reproducible, relevant, and reliable. Physicians can recognize when acutely ill patients with heart failure improve clinically, but the likely multiple subjective and objective variables that are assessed at the bedside and synthesized to reach these judgments have not been well understood. ‘Favorable clinical outcomes’ must be defined in a quantitative manner in order to develop new drugs for patients with decompensated congestive heart failure.” (G. S. Francis, Cleveland Clinic Foundation, Cleveland; francig@ccf.org)

Vitamin D & Falls: In ambulatory or institutionalized older individuals with stable health, vitamin D supplementation reduced the risk of falls among by more than 20%, according to a meta-analysis of 5 randomized controlled trials of 1,237 participants (pp. 1999-2006). “The number needed to treat (NNT) was 15 (95% CI, 8–53), or equivalently 15 patients would need to be treated with vitamin D to prevent 1 person from falling. The inclusion of 5 additional studies, involving 10,001 participants, in a sensitivity analysis resulted in a smaller but still significant effect size (corrected RR, 0.87; 95% CI, 0.80–0.96). Subgroup analyses suggested that the effect size was independent of calcium supplementation, type of vitamin D, duration of therapy, and sex, but reduced sample sizes made the results statistically nonsignificant for calcium supplementation, cholecalciferol, and among men.” (H. A. Bischoff-Ferrari, hbischof@hsph.harvard.edu)

HER-2 Testing in Breast Cancer: In women with breast cancer, response to trastuzumab is most accurately predicted by testing with immunohistochemistry as the method of choice, according to a study that also analyzed use of FISH, or fluorescence in situ hybridization (pp. 1972-7). FISH should be reserved for cancers with indeterminate results (2+ score), the researchers concluded, based on findings from 2,963 patients who were tested with both methods. (A. M. Gown, PhenoPath Laboratories, Seattle; gown@phenopath.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 29, 2004 Vol. 11, No. 82
Providing news and information about medications and their proper use

>>>Insulin Glulisine Approved
FDA has approved another rapid-acting insulin analogue, insulin glulisine (Apidra, Aventis). Joining ultrashort insulins such as aspart and lispro on the U.S. market, insulin glulisine is indicated for control of blood glucose in adult patients with diabetes mellitus.

Insulin glulisine was studied in clinical trials in adult patients with type 1 and type 2 diabetes. It is designed to be injected within 15 minutes before a meal or within 20 minutes after starting a meal by subcutaneous injection or continuous subcutaneous pump infusion.

Hypoglycemia is the most common adverse effect of insulin therapy. Adverse events commonly associated with human insulin therapy include allergic reactions, injection site reaction, lipodystrophy, pruritus, and rash.

>>>NEJM Highlights
Source:
Apr. 29 issue of the New England Journal of Medicine (content.nejm.org; 2004; 350).

HIV Regimens: Efavirenz combined with two or three antiretroviral nucleosides proved superior to the triple-nucleoside regimen of abacavir, zidovudine, and lamivudine in the initial treatment of 1,147 patients with HIV-1 infection (pp. 1850-61). Patients randomly were treated for a median of 32 weeks with the three nucleosides, zidovudine–lamivudine plus efavirenz, or zidovudine–lamivudine–abacavir plus efavirenz before the study was terminated early. The authors report that “82 of 382 subjects in the triple-nucleoside group (21 percent) and 85 of 765 of those in the combined efavirenz groups (11 percent) had virologic failure; the time to virologic failure was significantly shorter in the triple-nucleoside group (P<0.001).” CD4 cell counts and grade 3/4 adverse events occurred were among the treatment groups.

Comparing their findings with those of other recent studies, the investigators note, “Recent studies have documented an increasing prevalence of drug-resistant HIV-1 among previously untreated subjects with HIV-1 infection and, as a consequence, an increased risk of virologic failure of initial regimens. In the current study, substitutions in the viral genome were rare at base line, suggesting that preexisting drug resistance is unlikely to explain the higher rate of virologic failure in the triple-nucleoside group. At the time of virologic failure, viral isolates from about half the subjects in the triple-nucleoside group showed the M184V reverse-transcriptase substitution that is associated with lamivudine resistance—a finding that is also similar to those of previous studies. Although the resistance data from the combined efavirenz groups are not reported here so that we may maintain blinding, we would expect to find the M184V substitution, the K103N substitution associated with efavirenz resistance, or both in subjects with virologic failure.” (R. M. Gulick, rgulick@med.cornell.edu)

Osteoporosis Treatments:
In a brief review of animal studies, an author notes that “a better understanding of the function and expression of 12-lipoxygenase and 15-lipoxygenase isoenzymes type 1 and type 2 may hasten the development of novel antiosteoporotic drugs” (pp. 1902-3). A recent mouse study indicated that 12/15 lipoxygenase “contributes to natural variations in bone mass and skeletal development in mice, and showed that compounds that target this enzyme increase bone mass,” the author reported. (C. N. Serhan, Harvard U., Boston)

>>>PNN NewsWatch
* Diarrhea, ischemic colitis, and other forms of intestinal ischemia are the subjects of new warnings and precautions being added to the labeling of tegaserod (Zelnorm, Novartis). FDA yesterday announced the revisions along with new information that is being added to the adverse reactions section of the package insert and the patient information leaflet.

* CMS today launches a Web-based service for older Americans to use in comparing
prices of prescription drugs. On www.medicare.gov, seniors will be able to use Destination Rx software to compare prices of participating pharmacies in their ZIP code and determine which of the dozens of prescription drug discount cards would be best for them.

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 30, 2004 Vol. 11, No. 83
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
May issue of Diabetes Care (care.diabetesjournals.org; 2004; 27).

Adherence to Antidiabetic Medications: Many patients with diabetes fail to adhere to both oral and injectable antidiabetic agents , but their use of medications can be improved through use of electronic monitoring devices, according to a systematic review article (pp. 1218-24). “Adequate documentation of adherence was found in 15 retrospective studies of [oral hypoglycemic agents (OHAs)] prescription refill rates, 5 prospective electronic monitoring OHA studies, and 3 retrospective insulin studies....,” report the authors. “Retrospective analyses showed that adherence to OHA therapy ranged from 36% to 93% in patients remaining on treatment for 6–24 months. Prospective electronic monitoring studies documented that patients took 67–85% of OHA doses as prescribed. Electronic monitoring identified poor compliers for interventions that improved adherence (61–79%; P < 0.05). Young patients filled prescriptions for one-third of prescribed insulin doses. Insulin adherence among patients with type 2 diabetes was 62–64%.” (J. A. Cramer, joyce.cramer@yale.edu)

Metabolic Syndrome in Asians: The waist circumference component of metabolic syndrome criteria requires adjustment in Asian populations, conclude investigators who applied modified criteria to data on the diverse population of Singapore (pp. 1182-6). Rather than 40 inches (101 cm) for men and 35 inches (89 cm) for women, waist circumference cutoffs of 90 cm and 80 cm, respectively, were more appropriate definitions of central obesity in the 4,723 Chinese, Malay, and Asian–Indian individuals. Because of subgroup differences in the prevalence of metabolic syndrome using the new definition, the investigators conclude that further refinement for the various ethnic subgroups in Asia is likely needed. (C. E. Tan, Singapore Genl. Hosp., Singapore; ce_tan@sgh.com.sg)

Initial Intensive Insulin Therapy in Type 2 DM: In patients with newly diagnosed type 2 diabetes mellitus, a 2- to 3-week course of intensive insulin therapy can rapidly control blood glucose levels and provide prognostic information about the patient, if findings in 16 subjects prove applicable in broad clinical practice (pp. 1028-32). The authors write, “Fasting glucose fell from 13.3 ± 0.7 to 7.0 ± 0.4 mmol/l, and this improvement was maintained at the 1-year follow-up (6.7 ± 0.3 mmol/l). The insulin area under the curve for the posttreatment oral glucose tolerance test also improved (8,251 ± 1,880 before therapy, 18,404 ± 4,040 directly after insulin therapy, and 42,368 ± 8,517 pmol·min at the 1-year follow-up). At 1 year, seven of the subjects maintained good glycemic control on diet therapy alone, eight required oral hypoglycemic agent (OHA) therapy, and one required insulin therapy. The distinguishing features of those who did not require OHA or insulin therapy were that they required less insulin during the active insulin therapy phase (0.37 ± 0.05 vs. 0.73 ± 0.07 units · kg–1·day–1) and were able to attain a lower fasting serum glucose at the end of the period of insulin therapy (5.9 ± 0.3 vs. 7.7 ± 0.4 mmol/l).” (E. A. Ryan, U. Alberta, Edmonton, Canada; edmond.ryan@ualberta.ca)

Insulin Detemir: A long-acting basal insulin analog was superior to NPH insulin for glycemic control, according to a 408-patient study (pp. 1081-7). Used in open-label fashion for 16 weeks in patients with type 1 diabetes mellitus, insulin detemir provided better fasting plasma glucose levels, prebreakfast plasma glucose levels, and risks of minor hypoglycemia, compared with NPH insulin. Glycosylated hemoglobin values did not differ significantly among patient subgroups, but the pooled data favored insulin detemir. Likewise, the patients on NPH insulin gained weight during the study, while no change was noted among patients on insulin detemir. “The data provide a basis for tailoring the timing of administration of insulin detemir to the individual person’s needs,” the authors conclude. (Philip Home, U. Newcastle Upon Tyne, U.K.; philip.home@newcastle.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 3, 2004 Vol. 11, No. 84
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
May 1 issue of BMJ (www.bmj.org; 2004; 328).

Impact of Sildenafil on ED: Marketing of sildenafil had a profound but variable effect on the psyche of 40 men with erectile dysfunction, according to a report of semistructured interviews (pp. 1037 ff). “Erectile dysfunction caused serious distress to all those men who experienced it, with marked effects on their self esteem and their relationships,” the authors note. “Sildenafil, when it worked, caused a great improvement in wellbeing. The expectations raised by media hyperbole with the launch of sildenafil had an adverse effect on the morale of those who found it did not work. When, according to the patient, treatment did not work, the distress was severe and for many confirmed their lack of self worth.”

The group concludes, “Further study is needed to explore the feelings of men affected by erectile dysfunction and their perception of treatment. Health professionals should be aware of the extreme distress erectile dysfunction can cause.” (J. Tomlinson, Royal Hampshire County Hosp., Winchester, U.K.; john@jptomlinson.com)

>>>Lancet Report
Source:
May 1 issue of Lancet (www.thelancet.com; 2004; 363).

Fish Oil or Drugs for V Tach: In a pilot study of patients with implanted cardioverter defibrillators who were at high risk of sudden cardiac death, infusion of n-3 polyunsaturated fatty acids reduced sustained ventricular tachycardia without inducing arrhythmias in 5 of 7 patients (pp. 1441-2). The investigators propose that the beneficial effects might be the result of “stabilisation of myocardial excitability, which might be further indicated by the increase of the effective refractory period.” They add, “Since the two electrophysiological studies were done within 4 h, conditions were highly constant, suggesting that the stabilising effect was caused by n-3 PUFA. However, spontaneous variability in the induction of ventricular tachycardia in these patients cannot be excluded.” (A. Sellmayer, Universität München, Munich, Germany; alois.sellmayer@medpoli.med.uni-muenchen.de)

An editorialist supports further study of PUFA for this indication: “Three ... randomised trials of the effect of fish-oil supplementation on recurrent episodes of ventricular tachycardia and/or fibrillation in patients with implantable cardioverter defibrillators are in progress or have been completed. If these and other trials confirm the anti-arrhythmic properties of these n-3 acids, fish oil might become a less toxic and more appetising alternative to traditional antiarrhythmic drugs.” (C. Albert, calbert@partners.org)

Olpadronate in Osteogenesis Imperfecta: Fractures were reduced in a 2-year study of 34 children with osteogenesis imperfecta, but long-term impact of the drug on the clinical course of this disease remains uncertain (pp. 1427-31). Compared with children who received placebo, those on olpadronate therapy had a 31% reduction in risk of fracture, and the active treatment group had significantly greater increases in spinal bone mineral content and density. (R. Sakkers, U. Med. Ctr., Utrecht, the Netherlands; r.sakkers@wkz.azu.nl)

>>>PNN JournalWatch
* Smallpox Vaccination and Myopericarditis: A Clinical Review, in Journal of the American College of Cardiology, 2004; 43: 1503–10. Reprints: www.cardiosource.com; D. C. Cassimatis, dimitri.cassimatis@na.amedd.army.mil

* Pharmacogenetics of Psychotropic Drug Response, in
American Journal of Psychiatry, 2004; 161: 918–20. Reprints: ajp.psychiatryonline.org; A. K. Malhotra.

* Toward a Rapidly Acting Antidepressant: The Normetanephrine and Extraneuronal Monoamine Transporter (Uptake 2) Hypothesis, in
American Journal of Psychiatry, 2004; 161: 909–11. Reprints: ajp.psychiatryonline.org; J. J. Schildkraut.

* Recommendations for Influenza Immunization of Children, in
Pediatrics, 2004; 113: 1441–7. Reprints: www.pediatrics.org; American Academy of Pediatrics.

* Diagnosis and Management of Acute Otitis Media, in
Pediatrics, 2004; 113: 1441–7. Reprints: www.pediatrics.org; American Academy of Pediatrics.

* Physical Activity and Exercise Recommendations for Stroke Survivors, in
Circulation, 2004; 109: 2031–41. Reprints: circ.ahajournals.org; American Heart Association and other organizations.

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 4, 2004 Vol. 11, No. 85
Providing news and information about medications and their proper use

>>>Internal Medicine Update
Source:
May 4 issue of the Annals of Internal Medicine (www.annals.org; 2004; 140).

Pharmacotherapy Quality in the Elderly: Prescribing of inappropriate medications is not one of the more common prescribing problems among older patients, according to a study of 372 community-dwelling, high-risk patients older than 65 years (pp. 714-20). Rather, failures to prescribe indicated medications, monitor medications appropriately, document necessary information, educate patients, and maintain continuity were more common among the patients, all of whom were continuously enrolled in a managed care organization for a 13-month period in 1998–99. The investigators looked at 43 quality indicators covering four domains of pharmacologic care. They found, “The percentage of appropriate pharmacologic management ranged from 10% for documentation of risks of non-steroidal anti-inflammatory drugs to 100% for avoiding short-acting calcium-channel blockers in patients with heart failure and avoiding beta-blockers in patients with asthma. Pass rates for quality indicators in the ‘avoiding inappropriate medications’ domain (97% [95% CI, 96% to 98%]) were significantly higher than pass rates for ‘prescribing indicated medications’ (50% [CI, 45% to 55%]); ‘education, continuity, and documentation’ (81% [CI, 79% to 84%]); and ‘medication monitoring’ (64% [CI, 60% to 68%]).” (T. Higashi, UCLA, Los Angeles)

Costs of Diabetes Screening: Compared with universal screening, diabetes screening is more cost-effective when targeted at patients with hypertension, especially in the 55–75-year-old age group, conclude authors of a Markov model analysis done from the perspective of a health care system (pp. 689-99). Considering the general primary care population in the U.S., the researchers made these observations about costs per quality-adjusted life-years: “At all ages, incremental cost-effectiveness ratios were more favorable for screening targeted to people with hypertension than for universal screening. For example, at age 55 years, the cost per QALY for targeted screening compared with no screening was $34,375, whereas the cost per QALY for universal screening compared with targeted screening was $360,966. Screening was more cost-effective for ages 55 to 75 years than for younger ages.” (T. J. Hoerger, RTI International, Research Triangle Park, N.C.; tjh@rti.org)

Editorialists question whether “we [can] afford not to screen” for type 2 diabetes (pp. 756-8): “Although the evidence from clinical trials supporting early interventions in persons with diagnosed diabetes is increasingly persuasive, clinical trials that compare the benefit of screening for diabetes with the current state of practice do not exist. Cost-effectiveness analyses tell us how well dollars spent on screening for diabetes translate into improved outcomes relative to other health interventions. When clinical trial data on the long-term effect of screening on costs, quality of life, and health outcomes are not available, researchers use models that integrate evidence from diverse sources to make inferences about future economic, quality-of-life, and health outcomes and to provide data for decision making.... Models are only as good as the elements included, and the current study has several limitations.” (D. M. Nathan, Dnathan@Partners.org)

Early Diagnosis of Resistant TB: Positive results on an enzyme-linked immunospot assay may improve early diagnosis of subclinical active tuberculosis in immunosuppressed patients with false-negative tuberculin skin tests, according to clinicians who present a single case (pp. 709-13). The patient, an asymptomatic man receiving maintenance azathioprine therapy for Crohn’s disease whose wife had multidrug-resistant pulmonary TB, had a negative tuberculin skin test but a positive ELISPOT result. Presence of multidrug-resistant TB was confirmed with high-resolution computed tomography of the chest showing consolidation with early cavitation and bronchoalveolar lavage and culture. (A. Lalvani, U. Oxford, Oxford, U.K; ajit.lalvani@ndm.ox.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 5, 2004 Vol. 11, No. 86
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
May 5 issue of JAMA (www.jama.com; 2004; 291).

Long-term Efficacy of BCG Vaccine: A single dose of bacille Calmette-Guérin vaccine may protect against tuberculosis for 50–60 years, according to a longitudinal study of American Indians and Alaska natives (pp. 2096-91). Patients in the analysis had participated in a BCG vaccine trial in 1935–38, including 1,483 participants in the BCG vaccine group and 1,309 in the placebo group. Based on tuberculosis events occurring after the end of prospective funding of the trial (1947), the investigators report, “The overall incidence of tuberculosis was 66 and 138 cases per 100,000 person-years in the BCG vaccine and placebo groups, respectively, for an estimate of vaccine efficacy of 52% (95% confidence interval, 27%–69%). Adjustments for age at vaccination, tribe, subsequent BCG vaccination, chronic medical illness, isoniazid use, and bacille Calmette-Guérin strain did not substantially affect vaccine efficacy. There was slight but not statistically significant waning of the efficacy of BCG vaccination over time, greater among men than women.” (N. E. Aronson, Uniformed Services U. of the Health Sciences, Bethesda, Md., naronson@usuhs.mil)

An editorialist discusses the “plenty of questions about vaccination [left] unanswered” and notes these challenges (pp. 2127-8): “During 2001–2002, approximately 1 million sputum smear–positive patients were either cured or completed treatment with short-course chemotherapy under the internationally recommended strategy for TB control, known as DOTS (directly observed therapy, short course). However, these patients represent only one third of the increasing number of new TB cases that emerged worldwide during 2001. These incident cases were identified with an ancient diagnostic technique (sputum smear microscopy) that predates BCG and all of these cases had to be treated for at least 6 months, during which 12% were lost to follow-up. Outside of DOTS programs, default and death rates are typically higher and cure rates are lower. Moreover, as surveys continue to map the distribution of drug-resistant TB organisms, most physicians and other health care workers are acutely aware that all of the principal antituberculosis drugs were introduced during the 1950s and 1960s. No new drug has been added to the first-line treatment regimen for TB for more than 30 years.” (C. Dye, dyec@who.int)

Lipid Lowering & Postsurgical Mortality: Patients at 239 U.S. hospitals who were receiving lipid-lowering agents perioperatively had lower postsurgical mortality rates than did other patients undergoing noncardiac operations, according to a retrospective cohort study of 780,591 patients (pp. 2092-9). Investigators included patients who survived for at least 2 days following surgery, analyzed in-hospital mortality, and defined lipid-lowering therapy as use of any statin or other lipid-lowering medication during the first 2 days of hospitalization. Comparing the 77,082 patients who received lipid-lowering drugs with the other patients, the authors found a lower crude mortality rate (2.13% versus 3.05%) and an adjusted odds ratio for mortality of 0.62. “Based on this adjusted OR, the number needed to treat to prevent a postoperative death in the propensity matched cohort was 85 (95% CI, 77–98) and varied from 186 among patients at lowest risk to 30 among those with a revised cardiac risk index score of 4 or more. In a further analysis using the entire study cohort and adjusting for quintile of propensity, a significant effect of treatment persisted (adjusted OR, 0.71; 95% CI, 0.67–0.75).” (P. K. Lindenauer, Baystate Med. Ctr., Springfield, Mass.; peter.lindenauer@bhs.org)

Marijuana Use: While marijuana use remained stable at about 4% of Americans between 1992 and 2002, the prevalence of marijuana use disorders jumped, especially among young black men and women and young Hispanic men (pp. 2114-21). The increase, from 1.2% in 1991–92 to 1.5% in 2001–02, may be the result of increased potency of marijuana, the authors surmise. (W. M. Compton, compton@nida.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 6, 2004 Vol. 11, No. 87
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
May 6 issue of the New England Journal of Medicine (content.nejm.org; 2004; 350).

Treatment of Head and Neck Cancer: Two research articles and an accompanying editorial explore the role of concomitant postoperative chemotherapy and radiotherapy in patients with high-risk head and neck cancer.

The combination improved rates of local and regional control and disease-free survival but also adverse effects among 459 patients who received either radiotherapy alone (60–66 Gy in 30–33 fractions over a period of 6–6.6 weeks) or the identical treatment plus concurrent cisplatin 100 mg/sq m intravenously on days 1, 22, and 43 (pp. 1937-44). The investigators report, “After a median follow-up of 45.9 months, the rate of local and regional control was significantly higher in the combined-therapy group than in the group given radiotherapy alone (hazard ratio for local or regional recurrence, 0.61; 95 percent confidence interval, 0.41 to 0.91; P = 0.01). The estimated two-year rate of local and regional control was 82 percent in the combined-therapy group, as compared with 72 percent in the radiotherapy group. Disease-free survival was significantly longer in the combined-therapy group than in the radiotherapy group (hazard ratio for disease or death, 0.78; 95 percent confidence interval, 0.61 to 0.99; P = 0.04), but overall survival was not (hazard ratio for death, 0.84; 95 percent confidence interval, 0.65 to 1.09; P = 0.19). The incidence of acute adverse effects of grade 3 or greater was 34 percent in the radiotherapy group and 77 percent in the combined-therapy group (P < 0.001). Four patients who received combined therapy died as a direct result of the treatment.” (J. S. Cooper, New York U. Med. Ctr., New York)

In a similar study conducted with 167 European patients, researchers conclude that “postoperative concurrent administration of high-dose cisplatin with radiotherapy is more efficacious than radiotherapy alone in patients with locally advanced head and neck cancer and does not cause an undue number of late complications” (pp. 1945-52). With radiotherapy and/or chemotherapy regimens similar to those in the above study, patients’ rate of progression-free survival was significantly higher in those on combined treatment than with radiotherapy alone (hazard ratio, 0.75; P = .04). “The estimated five-year cumulative incidence of local or regional relapses (considering death from other causes as a competing risk) was 31 percent after radiotherapy and 18 percent after combined therapy,” add the authors. “Severe (grade 3 or higher) adverse effects were more frequent after combined therapy (41 percent) than after radiotherapy (21 percent, P = 0.001); the types of severe mucosal adverse effects were similar in the two groups, as was the incidence of late adverse effects.” (J. Bernier, Oncology Inst. of Southern Switzerland, Bellinzona, Switzerland; jacques.bernier@hcuge.ch)

Editorialists add these observations about a chemotherapy “cocktail with your PORT” (postoperative radiotherapy; pp. 1997-9): “The late-morbidity results seen so far in [these] trials indicate that this approach provides a real benefit. Therefore, the next obvious step toward further improving the outcome of concomitant chemotherapy and postoperative radiotherapy is identifying which radiotherapy regimen is most effective. Ultimately, the intensity of treatment is limited by the patient’s ability to tolerate it.” (M. I. Saunders, U. College, London)

Hospitalists in the U.S.: Authors of a perspectives article provide a brief status report on the estimated 8,000 hospitalists in the U.S. some 8 years after the specialty was first proposed (pp. 1935-6; R. M. Wachter, UCSF).

>>>PNN NewsWatch
* Tools and information for pharmacists to use in implementing the Medicare prescription drug discount cards are available on APhA’s www.pharmacist.com Web site.

* Research conducted by
Ranjit Kumar Chandra, including some landmark trials of vitamin therapy in the elderly published in Lancet and Nutrition, may be flawed, the New York Times reports this morning.

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 7, 2004 Vol. 11, No. 88
Providing news and information about medications and their proper use

>>>Pharmacotherapy Update
Source:
May Pharmacotherapy (www.accp.com; 2004; 24).

Statins & Liver Toxicity: Pravastatin, lovastatin, and simvastatin at low to moderate doses are not associated with a significant risk of liver-function test abnormalities, conclude authors of a meta-analysis of 13 trials that included 49,275 patients (pp. 584-91). “Additional data are required to determine whether other statins have a similar safety profile,” the group continues. “The proportion of patients having LFT abnormalities was low ... (statins 1.14% vs placebo 1.05%, odds ratio [OR] 1.26, 95% confidence interval [CI] 0.99–1.62, p = 0.07). Only fluvastatin was associated with a significant increase in the odds of having LFT abnormalities (fluvastatin 1.13% vs placebo 0.29%, OR 3.54, 95% CI 1.1–11.6, p = 0.04) compared with placebo, although this finding was based on only two trials.” (A. M. Peterson, a.peters@usip.edu)

Venlafaxine & Pain Syndromes: Despite animal and limited clinical data supporting use of venlafaxine in treatment of pain syndromes associated with major depressive disorder and generalized anxiety disorder, randomized, controlled clinical trials are needed to fully elucidate the antidepressant’s potential for this indication (pp. 621-9). That conclusion is reached by authors of a review article, who also note that some evidence supports use of the combination serotonin/norepinephrine reuptake inhibitor in treating neuropathic pain, headache, fibromyalgia, and postmastectomy pain syndrome. (D. R. Grothe, Wyeth Pharmaceuticals, Collegeville, Pa.)

Food & Loop Diuretic Resistance: Oral loop diuretics should be administered without food, argue authors of a review article, unless additional data rule out any possibility that food interferes with the drugs’ absorption (pp. 630-7). “Food significantly affects the pharmacokinetics of oral loop diuretics in healthy individuals, but studies have not been performed in patients with edema. Because of this omission, food’s effect on pharmacokinetics has been overlooked and may decrease the pharmacodynamic response in patients who rely on diuretics.... Peak plasma concentrations and urinary recovery were significantly decreased when taken with food, but only one study showed a corresponding decrease in total urine output, which is likely related to the diuretic threshold effect. These healthy subjects probably were always above the diuretic threshold under both fed and fasting conditions and thus could not augment their urine output.... Food is more likely to have a clinical effect on the diuretic threshold given its effect in healthy subjects and the special considerations for patients with edema. Additional studies are needed to help answer these questions. Until such data are available, the most conservative, effective clinical approach is to administer oral loop diuretics without food.” (R. L. Bard, bbard@umich.edu)

Migraine Misconceptions: Common misconceptions about migraine are refuted in a minireview (pp. 638-48). Erroneous ideas include the following: migraine is a vascular disease, triptans cause rampant cardiac-related morbidity and even mortality, a best oral triptan exists, sinus and tension headaches are prevalent, and migraine is a minor economic problem. (R. Wenzel, Saint Joseph Hosp., Chicago; rwenz@hotmail.com)

>>>PNN NewsWatch
* FDA yesterday denied a petition from Barr Laboratories requesting the Rx-to-OTC shift of Plan B, a levonorgestrel-only emergency contraceptive. Despite a 23–4 vote by an advisory panel in favor on nonprescription status for the product, FDA ruled that insufficient evidence existed to gauge the ability of girls younger than 17 to use Plan B without medical advice. Critics charged the decision was a political one influenced by a White House that continues to politicize medical and scientific debates. To continue pursuing OTC status, Barr must either conduct another study in girls ages 14–16 or propose a plan that would restrict sales to those older than 16. The latter option begs for a pharmacist-only category of drugs, but FDA does not feel it has statutory authority to approve products for anything other than prescription or OTC status.

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 10, 2004 Vol. 11, No. 89
Providing news and information about medications and their proper use

>>>Gastroenterology Update
Source:
May issue of Gastroenterology (www.gastrojournal.org; 2004; 126).

Trials of Crohn’s Disease: Efficacy trials of medications for Crohn’s disease are difficult to interpret because of wide variability in placebo response rates, according to a meta-analysis of randomized, controlled clinical trials published between 1966 and 2001 (pp. 1257-68). “The pooled estimates of the placebo rates of remission and response were 18% (95% confidence interval, 14%–24%; range, 0%–50%) and 19% (95% confidence interval, 13%–28%; range, 0%–46%), respectively, both with significant heterogeneity among studies (P < 0.01 for remission, P < 0.03 for response),” report the authors. “In multivariate models, study duration, number of study visits, and entry Crohn’s Disease Activity Index score were important predictors of the placebo remission rate, with study duration the most important. However, no single factor could account for all of the heterogeneity. Factors that influence the placebo response rates were similar to those affecting the placebo remission rates. The absolute benefit of active treatment beyond placebo was generally larger when outcome was measured by response than remission.” (C. Su, Chinyu.su@uphs.upenn.edu)

Statin Hepatotoxicity & Elevated Liver Enzymes: Elevated baseline liver enzymes should not preclude patients from beginning statin therapy, conclude investigators who studied patients from 1998 to 2002 (pp. 1287-92). Three cohorts were studied: 342 hyperlipidemic patients with elevated baseline enzymes (AST >40 IU/L or ALT >35 IU/L) who were prescribed a statin (cohort 1); 1,437 hyperlipidemic patients with normal transaminases who were prescribed a statin (cohort 2); and 2,245 patients with elevated liver enzymes but who were not prescribed a statin (cohort 3). “The incidence of mild-moderate elevations and severe elevations in liver biochemistries in cohort 1 were 4.7% and 0.6%, respectively,” the authors write. “Compared with cohort 1, individuals in cohort 2 had lower incidence of mild-moderate elevations (1.9%, P = 0.002) but not severe elevations (0.2%, P = 0.2). However, between cohorts 1 and 3, there were no differences in the incidence of mild-moderate elevations (4.7% vs. 6.4%, respectively, P = 0.2) or severe elevations (0.6% vs. 0.4%, respectively, P = 0.6). Statin discontinuation during the follow-up was similar between cohorts 1 and 2 (11.1% vs. 10.7%, respectively, P = 0.8).” (N. Chalasani, Indiana U., Indianapolis, nchalasa@iupui.edu)

>>>BMJ Highlights
Source:
May 8 issue of BMJ (www.bmj.org; 2004; 328).

Socioeconomics & HF: In a Scottish study, patients in lower socioeconomic groups were 44% more likely to develop heart failure and 23% less likely to seek care for it, compared with affluent patients (pp. 1110 ff). For patients who sought care, prescribed treatments did not vary among socioeconomic groups. “Overall, 812 (80.6%) patients were prescribed diuretics, 396 (39.3%) angiotensin converting enzyme inhibitors, 216 (21.4%) beta blockers, 208 (20.7%) digoxin, and 86 (8.5%) spironolactone,” the group notes. (J. J. V. McMurray, U. Liverpool, Liverpool, U.K.; j.mcmurray@bio.gla.ac.uk)

>>>PNN JournalWatch
* Colorectal Cancer Chemoprevention—An Overview of the Science, in Gastroenterology, 2004; 126: 1423–47. Reprints: www.gastrojournal.org; E. T. Hawk, eh51p@nih.gov

* The Effect of Alcohol Consumption on the Prevalence of Iron Overload, Iron Deficiency, and Iron Deficiency Anemia, in
Gastroenterology, 2004; 126: 1423– 47. Reprints: www.gastrojournal.org; G. N. Ioannou, georgei@medicine.washington.edu

* Prevention of Disabling and Fatal Strokes by Successful Carotid Endarterectomy in Patients Without Recent Neurological Symptoms, in
Lancet, 2004; 363: 1491–502. Reprints: www.thelancet.com; A. Halliday, St. George's Hosp. Med. Sch., London; acst@sghms.ac.uk

* U.S. Health Care Spending In An International Context, in
Health Affairs, 2004; 23(3): 10–25. Reprints: content.healthaffairs.org; U. E. Reinhardt.

* Think Globally, Protect Locally: A Conversation With Mark McClellan, in
Health Affairs, 2004; 23(3): 177–85. Reprints: content.healthaffairs.org; J. D. Kleinke.

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 11, 2004 Vol. 11, No. 90
Providing news and information about medications and their proper use

>>>Internal Medicine Update
Source:
May 10 issue of Archives of Internal Medicine (www.archinternmed.com; 2004; 164).

Sibutramine for Weight Loss: Sibutramine is effective in promoting weight loss, according to authors of a systematic review article, but the evidence regarding the drug’s long-term risk-benefit profile is lacking (pp. 994-1003). Based on analysis of data from 29 published and unpublished trials, the writers report, “The summary mean differences in weight loss, sibutramine minus placebo, for the 3-month and 1-year trials were –2.78 kg (95% confidence interval, –2.26 to –3.29 kg) and –4.45 kg (95% confidence interval, –3.62 to –5.29 kg), respectively. The 6-month trials were statistically heterogeneous, and evidence of publication bias was found. One trial found that sibutramine maintains weight loss better than placebo at 2 years. Weight loss with sibutramine was associated with modest increases in heart rate and blood pressure, small improvements in high-density lipoprotein cholesterol and triglycerides levels, and, among diabetic patients, small improvements in glycemic control. There was no direct evidence that sibutramine reduces obesity-associated morbidity or mortality.” (D. E. Arterburn, VA Med. Ctr., Cincinnati; david.arterburn@uc.edu)

CAM Use Among Ambulatory Patients: Broadly defined complementary and alternative medicine interventions—including diet, exercise, and prayer—were used by 85.4% of a poor, urban population seeking care at two publicly supported internal medicine centers (pp. 1004-9). Based on interviews with 371 patients, the authors found, “A smaller number (32.3%) were currently using alternate health care providers and products. About 5% of the population used 6 products or more. Use by this primarily poor urban population appeared similar to that in previous reports, with some exceptions. Expensive modalities were less frequently used, whereas use of prayer appears more prevalent.” The researchers conclude, “Although much of [CAM] use does not appear to be maladaptive, a small percentage of individuals have enthusiastically adapted CAM in ways that would not be endorsed by most allopathic physicians.” (C. O. Hershey, hershey@acsu.buffalo.edu)

Depression & CRP: Continuing the evaluation of the clinical utility of C-reactive protein concentrations in the blood, investigators identify a strong association between depression in men and increased CRP levels (pp. 1010-4). Using data on 6,914 noninstitutionalized men and women (age, 18–39 years) from the Third National Health and Nutrition Examination Survey, the authors report, “The prevalence of lifetime major depression was 5.7% for men and 11.7% for women. The prevalence of elevated CRP level was 13.7% for men and 27.3% for women. A history of major depression was associated with elevated CRP level (odds ratio [OR], 1.64; 95% confidence interval [CI], 1.20–2.24). The association between depression and CRP was much stronger among men than among women.... Compared with men without a history of depression, CRP levels were higher among men who had a more recent (within 1 year) episode of depression (adjusted OR, 3.00; 95% CI, 1.39–6.48) and who had recurrent (2 episodes) depression (adjusted OR, 3.55; 95% CI, 1.55–8.14).” (D. E. Ford, Johns Hopkins U., Baltimore; dford@jhmi.edu)

Good & Bad Dying: Exploring the views of terminally ill patients about what constitutes a good death or a bad death can enable clinicians to “focus on what might interfere with patients’ attainment of their preferred dying experience and what may be available to help them achieve a death that is most consistent with their wishes,” according to results of semistructured interviews of 26 men with terminal heart disease or cancer (pp. 977-81). The authors note, “Participants voiced multiple reasons for why dying in one’s sleep led to a good death and why prolonged dying or suffering led to a bad death. Participants did not hold uniform views about the presence of others at the very end of life or preferred location of dying.” (E. K. Vig, vigster@u.washington.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 12, 2004 Vol. 11, No. 91
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
May 12 issue of JAMA (www.jama.com; 2004; 291).

Hyperlipidemia Treatment in Women: Use of lipid-lowering interventions in women without cardiovascular disease fails to affect most outcomes, and while treatment of women with cardiovascular disease reduces the incidence of coronary events, total mortality remains unchanged (pp. 2243-52). After reviewing the data from 13 studies of lipid-lowering medications and their effects on coronary heart disease, authors recommend, “Decisions about treatment of hyperlipidemia and other CHD risk factors will thus depend not only on the woman’s lipid levels, but also her other risk factors for heart disease and her overall risk of experiencing a CHD event over a defined period (usually 10 years).”

The writers note, “Lipid lowering did not reduce total mortality (RR, 0.95; 95% confidence interval [CI], 0.62–1.46), CHD mortality (RR, 1.07; 95% CI, 0.47–2.40), nonfatal myocardial infarction (RR, 0.61; 95% CI, 0.22–1.68), revascularization (RR, 0.87; 95% CI, 0.33–2.31), or CHD events (RR, 0.87; 95% CI, 0.69–1.09). However, some analyses were limited by too few CHD events in the available trials. Eight trials included 8272 women with cardiovascular disease and assessed the effects of lipid-lowering medications. Lipid lowering did not reduce total mortality in women with cardiovascular disease (RR, 1.00; 95% CI, 0.77–1.29). However, lipid lowering reduced CHD mortality (RR, 0.74; 95% CI, 0.55–1.00), nonfatal myocardial infarction (RR, 0.71; 95% CI, 0.58–0.87), revascularization (RR, 0.70; 95% CI, 0.55–0.89), and total CHD events (RR, 0.80; CI, 0.71–0.91).” (J. M. E. Walsh, jmwalsh@itsa.ucsf.edu)

Vaccines, Racial Disparity, & Pneumococcal Disease: Black Americans remain at higher risk of pneumococcal disease, compared with whites, but use of the 7-valent pneumococcal vaccine is reducing this disparity, according to an analysis of data from seven states for 15,923 patients between 1998 and 2002 (pp. 2197-203). “Annual incidence rates for invasive pneumococcal disease decreased from 19.0 to 12.1 cases per 100,000 among whites and from 54.9 to 26.5 among blacks,” the researchers write. “Due to these declines, 14,730 fewer cases occurred among whites and 8,780 fewer cases occurred among blacks in the United States in 2002, compared with 2 prevaccine years, 1998 and 1999. Before vaccine introduction, incidence among blacks was 2.9 times higher than among whites (95% confidence interval [CI], 2.7–3.0); in 2002, the black–white rate ratio had been reduced to 2.2 (95% CI, 2.0–2.4). Incidence among black children younger than 2 years went from being 3.3 times higher (95% CI, 3.0–3.7) than among white children in the prevaccine period to 1.6 times higher (95% CI, 1.1–2.2) in 2002. By 2002, 74% of white children and 68% of black children aged 19 to 35 months in the 7 states had received at least 1 dose of pneumococcal conjugate vaccine; 43% of white and 39% of black children received 3 or more doses.” (B. Flannery, bflannery@cdc.gov)

An editorialist notes the need to improve vaccination of adults, a role that pharmacists could assume as part of immunization services (pp. 2253-5): “For the immediate future, pneumococcal prophylaxis for nonelderly high-risk adults can continue to rest principally on herd immunity conveyed by infants receiving PCV7 in ever greater numbers. Alternatively, those adults and their clinicians can be challenged to match the children, shot for shot. With the former approach, racial disparities in disease incidence may continue to decline among children but may stall among adults. If the latter strategy is pursued, entire communities stand to gain, regardless of their background.” (M. M. Davis, mattdav@med.umich.edu)

HRT & Fractures: Hormone therapy protects women against fractures, but the benefits subside within 1 year of drug discontinuation, according to a study of 138,737 postmenopausal patients (pp. 2212-20). Risk of fracture was reduced by 33% to 42% with estrogens, estrogen–progestin, and other hormones, but past users had risks similar to baseline. (E. Banks, Radcliffe Infirmary, Oxford, U.K.; emily.banks@anu.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 13, 2004 Vol. 11, No. 92
Providing news and information about medications and their proper use

>>>Psychiatry Highlights
Source:
May issue of the American Journal of Psychiatry (ajp.psychiatryonline.org; 2004; 161).

Sertraline for Recurrent MDD: Among 288 patients with highly recurrent major depressive disorder (at least three documented episodes within 4 years), sertraline was more effective than placebo for preventing recurrences (pp. 836-42). At the time of admission to the study, patients were in remission and had been treated for their last MDD episode for at least 4 months with antidepressants other than sertraline. “Recurrences were significantly lower in the sertraline groups compared with placebo (sertraline, 50 mg: 16 [16.8%] of 95; sertraline, 100 mg: 16 [17.0%] of 94; placebo: 33 [33.3%] of 99),” the authors report. “Patients treated with sertraline also had a significantly longer time until recurrence compared with placebo-treated patients.” (J-P Lépine)

Risperidone & Maturation: Treatment of children with risperidone for 11 or 12 months had on effect on growth or sexual maturation, according to a retrospective analysis of records on 700 children aged 5–15 years (pp. 918-20). “[Patients] evaluable for growth ... had baseline and 11- or 12-month height measurements (N = 350); girls 9 years and boys 10 years who were evaluable for sexual maturation also had baseline and 11- or 12-month Tanner staging (N =222),” the research group writes. “Risperidone-treated children had a mean increase in height 1.2 cm greater than the reference population, and they experienced no delay in progression through Tanner staging. Transient increases in prolactin did not correlate with growth or sexual maturation.” (F. Dunbar)

>>>Immunology Highlights
Source:
May issue of the Journal of Allergy and Clinical Immunology (www2.us.elsevierhealth.com; 2004; 113).

Asthma & Lidocaine: Nebulized lidocaine provides “effective and safe therapy in subjects with mild-to-moderate asthma,” conclude investigators who studied 50 subjects in a randomized, placebo-controlled trial (pp. 853-9). Patients had received daily inhaled glucocorticoids (but not systemic glucocorticoids) and bronchodilators for at least 2 months before the study began, and they then recorded symptoms and peak flows during a 2-week run-in phase. Subjects inhaled either nebulized placebo (saline) or 4% lidocaine (100 mg) four times daily and reduced their inhaled glucocorticoid dosage by one half each week for 3 weeks and discontinued glucocorticoid treatment at week 4. During 8 weeks of treatment on placebo or lidocaine plus bronchodilators, several indicators of asthma severity improved, including forced expiratory volume in 1 second, nighttime awakenings, symptoms, bronchodilator use, and blood eosinophil counts. (G. J. Gleich, U. Utah, Salt Lake City)

Beta-Blockers, Heart Disease, & Peanut Allergy: Beta-blockers “should still improve survival” when used for treating patients after postmyocardial infarction or with congestive heart failure who are at risk for peanut-induced anaphylaxis, according to researchers who used a Markov model to analyze life expectancy based on published data (pp. 977-82). Beta-blockers have the potential to increase mortality in patients who experience peanut-induced anaphylaxis, the authors note. However, they add, “the heart disease benefit of beta-blockers outweighs the increased likelihood of dying from anaphylaxis, increasing life expectancy by 9.4 and 17.4 months, respectively.” Use of the agents did not increase life expectancy in several situations, though, such as when the annual rate of moderate to severe anaphylaxis exceeded 6.0% for postmyocardial infarction and 15% for congestive heart failure patients. (J. B. Wong, jwong@tufts-nemc.org)

>>>PNN NewsWatch
* In today’s New England Journal of Medicine (content.nejm.org), authors of two articles and an accompanying editorial explore the evidence supporting a link between serum homocysteine levels and development of osteoporosis. Progress in developing laparoscopic surgical techniques for treatment of colon cancer is the subject of another article and editorial.

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 14, 2004 Vol. 11, No. 93
Providing news and information about medications and their proper use

>>>Pediatrics Highlights
Source:
May issue of Pediatrics (www.pediatrics.org; 2004; 113).

Ethnic Differences in Perceived Need for Antibiotics: Parental expectations regarding antibiotic treatment for their children vary considerably among the ethnic groups of Los Angeles, according to a 2000–01 cross-sectional survey of 38 pediatricians and 543 parents (e385-94). Among those responding to the survey (64% and 83% of the two respective groups), the authors found, “Forty-three percent of parents believed that antibiotics were definitely necessary, and 27% believed that they were probably necessary for their child’s illness. Latino and Asian parents were both 17% more likely to report that antibiotics were either definitely or probably necessary than non–Hispanic white parents. Physicians correctly perceived that Asian parents expected antibiotics more often than non–Hispanic white parents but underestimated the greater expectations of Latino parents for antibiotics. Physicians also correctly perceived that parents of children with ear pain or who were very worried about their child’s condition were significantly more likely to expect antibiotics. Physicians were 7% more likely to make a bacterial diagnosis and 21% more likely to prescribe antibiotics when they perceived that antibiotics were expected.” (R. Mangione-Smith, UCLA)

Zinc Supplementation in SGA Infants: Among 200 infants born full term but small for gestational age, zinc supplementation had little effect on development or behavior (pp. 1297-305). Field workers administered zinc 5 mg or placebo daily to the infants—born in a low-income, urban community in Delhi, India—from 10 days to 9 months of age. Measured at 6 and 10 months, infants’ development and behavior were not affected by zinc supplements. “In a subgroup analysis among the zinc-supplemented infants, lower birth weight infants were perceived to be more temperamentally difficult than higher weight infants; in the control group, birth weight was not associated with temperament,” write the researchers. “Heavier birth weight infants had better scores on all measures of development and behavior at 6 months and on changes in mental and motor development from 6 to 10 months, compared with lighter birth weight infants. Boys had better weight gain and higher scores on mental development and emotional regulation than girls. ” (M. M. Black, U. Maryland, Baltimore)

>>>PNN NewsWatch
* Medicare drug discount cards will save seniors more than 20% on their prescription drug costs, according to a study conducted by the Lewin Group. A typical beneficiary without drug coverage who spends $1,727 per year on medicines will save nearly $350, the report estimates. For Medicare patients with hypertension, annual drug costs should be reduced from more than $956 to $713, a savings of 25%. Persons with multiple chronic conditions could see annual savings of $1,000 or more (www.hlc.org).

* The federal government should —but is unlikely to—increase its funding of
HIV/AIDS treatments. A new federal benefits program is needed, concluded an Institute of Medicine panel in a report released yesterday. The plan would combine federal spending into a single entitlement program, the IOM panel said, and the cost of expanded coverage could reach $5.6 billion over 10 years. The sponsor of the report, the Department of Health and Human Services, termed the findings “overreaching” and noted that such a program would require Congressional legislation.

* Illegal promotions of
Neurontin by Warner-Lambert—now a part of Pfizer—will result in a fine of $430 million, including a $240 million criminal fine. Pfizer reportedly will plead guilty in the case, which involves promotion of the antiepileptic agent for migraines, psychiatric disorders, and pain. As part of the fine, a former company employee will receive some $26 million as the “whistleblower” in the case, and $38 million is earmarked to warn physicians and consumers of the dangers of off-label drug use.

* May 31 is
World No Tobacco Day, and the International Pharmaceutical Federation is promoting the event by focusing on “The Role of the Pharmacist in Promoting a Tobacco Free Future” (www.pharmacistsagainsttobacco.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 17, 2004 Vol. 11, No. 94
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
May 15 issue of Lancet (www.thelancet.com; 2004; 363).

Psychologic Interventions & Type 2 DM: Long-term glycemic control—as measured by glycosylated hemoglobin—was improved in patients with type 2 diabetes mellitus who received psychologic interventions, but no benefits were noted with regard to their body weights or blood glucose concentrations, according to a meta-analysis that included a total of 25 clinical trials (pp. 1589-97). Interventions were usually some variation on cognitive-behavioral therapy; most were conducted in the U.S., where group therapies were most often employed because of the influence of health insurance on resources use. “The pooled mean difference [in A1c levels] was –0.32 (95% CI –0.57 to–0.07) equivalent to an absolute difference of –0.76%,” the authors explain. “There were non-significant differences in blood glucose concentration (eight trials; –0.11 [–0.65 to 0.42]) and weight gain (nine trials; 0.37 [–0.18 to 0.93]). Psychological distress was significantly lower in the intervention groups (five trials; –0.58 [–0.95 to –0.20]).” (K. Ismail, Weston Education Ctr., London, U.K.; khalida.ismail@iop.kcl.ac.uk)

Simvastatin for MS: Thirty patients with relapsing-remitting multiple sclerosis had fewer causative lesions while taking oral simvastatin 80 mg daily (pp. 1607-8). “The mean number of gadolinium-enhancing lesions at months 4, 5, and 6 of treatment was compared with the mean number of lesions noted on pretreatment brain MRI scans,” the researchers write. “Number and volume of Gd-enhancing lesions declined by 44%, (p < 0.0001) and 41% (p = 0.0018), respectively. Treatment was well tolerated. Oral simvastatin might inhibit inflammatory components of multiple sclerosis that lead to neurological disability.” (I. Singh, singhi@musc.edu)

>>>BMJ Highlights
Source:
May 15 issue of BMJ (www.bmj.org; 2004; 328).

Deficiencies in Electronic Prescribing Software: Analyzing the computing systems in use in the U.K. for physician prescribing, investigators find that about three quarters of them “have clinically important deficiencies” (pp. 1171-2). “All may fail to warn in a situation when a warning is expected, thus potentially creating a health hazard to patients,” the authors conclude based on results of a Delphi process involving 22 members of an expert panel. “One solution to this problem is to have more explicit regulations about the situations in which suppliers should implement specific alerts. Because information technology, pharmacology, and medicine are dynamic fields, suppliers of systems and drug databases would need to have regular dialogue with end users about ways of further improving the safety features of these important aides to clinical management.”(A. J. Avery, U. Nottingham, Nottingham, U.K.; tony.avery@nottingham.ac.uk)

>>>PNN NewsWatch
* Simvastatin (Zocor, Merck) has been approved for pharmacy-only nonprescription sales in the U.K., beginning in July. Patients will fill out risk-assessment questionnaires and will be encouraged to get a blood cholesterol test.

* An urgent plea to all national governments and health professionals to stop procrastinating on the
HIV/AIDS pandemic has been issued by the world’s nursing, pharmacy, and medical leaders at a historic first conference of the World Health Professions Alliance in Geneva.

>>>PNN JournalWatch
* Psychological and Social Sequelae of Cannabis and Other Illicit Drug Use by Young People: A Systematic Review of Longitudinal, General Population Studies, in Lancet, 2004; 363: 1579–88. Reprints: www.thelancet.com; J. Macleod, U. Birmingham, Birmingham, U.K.; j.a.macleod@bham.ac.uk

* Patients’ Experience with a Diabetes Support Programme Based on an Interactive Electronic Medical Record: Qualitative Study, in
BMJ, 2004; 328: 1159 ff. Reprints: www.bmj.org; J. D. Ralston, Group Health Cooperative, Seattle;
ralston.j@ghc.org

* The Pathophysiology of Cigarette Smoking and Cardiovascular Disease: An Update, in
Journal of the American College of Cardiology, 2004; 43: 1731–7. Reprints: www.cardiosource.com; J. A. Ambrose, New York Med. College, New York City; jamambrose@yahoo.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 18, 2004 Vol. 11, No. 95
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
May 18 issue of the Annals of Internal Medicine (www.annals.org; 2004; 140).

Rosiglitazone & HIV Lipodystrophy: Rosiglitazone improved lipoatrophy, insulin sensitivity, and metabolic indices in a study of 28 HIV-infected men and women with lipodystrophy (pp. 786-94). The patients, all of whom had hyperinsulinemia and lipoatrophy as a result of their antiretroviral medications, took rosiglitazone 4 mg daily for 3 months. The investigators report, “Rosiglitazone, when compared with placebo, improved insulin sensitivity (mean [±SD] change, 1.5 ± 2.1 mg of glucose/kg of lean body mass per minute vs. –0.4 ± 1.6 mg/kg per minute; P = 0.02), increased adiponectin levels (mean [±SD], 2.2 ± 2.2 µg/mL vs. 0.1 ± 1.1 µg/mL; P = 0.006), and reduced free fatty acid levels (mean [±SD], –0.09 ± 0.1 mmol/L vs. 0.01 ± 0.1 mmol/L; P = 0.02). Mean percentage (±SD) of body fat (1.38% ± 3.03% vs. –0.83% ± 2.76%; P = 0.03) and subcutaneous leg fat area (2.3 ± 8.4 cm2 vs. –0.9 ± 1.9 cm2; P = 0.02) increased significantly with rosiglitazone compared with placebo. Mean total cholesterol levels (±SD) also increased with rosiglitazone compared with placebo (0.6 ± 1.0 mmol/L [25 ± 37 mg/dL] vs. –0.4 ± 0.6 mmol/L [–15 ± 25 mg/dL]; P = 0.007).” (C. Hadigan, Mass. Genl. Hosp., Boston; chadigan@partners.org)

Beta-2–Agonists & Asthma: Regular beta-2–agonist use leads to tolerance to the beneficial effects of the drugs within 1 week, according to a meta-analysis of 22 trials (pp. 802-13). The studies all used randomized, controlled designs that included regular medication use without any as-needed use of beta-2–agonists. Forced expiratory volume in 1 second did not change after treatment with beta-2–agonists, but regular use of the drugs reduced the peak FEV1 response to subsequent beta-2–agonist administration; the provocative concentration of bronchoconstrictive agents causing a 20% reduction in FEV1; and leukocyte beta-2 receptor density, binding affinity, and in vitro response to isoproterenol.

The authors conclude, “Our analysis reinforces the accumulating evidence that regular beta-2–agonist use leads to increased airway inflammation and worsening of asthma control. To help clarify the issue, long-term trials are needed comparing beta-2–agonist use with other therapies, such as ipratropium or corticosteroids, without allowing as-needed beta-2–agonist use in the comparison group. Until then, the available evidence suggests that beta-2–agonists should not be used regularly in patients with asthma.” (S. R. Salpeter, Santa Clara Valley Med. Ctr., San Jose, Calif.; salpeter@stanford.edu)

Clarifying ADRs: A case discussion of drug-related harm is used to illustrate determination of the causal relationship between a suspected drug and an adverse event (pp. 795-801). The authors suggest that the term “side effect” be avoided and propose the following definitions:

*
Adverse event and adverse drug reaction are regulatory terms; the first does not require a causal link between the drug and the event, the second does.

*
Adverse drug events extend beyond adverse drug reactions to include harm from overdoses and underdoses usually related to medication errors. A minority of adverse drug events are medication errors, and medication errors rarely result in adverse drug events.

“After a drug is marketed, physicians may be the only source of information the FDA has for rare and potentially fatal adverse drug events,” the writers note. “However, physicians frequently neglect this crucial role. As few as 1% of serious and unexpected events are estimated to be reported to the FDA. Underreporting can lead to substantial delays in dissemination of warnings and product labeling changes. Most institutions facilitate reporting by making pharmacists available to complete and submit these reports. If a pharmacist is not available in the outpatient setting, the physician can use online tools to fill out a MedWatch report; personnel at the FDA will communicate with the physician if the report needs clarification or correction.” (J. R. Nebeker, Jonathan. Nebeker@hsc.utah.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 19, 2004 Vol. 11, No. 96
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
May 19 issue of JAMA (www.jama.com; 2004; 291).

Pexelizumab & CABG: The C5 complement inhibitor pexelizumab provided a significant reduction in cardiac events on one measure, but a second test failed to reach significance in a study of 2,746 patients who underwent coronary artery bypass graft surgery (pp. 2319-27). Beginning 10 minutes before undergoing the procedure, patients randomly received placebo or intravenous pexelizumab 2.0 mg/kg bolus plus 0.05 mg/kg per hour for 24 hours. Based on a composite endpoint of death or myocardial infarction within 30 days of randomization, the investigators found a significant reduction (11.5% of those on pexelizumab versus 14.0% of placebo patients; relative risk, 0.82; P = .03) in their intent-to-treat analysis of patients undergoing CABG either with or without valve surgery. But considering those who underwent CABG only in an intent-to-treat analysis, the difference in outcomes (9.8% versus 11.8%) failed to reach significance (RR, 0.82, P = .07). (E. D. Verrier, edver@u.wash.edu)

Sodium Bicarbonate & Contrast-Induced Nephropathy: For preventing contrast-induced nephropathy, hydration with sodium bicarbonate proved more effective than hydration with sodium chloride, according to findings from a 119-patient study (pp. 2328-34). The patients, who had stable renal function coming into the study, received 154 meq/L of either sodium chloride or sodium bicarbonate, as a bolus of 3 mL/kg per hour for 1 hour before iopamidol contrast, followed by an infusion of 1 mL/kg per hour for 6 hours after the procedure. The authors report, “There were no significant group differences in age, sex, incidence of diabetes mellitus, ethnicity, or contrast volume. Baseline serum creatinine was slightly higher but not statistically different in patients receiving sodium bicarbonate treatment (mean [SD], 1.71 [0.42] mg/dL [151.2 {37.1} µmol/L] for sodium chloride and 1.89 [0.69] mg/dL [167.1 {61.0} µmol/L] for sodium bicarbonate; P = .09). The primary end point of contrast-induced nephropathy occurred in 8 patients (13.6%) infused with sodium chloride but in only 1 (1.7%) of those receiving sodium bicarbonate(mean difference, 11.9%; 95% confidence interval [CI], 2.6%-21.2%; P = .02). A follow-up registry of 191 consecutive patients receiving prophylactic sodium bicarbonate and meeting the same inclusion criteria as the study resulted in 3 cases of contrast-induced nephropathy (1.6%; 95% CI, 0%–3.4%).” (T. P. Kennedy, Carolinas Med. Ctr., Charlotte; tkennedy@carolinas.org)

An editorialist supports this “back-to-basics” approach for preventing renal dysfunction in patients receiving contrast agents (pp. 2376-7): “Sodium bicarbonate is inexpensive, readily available, and apparently safe. Although no head-to-head comparison was made, its use is far more solidly justified than the expensive, elaborate, and potentially harmful treatment of hemofiltration. A brief infusion of isotonic sodium bicarbonate preexposure and postexposure to radiocontrast should now be considered the treatment of choice for prevention of radiocontrast nephropathy. Future studies, if conducted, should require the administration of basic solutions rather than isotonic or hypotonic sodium chloride.” (G. M. Chertow, chertowg@medicine.ucsf.edu)

Copayments & Drug Use: Changes in patients’ copayments significantly affect their use of medications in a variety of therapeutic categories, conclude investigators who analyzed pharmacy claims data from 30 employers and 52 health plans (pp. 2344-50). Based on the relative change in drug days supplied when copayments doubled, use declined in eight therapeutic classes: NSAIDs, 45%; antihistamines, 44%; antihyperlipidemics, 34%; antiulcerants, 33%; antiasthmatics, 32%; antihypertensives, 26%; antidepressants, 26%; and antidiabetics, 25%. “The reduction in use of medications for individuals in ongoing care was more modest,” conclude the authors. “Still, significant increases in co-payments raise concern about adverse health consequences because of the large price effects, especially among diabetic patients.” (D. P. Goldman; dgoldman@rand.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 20, 2004 Vol. 11, No. 97
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
May 20 issue of the New England Journal of Medicine (content.nejm.org; 2004; 350).

Gefitinib & EGFR Mutations: Clinical responsiveness of patients with non–small-cell lung cancer to gefitinib can be assessed by testing for presence of specific mutations in the epidermal growth factor receptor gene, according to a small study (pp. 2129-39). While most patients with this type of cancer do not respond to gefitinib, these authors explain that about 10% of such patients have exhibited a rapid and often dramatic clinical response to the drug. Searching for a reason for the variability in response, the investigators found, “Somatic mutations were identified in the tyrosine kinase domain of the EGFR gene in eight of nine patients with gefitinib-responsive lung cancer, as compared with none of the seven patients with no response (P < 0.001). Mutations were either small, in-frame deletions or amino acid substitutions clustered around the ATP-binding pocket of the tyrosine kinase domain. Similar mutations were detected in tumors from 2 of 25 patients with primary non–small-cell lung cancer who had not been exposed to gefitinib (8 percent). All mutations were heterozygous, and identical mutations were observed in multiple patients, suggesting an additive specific gain of function. In vitro, EGFR mutants demonstrated enhanced tyrosine kinase activity in response to epidermal growth factor and increased sensitivity to inhibition by gefitinib.” (D. A. Haber, haber@helix.mgh.harvard.edu)

Even though the percentage of responding patients may be small, an editorialist notes that this translates into thousands of NSCLC patients who could benefit from gefitinib therapy (pp. 2191-3): “[This] work, if borne out by additional studies, will fundamentally change targeted therapy for solid tumors. For patients with lung cancer, mutational analysis of EGFR by experienced laboratories should provide guidance about treatment. More generally, this work suggests the relevance of a two-step evaluation of targeted therapy. Identification of the target and a therapeutic ligand will remain a critical but relatively crude initial step. Subsequent work must then facilitate the identification of the responsive subgroup. Seeking gain-of-function mutations clustered around the critical binding pocket of the tyrosine kinase domain, analogous to what has been demonstrated [in this study], seems a reasonable way to begin.” (M. R. Green, Med. U. South Carolina, Charleston)

National Security & Biomedical Research: As the 9/11 commission continues its deliberations, authors provide a perspective on how the nation’s biomedical researchers have responded to the threat of terrorist attacks using biologic, chemical, nuclear or radiologic assaults (pp. 2119-21). They write, “Among a variety of new and expanded programs, the Regional Centers of Excellence for Biodefense and Emerging Infectious Diseases Research (RCEs) and the National and Regional Biocontainment Laboratories deserve particular mention. The RCE program has established regional consortia of investigators who operate within a synergistic and coordinated framework. The goals of the program are to develop and conduct programs of investigator-directed research, particularly in the area of agents in CDC categories A, B, and C5; train people to conduct research related to biodefense and emerging infectious diseases; develop and maintain comprehensive core facilities that support the research and training activities of the RCE; make these core facilities available to qualified investigators from academia, biotechnology companies, the pharmaceutical industry, and other appropriate entities in the geographic region of the center; develop translational research capacity for the testing and validation of concepts for vaccines, therapies, and diagnostic tools for biodefense and emerging infectious diseases; and provide facilities and scientific support to first-line responders in the event of a national biodefense emergency. The [National Institute of Allergy and Infectious Diseases] funded eight RCEs in the fall of 2003.” (A. S. Fauci, National Institute of Allergy and Infectious Diseases, 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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 21, 2004 Vol. 11, No. 98
Providing news and information about medications and their proper use

>>>JAPhA Highlights
Source:
May/June issue of the Journal of the American Pharmacists Association (www.japha.org; 2004; 44).

Pharmacists’ Worklife: Physical and mental health of current and future pharmacists and perhaps even patient safety are at risk because of currently high levels of role stress among pharmacists, report researchers who surveyed 1,737 pharmacists (pp. 326-36). The national survey reveals, “Although 67.2% of pharmacists were satisfied with their job, more than 68% experienced job stress and role overload, and 48% experienced work– home conflict. The levels of role ambiguity, role conflict, and job stress were significantly higher in chain, mass merchandiser, and hospital settings relative to independent settings. Wanting to spend more time in consultation was most positively associated with role ambiguity, role overload, and role conflict and most negatively associated with job satisfaction. Gender, race, years of experience, marital status, and children also affected work attitudes.” (D. A. Mott, damott@pharmacy.wisc.edu)

An editorialist maintains that these findings call for a shift in job focus for pharmacists (pp. 317-8): “A purpose of research, artfully illustrated by the extensive analysis presented in the work attitudes study by Mott and colleagues, is to ‘slice and dice’ the data and thereby provide insights into the differences among an outwardly similar group, in this case pharmacists. While the authors have successfully and convincingly identified differences in work attitudes by gender and practice setting (e.g., women pharmacists report higher job satisfaction, as do pharmacists practicing in independent community pharmacies), and while these differences merit additional exploration in future research efforts, a compelling aspect of this study is the strength and unity of pharmacists’ voices for a change in the focus of pharmacy practice in all settings—away from the distributive and business aspects and toward meeting the needs of patients in their use of medications.” (K. K. Knapp, kknapp@westernu.edu)

Iowa Pharmaceutical Case Management Program: Three research articles explore various aspects of the Iowa Medicaid Pharmaceutical Case Management program. In a state-mandated evaluation of the initial experiences of pharmacists, physicians, and patients in the PCM program, the authors report (pp. 337-49), “Pharmacists in 114 pharmacies had eligible patients during at least one quarter during the study period; 28 pharmacies were classified as high intensity based on the number of PCM patients they managed. A total of 524 of the eligible patients received 1,599 PCM services; 90% of claims were filed by pharmacists, and the remainder by physicians. Nearly one half (46.1%) of medications and 92.1% of patients had at least one medication problem before PCM. By closeout, the percentage of medications with problems decreased in 8 of 10 [Medication Appropriateness Index] domains for those who received PCM. Compared with baseline, mean MAI score improved significantly from 9.4 to 8.3 among PCM recipients (P < .001).” (E. A. Chrischilles, e-chrischilles@uiowa.edu)

Tablet-Splitting Protocol: An APhA-developed tablet-splitting protocol provides pharmacists with guidance concerning product- and patient-specific factors that should be considered before tablet splitting is attempted (pp. 324-5; S. C. Winckler; swinckler@aphanet.org)

>>>PNN NewsWatch
* FDA has approved azacitidine (Vidaza, Pharmion Corp.) injection, the first treatment for patients with myelodysplastic syndrome. The orphan drug is thought to work by restoring normal growth and differentiation of bone marrow cells. In clinical trials involving 268 patients, about 15% responded to the agent. Common adverse effects included nausea, anemia, thrombocytopenia, diarrhea, fatigue, irritation at the injection site, and constipation.

* Important indications of older drugs have also been approved by FDA:
docetaxel injection with prednisone for treatment of advanced metastatic prostate cancer; gemcitabine in combination with paclitaxel for first-line treatment of metastatic breast cancer; and moxifloxacin for treating community-acquired pneumonia caused by multidrug-resistant Streptococcus pneumoniae.

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 24, 2004 Vol. 11, No. 99
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
May 22 issue of Lancet (www.thelancet.com; 2004; 363).

OTC Statins: The editors of the Lancet are critical of a recent decision to allow nonprescription, pharmacy-only sales of simvastatin in the U.K.: “There are no trials of OTC statins for primary prevention of heart disease. There are no data on compliance with OTC statins, which for products that need to be taken daily long-term is a concern. Will those who buy simvastatin also stop smoking, lose weight, and do more exercise, or will they substitute drug use for lifestyle modification? Will pharmacists have the time to determine the individual's risk of coronary heart disease before selling the drug and also to give lifestyle advice? All these are unknowns, which is unfortunate for the UK public, who will be the guinea pigs in this large-scale OTC experiment. Americans have escaped this role, with two applications for OTC statins (pravastatin 10 mg and lovastatin 10 mg) being rejected in 2000 because of insufficient evidence that either drug could be used safely and effectively in an OTC setting.”

Adjuvant Zinc in Children with Pneumonia: In a study from Bangladesh, 270 infants and young children with severe pneumonia had better clinical outcomes when they received adjuvant treatment with zinc 20 mg daily (pp. 1683-8). In a double-blind, placebo-controlled trial in which all patients received standard inpatient antimicrobial treatment, investigators found, “The group receiving zinc had reduced duration of severe pneumonia (relative hazard [RH]=0.70, 95% CI 0.51–0.98), including duration of chest indrawing (0.80, 0.61–1.05), respiratory rate more than 50 per min (0.74, 0.57–0.98), and hypoxia (0.79, 0.61–1.04), and overall hospital duration (0.75, 0.57–0.99). The mean reduction is equivalent to 1 hospital day for both severe pneumonia and time in hospital. All effects were greater when children with wheezing were omitted from the analysis.” (W. A. Brooks, Intl. Ctr. for Diarrhoeal Disease Research, Mohakhali, Dhaka, Bangladesh; abrooks@icddrb.org)

Morphine in Preterm Neonates: Outcomes were mixed among preterm neonates who received morphine bolus and maintenance infusions for pre-emptive analgesia (pp. 1673-82). In the Neurologic Outcomes and Pre-emptive Analgesia in Neonates (NEOPAIN) trial, 898 preterm neonates received placebo or morphine infusions. Composite and individual rates of neonatal death, severe intraventricular hemorrhage, and periventricular leukomalacia were largely unaffected by the intervention, and intermittent boluses of open-label morphine were associated with an increased rate of the composite outcome and of severe IVH. In addition, while clinical signs of pain were reduced, significant adverse effects of morphine were noted in ventilated preterm neonates. (K. S. Anand, Ark. Children’s Hosp., Little Rock; anandsunny@uams.edu)

>>>PNN JournalWatch
* Preventing Childhood Obesity by Reducing Consumption of Carbonated Drinks: Cluster Randomised Controlled Trial, in BMJ, 2004; 328: 1237 ff. Reprints: www.bmj.org; J. James, Royal Bournemouth Hosp., Dorset, U.K.; janet.james@rbch-tr.swest.nhs.uk

* Interaction Strategies of Lesbian, Gay, and Bisexual Healthcare Practitioners in the Clinical Examination of Patients: Qualitative Study, in
BMJ, 2004; 328: 1227-9. Reprints: www.bmj.org; D. C. Riordan, St. George’s Hosp. Med. Sch., London; driordan@sghms.ac.uk

* Intravenous Immunoglobulin in Autoimmune Neuromuscular Diseases, in
JAMA, 2004; 291: 2367–75. Reprints: www.jama.com; M. C. Dalakas, dalakasm@ninds.nih.gov

* Analgesic Overuse Among Subjects with Headache, Neck, and Low-Back Pain, in
Neurology, 2004; 62: 1540–4. Reprints: www.neurology.org; J.-A. Zwart, Norwegian U. of Science and Technology, Trondheim, Norway; john-anker.zwart@medisin.ntnu.no

* Nonsteroidal Anti-Inflammatory Drugs, Alone or Combined with Opioids, for Cancer Pain, in
Journal of Clinical Oncology, 2004; 22: 1975–92. Reprints: www.jco.org; E. McNicol, New England Med. Ctr., Boston; EMcNicol@tufts-nemc.org

* Compounding for Animal Patients: Contemporary Issues, in
Journal of the American Pharmacists Association, 2004; 44: 375–86. Reprints: www.japha.org; E. Lust, elainel@creighton.edu

* Using Buzz Marketing to Promote Ideas, Services, and Products, in
Journal of the American Pharmacists Association, 2004; 44: 375–86. Reprints: www.japha.org; D. A. Holdford, daholdfo@vcu.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 25, 2004 Vol. 11, No. 100
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
May 24 issue of Archives of Internal Medicine (www.archinternmed.com; 2004; 164).

VTE Treatment: Dosed properly, unfractionated heparin is as safe and effective as fixed-dose low molecular weight heparin, according to an open-label study of 720 patients with acute symptomatic venous thromboembolism (pp. 1077-83). The study population included 119 noncritically ill patients with pulmonary embolism and 102 individuals with recurrent VTE. During 3 months of oral anticoagulation therapy, patients received either subcutaneous UFH dosed according to a weight-based algorithm or fixed-dose subcutaneous nadroparin calcium that was adjusted only for body weight. “Fifteen (4.2%) of the 360 patients assigned to UFH had recurrent thromboembolic events, as compared with 14 (3.9%) of the 360 patients assigned to nadroparin (absolute difference between rates, 0.3%; 95% confidence interval, –2.5% to 3.1%),” note the investigators. “Four patients assigned to UFH (1.1%) and 3 patients assigned to nadroparin (0.8%) had episodes of major bleeding (absolute difference between rates, 0.3%; 95% confidence interval, –1.2% to 1.7%). Overall mortality was 3.3% in each group.” (P. Prandoni, U. Padua, Padua, Italy; paoloprandoni@tin.it)

BMD Thresholds for Treatment: Only a small fraction of fractures occur in women whose bone mineral density places them in the treatment category, report authors who analyzed data on 149,524 white postmenopausal women who participated in the National Osteoporosis Risk Assessment (pp. 1108-12). “New fractures [during 12 months] were reported by 2259 women, including 393 hip fractures; only 6.4% had baseline T scores of –2.5 or less (World Health Organization definition for osteoporosis),” the authors write. “Although fracture rates were highest in these women, they experienced only 18% of the osteoporotic fractures and 26% of the hip fractures. By National Osteoporosis Foundation treatment guidelines, 22.6% of the women had T scores of 2.0 or less, or –1.5 or less with 1 or more clinical risk factors. Fracture rates were lower, but 45% of osteoporotic fractures and 53% of hip fractures occurred in these women.” (E. S. Siris, es27@columbia.edu)

Niacin ER Plus Lovastatin: Extended-release niacin in combination therapy with lovastatin positively affects the four major lipoprotein levels that are associated with atherosclerotic disease, conclude authors who followed 85 men and 79 with during five sequential 4-week treatment periods (pp. 1121-7). Patients took niacin ER (starting at 500 mg/day, increasing in 500-mg increments to 2,500 mg/day); lovastatin (starting at 10 mg, increasing to 20 mg, then 40 mg/day); and 3 combinations regimens, each with a constant lovastatin dose and escalating niacin ER doses. The researchers found, “For primary comparisons, mean LDL-C level reductions from baseline were greater with niacin ER/lovastatin (1500/20 mg) than with lovastatin (20 mg) (35% vs 22%, P < .001) and with niacin ER/lovastatin (2000/40 mg) than with lovastatin (40 mg) (46% vs 24%, P < .001). Each 500-mg increase in niacin ER, on average, decreased LDL-C levels an additional 4% and increased HDL-C levels 8%. The maximum recommended dose (2000/40 mg/d) increased HDL-C levels 29% and decreased LDL-C levels 46%, triglyceride levels 38%, and lipoprotein(a) levels 14%. All lipid responses were dose dependent and generally additive. Graphs of the dose-response relationships as 3-dimensional surfaces documented the strength and consistency of these responses.” (W. Insull, Jr, Baylor College of Med. and Methodist Hosp., Houston; winsull@tcm.org)

Benefits of Exercise: Women in their early postmenopausal years who participated in exercise programs that emphasized bone mineral density had improved bone status, back pain, and lipid levels (pp. 1084-91). Compared with 33 women who did not exercise, 50 women in fitness programs had significantly improved parameters for several health measures. (W. Kemmler, U. Erlangen, Erlangen, Germany; wolfgang.kemmler@imp.uni-erlangen.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 26, 2004 Vol. 11, No. 101
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
May 26 issue of JAMA (www.jama.com; 2004; 291).

Aspirin & Breast Cancer: Inhibition of prostaglandin synthesis by aspirin and NSAIDs contributes to prevention of hormone-receptor–positive breast cancer in women, conclude investigators who conducted a population-based case–control study on Long Island during 1996–97 (pp. 2433-40). Among 1,442 cases and 1,420 controls, the authors found, “Ever use of aspirin or other NSAIDs at least once per week for 6 months or longer was reported in 301 cases (20.9%) and 345 controls (24.3%) (odds ratio [OR], 0.80; 95% confidence interval [CI], 0.66–0.97 for ever vs nonusers). The inverse association was most pronounced among frequent users (7 tablets per week) (OR, 0.72; 95% CI, 0.58–0.90). The results for ibuprofen, which was used by fewer women on a regular basis, were generally weaker (OR, 0.78; 95% CI, 0.55–1.10 for <3 times per week vs OR, 0.92; 95% CI, 0.70–1.22 for 3 times per week). Use of acetaminophen, an analgesic that does not inhibit prostaglandin synthesis, was not associated with a reduction in the incidence of breast cancer. The reduction in risk with aspirin use was seen among those with hormone receptor–positive tumors (OR, 0.74; 95% CI, 0.60–0.93) but not for women with hormone receptor–negative tumors (OR, 0.97; 95% CI, 0.67–1.40).” (A. I. Neugut, ain1@columbia.edu)

After summarizing the history of aspirin as a pharmaceutical agent and discussing the possible mechanisms by which it might prevent breast cancer, an editorialist notes (pp. 2488-9): “Despite the longstanding and ubiquitous nature of aspirin use, researchers are still exploring the clinical outcome of aspirin treatment in humans. Unfortunately, all the answers are not available and current information is insufficient to make any definite recommendations to patients. Women who take daily aspirin for cardiovascular indications may gain additional benefits with regard to reduction in their risk for certain cancers, such as hormone receptor–positive breast cancer. However, the optimal aspirin dose or regimen required to achieve a maximal reduction in cancer risk remains unknown.” (R. N. DuBois, (ray mond.dubois@vanderbilt.edu)

Prenatal Cocaine Exposure: Prenatal cocaine exposure is associated with specific cognitive impairments and reduced odds of an above-average IQ at 4 years of age, conclude authors of a prospective study of 376 children (pp. 2448-56). “Prenatal cocaine exposure was related to small but significant deficits on several [IQ] subscales (mean [SE]): visual-spatial skills (cocaine exposed [7.3 (0.22)] vs nonexposed [8.2 (0.22)]; P = .01), general knowledge (cocaine exposed [6.1 (0.18)] vs nonexposed [6.7 (0.17)]; P = .04), and arithmetic skills (cocaine exposed [6.2 (0.20)] vs nonexposed [6.8 (0.20)]; P = .05),” write the authors. “Prenatal cocaine exposure was also associated with a lower likelihood of achievement of IQ above normative means (odds ratio, 0.26 [95% confidence interval, 0.10–0.65]; P = .004).” (L. T. Singer, Case Western Reserve U., Cleveland; Lynn.Singer@case.edu)

>>>Health Affairs Report
Source:
Paper posted early to the Health Affairs Web site (content.healthaffairs.org).

Electronic Prescribing: An expert panel assembled by the RAND Corporation recommends that physicians and other health care providers wanting to pursue electronic prescribing should look for systems that allow them to access patients’ computerized records and current medications and can transmit prescriptions according to established standards. The panel recommended that electronic prescribing systems should import patient identification and demographic data from electronic medical records used by the organization, provide the patient’s complete current medication list to prescribers who have care responsibility for the patient, display a list of medications appropriate to the diagnosis when it is entered, and guard against efforts to promote specific medications by third parties such as drug manufacturers or pharmacy benefit managers. (D. Bell, RAND Health)

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 27, 2004 Vol. 11, No. 102
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
May 27 issue of the New England Journal of Medicine (content.nejm.org; 2004; 350).

Colloid Versus Crystalloid Fluid Resuscitation: Contrary to the findings of a Cochrane meta-analysis, a controlled trial finds no difference in 28-day mortality rates among patients in intensive-care units who received normal saline or 4% albumin for fluid resuscitation (pp. 2247-56). The Cochrane Injuries Group Albumin Reviewers had previously identified a 6% increase in the absolute risk of death among patients give albumin solutions, compared with crystalloid solutions, but these results were challenged in a subsequent meta-analysis that found no difference. In the Saline versus Albumin Fluid Evaluation Study, investigators report on the experiences of 6,997 patients: “There were 726 deaths in the albumin group, as compared with 729 deaths in the saline group (relative risk of death, 0.99; 95 percent confidence interval, 0.91 to 1.09; P = 0.87). The proportion of patients with new single-organ and multiple-organ failure was similar in the two groups (P = 0.85). There were no significant differences between the groups in the mean (± SD) numbers of days spent in the ICU (6.5 ± 6.6 in the albumin group and 6.2 ± 6.2 in the saline group, P = 0.44), days spent in the hospital (15.3 ± 9.6 and 15.6 ± 9.6, respectively; P = 0.30), days of mechanical ventilation (4.5 ± 6.1 and 4.3 ± 5.7, respectively; P = 0.74), or days of renal-replacement therapy (0.5 ± 2.3 and 0.4 ± 2.0, respectively; P = 0.41).” (S. Finfer, ANZICS CTG, Carlton, Victoria, Australia; ctg@anzics.com.au)

After effusively praising the SAFE researchers for addressing “one of the most fundamental and contentious issues in critical care,” an editorialist writes (pp. 2294-6): “The SAFE Study was a randomized, concealed, blinded trial that examined a ubiquitous intervention in the intensive care unit: intravenous fluid. Commendably conducted, carefully analyzed, and transparently reported, this study has raised the bar for future trials by using multidisciplinary implementation strategies and Web-based management and by demonstrating excellent protocol adherence in thousands of patients. The SAFE Study is not only a landmark trial; it is also a milestone for the discipline of critical care medicine.” (D. Cook, McMaster U., Hamilton, Ont., Canada)

Suboptimal Hepatitis C Response Rates: Compared with 100 non-Hispanic white patients, 100 black patients had significantly poorer rates of virologic response to therapies for hepatitis C virus infection (pp. 2265-71). Treating the patients with peginterferon alfa-2b and ribavirin for 48 weeks, the investigators found, “In both cohorts, 98 percent of patients had genotype 1 infection. The rate of sustained virologic response was higher among non-Hispanic white patients than among black patients (52 percent vs.19 percent, P < 0.001). The black patients also had significantly lower rates of virologic response at 12 weeks and at the end of treatment. Multivariable analyses examining sociodemographic and clinical characteristics found that black race was the only variable significantly associated with the difference in response rate.” Reasons for the difference are unclear; blacks are also less likely to clear acute hepatitis C infection, and investigators are researching viral kinetics and increased iron stores among blacks with hepatitis C. (A. J. Muir, muir0002@mc.duke.edu)

Forcible Medication & Courtroom Competence: Four factors must be considered by judges when deciding whether defendants should be forcibly medicated with psychotropic drugs for the purpose of making them competent to stand trial, the Supreme Court ruled last summer (pp. 2297-301). These findings are that important government interests are at stake, forced medication will significantly further those interests, only involuntary medications are likely to advance those interests, and administration of the drug is medically appropriate. This article explores the legal and ethical conflicts inherent in this situation, including the dilemma faced by forensic psychiatrists and prison physicians, who may have split loyalties. (G. J. Annas, Boston U. Sch. of Public Health, 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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 28, 2004 Vol. 11, No. 103
Providing news and information about medications and their proper use

>>>FDA OKs Rifaximin for Traveler’s Diarrhea
FDA has approved rifaximin (Xifaxan, Salix Pharmaceuticals), an oral, gastrointestinal-selective antibiotic indicated for treatment of patients aged 12 years or older with travelers’ diarrhea caused by noninvasive strains of Escherichia coli. Salix licensed rifaximin from Alfa Wassermann S.p.A. More than 500 million tablets of rifaximin have been distributed in Italy since its approval in 1987. Currently, rifaximin is approved in 17 countries worldwide.

In clinical trials, rifaximin shortened the duration of diarrhea for the most common cause of this disease, noninvasive strains of E. coli. Unlike systemically absorbed anti-infective agents, rifaximin’s beneficial effect was achieved with minimal systemic absorption (about 0.4%), thus reducing the potential for development of systemic antimicrobial resistance and other systemic concerns such as drug–drug interactions.

Additionally, rifaximin’s tolerability profile was comparable with that observed with placebo. The most common adverse effects were flatulence in 11.3% of patients taking rifaximin (19.7% of placebo recipients had this adverse effect); headache, 9.7% (9.2%); abdominal pain, 7.2% (10.1%); and rectal tenesmus, 7.2% (8.8%). The drug should be discontinued and alternative antibiotic therapy considered if diarrhea symptoms get worse or persist more than 24–48 hours.

Xifaxan is expected to be available to physicians and patients in August.

>>>California Pharmacists Gear Up for World No Tobacco Day 2004
The World No Tobacco Day will be celebrated around the world on Monday, and California pharmacists will be ready, thanks to a promotional campaign launched earlier this week.

The International Pharmaceutical Federation (FIP) has prepared a campaign for its member organizations and pharmacists around the world with the following theme: “The Role of the Pharmacist in Promoting a Tobacco Free Future.” All campaign materials are available at www.pharmacistsagainsttobacco.org (click on “Activities&rdquoWinking. An events calendar is available on the World Health Organization Web site at: http://www.who.int/tobacco/areas/com munications/events/wntd/2004/calendar/en/.

The California Pharmacists Association, the California Smokers’ Helpline, and Assembly Majority Leader Dario Frommer have joined forces to promote the California Pharmacists Take Charge campaign. This new campaign has been designed so that pharmacists can offer consumers the opportunity to quit smoking through a free, tobacco quit-line. Pharmacists throughout California have placed a Ready to Quit Smoking counter stand and 100 Take Charge cards in their pharmacies to help launch the campaign.

“Pharmacists are one of the nation’s most accessible health care providers, so it makes perfect sense that we should do everything in our power to help consumers become smoke free,” said Michael Negrete, PharmD, and Vice President of Clinical Affairs for CPhA. “Each year approximately 440,000 people die of tobacco related deaths. The Smokers’ Helpline is a proven program that has helped consumers kick the habit for good.”

>>>PNN NewsWatch
* WhistleWatch is an early warning system for children with asthma who come home to an unattended house after school. When the child returns from school, the working parent calls the latchkey child. The child blows the WhistleWatch into the phone. The whistle sound assures the parent that the asthmatic child's lungs are in good condition. WhistleWatch will not produce a sound if there is increased airway resistance or the child’s peak flow has fallen below a preset value, indicating that the lungs may be failing. The parent instructs the child to take his/her medication or contacts the family’s medical professional.

* Sentencing began this week for former
Rite Aid executives who have pleaded guilty to various accounting-related charges.

*
PNN will not be published on Monday, May 31, 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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 1, 2004 Vol. 11, No. 104
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
May 29 issue of Lancet (www.thelancet.com; 2004; 363).

COX-2 Inhibitors, NSAIDs, & CHF: A higher rate of hospital admission for congestive heart failure was observed in a retrospective cohort study in elderly patients who used rofecoxib or nonselective NSAIDs but not celecoxib (pp. 1751-6). The study compared 100,000 nonusers of NSAIDs with 14,583 patients newly started on rofecoxib, 18,908 patients who began celecoxib, and 5,391 individuals starting nonselective NSAIDs. Based on drug use and hospital admissions between April 17, 2000, and March 31, 2001, the authors report, “Relative to non-NSAID users, patients on rofecoxib and non-selective NSAIDS had an increased risk of admission for congestive heart failure (adjusted rate ratio 1.8, 95% CI 1.5–2.2, and 1.4, 1.0–1.9, respectively), but not celecoxib (1.0, 0.8–1.3). Compared with celecoxib users, admission was significantly more likely in users of non-selective NSAIDs (1.4, 1.0–1.9) and rofecoxib (1.8, 1.4–2.4). Risk of admission for rofecoxib users was higher than that for non-selective NSAID users (1.5, 1.1–2.1). Of patients with no admission in the past 3 years, only rofecoxib users were at increased risk of subsequent admission relative to controls (1.8, 1.4–2.3).”

“Our findings suggest significant differences between non-selective NSAIDs and individual COX-2 inhibitors with respect to risk of admission for congestive heart failure,” the researchers conclude. “The clinical relevance of these findings, in view of the widespread use of the drugs, warrants the implementation of large-scale randomised controlled trials to examine this issue further.” (M. Mamdani, Inst. for Clinical Evaluative Sciences, Toronto; muhammad.mamdani@ices.on.ca)

Treatment of Cryptococcal Meningitis: In a study of 64 patients with first-episode HIV-associated cryptococcal meningitis, the combination of amphotericin B plus flucytosine proved to be the most rapidly fungicidal regimen (pp. 1764-7). Patients received either amphotericin B 0.7 mg/kg/day, amphotericin B plus flucytosine 100 mg/kg/day, amphotericin B plus fluconazole 400 mg daily, or triple therapy with all three agents. “Clearance of cryptococci from the CSF was exponential and was significantly faster with amphotericin B plus flucytosine than with amphotericin B alone (p = 0.0006), amphotericin B plus fluconazole ( p = 0.02), or triple therapy (p = 0.02),” note the authors. (T. Harrison, St. George’s Hosp. Med. Sch., London; tharriso@sghms.ac.uk)

>>>PNN NewsWatch
* The American Academy of Pediatrics and the Society for Adolescent Medicine have sent a letter to FDA and Barr Research, Inc., calling on the federal agency to reconsider its decision on Plan B and allow it to be distributed over-the-counter to women and sexually active adolescents. Safety information is adequate for the drug to be used by adolescents, and it is needed to prevent teenage pregnancy, the two organizations wrote.

* Writing in his usual humorous style,
Richard Smith announced his intention to step down as editor of BMJ. He will become CEO of a company being created by the UnitedHealth Group to work with European public health systems.

>>>PNN JournalWatch
* Atazanavir: New Option for Treatment of HIV Infection, in Clinical Infectious Diseases, 2004; 38: 1599–604. Reprints: www.journals.uchicago.edu/CID; D. V. Havlir, San Francisco Genl. Hosp., UCSF, San Francisco.

* Daily Scheduled Opioids for Intractable Head Pain, in
Neurology, 2004; 62: 1687–94. Reprints: www.neurology.org; J. R. Saper, Mich. Head-Pain and Neurological Inst., Ann Arbor; jrsaper@aol.com

* Lipids and Lipoproteins in Patients with Type 2 Diabetes, in
Diabetes Care, 2004; 27: 1496–504. Reprints: care.diabetesjournals.org; R. M. Krauss, Children’s Hosp., Oakland, Calif.; rmkrauss@lbl.gov

* Thalidomide, in
Lancet, 2004; 363: 1802–11. Reprints: www.thelancet.com; W. D. Figg, wdfigg@helix.nih.gov

* Severe Acute Respiratory Syndrome (SARS): The Pharmacist’s Role, in
Pharmacotherapy, 2004; 24: 705–12. Reprints: www.accp.com; T. W. F. Chin, St. Michael’s Hosp., Toronto.

* Anemia Management in Heart Failure: A Thick Review of Thin Data, in
Pharmacotherapy, 2004; 24: 757–67. Reprints: www.accp.com; C. M. White, Hartford Hosp., Hartford, Conn.; cmwhite@harthosp.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 2, 2004 Vol. 11, No. 105
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
June 1 issue of the Annals of Internal Medicine (www.annals.org; 2004; 140).

Statins & ACS: A randomized trial of statin therapy is warranted in patients with acute coronary syndromes, based on findings of a cohort study conducted in 94 hospitals in 14 countries (pp. 857-66). Investigators in the Global Registry of Acute Coronary Events (GRACE) trial made these observations about 19,537 patients who presented with ACS in 1999–2002: “Patients who were already taking statins when they presented to the hospital were less likely to have ST-segment elevation (odds ratio [OR], 0.79 [95% CI, 0.71 to 0.88]) or myocardial infarction (OR, 0.78 [CI, 0.70 to 0.86]). Patients who continued to take statins in the hospital were less likely to experience complications or die than patients who never received statins (OR, 0.66 [CI, 0.56 to 0.77]). Patients not previously taking statins who began statin therapy in the hospital were less likely to die than patients who never received statin therapy (OR, 0.38 [CI, 0.30 to 0.48]).” (F. A. Spencer, U. Mass. Med. Sch., Worcester; spencerf@ummhc.org)

Editorialists concur with the need for controlled trials to test the effects of statins in ACS (pp. 923-4): “The current evidence leaves us uncertain about whether starting statin therapy at the time of admission for an acute coronary syndrome is more effective than starting this therapy later. The matter is important to resolve, and additional large randomized trials are needed to clarify the issue. While we wait for the results, we can reflect on the many reasons for caution in drawing firm conclusions from observational studies of treatment effectiveness.” (A. Laupacis, Inst. for Clinical Evaluative Sciences, Toronto; alaupacis@ices.on.ca)

Initial DVT Treatment: Once-daily fondaparinux was at least as effective and safe as twice-daily enoxaparin for initial treatment of deep-vein thrombosis, conclude the Matisse investigators (pp. 867-73). At 154 centers worldwide, 2,205 patients with acute symptomatic DVT received fondaparinux 7.5 mg (5 mg in patients weighing less than 50 kg and 10 mg in those weighing more than 100 kg) subcutaneously once daily or enoxaparin 1 mg/kg of body weight subcutaneously twice daily for at least 5 days and until vitamin K antagonists induced an international normalized ratio greater than 2.0. At 3 months, the researchers found, “43 (3.9%) of 1098 patients randomly assigned to fondaparinux had recurrent thromboembolic events compared with 45 (4.1%) of 1107 patients randomly assigned to enoxaparin (absolute difference, –0.15 percentage point [95% CI, –1.8 to 1.5 percentage points]). Major bleeding occurred in 1.1% of patients receiving fondaparinux and 1.2% of patients receiving enoxaparin. Mortality rates were 3.8% and 3.0%, respectively.” (H. R. Büller, Academic Med. Ctr., Amsterdam, the Netherlands)

An editorialist notes that concern about laboratory monitoring of ambulatory patients will limit use of fondaparinux (pp. 925-6): “Is there room for further improvement and simplification of the antithrombotic treatment of patients with venous thromboembolism? Yes, there is. Simultaneous administration of fondaparinux and oral anticoagulants still requires careful laboratory monitoring during the first days of therapy. Even now, most physicians view laboratory monitoring as a serious obstacle to providing ambulatory treatment to their patients. One new development points to effective and safe treatment of venous thromboembolism with selective antithrombin drugs (such as ximelagatran) in fixed doses from the first dose without the need for laboratory monitoring.” ( P. Prandoni, U. Padua, Padua, Italy)

>>>JAMA Highlights
Source:
June 2 issue of JAMA (www.jama.com; 2004; 291).

Antibiotics & HIV: Compared with placebo, monthly antibiotics lowered the incidence of bacterial infections but not HIV transmission among 466 Kenyan female sex workers (pp. 2555-62). Bacterial infections may play a role in HIV susceptibility, but herpes simplex virus type 2 infection was a cofactor in these patients. (R. Kaul, rupert.kaul@utoronto.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 3, 2004 Vol. 11, No. 106
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
June 3 issue of the New England Journal of Medicine (content.nejm.org; 2004; 350).

Treatment of Colorectal Cancer: Two research articles and an editorial analyze progress in treatment of colorectal cancer using the recently marketed agents bevacizumab (approved in Feb. 2004) and oxaliplatin (first approved in Aug. 2002 and indications expanded in Jan. 2004).

In a Phase III trial, bevacizumab significantly improved survival among patients with metastatic colorectal cancer (pp. 2335-42). The study included 813 patients with previously untreated metastatic colorectal cancer, and they were randomized to treatment with irinotecan, bolus fluorouracil, and leucovorin (IFL) plus bevacizumab (5 mg/kg every 2 weeks) or IFL plus placebo. Median duration of survival was 20.3 months with IFL plus bevacizumab, a clinically and significantly improved value compared with 15.6 months for IFL plus placebo. The respective values for median duration of progression-free survival were 10.6 and 6.2 months, a significant 46% decrease in risk. Grade 3 hypertension occurred more often in those given bevacizumab (11% versus 2.3% in the placebo group), but the researchers write that it was “easily managed.” (H. Hurwitz, hurwi004@mc.duke.edu)

A 2,246-patient study assessed the oxaliplatin in patients who had undergone curative resections of stage II or III colon cancer (pp. 2343-51). After 6 months of fluorouracil plus leucovorin (FL) or FL plus oxaliplatin, the authors found, “After a median follow-up of 37.9 months, 237 patients in the group given FL plus oxaliplatin had had a cancer-related event, as compared with 293 patients in the FL group (21.1 percent vs. 26.1 percent; hazard ratio for recurrence, 0.77; P = 0.002). The rate of disease-free survival at three years was 78.2 percent (95 percent confidence interval, 75.6 to 80.7) in the group given FL plus oxaliplatin and 72.9 percent (95 percent confidence interval, 70.2 to 75.7) in the FL group (P = 0.002 by the stratified log-rank test). In the group given FL plus oxaliplatin, the incidence of febrile neutropenia was 1.8 percent, the incidence of gastrointestinal adverse effects was low, and the incidence of grade 3 sensory neuropathy was 12.4 percent during treatment, decreasing to 1.1 percent at one year of follow-up. Six patients in each group died during treatment (death rate, 0.5 percent).” (A. de Gramont, Hôpital Saint Antoine, Paris; aimery.de-gramont@sat.ap-hop-paris.fr)

An editorialist describes these articles as “two steps forward in the treatment of colorectal cancer” but bemoans the price (pp. 2406-8): “Such a prolongation of survival comes at a price. Treating a patient who weighs 80 kg with the dose of 5 mg per kilogram of body weight used by Hurwitz et al. for a median of 40.4 weeks (i.e., 20 doses) would add from $42,800 (given a cost of $2,140 per 400-mg vial of IFL) to $55,000 (given a cost of $2,750 per 400-mg vial) to the cost of noncurative care for advanced colorectal cancer, depending on the type of purchasing contract for the drug. Since the FDA granted a surprisingly broad indication for the use of bevacizumab (i.e., together with any fluorouracil-based combination, not just IFL, when given as first-line therapy), the antibody could be prescribed for most patients with advanced colorectal cancer. With approximately 30,000 to 40,000 such patients identified annually in the United States, the fiscal impact of the FDA’s approval could exceed $1.5 billion each year.” (R. J. Mayer, Dana–Farber Cancer Inst., Boston)

FDA & Plan B: “Political considerations—such as a desire to put the matter off until after the presidential election in November—have been the spoken and unspoken subtext of [FDA’s] decision” about the emergency contraceptive product Plan B, writes the author of a Perspectives article (pp. 2327-9). He also describes a proposal made in March by Barr Pharmaceuticals to FDA under which Plan B would have been a prescription product for those younger than 16 but an OTC products for older patients, presenting the federal agency with a legal question as to whether it has statutory authority to approve a product under such a dual status. (R. Steinbrook)

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 4, 2004 Vol. 11, No. 107
Providing news and information about medications and their proper use

>>>Psychiatry Highlights
Source:
June issue of the American Journal of Psychiatry (ajp.psychiatryonline.org; 2004; 161).

Atypical Antipsychotics & CVAs: A possible association between cerebrovascular accident and use of atypical antipsychotic agents is not supported by a retrospective population-based cohort study of patients (pp. 1113-5). Such a link had been made for one atypical agent used by elderly patients with dementia who participated in a randomized controlled trial. However, after reviewing administrative health care databases, authors of this study report, “Subjects treated with typical antipsychotics (N = 1,015) were compared with those given risperidone (N = 6,964) and olanzapine (N = 3,421). Model-based estimates adjusted for covariates hypothesized to be associated with stroke risk revealed relative risk estimates of 1.1 (95% CI = 0.5–2.3) for olanzapine and 1.4 (95% CI = 0.7–2.8) for risperidone.... Olanzapine and risperidone use were not associated with a statistically significant increased risk of stroke compared with typical antipsychotic use.” (N. Herrmann)

Novel Antipsychotic Medications: Four investigational antipsychotic agents were tested using a novel design that permitted use of smaller numbers of patients for each compound (pp. 975-84). The drugs—a neurokinin (NK3) antagonist (SR142801), a serotonin 2A/2C (5-HT2A/2C) antagonist (SR46349B), a central cannabinoid (CB1) antagonist (SR141716), and a neurotensin (NTS1) antagonist (SR48692)—were compared with haloperidol and placebo in 481 adult patients with schizophrenia. The investigators report, “The NK3 and 5-HT2A/2C antagonists showed evidence of efficacy in the treatment of schizophrenia and schizoaffective disorder. Study limitations preclude a definitive conclusion on the efficacy of CB1 and NTS1 antagonists in the treatment of schizophrenia. Further study of these two promising nondopaminergic mechanisms to treat schizophrenia and schizoaffective disorder appears indicated.” (H. Y. Meltzer)

Risperidone Monotherapy of Mania: Compared with placebo, risperidone was significantly more efficacious for relieving symptoms of acute mania, and the drug demonstrated a rapid onset of action (pp. 1057-65). In a 259-patient study, flexible-dose risperidone (1–6 mg/day) was administered, and baseline-to-endpoint changes in the Young Mania Rating Scale were recorded before, during, and after 3 weeks of treatment. “Improvement in mean ... total score (adjusted for covariates) was significantly greater in the risperidone than in the placebo group at endpoint (mean change = –10.6 [SD = 9.5] versus –4.8 [SD = 9.5], respectively), with significant between-group differences seen as early as 3 days after start of treatment (change with risperidone: mean = –6.8 [SD = 5.8]; change with placebo: mean = –4.0 [SD = 5.8]) and continuing throughout all time points,” note the researchers. “The most common adverse event reported among risperidone patients was somnolence. While Extrapyramidal Symptom Rating Scale scores were significantly greater in patients receiving risperidone, mean total and subscale scores were low.” (R. M. A. Hirschfeld)

Citalopram Treatment of Children: Citalopram was significantly more effective than placebo for reducing depressive symptoms among 174 children and adolescents with major depression (pp. 1079-83). In the 8-week study, citalopram was dosed at 20 mg/day, with the option of increasing the dose to 40 mg/day after 4 weeks if clinically indicated. “Mean Children’s Depression Rating Scale—Revised scores decreased significantly more from baseline in the citalopram treatment group than in the placebo treatment group, beginning at week 1 and continuing at every observation point to the end of the study (effect size = 2.9),” the authors note. “The difference in response rate at week 8 between placebo (24%) and citalopram (36%) also was statistically significant. Citalopram treatment was well tolerated. Rates of discontinuation due to adverse events were comparable in the placebo and citalopram groups (5.9% versus 5.6%, respectively).” (K. D. Wagner)

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 7, 2004 Vol. 11, No. 108
Providing news and information about medications and their proper use

>>>Trospium Approved for Overactive Bladder
U.S. patients with overactive bladder—including symptoms of urge urinary incontinence, urgency, and urinary frequency—will soon have access to an additional muscarinic receptor antagonist, thanks to FDA’s approve of trospium chloride (Sanctura, Indevus Pharmaceuticals). The product, with a third quarter release expected, will be comarketed by Indevus and Odyssey Pharmaceuticals.

Approval of the quaternary ammonium compound was based on a review of data from clinical studies conducted in the U.S. and Europe involving approximately 3,000 subjects. Urinary frequency, urge incontinence episodes, and urinary void volumes were significantly improved in patients on active drug, compared with placebo, in 12-week studies.

Trospium was well tolerated, and the most commonly reported adverse effects in Phase III U.S. clinical trials were dry mouth (20.1% for trospium versus 5.8% for placebo) and constipation (9.6% for trospium versus 4.6% for placebo). Patients who have urinary retention, gastric retention, uncontrolled narrow-angle glaucoma, or hypersensitivity to the drug should not use this product.

>>>BMJ Highlights
Source:
June 5 issue of BMJ (www.bmj.org; 2004; 328).

Chemoprophylaxis After Meningococcal Case: Antibiotic prophylaxis reduces the risk of meningococcal disease by 89% among household contacts of patients with the disease, according to a systematic review of four observational studies and one small trial (pp. 1339 ff). “Meta-analysis of studies on chemoprophylaxis given to household contacts showed a significant reduction in risk (risk ratio 0.11, 95% confidence interval 0.02 to 0.58),” note the authors. “The number needed to treat to prevent a case was estimated as 218 (121 to 1135). Primary outcome data were not available in studies of chemoprophylaxis given to the index patient: when prophylaxis had not been given, rate of carriage after discharge from hospital was estimated as 3% (0 to 6), probably an underestimate of the true rate. No studies of chemoprophylaxis in day care settings were identified that met the inclusion criteria.” (J. Stuart, Communicable Disease Surveillance Ctr. South West, Gloucester, U.K.; james.stuart@hpa.org.uk)

>>>PNN JournalWatch
* Pharmacoinvasive Therapy: The Future of Treatment for ST-Elevation Myocardial Infarction, in Circulation, 2004; 109: 2480–6. Reprints: circ.ahajournals.org; E. M. Antman.

* Combined Blockade of the Renin-Angiotensin System with Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Type 1 Receptor Antagonists, in
Circulation, 2004; 109: 2480–6. Reprints: circ.ahajournals.org; M. Azizi.

* Scientific Rationale for a Change in the Composition of Oral Rehydration Solution and Clinical Concerns About Reduced-Osmolarity Oral Rehydration Solution, in
JAMA, 2004; 291: 2628–31 and 2632–5. Reprints: www.jama.com; C. Duggan et al. and D. R. Nalin et al.

* A New Model for Accreditation of Residency Programs in Internal Medicine, in
Annals of Internal Medicine, 2004; 140: 902–9. Reprints: www.annals.org; A. H. Goroll, ahgoroll@partners.org

* Systematic Review: Surveillance Systems for Early Detection of Bioterrorism-Related Diseases, in
Annals of Internal Medicine, 2004; 140: 910–22. Reprints: www.annals.org; D. M. Bravata, bravata@healthpolicy.stanford.edu

* Usefulness of the American Academy of Pediatrics Recommendations for Identifying Youths with Hypercholesterolemia, in
Pediatrics, 2004; 113: 1723–7. Reprints: www.pediatrics.org; J. O’Loughlin, Direction de santé publique de Montréal-Centre, Montreal.

* AAP Policy Statement: Legalization of Marijuana: Potential Impact on Youth, in
Pediatrics, 2004; 113: 1825–6. Reprints: www.pediatrics.org; Committees on Substance Abuse and Adolescence of the American Academy of Pediatrics.

* Practice Guidelines for Outpatient Parenteral Antimicrobial Therapy, in
Clinical Infectious Diseases, 2004; 38: 1651–72. Reprints: www.journals.uchicago.edu/CID; A. D. Tice, U. Hawaii, Honolulu; alantice@idlinks.com

* Four Decades of Continuing Innovation with Fluorouracil: Current and Future Approaches to Fluorouracil Chemoradiation Therapy, in
Journal of Clinical Oncology, 2004; 22: 2214–32. www.jco.org; T. A. Rich, U. Virginia Health System, Charlottesville; tar4d@virginia.edu

* Cognitive Impairment Associated with Chemotherapy for Cancer: Report of a Workshop, in
Journal of Clinical Oncology, 2004; 22: 2233–9. www.jco.org; I. F. Tannock, Princess Margaret Hosp. Toronto; ian.tannock@uhn.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 8, 2004 Vol. 11, No. 109
Providing news and information about medications and their proper use

>>>Geriatrics Highlights
Source: June issue of the Journal of the American Geriatrics Society (www.blackwellpublishing.com/toc.asp?ref=0002-8614; 2004; 52).

Clinical Pharmacists’ Impact on Inappropriate Prescribing for Ontario Seniors: Clinical pharmacist services to residents of nursing homes, mandated in Ontario, may be responsible for prescribing patterns that are better than those among the general senior population in that Canadian province (pp. 861-6). An analysis of 2001 data from Ontario’s comprehensive drug plan focused on potentially inappropriate drug prescribing (those agents to always avoid and therapies considered rarely appropriate to prescribe) for community-dwelling and nursing home residents.

The authors report, “Community-dwelling older adults were significantly more likely to be dispensed at least one drug therapy in the always avoid or rarely appropriate category than nursing home residents (3.3% vs 2.3%, P < .001). Using a logistic regression model that controlled for age, sex, and comorbidity (number of distinct drug therapies dispensed in the prior year), nursing home residents were close to half as likely to be dispensed one of these potentially inappropriate drug therapies as community-dwelling older adults (odds ratio = 0.52, 95% confidence interval=0.49– 0.55, P < .001).” (P. A. Rochon, paula.rochon@utoronto.ca)

Pain & Analgesics in Nursing Homes: Persistent nonmalignant pain is highly prevalent and poorly managed among older residents of nursing homes, according to a study of nursing homes in 10 U.S. states (pp. 867-74). Minimum Data Set assessments for 21,380 residents showed, “Persistent pain ... was identified in 49% of residents with an average age of 83; 83% were female. Persistent pain was prevalent in patients with a history of fractures (62.9%) or surgery (63.6%) in the past 6 months. One-quarter received no analgesics. The most common analgesics were acetaminophen (37.2%), propoxyphene (18.2%), hydrocodone (6.8%), and tramadol (5.4%). Only 46.9% of all analgesics were given as standing doses. Acetaminophen was usually prescribed as needed (65.6%), at doses less than 1,300 mg per day. Nonsteroidal antiinflammatory drugs (NSAIDs) were prescribed as a standing dose more than 70% of the time, and one-third of NSAIDs were prescribed at high doses.” (A. B. Won, won@mail.hrca.harvard.edu)

>>>Nephrology Update
Source:
June issue of the American Journal of Kidney Diseases (www.ajkd.org; 2004; 43).

Obesity & Transplantation: “Rigorous efforts should be made to optimize weight before and after solid-organ transplantation by a judicious combination of diet, exercise, minimization of steroid therapy, surgery, and psychological therapies,” according to authors of a review article (pp. 943-52). “Obesity increases the risk for delayed graft function and local wound complications after technically successful kidney transplantation. Obese patients are more likely to have comorbid factors leading to premature death with a functioning kidney transplant.” (R. M. Jindal, Avera Mckennan U. Hosp., Sioux Falls, S.D.; rahul.jindal@mckennan.org)

New-Onset DM After Transplantation: New-onset diabetes after transplantation affects patient and graft outcomes and presents a serious clinical situation, conclude authors of a review article (pp. 953-65). “For patients in high-risk groups, including certain ethnic backgrounds, older adults, and the very young, and patients with hepatitis C, consideration should be given to initiating immunosuppressive therapy with agents that are less diabetogenic. Recent guidelines include more stringent criteria for diagnosis and stress the importance of strict glycemic control. Diet, exercise, and weight management are core components of treatment with addition of oral hypoglycemic agents and/or insulin as needed to achieve control. Concomitant measures include aggressive control of lipids and blood pressure to reduce the risk of cardiovascular disease.” (M. Markell, MD, SUNY Downstate Med. Ctr., Brooklyn; mariana.markell@downstate.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 9, 2004 Vol. 11, No. 110
Providing news and information about medications and their proper use

>>>Pharmacotherapy Update
Source:
June Pharmacotherapy (www.accp.com; 2004; 24).

Multicomponent Heparin Model: Compared with weight-based heparin dosing, a computerized protocol that included patient gender, age, height, and weight produced more favorable initial target antifactor Xa levels in a study of 372 patients (pp. 713-9). Eight different indications for heparin therapy were present in the patients, 197 of whom were included in a final validation group. “A regression model using sex, age, height, and weight was superior to a weight-only model in predicting UFH dosage,” write the authors. “Target-range antifactor Xa levels were achieved with the new protocol in 122 (87%) of 140 patients within 24 hours of start of therapy.” (M. F. Shepherd, Abbott Northwestern Hosp., Minneapolis; shelley.shepherd@allina.com)

Pyrosequencing for CYP 2C9 Genotyping: For determining patient genotypes of the cytochrome P450 2C9 gene, Pyrosequencing proved a more time-efficient, cost-effective, and robust method than restriction fragment length polymorphism using polymerase chain reaction (pp. 720-6). Pyrosequencing, a product of the Swedish company Biotage AB, uses automated real-time sequencing of short DNA fragments to directly assess allelic variants and the surrounding sequence, while RFLP is the most commonly used method of genotyping using single nucleotide polymorphisms, or SNPs. Using 15-mL mouthwash samples from 253 subjects in a warfarin pharmacogenomic study, researchers sought to genotype the 2C9 gene for an isoleucine-to-leucine change at codon 359 and an arginine-to-cysteine substitution at codon 144. The authors report, “Pyrosequencing and PCR-RFLP produced similar success rates on the first genotyping attempt for the Arg144Cys variant (93.3% vs 90.4%, respectively) and the Ile359Leu variant (83.8% vs 79.1%, respectively). With Pyrosequencing, genotyping 96 samples for either polymorphism could be performed in 1 hour. In contrast, genotyping 96 samples by RFLP took 10 hours for the Arg144Cys variant and 20 hours for the Ile359Leu variant. Total cost/sample for Arg144Cys genotyping was $1.90 with PCR-Pyrosequencing and $3.14 with PCRRFLP. Total cost/sample for Ile359Leu genotyping was $1.88 with PCR-Pyrosequencing and $10.18 with PCR-RFLP.” (J. A. Johnson, johnson@cop.ufl.edu)

Diarrhea & PIs: Compared with the protease inhibitor nelfinavir, lopinavir–ritonavir produced diarrhea less often, and when it did occur, in less severe episodes for shorter time periods in 401 patients with HIV infection (pp. 727-35). A retrospective cohort analysis showed, “The average number of months/person-year of diarrhea treatment was 2.0 for the nelfinavir group and 0.13 for the lopinavir–ritonavir group. Of the 10 antiretroviral-naive patients who received lopinavir–ritonavir, none needed treatment for diarrhea, whereas 78 (36%) of 217 antiretroviral-naive patients who received nelfinavir required treatment for diarrhea. Of the 52 patients who had been taking nelfinavir and were switched to lopinavir–ritonavir, they were more likely to start antidiarrheal treatment while taking nelfinavir (14 [27%]) than while receiving lopinavir–ritonavir (3 [6%]) (p = 0.004).” (J. L. Guest, Atlanta VA Med. Ctr., Decatur, Ga.)

Experiences with Insulin Glargine: Insulin glargine therapy, used in the place of NPH insulin or in addition to oral antidiabetic therapy, produced a decline in mean A1C levels of 0.53 percentage points during 1 year of treatment of 197 patients with type 1 or 2 diabetes mellitus (pp. 736-42). In a retrospective analysis of patients in a private endocrinology practice, investigators assessed those patients who began insulin glargine in May 2001 through April 2002 and were evaluable after 1 year on the drug. Decreases in A1C averaged 0.57 ± 1.5% from baseline among 129 patients with type 2 diabetes previously treated with NPH insulin and 0.71 ± 1.3% in 33 patients with type 2 diabetes who previously received oral agents only. In 35 patients with type 1 diabetes, A1C levels did not change significantly (–0.22 ± 1.0%) from baseline. (M. P. Kane, kanem@acp.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 10, 2004 Vol. 11, No. 111
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
June 10 issue of the New England Journal of Medicine (content.nejm.org; 2004; 350).

Prevention of Postoperative Nausea & Vomiting: In a study that evaluated 64 combinations of six preventive strategies for postoperative nausea and vomiting, investigators conclude that prophylaxis is rarely needed in low-risk patients, single interventions are usually sufficient in moderate-risk patients, and multiple interventions should be reserved for high-risk patients. (pp. 2441-51). A total of 5,199 patients at high risk for postoperative nausea and vomiting were enrolled in the study, and 4,123 of them randomly received 1 of 64 combinations of the six interventions: ondansetron 4 mg or no ondansetron; dexamethasone 4 mg or no dexamethasone; droperidol 1.25 mg or no droperidol; propofol or a volatile anesthetic; nitrogen or nitrous oxide; and remifentanil or fentanyl. The remaining patients were randomly assigned to one of the first four interventions.

The authors found, “Ondansetron, dexamethasone, and droperidol each reduced the risk of postoperative nausea and vomiting by about 26 percent. Propofol reduced the risk by 19 percent, and nitrogen by 12 percent; the risk reduction with both of these agents (i.e., total intravenous anesthesia) was thus similar to that observed with each of the antiemetics. All the interventions acted independently of one another and independently of the patients’ baseline risk. Consequently, the relative risks associated with the combined interventions could be estimated by multiplying the relative risks associated with each intervention. Absolute risk reduction, though, was a critical function of patients’ baseline risk.” (C. C. Apfel, Outcomes Research Inst., Louisville, Ky.; apfel@ponv.org)

Noting that the incidence of postoperative nausea and vomiting has remained unchanged over the past two decades despite advances in minimally invasive surgery and pharmacotherapy, an editorialist writes (pp. 2511-2): “Several conclusions of the current study have importance for practitioners. First, the efficacy of prophylactic antiemetic drug therapy is dependent on the patient’s overall risk of postoperative nausea and vomiting. Second, the benefit of using two inexpensive antiemetics (e.g., droperidol and dexamethasone) is significantly greater than the benefit of using an expensive 5-HT
3 antagonist (e.g., ondansetron). Third, with the addition of each successive therapeutic intervention, the incremental antiemetic benefit diminishes. Finally, from a societal cost–benefit perspective, the current data do not support the use of 5-HT3 antagonists for routine antiemetic prophylaxis.” (P. F. White, U. Texas Southwestern Med. Ctr., Dallas)

Antiretroviral Therapy in Children: Better long-term viral outcomes were observed among 52 HIV-infected children when antiretroviral therapy was initiated before the age of 3 months and when regimens included stavudine, lamivudine, nevirapine, and nelfinavir (pp. 2471-80). The trial, which continued therapy for up to 200 weeks, showed that 83% and 72% of children treated with one of the above four agents had HIV-1 RNA levels of less than 400 copies/ mL at 48 and 200 weeks of therapy, respectively, significantly better responses than among children taking only reverse transcriptase inhibitors. (K. Luzuriaga, katherine.luzuriaga@umassmed.edu)

Erythropoietin & Neuroprotection: Methods are being developed to permit erythropoietin application directly to nerve cells and thereby prevent systemic effects but permit use for neuroprotection, according to the author of a brief review (pp. 2516-7): “Clinical trials of erythropoietin or its derivatives in patients with diabetic neuropathy and neurodegenerative disorders seem to be a good idea. Recent data from my laboratory suggest that when given in combination with other growth factors, such as insulin-like growth factor I, erythropoietin may act synergistically to activate neuroprotective pathways— an approach that should allow the use of lower and consequently even better-tolerated doses of both factors. The discovery that previously approved, clinically tolerated drugs such as erythropoietin can protect neurons and ameliorate neuropathic pain should expedite neurologic clinical trials.” (S. A. Lipton, 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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 11, 2004 Vol. 11, No. 112
Providing news and information about medications and their proper use

>>>Rheumatology Update
Source:
June issue of Arthritis & Rheumatism (www.rheumatology.org; 2004; 50).

RA Treatments & Risk of Lymphomas: Patients with rheumatoid arthritis are at higher risk of lymphomas, but the odds are highest when they are being treated with anti-tumor necrosis factor therapies, according to authors of a 18,572-patient study (pp. 1740-51). Using data that the patients report biannually to the National Data Bank for Rheumatic Diseases, the investigators calculated the standardized incidence ratios for lymphoma: “The overall SIR for lymphoma was 1.9 (95% confidence interval [95% CI] 1.3– 2.7). The SIR for biologic use was 2.9 (95% CI 1.7–4.9) and for the use of infliximab (with or without etanercept) was 2.6 (95% CI 1.4– 4.5). For etanercept, with or without infliximab, the SIR was 3.8 (95% CI 1.9–7.5). The SIR for MTX was 1.7 (95% CI 0.9–3.2), and was 1.0 (95% CI 0.4–2.5) for those not receiving MTX or biologics. Lymphoma was associated with increasing age, male sex, and education.” (F. Wolfe, U. Kansas, Wichita; fwolfe@arthritis-research.org)

Coccidioidomycosis & TNF Antagonists: Anti-TNF therapy was linked to symptomatic respiratory fungal infections in a second study, this one of patients cared for in five practices located in areas endemic for coccidioidomycosis (Arizona, California, and Nevada; pp. 1959-66). From Jan. 2000 through Feb. 2003, the authors observed: “Thirteen cases of documented coccidioidomycosis were associated with TNF antagonist therapy. Twelve cases were associated with the use of infliximab and 1 case with etanercept. Among the cohort of patients from a single medical center, 7 of the 247 patients receiving infliximab and 4 of the 738 patients receiving other therapies developed symptomatic coccidioidomycosis (relative risk 5.23, 95% confidence interval 1.54-17.71; P < 0.01).” (L. Bergstrom, laurieb@arthritis.arizona.edu)

>>>Diabetes Highlights
Source:
June issue of Diabetes Care (care.diabetesjournals.org; 2004; 27).

Repaglinide vs. Nateglinide: During 16 weeks of therapy, 150 patients with type 2 diabetes had significantly better A1C and fasting plasma glucose values when treated with repaglinide monotherapy rather than nateglinide alone (pp. 1265-70). In the open-label trial, patients—who previously had been treated with diet and exercise—randomly received either repaglinide 0.5–4 mg/meal or nateglinide 60–120 mg/meal. Mean baseline A1C levels were 8.9% for both groups, and these fell to 7.3% and 7.9% in the two groups, respectively. “HbA1c values <7% were achieved by 54% of repaglinide-treated patients versus 42% for nateglinide,” the authors write. “Median final doses were 6.0 mg/day for repaglinide and 360 mg/day for nateglinide. There were 7% of subjects treated with repaglinide (five subjects with one episode each) who had minor hypoglycemic episodes (blood glucose <50 mg/dl) versus 0 patients for nateglinide. Mean weight gain at the end of the study was 1.8 kg in the repaglinide group as compared with 0.7 kg for the nateglinide group.” (J. Rosenstock, Dallas Diabetes and Endocrine Ctr., Dallas; juliorosenstock@dallasdiabetes.com)

Alcohol & Insulin Action: Acute ingestion of 40 grams of alcohol improves insulin action without affecting beta-cell secretion, according to investigators who studied eight healthy and eight type 2 diabetic volunteers (pp. 1369-74). Seeking to explain the increases in lactate area under the curve and free fatty acid concentrations they observed, the authors conclude, “[Improvements in insulin action] may be partly due to the inhibitory effect of alcohol on lipolysis. Alcohol intake increases insulin sensitivity and may partly explain both the J-shaped relationship between the prevalence of diabetes and the amount of alcohol consumption and the decreased mortality for myocardial infarction.” (A. Avogaro, U. Padova, Padova, Italy; angelo.avogaro@unipd.it)

>>>PNN NewsWatch
* Take with Care is a new consumer educational campaign designed to reduce OTC medication errors occurring in the home (www.nclnet.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 14, 2004 Vol. 11, No. 113
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
June 12 issue of BMJ (www.bmj.org; 2004; 328).

NSAIDs vs. Opioids for Renal Colic: For managing acute renal colic, NSAIDs trump opioids, according to a systematic review of 20 studies (pp. 1401 ff). Assessing several outcomes as recorded among 1,613 study participants with a sudden onset of severe pain radiating from the flank to the groin, the authors note: “Pooled analysis of six trials showed a greater reduction in pain scores for patients treated with NSAIDs than with opioids. Patients treated with NSAIDs were significantly less likely to require rescue analgesia (relative risk 0.75, 95% confidence interval 0.61 to 0.93). Most trials showed a higher incidence of adverse events in patients treated with opioids. Compared with patients treated with opioids, those treated with NSAIDs had significantly less vomiting (0.35, 0.23 to 0.53). [Meperidine] was associated with a higher rate of vomiting.” (A. Holdgate, St. George Hosp., Kogarah, Australia; holdgatean@sesahs.nsw.gov.au)

GI Bleeds & COX-2 Inhibitors: In Ontario, a 41% increase in use of NSAIDs—driven by the adoption of the COX-2–selective members of this class—was associated with a 10% increase in hospitalizations for upper gastrointestinal bleeding (pp. 1415-6). “The prevalence of use of NSAIDs among Ontario’s population of older people increased from 14.0% just before the introduction of COX 2 inhibitors to 19.8% by the end of the observation period (P < 0.01), representing an absolute increase of more than 90,000 additional individuals annually using NSAIDs, entirely attributable to the use of COX 2 inhibitors rather than switching from non-selective NSAIDs to COX 2 inhibitors,” write the authors of the epidemiologic study. “The rate of hospitalisation for upper gastrointestinal haemorrhage was decreasing before the introduction of COX 2 inhibitors, but increased from about 15.4 to 17.0 per 10,000 older persons after their introduction (P < 0.01), representing an absolute increase of more than 650 upper gastrointestinal haemorrhage hospitalisations annually.” (M. Mamdani, Inst. for Clin. Evaluative Sciences, Toronto; muhammad.mamdani@ices.on.ca)

Nutrition & Pancreatitis: For nutritional support of patients with acute pancreatitis, enteral administration should be preferred over the parenteral route, conclude authors who conducted a meta-analysis of six studies with 263 participants (pp. 1407 ff). The researchers report: “Enteral nutrition was associated with a significantly lower incidence of infections (relative risk 0.45; 95% confidence interval 0.26 to 0.78, P = 0.004), reduced surgical interventions to control pancreatitis (0.48, 0.22 to 1.0, P = 0.05), and a reduced length of hospital stay (mean reduction 2.9 days, 1.6 days to 4.3 days, P < 0.001). There were no significant differences in mortality (relative risk 0.66, 0.32 to 1.37, P = 0.3) or non-infectious complications (0.61, 0.31 to 1.22, P = 0.16) between the two groups of patients.” (P. Marik, U. Pittsburgh, Pittsburgh; maripe@ccm.upmc.edu)

>>>PNN JournalWatch
* Rates of Caesarean Section and Instrumental Vaginal Delivery in Nulliparous Women After Low Concentration Epidural Infusions or Opioid Analgesia: Systematic Review, in BMJ, 2004; 328: 1410 ff. Reprints: www.bmj.org; E. H. C. Liu, Natl. U. Hosp., Singapore; analiue@nus.edu.sg

* Growth Hormone Deficiency and Related Disorders: Insights into Causation, Diagnosis, and Treatment, in
Lancet, 2004; 363: 1977–87. Reprints: www.thelancet.com; M. Preece, U. College, London; mpreece@ich.ucl.ac.uk

* Pneumocystis Pneumonia, in
New England Journal of Medicine, 2004; 350: 2487–98. Reprints: www.nejm.org; A. H. Limper, limper.andrew@mayo.edu

* The Medicare Prescription Drug, Improvement, and Modernization Act of 2003, in
Journal of the American Geriatrics Society, 2004; 52: 1013 ff. Reprints: www.blackwell-synergy.com; S. Emmer, Emmer Consulting, Bethesda, Md.; emmerconsulting@verizon.net

* Obstructive Sleep Apnea Syndrome, Sleepiness, and Quality of Life, in
Chest, 2004; 125: 2091–6. Reprints: www.chestjournal.org; M. A. Goncalves.

* Accumulated Evidence on Fish Consumption and Coronary Heart Disease Mortality: A Meta-Analysis of Cohort Studies , in
Circulation, 2004; 109: 2705–11. Reprints: circ.ahajournals.org; K. He, kahe@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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 15, 2004 Vol. 11, No. 114
Providing news and information about medications and their proper use

>>>Internal Medicine Update
Source:
June 15 issue of the Annals of Internal Medicine (www.annals.org; 2004; 140).

Withholding Anticoagulation After First DVT: In nonpregnant patients with a suspected first episode of symptomatic deep-vein thrombosis of the leg who have negative results on comprehensive duplex ultrasonography, anticoagulation can be safely withheld, according to a study of 445 such patients (pp. 985-91). “Comprehensive duplex ultrasonography yielded normal results in 384 patients (86.3%) and showed DVT in 61 patients (13.7%),” write the authors. After excluding nine patients with normal scans because they received anticoagulation for other reasons, the investigators noted that only “three of 375 patients (0.80% [95% CI, 0.16% to 2.33%]) in the normal cohort had symptomatic venous thrombosis during the 3-month follow-up.” (S. M. Stevens, LDS Hosp., Salt Lake City; scott.stevens@ihc.com)

“Stevens and colleagues’ study adds credible results to the growing body of evidence about excluding symptomatic DVT by normal results on a single ankle-to-groin comprehensive examination with compression ultrasonography,” writes an editorialist. “This method has the potential to obviate the need for repeated testing and will be more convenient for patients, although the examination may take up to 30 minutes. Using comprehensive compression ultrasonography in conjunction with pretest clinical probability or d-dimer testing would probably further improve the cost-effectiveness of this novel diagnostic approach, but this conjecture will require testing in clinical trials.” (D. El Kheir, Academic Med. Ctr., Amsterdam, the Netherlands)

Provocation Tests for Drug Allergy: Drug-provocation tests can safely rule out allergies in substantial numbers of patients, according to a retrospective case series of 898 consecutive patients (pp. 1001-6). The patients, referred to a department for drug allergy at a university hospital, underwent single-blinded administration of increasing doses of the suspected drugs, up to the usual daily doses, while under strict hospital surveillance. The authors found, “1372 drug provocation tests were performed using various drugs, including beta-lactams (30.3%), aspirin (14.5%), other nonsteroidal anti-inflammatory drugs (11.7%), [acetaminophen] (8.9%), macrolides (7.4%), and quinolones (2.4%). There were 241 (17.6%) positive drug provocation test results. Drug provocation reproduced the same symptoms, albeit milder and of a shorter duration, in the following patients: 13 (5.4%) with a history of anaphylactic shock, 17 (7.0%) with a history of anaphylaxis without shock, 10 (4.1%) with a history of laryngeal edema, 19 (7.9%) with a history of bronchospasm, 160 (66.4%) with a history of urticaria, and 22 (9.1%) with a history of maculopapular eruption. All adverse reactions were completely reversed by prednisolone, H1-antihistamines, and epinephrine as needed.” (P. Demoly, Hôpital Arnaud de Villeneuve, Montpellier, France; demoly@montp.inserm.fr)

Depression & Diabetes: Depressive symptoms and functional status were improved when 417 patients with diabetes received collaborative care for depression (pp. 1015-24). Compared with those provided only usual care, the patients receiving education, problem-solving treatment, and antidepressant management support had less severe depression at 12 months and a greater improvement in overall functioning. Weekly exercise days also increased among those in the intervention group. (J. W. Williams, VA Med. Ctr., Durham, N.C.)

“Much work remains to be done in this area,” an editorialist observes. “Although a correlation exists between depression and alterations in many of the body’s homeostatic systems, the mechanism of this relationship remains unknown. Researchers are only just beginning to penetrate the labyrinth of the interactive relationships between depression and comorbid illness. Future research may uncover interactive mind–body relationships that will spawn radical new approaches to the practice of medicine.” (J. L. Jackson, Uniformed Services U. of the Health Sciences, Bethesda, Md.; jejackson@usuhs.mil)

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 16, 2004 Vol. 11, No. 115
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
June 16 issue of JAMA (www.jama.com; 2004; 291).

Pharmacogenetics & Statin Therapy: People who are heterozygous for a genetic variation involving two common and tightly linked single nucleotide polymorphisms in the HMG-CoA reductase gene have smaller responses to pravastatin, according an analysis of 10 candidate genes in 1,536 patients (pp. 2821-7). The pharmacogenetic analysis considered changes in lipid levels over 24 weeks in the study subjects, all of whom were taking pravastatin 40 mg/day. The authors report, “Compared with individuals homozygous for the major allele of one of the SNPs, individuals with a single copy of the minor allele had a 22% smaller reduction in total cholesterol (–32.8 vs –42.0 mg/dL [–0.85 vs –1.09 mmol/L]; P = .001; absolute difference, 9.2 mg/dL [95% confidence interval {CI}, 3.8–14.6 mg/dL]) and a 19% smaller reduction in low-density lipoprotein (LDL) cholesterol (–27.7 vs –34.1 mg/dL [–0.72 vs –0.88 mmol/L]; P = .005; absolute difference, 6.4 mg/dL [95% CI, 2.2–10.6 mg/dL]). The association for total cholesterol reduction persisted even after adjusting for multiple tests on all 33 SNPs evaluated in the HMG-CoA reductase gene as well as for all 148 SNPs evaluated was similar in magnitude and direction among men and women and was present in the ethnically diverse total cohort as well as in the majority subgroup of white participants.” (P. M Ridker, Brigham and Women’s Hosp., Boston; pridker@partners.org)

Editorialists, commenting on the importance of pharmacogenetics in improving drug safety and efficacy, explore the obstacles to action in this area and call for action, “An efficient [pharmacogenetic] research program could yield benefits in a relatively short period, representing a substantial contribution to the public’s health. But neither market forces nor academic incentives are likely to produce the quality or type of data needed to proceed with confidence. An active effort is needed to ensure a rigorous assessment of this promising application of genomic technology, through partnerships and collaborative efforts among the federal, academic, and private sectors or, possibly, enhanced regulations.” (pp. 2869-71). (W. Burke, wburke@u.washington.edu)

>>>Internal Medicine Report
Source:
June 14 issue of Archives of Internal Medicine (www.archinternmed.com; 2004; 164).

Benzocaine & Methemoglobinemia: A report from the Institute of Safe Medication Practices describes life-threatening and fatal reactions to benzocaine involving rapid development of methemoglobinemia (pp. 1192-6). From 818,439 adverse event reports submitted to FDA between Nov. 1997 and Mar. 2002, the researchers focused on 198 patients who had received benzocaine for procedures such as intubation, bronchoscopy, and endoscopy. Two thirds of the MHb cases were definite or probable, the authors noted, and 81% of those 132 cases were serious. Two deaths occurred. “In 123 cases (93.2%), the product was a spray; in 2 cases (1.5%), a benzocaine-containing lozenge; and 1 case, a gel,” the group wrote. “In the 69 cases that specified a dose, 37 (53.6%) indicated that a single spray was applied (approximately the recommended amount).”

Severe cases of MHb—when the patient is symptomatic or has an MHb level above 30%—should be treated immediately with intravenous administration of 1 to 2 mg/kg of methylene blue. While cooximetry is useful for determining the severity of MHb, these authors note that clinical symptoms can be used to assess the problem more quickly (anxiety, fatigue, and tachycardia occurs at MHb levels of 20% to 50%; coma and death are possible at levels of 50% to 70%). (T. J. Moore, tmoore@ismp.org)

Antidepressant Responses: In a 9-month naturalistic trial of SSRIs, 46% of patients did not respond to the antidepressants (pp. 1197-204). A total of 53% of patients who received at least 6 months of continuous treatment did not achieve remission, and 13% required aggressive therapy associated with treatment resistance, the authors explain. (R. Swindle, Eli Lilly & Company, Indianapolis; swindle@lilly.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 17, 2004 Vol. 11, No. 116
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
June 17 issue of the New England Journal of Medicine (content.nejm.org; 2004; 350).

Liposuction Is Not Enough: For reversing the detrimental effects of metabolic syndrome, simply using liposuction to remove the patient’s fat fails to improve insulin sensitivity, according to a study of 15 obese women (pp. 2549-57). Comparing values obtained before and 10–12 weeks after abdominal liposuction, the investigators found, “Liposuction decreased the volume of subcutaneous abdominal adipose tissue by 44 percent in the subjects with normal glucose tolerance and 28 percent in those with diabetes; those with normal oral glucose tolerance lost 9.1 ± 3.7 kg of fat (18 ± 3 percent decrease in total fat, P = 0.002), and those with type 2 diabetes lost 10.5 ± 3.3 kg of fat (19 ± 2 percent decrease in total fat, P < 0.001). Liposuction did not significantly alter the insulin sensitivity of muscle, liver, or adipose tissue (assessed by the stimulation of glucose disposal, the suppression of glucose production, and the suppression of lipolysis, respectively); did not significantly alter plasma concentrations of C-reactive protein, interleukin-6, tumor necrosis factor , and adiponectin; and did not significantly affect other risk factors for coronary heart disease (blood pressure and plasma glucose, insulin, and lipid concentrations) in either group.” (S. Klein, Washington U., St. Louis)

Targeting B Cells in RA: In 161 patients whose rheumatoid arthritis remained active despite methotrexate therapy, two infusions of rituximab provided significant improvement at weeks 24 and 48 (pp. 2572-81). Patients received oral methotrexate 10 mg/week (control group); rituximab 1,000 mg on days 1 and 15; rituximab plus cyclophosphamide 750 mg on days 3 and 17; or rituximab plus methotrexate. Responses on the American College of Rheumatology (ACR) and the European League against Rheumatism (EULAR) scales were as follows: “At week 24, the proportion of patients with 50 percent improvement in disease symptoms according to the ACR criteria, the primary end point, was significantly greater with the rituximab–methotrexate combination (43 percent, P = 0.005) and the rituximab–cyclophosphamide combination (41 percent, P = 0.005) than with methotrexate alone (13 percent). In all groups treated with rituximab, a significantly higher proportion of patients had a 20 percent improvement in disease symptoms according to the ACR criteria (65 to 76 percent vs. 38 percent, P ≤ 0.025) or had EULAR responses (83 to 85 percent vs. 50 percent, P ≤ 0.004). All ACR responses were maintained at week 48 in the rituximab–methotrexate group. The majority of adverse events occurred with the first rituximab infusion: at 24 weeks, serious infections occurred in one patient (2.5 percent) in the control group and in four patients (3.3 percent) in the rituximab groups. Peripheral-blood immunoglobulin concentrations remained within normal ranges.” (J. C. W. Edwards, U. College, London; jo.edwards@ucl.ac.uk)

In a Perspectives article, a writer makes these observations about how depletion of B cells in peripheral blood contributes to improvements in rheumatoid arthritis (pp. 2546-8): “We do not know whether the rituximab-mediated depletion affects the numbers or function of B cells that home to the synovium. Nor do we know which subgroups of B cells located in the spleen, lymph nodes, and other lymphoid organs are affected by the administration of anti-CD20 antibody or the extent to which they are affected. The therapeutic efficacy of rituximab in rheumatoid arthritis suggests that rituximab affects B cells in the synovium and causes clinically significant disruption of the inflammatory process.... Additional research may lead to strategies for selectively depleting certain subgroups of B cells or dislodging B cells from lymphoid tissues and the synovium before depleting them with anti-CD20 antibody. ” (G. C. Tsokos, Walter Reed Army Inst. of Research, Silver Spring, Md.)

A review article describes challenges in early diagnosis of rheumatoid arthritis, lack of comparative trials and indicators of responses, and cost of agents (pp. 2591-602; J. R. O’Dell, U. Nebraska Med. Ctr., Omaha)

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 18, 2004 Vol. 11, No. 117
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
Article released early by and June 16 issue of the Journal of the American College of Cardiology (www.cardiosource.com; 2004; 43).

Cardiac Complications of Smallpox Vaccination: Postvaccinial myopericarditis should be considered in patients who present with chest pain within 30 days of smallpox vaccination, according to an analysis of adverse reactions to the military’s smallpox vaccination program (released early on Web site). In the first year of the widespread immunization, the authors found, “A total of 540,824 military personnel were vaccinated with a New York City Board of Health strain of vaccinia from December 2002 through December 2003. Of these, 67 developed myopericarditis at 10.4 ± 3.6 days after vaccination. The ST-segment elevation was noted in 57%, mean troponin on admission was 11.3± 22.7 ng/dl, and peak cardiac enzymes were noted within 8 h of presentation. On follow-up of 64 patients (96%) at a mean of 32 ± 16 weeks, all patients had objective normalization of echocardiography, electrocardiography, laboratory testing, graded exercise testing, and functional status; 8 (13%) reported atypical, non-limiting persistent chest discomfort.” (R. E. Eckart, Brooke Army Med. Ctr., Fort Sam Houston, Tex.)

Verapamil After PCI: The need for target vessel revascularization (TVR) was decreased by treatment with verapamil after percutaneous coronary interventions in a 6-month study of 700 consecutive patients (pp. 2160-5). The study subjects, 83% of whom received stents during the PCI, took either placebo or verapamil 240 mg twice daily. Supporting the results of five prior small studies that showed benefits with calcium-channel blockers, these investigators found a reduced rate of a composite end point of death, myocardial infarction, or TVR with verapamil (19.3% of patients, compared with 29.3% of those on placebo). This 34% risk reduction was driven by the reduced need for TVR (17.5% with verapamil; 26.2% with placebo). (H-P Bestehorn, Herz-Zentrum, Bad Krozingen, Germany)

Fondaparinux vs. Enoxaparin for ACS: A dose-ranging study of fondaparinux indicates that the pentasaccharide is equivalent to enoxaparin for prevention of death, myocardial infarction, or recurrent ischemia in patients with acute coronary syndromes (pp. 2183-90). The 929 patients included in a per-protocol analysis received one of four doses of fondaparinux (2.5, 4, 8, or 12 mg once daily) or enoxaparin (1 mg/kg twice daily) for 3–7 days. For these respective doses, the rates of the composite end point were 30.0%, 43.5%, 41.0%, 34.8%, and 40.2%. The authors report, “The lowest event rates were observed in the 2.5-mg fondaparinux group, which had significantly lower rates than the enoxaparin group as well as for 4 and 8 mg fondaparinux in the per-protocol analysis (p < 0.05). Bleeding rates were low and not different among the patient groups. No differences were observed in fondaparinux concentrations in patients with or without death, myocardial infarction, recurrent ischemia, or bleeding events.” (M. L. Simoons, Erasmus Med. Ctr., Rotterdam, the Netherlands)

>>>PNN NewsWatch
* The Health Services Purchasing Coalition yesterday launched a public education campaign outlining the benefits of generic medications and emphasizing that generic drugs are just as safe and effective as their brand-name counterparts; are reviewed rigorously and approved by FDA; and cost up to 75% less than brand-name equivalents.

* In its first 3 years, the
Generics First program has distributed 265,000 generic drug samples to Pennsylvania physicians. The initiative is a joint venture between Highmark (a licensee of Blue Cross and Blue Shield) and Medco Health Solutions.

* Even as FDA and NABP begin state-level campaigns warning of the dangers of
imported prescription drugs, the political tide appears to be turning in favor of legalizing the practice. AARP is the latest group to switch its support in favor of bipartisan legislation allowing Canadian imports.

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 21, 2004 Vol. 11, No. 118
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
June 19 issue of Lancet (www.thelancet.com; 2004; 363).

Statins & RA: Atorvastatin had “modest but clinically apparent anti-inflammatory effects” in a study of 116 patients with rheumatoid arthritis, indicating a possible role for statins in treating the disease (pp. 2015-21). The 6-month, intention-to-treat, placebo-controlled used comparisons of disease activity score (DAS28) and proportion of patients meeting European League Against Rheumatism (EULAR) response criteria, and the authors found, “DAS28 improved significantly on atorvastatin (–0.5, 95% CI –0.75 to –0.25) compared with placebo (0.03, –0.23 to 0.28; difference between groups –0.52, 95% CI –0.87 to –0.17, p=0.004). DAS28 EULAR response was achieved in 18 of 58 (31%) patients allocated atorvastatin compared with six of 58 (10%) allocated placebo (odds ratio 3.9, 95% CI 1.42–10.72, p = 0.006). C-reactive protein and erythrocyte sedimentation rate declined by 50% and 28%, respectively, relative to placebo (p < 0.0001, p = 0.005, respectively). Swollen joint count also fell (–2.69 vs –0.53; mean difference –2.16, 95% CI –3.67 to –0.64, p = 0.0058). Adverse events occurred with similar frequency in patients allocated atorvastatin and placebo.” (I. McInnes, Royal Infirmary, Glasgow, Scotland; i.b.mcinnes@clinmed.gla.ac.uk)

Valsartan vs. Amlodipine for Hypertension: No difference in cardiac morbidity and mortality was found among 15,254 patients at high cardiovascular risk who received valsartan versus amlodipine for hypertension, but study findings do emphasize the importance of blood pressure reductions in such patients (pp. 2022-31). The subjects, all older than 50 years of age, were treated with one of the two agents to the same levels of blood pressure control, and the study continued until at least 1,450 patients had reached a primary composite end point (time to first cardiac event; secondary end points included fatal and nonfatal myocardial infarction, heart failure, or stroke). “Blood pressure was reduced by both treatments, but the effects of the amlodipine-based regimen were more pronounced, especially in the early period (blood pressure 4.0/2.1 mm Hg lower in amlodipine than valsartan group after 1 month; 1.5/1.3 mm Hg after 1 year; p < 0.001 between groups),” report the authors. “The primary composite endpoint occurred in 810 patients in the valsartan group (10.6%, 25.5 per 1000 patient-years) and 789 in the amlodipine group (10.4%, 24.7 per 1000 patient–years; hazard ratio 1.04, 95% CI 0.94–1.15, p = 0.49).”

In a second paper from the same study (pp. 2049-51), the investigators observed, “Reaching blood pressure control (systolic <140 mm Hg) by 6 months, independent of drug type, was associated with significant benefits for subsequent major outcomes; the blood pressure response after just 1 month of treatment predicted events and survival.” (S. Julius, sjulius@med.umich.edu)

>>>PNN JournalWatch
* Steroid Prophylaxis for Prevention of Nerve Function Impairment in Leprosy: Randomised Placebo Controlled Trial (TRIPOD 1), in BMJ, 2004; 328: 1459 ff. Reprints: www.bmj.org; W. C. S. Smith, U. Aberdeen, Aberdeen, Scotland; w.c.s.smith@abdn.ac.uk

* What Is the Role of High-Dose Chemotherapy in the Era of Targeted Therapies?, in
Journal of Clinical Oncology, 2004; 22: 2263–6. Reprints: www.jco.org; G. N. Hortobagyi.

* Herbs and the Kidney, in
American Journal of Kidney Diseases, 2004; 44: 1– 11. Reprints: www.ajkd.org; C. I. Bagnis, Hôpital Pitié Salpêtrière, Paris, France; corinne.bagnis@psl.ap-hop-paris.fr

* Prevention of Radiocontrast-Induced Nephropathy, in
American Journal of Kidney Diseases, 2004; 44: 12–24. Reprints: www.ajkd.org; M. Epstein, U. Miami, Miami; murraye@gate.net

* Evaluation of eHealth Web Sites for Patients with Chronic Kidney Disease, in
American Journal of Kidney Diseases, 2004; 44: 71–6. Reprints: www.ajkd.org; J. B. Jaffery, jbj@medicine.wisc.edu

* Travel Medicine Considerations for North American Immigrants Visiting Friends and Relatives, in
JAMA, 2004; 291: 2856–64. Reprints: www.jama.com; J. S. Keystone, Ctr. for Travel and Tropical Medicine, Toronto Genl. Hosp., Toronto; Jay.Keystone@utoronto.ca

* Should C-Reactive Protein Be Added to Metabolic Syndrome and to Assessment of Global Cardiovascular Risk?, in
Circulation, 2004; 109: 2818–25. Reprints: circ.ahajournals.org; P. M. Ridker, Brigham and Women’s Hosp. Boston; pridker@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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 22, 2004 Vol. 11, No. 119
Providing news and information about medications and their proper use

>>>Pediatrics Highlights
Source:
June issue of Pediatrics (www.pediatrics.org; 2004;113).

Pediatricians, Vaccinations, & Reimbursements: The ratio of reimbursement to cost of pediatric immunizations is declining, leaving some physician practices giving shots at a loss, according to an analysis of four pediatric practices, four family practices, and four public health agencies in rural and urban Colorado settings (pp. 1582-7). “Variable costs per shot (excluding vaccine cost) were $8.15 for pediatric practices, $5.79 for family practices, and $5.41 for public health agencies,” write the authors. “Total costs per shot, including fixed costs, were $10.67 for pediatric practices and $7.57 for family practices. Average reimbursement for pediatricians and private family practices was $8.27 and $6.68, respectively. For pediatric practices, average variable costs were barely exceeded by average reimbursement, and reimbursement was 22% less than average total costs.” The group concludes, “The decline in the ratio of reimbursement to cost for private practices, particularly for pediatric practices, suggests that referral to public agencies by private providers for vaccinations may increase and that if vaccinations are not as frequently provided in the child’s medical home, then the currently high childhood immunization rates may be in jeopardy.” (J. E. Glazner, U. Colorado Health Sci. Ctr., Denver)

Anonymous Medical-Error Reporting: Access to an Internet-based system for anonymous reporting of medical errors identified a broad range of problems in neonatal intensive units at 54 hospitals in the Vermont Oxford Network and promoted multidisciplinary collaborative learning (pp. 1609-18). A total of 739 health professionals had access to the site, which permitted free-text entry during a 17-month initial phase and used a structured form during a subsequent 10-month period. The investigators report, “Of 1230 reports ... the most frequent event categories were wrong medication, dose, schedule, or infusion rate (including nutritional agents and blood products; 47%); error in administration or method of using a treatment (14%); patient misidentification (11%); other system failure (9%); error or delay in diagnosis (7%); and error in the performance of an operation, procedure, or test (4%). The most frequent contributory factors were failure to follow policy or protocol (47%), inattention (27%), communications problem (22%), error in charting or documentation (13%), distraction (12%), inexperience (10%), labeling error (10%), and poor teamwork (9%).” (G. Suresh, U. Vermont, Burlington)

Long-Term Budesonide & HPA Suppression: No effects on the hypothalamic–pituitary– adrenal axis was identified among 63 children using scheduled budesonide inhalations at a dose of 400 mcg/day for 3 years (pp. 1693-9). The patients had mild or moderate asthma and underwent HPA axis function tests using adrenocorticotrophic hormone stimulation before and 12 and 36 months after receiving continuous therapy with inhaled budesonide, nedocromil 16 mg/day, or placebo. “There were no differences in serum cortisol levels after ACTH stimulation between treatment groups, regardless of time after ACTH administration or months of follow-up,” the researchers write. “Urinary cortisol excretion per body surface area was similar in both treatment groups at 36 months, after adjusting for age at randomization, race, gender, and clinic. Cumulative inhaled corticosteroid exposure did not influence serum cortisol response to ACTH or urinary free cortisol excretion at 36 months.” (L. B. Bacharier, Washington U., St. Louis)

>>>PNN NewsWatch
* This morning’s Wall Street Journal contrasts the risks associated with the insect repellent DEET versus those of acquiring West Nile virus or Lyme disease. Fewer than 50 serious adverse effects from DEET have been published over nearly 60 years of use, and some say that DEET use—especially in children who are at low risk of disease complications—should be moderated in areas where the risks of mosquito-borne diseases are small.

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 23, 2004 Vol. 11, No. 120
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
June 23/30 issue of JAMA (www.jama.com; 2003; 291).

Estrogens & Dementia: Two articles from the Women’s Health Initiative Memory Study (WHIMS) and an editorial analyze the impact of estrogen- and hormone-replacement therapy on dementia and mental status in postmenopausal women.

Estrogen therapy failed to protect against dementia and mild cognitive impairment (MCI) in older women, and pooled data on those who received either estrogen or estrogen plus medroxyprogesterone showed that the agents increased risks significantly (pp. 2947-58). The study included 2,947 women who received either placebo or conjugated equine estrogen 0.625 mg/day from 1995 through 2004 and 4,532 women treated with either placebo or CEE plus medroxyprogesterone acetate 2.5 mg/day from 1995 through 2002. The odds of being diagnosed with probable dementia were elevated by 49% among those on active therapy in the CEE-only group, and the incidence rates were statistically similar for those on CEE only or combined therapy (45 versus 22 patients with probable dementia per 10,000 person-years). Pooled data showed a significantly elevated risk of probable dementia, with a risk that was 76% higher with treatment, and odds were increased even more, by 119%, when patients with low baseline cognitive function scores were excluded. (S. A. Shumaker, Wake Forest U., Winston-Salem, N.C.; sshumake@wfubmc.edu)

The second WHIMS study focused on cognitive function in these older women, and it shows declining cognition among those on estrogen therapy, with decrements greatest among those whose baseline scores were lower (pp. 2959-68). This analysis included 2,808 women who had a baseline and at least one follow-up global assessment of cognition. During a mean follow-up period of 5.4 years, scores on the Modified Mini-Mental State Examination were on average 0.26 units lower among those taking estrogen, compared with placebo, a significant difference. Combined treatment with estrogen plus medroxyprogesterone also significantly lowered 3MSE scores, by an average of 0.21 units. “The adverse effect of hormone therapy was more pronounced among women with lower cognitive function at baseline (all P < .01),” the authors add. “For women assigned to CEE compared with placebo, the relative risk of having a 10-unit decrease in 3MSE scores (>2 SDs) was estimated to be 1.47 (95% confidence interval, 1.04–2.07).” (M. A. Espeland, Wake Forest U., Winston-Salem, N.C.; mespelan@wfubmc.edu)

Commenting on the increasing difficulty to justify further studies into estrogen- and hormone-replacement therapy even for subsets of patients in whom glimmers of hope seem apparent, an editorialist writes (pp. 3005-7): “The WHIMS results do not prove that estrogen therapy has no effect on [Alzheimer’s disease] or dementia, but they do clearly indicate that women older than 65 years should not be treated with CEE with or without MPA to attempt to prevent dementia or enhance cognition. Whether with different populations, lower doses of CEE, other forms of estrogen or receptor modulators, or delivered in lower more physiological doses, estrogen therapy could eventually be proven beneficial remains to be seen. However, the harmful to neutral effects of estrogen in the WHI and WHIMS trials will make further development of and research with estrogen therapy a daunting task.” (L. S. Schneider, lschneid@usc.edu)

Lifestyle, Obesity, & Erectile Dysfunction: About one third of obese men with erectile dysfunction can expect improved sexual function after they lose weight and increase their physical activity, according to a study of 110 middle-aged men with baseline body mass indexes greater than 30 kg/sq m (pp. 2978-84). Intervention patients lost significantly more weight over a 2-year period—an average of nearly 6 kg off an initial BMI of 36.9 kg—and as a result 17 of 55 men in the intervention group had adequate erectile function scores, compared with 3 of 55 men in the control group. (K. Esposito, Policlinico Universitario, Naples, Italy; katherine.esposito@unina2.it)

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 24, 2004 Vol. 11, No. 121
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
June 24 issue of the New England Journal of Medicine (content.nejm.org; 2004; 350).

Folate Therapy After Coronary Stenting: In all but a few patient subgroups, folate therapy increases the rate of restenosis and need for target-vessel revascularization, a finding that flies in the face of prior studies and conventional wisdom (pp. 2673-81). Following administration of intravenous folate doses to 636 patients in the study, placebo or oral folic acid 1.2 mg, vitamin B6 48 mg, and vitamin B12 60 mcg was given daily for 6 months, at which time end points were assessed using quantitative coronary angiography. The authors found, “At follow-up, the mean (±SD) minimal luminal diameter was significantly smaller in the folate group than in the placebo group (1.59 ± 0.62 mm vs. 1.74 ± 0.64 mm, P = 0.008), and the extent of late luminal loss was greater (0.90 ± 0.55 mm vs. 0.76 ± 0.58 mm, P = 0.004). The restenosis rate was higher in the folate group than in the placebo group (34.5 percent vs. 26.5 percent, P = 0.05), and a higher percentage of patients in the folate group required repeated target-vessel revascularization (15.8 percent vs. 10.6 percent, P = 0.05). Folate therapy had adverse effects on the risk of restenosis in all subgroups except for women, patients with diabetes, and patients with markedly elevated homocysteine levels (15 µmol per liter or more) at baseline.” (H. Suryapranata, Hospital De Weezenlanden, JW Zwolle, the Netherlands; h.suryapranata@diagram-zwolle.nl)

An editorialist summarizes state-of-the-art treatment of patients after percutaneous coronary interventions (pp. 2708-10): “As restenosis becomes less of a problem after percutaneous coronary intervention, we need to refocus on the underlying disease process in order to treat vulnerable plaques and atherosclerosis and prevent subsequent cardiac events and new and progressive atherosclerotic lesions. Data now exist to recommend the use of aspirin, clopidogrel, statins, ACE inhibitors, control of diabetes and hypertension, nutritional counseling, smoking cessation, and exercise for all patients who have received an intracoronary stent. Pending the completion of clinical trials, some physicians may recommend folate (and vitamins B6 and B12) therapy to patients with hyperhomocysteinemia.” (H. C. Herrmann, U. Penn., Philadelphia)

Survival & ESRD in Children: “Despite improvement in long-term survival, mortality rates among children requiring renal-replacement therapy remain substantially higher than those among children without end-stage renal disease,” conclude researchers who followed 1,634 children and adolescents for a median of 9.7 years (pp. 2654-62). “Increasing the proportion of children treated with renal transplantation rather than with dialysis can improve survival further.” Patients on indefinite dialysis had long-term survival rates of 79% at 10 years and 66% at 20 years, reflecting mortality rates about 30 times as high as among non–ESRD children. On the positive side, a trend toward increased survival was observed over the four decades of the study, which stretched from 1963 to 2002. (S. P. McDonald, Australia and New Zealand Dialysis and Transplant Registry, Queen Elizabeth Hosp., Woodville South, Australia, stephenm@anzdata.org.au)

Lactalbumin–Oleic Acid & Skin Papillomas: A complex of alpha-lactalbumin and oleic acid (human alpha-lactalbumin made lethal to tumor cells [HAMLET]) produces a “beneficial and lasting effect on skin papillomas,” report researchers who studied for 3 weeks 40 patients with cutaneous papillomas that were resistant to conventional treatment (pp. 2663-72). “The lesion volume was reduced by 75 percent or more in all 20 patients in the alpha-lactalbumin–oleic acid group, and in 88 of 92 papillomas; in the placebo group, a similar effect was evident in only 3 of 20 patients (15 of 74 papillomas) (P<0.001),” the authors write. “At follow-up two years after the end of [a subsequent 3-week open-label] phase, all lesions had completely resolved in 83 percent of the patients treated with alpha-lactalbumin–oleic acid.” (C. Svanborg, U. Lund, Lund, Sweden; catharina.svanborg@mig.lu.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 25, 2004 Vol. 11, No. 122
Providing news and information about medications and their proper use

>>>Infectious Disease Update
Source:
July 1 issue of Clinical Infectious Diseases (www.journals.uchicago.edu/CID; 2004; 39).

Antibiotic Consumption: Per capita consumption rates for fluoroquinolones, newer macrolides, and cephalosporins were higher in British Columbia than in Denmark, according to a study that compares North American and European patterns of antibiotic use (pp. 11-7). “During 1996– 2000, consumption in British Columbia decreased from 19.5 to 17.9 [defined daily doses]/1000 inhabitant-days,” the authors explain. “Although antibiotic consumption in British Columbia was less than the European median in 2000, it exceeded that in northern European countries with established antibiotic surveillance and control programs.... The observed increase in and pattern of consumption associated with newer antimicrobials may increase the risk for emergence of antimicrobial-resistant organisms in British Columbia.” (D. M. Patrick, Ctr. for Disease Control, Vancouver, B.C.)

Pharmacogenetics of Antiretroviral Therapy: A review article assesses progress and research needs in pharmacogenetics of antiretroviral therapy (pp. 98-106). “Although the ever-expanding armamentarium of antiretroviral drugs has significantly decreased the morbidity and mortality due to human immunodeficiency virus infection, patients and clinicians are increasingly faced with the problems of inadequate or toxic response to therapy that may be genetically mediated,” write the authors. “Significant evidence now exists that interindividual differences, such as efficacy of therapy, hypersensitivity reactions, and metabolic complications as a result of antiretroviral therapy, are in part genetically determined.” (E. Quirk, Washington U., St. Louis)

Costs of Acellular Pertussis Vaccine in Adolescents and Adults: A cost-benefit analysis of use of acellular pertussis vaccine in adolescents and adults finds that the most economical approach is routine vaccination of adolescents but concludes that routine, once-per-decade immunizations of adults requires more information (pp. 20-8). After evaluating seven independent strategies, the investigators found, “The most economical [strategy] would be to immunize adolescents 10–19 years of age, which would prevent 0.7–1.8 million pertussis cases and save $0.6–$1.6 billion over a decade. Although justified by our analysis, routine adult booster vaccinations every decade would be more expensive and more difficult to implement. A recommendation for booster vaccinations every 10 years requires more information about duration of immunity, program costs, compliance, and nonmedical costs associated with pertussis.” (K. W. Purdy, UCLA, Los Angeles)

Antibiotic Therapy for Klebsiella pneumoniae Bacteremia: Extremely high mortality rates result from failure to use an antibiotic that is active against bacteremias caused by extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae (pp. 31-7). In a prospective study of 455 consecutive of the condition in 12 hospitals in seven countries, the investigators found, “Use of a carbapenem (primarily imipenem) was associated with a significantly lower 14-day mortality than was use of other antibiotics active in vitro. Multivariate analysis including other predictors of mortality showed that use of a carbapenem during the 5-day period after onset of bacteremia due to an ESBL-producing organism was independently associated with lower mortality. Antibiotic choice is particularly important in seriously ill patients with infections due to ESBL-producing K. pneumoniae.” (D. L. Paterson, VA Med. Ctr., Pittsburgh)

>>>PNN NewsWatch
* No “meaningful interaction” between NSAIDs and aspirin used for cardioprotection was found in a cohort study reported in this week’s Circulation (circ.ahajournals.org; 2004; 109: 3000-6; L. A. García Rodríguez, Madrid; lagarcia@ceife.es)

* FDA posted on its Web site this week information and copies of letters recently mailed to health professionals about changes in
antidepressant labeling cautioning about emergence of suicidal ideation, especially in the early phases of therapy.

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 28, 2004 Vol. 11, No. 123
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
June 26 issue of Lancet (www.thelancet.com; 2004; 363).

Long-Term Donepezil in AD: Donepezil was found not to be sufficiently effective in an analysis of 565 community-dwelling patients with mild or moderate Alzheimer’s disease (pp. 2105-15). Patients received donepezil 5 mg/day or placebo during a 12-week run-in phase, and 486 patients were then rerandomized to donepezil 5 or 10 mg/day or placebo for as long as judged appropriate. The authors report, “Cognition averaged 0.8 MMSE (mini-mental state examination) points better (95% CI 0.5–1.2; p < 0.0001) and functionality 1.0 [Bristol activities of daily living scale] points better (0.5–1.6; p < 0.0001) with donepezil over the first 2 years. No significant benefits were seen with donepezil compared with placebo in institutionalisation (42% vs 44% at 3 years; p = 0.4) or progression of disability (58% vs 59% at 3 years; p = 0.4). The relative risk of entering institutional care in the donepezil group compared with placebo was 0.97 (95% CI 0.72–1.30; p = 0.8); the relative risk of progression of disability or entering institutional care was 0.96 (95% CI 0.74–1.24; p = 0.7). Similarly, no significant differences were seen between donepezil and placebo in behavioural and psychological symptoms, carer psychopathology, formal care costs, unpaid caregiver time, adverse events or deaths, or between 5 mg and 10 mg donepezil.” (AD2000 Collaborative Group, U. Birmingham, Birmingham; AD2000@bham.ac.uk)

An editorialist describes the research needed to build on this study (pp. 2100-1): “Needed ... are fair long-term randomised head-to-head comparisons of cholinesterase inhibitors, memantine, aspirin, ginkgo biloba, and other drugs. Trials can be focused to address particular issues or outcomes. The three recently completed but unpublished 2–4-year-long trials of cholinesterase inhibitors in mild cognitive impairment, a condition likely to progress to dementia, might provide further information on longer-term efficacy and safety.” (L. S. Schneider, lschneid@usc.edu)

CMV & HIV: Presence in serum of cytomegalovirus remains predictive of poor prognosis in patients with HIV infection, despite the availability of highly active antiretroviral therapy, report authors of a 374-patient study (pp. 2116-21). During 37 months of monitoring with polymerase chain reaction, investigators found, “Cytomegalovirus PCR-positive status as a time-updated covariate was significantly associated with increased relative rates of progression to a new AIDS-defining disorder (2.22 [95% CI 1.27–3.88] p = 0.005) and death (4.14 [1.97–8.70] p = 0.0002).” (P. D. Griffiths, Royal Free and U. Coll. Med. Sch., London; pgriffiths@rfc.ucl.ac.uk)

Describing HIV and CMV as “inextricably entwined pathogens,” an editorialist observes (pp. 2101-2): “Patients failing current HIV treatments could be probed for persistent detection of CMV DNA. Clearly such a strategy is not without expense. However, the potential benefits to individuals with HIV disease must be considered, particularly with existing orally bioavailable drugs such as valganciclovir or new antivirals, that approach clinical development, including maribavir.” (R. J. Whitley, U. Alabama, Birmingham; rwhitley@peds.uab.edu)

>>>PNN JournalWatch
* Mortality in Relation to Smoking: 50 Years’ Observations on Male British Doctors, in BMJ, 2004; 328: 1519 ff. Reprints: www.bmj.org; R. Doll, Radcliffe Infirmary, Oxford, U.K.; secretary@ctsu.ox.ac.uk

* Acute Uncomplicated Cystitis in an Era of Increasing Antibiotic Resistance: A Proposed Approach to Empirical Therapy, in
Clinical Infectious Diseases, 2004; 39: 75–80. Reprints: www.journals.uchicago.edu/CID; T. M. Hooton.

* The Pharmacogenetics of Antiretroviral Therapy: A Review of Studies to Date, in
Clinical Infectious Diseases, 2004; 39: 75– 80. Reprints: www.journals.uchicago.edu/ CID; E. Quirk, Washington U., St. Louis.

* Hypertensive Therapy: Part I, in
Circulation, 2004; 109: 2953–8. Reprints: circ.ahajournals.org; V. Franco.

* Tests of Glycemia in Diabetes, in
Diabetes Care, 2004; 27: 1761–73. Reprints: care.diabetesjournals.org; R. R. Little, littler@health.missouri.edu

* Preventing Cancer, Cardiovascular Disease, and Diabetes: A Common Agenda for the American Cancer Society, the American Diabetes Association, and the American Heart Association, in
Diabetes Care, 2004; 27: 1812–24. Reprints: care.diabetesjournals.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 29, 2004 Vol. 11, No. 124
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
June 28 issue of Archives of Internal Medicine (www.archinternmed.com; 2004; 164).

Antipsychotics & Sudden Death: Antipsychotic agents—several of which prolong the corrected QT interval—increase the risk of sudden cardiac death by 3-fold among current users, report authors of a population-based case–control study (pp. 1293-7). In the Integrated Primary Care Information project, a longitudinal observational database with complete medical records from 150 general practitioners was searched for all instances of death over a 6-year period. Cases of sudden cardiac death (n = 554) were each matched with 10 randomly selected controls. The authors report, “Current use of antipsychotics was associated with a 3-fold increase in risk of sudden cardiac death. The risk of sudden cardiac death was highest among those using butyrophenone antipsychotics [e.g., haloperidol], those with a defined daily dose equivalent of more than 0.5 and short-term (90 days) users. The association with current antipsychotic use was higher for witnessed cases (n = 334) than for unwitnessed cases.” (B. H. C. Stricker, Erasmus Med. Ctr., Rotterdam, the Netherlands; b.stricker@erasmusmc.nl)

Patient Preferences for Treating Osteoarthritis: Older patients with osteoarthritis of the knee often prefer no treatment rather than risking adverse drug effects, a conclusion that conflicts with the widespread use of non-selective NSAIDs (pp. 1299-304). In community rheumatology practices associated with a university hospital, 100 consecutive patients with symptomatic osteoarthritis were interviewed and presented with various pharmacologic options that were described as having varying risks, benefits, and costs. Because many patients are already taking acetaminophen when they present to a physician, it was not described to patients as one of their choices. “Variation in the risk of common adverse effects and gastrointestinal ulcer had the greatest impact on patients’ choice,” the investigators report. “Assuming patients are responsible for the full cost of their medications, over 40% prefer capsaicin. Cyclooxygenase-2 inhibitors become patients’ preferred choice only if they are described as being 3 times as effective as capsaicin and are covered by insurance. Nonselective NSAIDs are among the least preferred options across all simulations.” (L. Fraenkel, liana.fraenkel@yale.edu)

LMWH Bridge During Warfarin Interruption: Among 650 consecutive patients who required warfarin therapy interruption because of an invasive procedure, subcutaneous dalteparin sodium 100 IU/kg twice daily provided an effective and safe prophylaxis against thromboembolism (pp. 1319-26). Warfarin was stopped 6 days before the procedure, and low molecular weight heparin therapy was started 3 days later. The researchers write, “In 542 patients who underwent a non–high-bleeding-risk procedure, there were 2 thromboembolic events (0.4%), 4 major bleeding episodes (0.7%), and 32 episodes of increased wound-related blood loss that precluded postprocedural dalteparin administration (5.9%). In 108 patients who underwent a high-bleeding-risk procedure, there were 2 deaths (1.8%) possibly due to thromboembolism and 2 major bleeding episodes (1.8%).” (J. D. Douketis, jdouket@mcmaster.ca)

Prickly Pear Extract for Hangover: An extract of the Opuntia ficus-indica plant alleviated symptoms of alcohol hangover and reduced serum concentrations of C-reactive protein, a marker for liver inflammation, damage, and related symptoms (pp. 1334-40). In 55 healthy, young adult volunteers who consumed 1.75 grams of alcohol in a crossover study, 3 of 9 hangover symptoms—nausea, dry mouth, and anorexia—were significantly reduced by OFI 1,600 IU administered 5 hours before alcohol ingestion, compared with placebo. The average score for well-being the next morning was 2.75 for volunteers who took OFI and 3.10 for those who took placebo. Levels of C-reactive were 40% higher in volunteers who took placebo than among those who took OFI. (J. Wiese, jwiese@tulane.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 30, 2004 Vol. 11, No. 125
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
July Diabetes Care (care. diabetesjournals.org; 2004; 27).

Triple Therapy in Type 2 DM: A three-drug regimen consisting of metformin, insulin, and a thiazolidinedione enabled all of 28 patients with type 2 diabetes mellitus to achieve A1C levels less than 7, and it did so without inducing weight gain when metformin therapy preceded troglitazone treatment (pp. 1577-83). The patients, all of whom continued their prestudy insulin therapy, randomly received dual therapy through addition of metformin or troglitazone for 4 months. All patients then continued the study, using all three agents together for an additional 4 months. A1C levels, which averaged about 8.5% at baseline in the two dual-therapy groups, dropped significantly when metformin or troglitazone was added (to means of 7.0% and 6.2%, respectively) , and these levels declined further on triple therapy (to means of 6.1% and 5.8%, respectively). Total daily insulin doses declined significantly among patients who added troglitazone and with triple therapy. Patients did not gain weight when metformin was added or during triple therapy, but those on insulin plus troglitazone gained a significant 4.4 kg during the 4 months of therapy. (S. Strowig, U. Tex. Southwestern Med. Ctr., Dallas; suzanne.strowig@utsouthwestern.edu)

An editorialist, seeking to put triple therapy for type 2 diabetes in perspective, notes (pp. 1834-5): “Therapy [can be] progressively increased from diet/exercise in asymptomatic patients to monotherapy with metformin or a sulfonylurea agent, and to dual oral therapy with both of these. An important factor in [the success of one prior study] was the imperative to raise the doses of metformin or the sulfonylurea agent every 2 weeks until either the American Diabetes Association’s fasting plasma glucose goal was achieved or the maximal dose was reached, at which time the other medication was added. In this manner, patients did not remain out of control for long periods of time. Before glitazones became available, the next step was to add bedtime NPH insulin. If the cost of glitazones is a factor, this still remains an attractive option. In our institution, glitazones have been added to the formulary to be used for either triple oral therapy (metformin, glipizide or glyburide, glitazone) (or if patients take >80 units insulin/day and remain in poor control). If triple oral therapy fails, bedtime insulin is substituted for the glitazone. ” (M. B. Davidson, Charles R. Drew U., Los Angeles; madavids@cdrewu.edu)

ACE Inhibitor Attenuates Metabolic Syndrome Marker: In 40 patients with metabolic syndrome, markers of vascular oxidative stress were improved when the ACE inhibitor quinapril was added to therapy (pp. 1712-5). Compared with placebo during 4 weeks of treatment, quinapril reduced serum 8-isoprostane levels by 12%, erythrocyte superoxide dismutase activity was reduced by 35%, and lag time to oxidation of LDL was increased by 48%. (B. V. Khan, bkhan@emory.edu)

Focusing on Cancer, Cardiovascular Disease, & Diabetes: Two of every three American deaths and $700 billion in annual direct and indirect economic costs result from cancer, cardiovascular disease, or diabetes, leading three medical groups to join forces in an effort to encourage lifestyle changes that could reduce the incidence of these conditions and improve primary prevention of them (pp. 1812-24). In describing a common agenda, the American Cancer Society, American Diabetes Association, and American Heart Association describe five opportunities: (1) achieving greater progress in health promotion and disease prevention; (2) jointly promoting a set of core recommendations that could reduce individual and collective risk and thereby serve as a unifying force for action and advocacy for individuals, families, communities, health care professionals, and other organizations; (3) stimulating new initiatives that could improve health care delivery and new directions in health promotion; (4) increasing collective advocacy by local units of the three organizations; and (5) setting an ambitious agenda that serves to consistently remind the groups that jointly they can achieve greater progress in health promotion and disease prevention than by working alone.

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 1, 2004 Vol. 11, No. 126
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
July 1 issue of the New England Journal of Medicine (content.nejm.org; 2004; 351).

Multivitamins & HIV: Daily multivitamin supplements enabled HIV-positive pregnant women to delay the start of antiretroviral therapy in a study conducted in Tanzania (pp. 23-32). During a median of 71 months of follow-up among 1,078 women, the investigators found, “Of 271 women who received multivitamins, 67 had progression to World Health Organization (WHO) stage 4 disease or died — the primary outcome — as compared with 83 of 267 women who received placebo (24.7 percent vs. 31.1 percent; relative risk, 0.71; 95 percent confidence interval, 0.51 to 0.98; P = 0.04). This regimen was also associated with reductions in the relative risk of death related to the acquired immunodeficiency syndrome (0.73; 95 percent confidence interval, 0.51 to 1.04; P = 0.09), progression to WHO stage 4 (0.50; 95 percent confidence interval, 0.28 to 0.90; P = 0.02), or progression to stage 3 or higher (0.72; 95 percent confidence interval, 0.58 to 0.90; P = 0.003). Multivitamins also resulted in significantly higher CD4+ and CD8+ cell counts and significantly lower viral loads. The effects of receiving vitamin A alone were smaller and for the most part not significantly different from those produced by placebo. Adding vitamin A to the multivitamin regimen reduced the benefit with regard to some of the end points examined.” (W. W. Fawzi, mina@hsph.harvard.edu)

Editorialists comment on the relationship between micronutrients and HIV pathogenesis (pp. 78-80): “As donor-funded initiatives expand in Africa, it has become clear that nutrition will have to be addressed in the treatment of HIV disease and AIDS. In the focus-group discussions that we conducted when starting an antiretroviral treatment program in a large Nairobi slum, every group interviewed listed the lack of food as the most likely cause of nonadherence to antiretroviral (ARV) drug therapy. One participant succinctly stated, ‘If you give us ARVs, please give us food, just food.’ There truly is irony, not captured in the language of treatment advocacy, in providing antiretroviral drugs to populations that lack access to safe water or food.” (B. Marston, CDC, Nairobi, Kenya)

Alzheimer’s Disease: In a review article on Alzheimer’s disease, an author assesses five components of treatment: neuroprotective strategies, cholinesterase inhibitors, nonpharmacologic interventions and psychopharmacologic agents to reduce behavioral disturbances, health maintenance activities, and an alliance between clinicians and family members and other caregivers responsible for the patient (pp. 56-67). With regard to cholinesterase inhibitors, the author emphasizes, “Whether some patients respond to one agent better than another has not been established. Indications for switching from one cholinesterase inhibitor to another include allergic responses, unmanageable side effects, the preferences of the family, and unmitigated cognitive decline after a treatment trial lasting at least six months. Specific strategies for switching agents have not been tested in adequate numbers of patients, though it is thought that interruption of therapy for a month or more might be detrimental. Patients who took donepezil after a three-week wash-out period, during which they received placebo, attained higher levels of function than patients who underwent a six-week washout period with placebo. Concurrent administration of more than one cholinesterase inhibitor has not been studied and is not advised. Cholinesterase inhibitors are commonly administered with vitamin E and memantine.” (J. L. Cummings, jcummings@mednet.ucla.edu)

Journal Clubs: A second-year medical student writes about the benefits of participating in voluntary journal clubs in which peers converse about articles on therapeutic areas of interest (pp. 10-2): “Science makes its splashes with new results. Science lives, however, not by results, but by the exchanges of ideas that follow them. And so journal clubs are a way of keeping science alive — even in medical school, and beyond.” (J. Wright, 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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 2, 2004 Vol. 11, No. 127
Providing news and information about medications and their proper use

>>>Psychiatry Highlights
Source: July issue of the American Journal of Psychiatry (ajp.psychiatryonline.org; 2004; 161).

Antidepressant Selection: Lacking empirical guidance as to which antidepressants should be preferred in clinical situations, psychiatrists most often seek to avoid specific adverse effects and to manage concomitantly comorbid psychiatric disorders and/or specific clinical symptoms (pp. 1285-9). Based on a questionnaire of psychiatrists who prescribed a new antidepressant medication to 1,137 patients, investigators found these other influences on prescribing patterns: “Prior treatment history, including prior positive or failed response to a drug, was the next most frequently endorsed factor influencing medication choice. Some factors that have been commonly discussed in the literature, such as concern about discontinuation syndrome and drug–drug interactions, rarely influenced antidepressant selection.” The authors suggest that future research in this area focus on treatment of depression with coexisting anxiety symptoms/anxiety disorders and the influence of particular symptoms on response to different medications. (M. Zimmerman)

Antipsychotic Selection: In a similar analysis of psychiatrists’ choices of antipsychotic medications, patient variables rarely influenced treatment decisions (pp. 1301-4). Based on choices made by 100 psychiatrists for 200 patients with schizophrenia, researchers showed that older physicians were five times more likely to prescribe first-generation agents, compared with younger doctors. Based on the lack of consideration given to patient factors, the investigators conclude, “There is an urgent need for more research on clinical decision making and quality management.” (J. Hammann)

Supplementing ADHD Therapy with Interesting Schoolwork: Methylphenidate probably needs to be supplemented with interesting tasks to have beneficial effects on brain chemistry, according to an imaging study of 16 healthy subjects (pp. 1301-4). Positron emission tomography was used to assess the effects of methylphenidate 20 mg on extracellular dopamine in the striatum while subjects either solved mathematical problems with monetary reinforcement or passively viewed cards with no remuneration. Dopamine was increased significantly during the math exercise when the drug was present but not with the exercise alone and not during the viewing of the cards, either with or without the drug. (N. D. Volkow)

>>>PNN NewsWatch
* FDA has for the first time formally approved the marketing of medicinal leeches in the U.S. Ricarimpex SAS, a French firm, for 150 years has been breeding leeches, which are handled in a certified facility that tracks each lot. Other leeches that have been on the U.S. market were grandfathered based on pre-1976 marketing and have not been considered formally by FDA.

* Product labeling for
venlafaxine (Effexor) has been revised to warn of complications in neonates exposed to the drug in utero late in the third trimester of pregnancy. Problems arising sometimes immediately upon delivery include prolonged hospitalization, respiratory support, and tube feeding.

* An
abuse-resistant form of oxycodone is under development by Pain Therapeutics, a small biotechnology company headquartered in South San Francisco, according to an article in the June 29 issue of the Wall Street Journal.

*
Celiac disease is present in 0.5–1.0% of Americans, according to a consensus development conference held earlier this week at NIH in Bethesda, Md. This estimate is 10 times higher than was previously believed. The condition, caused by an immune response to gluten in grains, can be managed after diagnosis using six strategies that can be recalled using the mnemonic CELIAC: consultation with a skilled dietitian; education about the disease; lifelong adherence to a gluten-free diet; identification and treatment of nutritional deficiencies; access to an advocacy group; and continuous long-term follow-up.

*
PNN will not be published on Mon., July 5, American Independence Day (observed).

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 6, 2004 Vol. 11, No. 128
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
July 3 issue of BMJ (www.bmj.org; 2004; 329).

ADR Burden in Britain: Mostly avoidable adverse drug reactions lead directly to hospitalizations costing $847 million annually in just two hospitals in the U.K., report authors who analyzed admissions related to ADRs over a 6-month period (pp. 15-9). The 1,225 admissions, accounting for 6.5% of annual hospitalizations at two Merseyside, England, hospitals, had a median length of stay of 8 days, accounting for 4% of the hospital’s bed capacity. The mortality rate was 0.15%, and most reactions were considered definitely or possibly preventable. Gastrointestinal bleeding was the most common ADR, and low-dose aspirin, diuretics, warfarin, and NSAIDs other than aspirin were the most commonly involved drugs. (M. Pirmohamed, U. Liverpool, Liverpool, U.K.; munirp@liv.ac.uk)

>>>Lancet Report
Source:
July 3 issue of Lancet, a theme issue on the global HIV/ AIDS epidemic, (www.thelancet.com; 2004; 364).

Generic, Fixed-Dose Combination Antiretroviral Product: A generic fixed-dose combination of nevirapine, stavudine, and lamivudine appeared to be safe and effective in 60 patients in an open-label, 24-week multicenter trial in Cameroon (pp. 29-34). Hematologic and virologic indicators improved acceptably during treatment, and only 8 cases of virologic failure were noted. One instance of genotypic resistance to nonnucleoside reverse transcriptase inhibitors occurred, and it was in a nonadherent patient who was subsequently lost to follow-up. Assayed tablets contained 96% of expected values for nevirapine, 89% for stavudine, and 99% for lamivudine. The authors conclude, “We have documented the quality, safety, and effectiveness of a generic fixed-dose antiretroviral combination in an African setting. Although controlled trials including more patients and longer follow-up will be important, our results lend support to the use and funding of generic fixed-dose combinations as first-line antiretroviral treatment in developing countries.” (E. Delaporte, Institut de Recherche pour le Développement, Montpellier, France; Eric.Delaporte@mpl.ird.fr)

>>>Internal Medicine Report
Source:
July 6 issue of the Annals of Internal Medicine (www.annals.org; 2004; 140).

Ginseng–Warfarin Interaction: American ginseng reduced the anticoagulant effect of warfarin in a small study of healthy volunteers (pp. 23 ff). At the end of the 4-week study involving 20 young, healthy volunteers, those who took ginseng had lower blood levels of warfarin and less of an effect on blood clotting than those volunteers who were given placebo. The authors write that patients and professionals should realize that ginseng can undermine the blood-thinning effects of warfarin and that when warfarin is prescribed or dispensed, health care professionals should ask patients about use of ginseng.

>>>PNN JournalWatch
* Interaction of St. John’s Wort with Conventional Drugs: Systematic Review of Clinical Trials, in BMJ, 2004; 329: 27–30. Reprints: www.bmj.org; E. Mills, McMaster Health Sci. Ctr., Hamilton, ON, Canada; millsej@mcmaster.ca

* Balancing Benefits and Harms: The Example of Non-steroidal Anti-inflammatory Drugs, in
BMJ, 2004; 329: 31–4. Re-prints: www.bmj.org; P. Dieppe, U. Bristol, Bristol, U.K.; p.dieppe@bristol.ac.uk

* Antidepressants and Suicide: What Is the Balance of Benefit and Harm, in
BMJ, 2004; 329: 34–8. Reprints: www.bmj.org; D. Gunnell, U. Bristol, Bristol, U.K.; d.j.gunnell@bristol.ac.uk

* Antimicrobial Stewardship Programs as a Means to Optimize Antimicrobial Use: Insights from the Society of Infectious Diseases Pharmacists, in
Pharmacotherapy, 2004; 24: 896–908. Reprints: www.accp.com; R. C. Owens, Jr., Maine Med. Ctr., Portland; owensr@mmc.org

* Clopidogrel Resistance: A New Chapter in a Fast-Moving Story, in
Circulation, 2004; 109: 3064–7. Reprints: circ.ahajournals.org; S. D. Wiviott.

* Inhaled Nitric Oxide: A Selective Pulmonary Vasodilator: Current Uses and Therapeutic Potential, in
Circulation, 2004; 109: 3106–11. Reprints: circ.ahajournals.org; F. Ichinose.

* Small-Cell Carcinomas of the Gastrointestinal Tract: A Review, in
Journal of Clinical Oncology, 2004; 22: 2730–9. Reprints: www.jco.org; D. P. Kelsen, Memorial Sloan-Kettering Cancer Center, New York City; kelsend@mskcc.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 7, 2004 Vol. 11, No. 129
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
July 7 issue of JAMA (www.jama.com; 2004; 292).

Enoxaparin vs. Heparin for Non–ST-Segment ACS: Two studies, a systematic overview, and an editorial find similar effects with enoxaparin and heparin but some distinctions between the agents when used for treating non–ST-segment elevation acute coronary syndromes.

The advantage of subcutaneous dosing of enoxaparin over intravenous heparin must be balanced by a moderately increased risk of major bleeding with the low molecular weight heparin, conclude authors of the first study (pp. 45-54). In the Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial, 10,027 high-risk patients with NSTE ACS were treated with an early invasive strategy. All-cause death or nonfatal myocardial infarction during the first 30 days occurred in 14.0% of patients on enoxaparin, compared with 14.5% of those receiving heparin, not a significant difference. Major bleeding was observed in significantly more patients on enoxaparin (9.1%, compared with 7.6% of those on heparin), but rates of severe bleeding (2.7% vs. 2.2%) and transfusion (17.0% vs. 16.0%) did not reach significance. (K. W. Mahaffey, mahaf002@mc.duke.edu)

In combination with aspirin and the glycoprotein IIb/IIIa inhibitor tirofiban, enoxaparin and heparin produced similar clinical outcomes in 3,987 patients with NSTE ACS (pp. 55-64). Death, recurrent myocardial infarction, or refractory ischemia at 7 days occurred in 8.4% of patients on enoxaparin 1 mg/kg every 12 hours, compared with 9.4% of those on weight-adjusted heparin, yielding a nonsignificant hazard ratio of 0.88. Rates of death were 1% in both patient groups, and rates of recurrent MI and refractory ischemia favored enoxaparin. “Rates for any TIMI grade bleeding were low (3.0% for enoxaparin and 2.2% for unfractionated heparin; P = .13),” note the authors of the A to Z study. “Using a worst-case approach that combined 2 independent bleeding evaluations, use of enoxaparin was associated with 1 additional TIMI major bleeding episode for each 200 patients treated.” (M. A. Blazing, MD, blazi001@mc.duke.edu)

A “systematic overview” of nearly 22,000 patients provides the most optimistic news about enoxaparin, concluding that it is “more effective than unfractionated heparin in preventing the combined end point of death or MI” (pp. 89-96). Analyzing the six data sets generated in the ESSENCE, A to Z, and SYNERGY comparisons of enoxaparin and unfractionated heparin, the authors found no significant difference in mortality at 30 days (3.0% in each group), a significant reduction in the combined endpoint of death or nonfatal MI at 30 days with enoxaparin (10.1%, compared with 11.0% with heparin), and a significant reduction in the rates of death or MI at 30 days with enoxaparin (8.0%, compared with 9.4% with heparin). The rates of transfusion and major bleeding did not differ between the groups overall or among patients initially given antithrombin therapy. (K. W. Mahaffey, mahaf002@mc.duke.edu)

Editorialists write that the articles “provide evidence that enoxaparin remains a reasonable alternative to unfractionated heparin in contemporary ACS treatment,” one with “unique benefits and apparently few limitations” (pp. 101-3). They add: “How might cardiologists and other physicians caring for patients with ACS interpret the findings from A to Z and SYNERGY relative to other major trials and in the context of the current ... guidelines? Several recent studies ... have either formed the supporting basis or provided additional evidence for the benefit of early coronary revascularization among high-risk patients with ACS. Each trial randomized patients to an initial conservative vs an early invasive strategy and has shown a relative risk reduction in 30-day death or MI in the invasive group ranging from 33% to 49%. Importantly, the occurrence of adverse events abated soon after the interventional procedure was completed. This has been observed in several studies and suggests that the benefits of potent antithrombotic therapy are most evident prior to and during percutaneous coronary revascularization.” (D. J. Moliterno, moliterno@uky.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 8, 2004 Vol. 11, No. 130
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
July 8 issue of the New England Journal of Medicine (content.nejm.org; 2004; 351).

Dexrazoxane for Myocardial Injury of Doxorubicin: In 206 children with acute lymphoblastic leukemia who were treated with doxorubicin, administration of dexrazoxane prevented or reduced cardiac injury (pp. 145-53). Dexrazoxane is a free-radical scavenger that has been cardioprotective in adults receiving anthracyclines, and it was administered to about one half of these children in doses of 300 mg/sq m just before every-3-week doxorubicin doses. Elevations in serum levels of cardiac troponin T, a marker for myocardial injury in children, were significantly less likely in those children given dexrazoxane (21% of patients, compared with 50% of those who did not receive the protective agent), and extremely elevated troponin T levels occurred significantly less often (10% vs. 32%). During a median follow-up period of 2.5 years, event-free survival was noted in 83% of both groups, indicating that dexrazoxane did not compromise doxorubicin’s effectiveness. (S. E. Lipshultz, slipshultz@med.miami.edu)

Editorialists call for larger studies of this new drug but caution that, given the infrequency of clinical cardiotoxic effects of anthracyclines, surrogate endpoints will continue to be needed for assessing efficacy (pp. 120-1): “Is a small elevation in the troponin T level an accurate predictor of cardiotoxic effects in patients treated with anthracyclines? The predictive value of low-level elevations of troponin T has to be validated in a large cohort of patients treated with anthracyclines. In addition, does dexrazoxane diminish the response of the tumor to anthracyclines? In the current study, no differences in survival were found. However, information about the statistical power of the study to detect a specific difference in survival is lacking.” (L. C. M. Kremer, U. Amsterdam, Amsterdam)

PSA Velocity & Prostate Cancer Deaths: Rapid increases in men’s prostate-specific antigen concentrations indicate a poor prognosis for survival, report authors of a 1,095-patient study with localized prostate cancer (pp. 125-35). “As compared with an annual PSA velocity of 2.0 ng per milliliter or less, an annual PSA velocity of more than 2.0 ng per milliliter was associated with a significantly shorter time to death from prostate cancer (P < 0.001) and death from any cause (P = 0.01),” the authors report. “An increasing PSA level at diagnosis (P = 0.01), a Gleason score of 8, 9, or 10 (P = 0.02), and a clinical tumor stage of T2 (P < 0.001) also predicted the time to death from prostate cancer. For men with an annual PSA velocity of more than 2.0 ng per milliliter, estimates of the risk of death from prostate cancer and death from any cause seven years after radical prostatectomy were also influenced by the PSA level, tumor stage, and Gleason score at diagnosis.” (A. V. D’Amico, adamico@lroc.harvard.edu)

>>>Gastroenterology Report
Source:
July issue of Gastroenterology (www2.gastrojournal.org; 2004; 127).

ASA & Mucosal Injury: Reflecting on a mouse study published in this issue (pp. 94-104), editorialists describe research opportunities and clinical approaches for reducing gastrointestinal problems associated with aspirin therapy (pp. 341-3): “Alternative approaches to reducing aspirin-induced gastric mucosal damage include continuous cotreatment with proton-pump inhibitors or the use of [nitric oxide]-releasing derivatives of aspirin (NO-aspirin). NO-aspirin has been shown to inhibit COX-1 and COX-2 activity in vivo and in vitro, to exert potent antiplatelet and antithrombotic action, and to cause significantly less gastric mucosal injury than standard aspirin. Importantly, adding celecoxib (200 mg twice per day) significantly increased gastric injury in the conventional aspirin treatment group but not in the NO-aspirin treatment group.

“Associating aspirin with either [phosphatidylcholine] or NO may therefore result in a safer formulation, making aspirin an even greater wonder drug.” (A. S. Tarnawski, Long Beach Healthcare System, Long Beach, CA; andrzej.tarnawski@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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 9, 2004 Vol. 11, No. 131
Providing news and information about medications and their proper use

>>>Pharmacotherapy Update
Source:
July Pharmacotherapy (www.accp.com; 2004; 24).

Pediatric Weight Gain with Antipsychotic Agents: Among 103 children and adolescents at an inpatient psychiatric facility, olanzapine increased weight and body mass index more than did quetiapine, according to authors who conducted a retrospective chart analysis (pp. 824-30). Included in the study were patients who received either agent for at least 2 weeks between 1997 and 2001. The authors report, “Mean ± SD daily doses of olanzapine and quetiapine were 13.9 ± 7.3 and 510.9 ± 250.3 mg, respectively.... The olanzapine group gained an average of 3.8 kg, the quetiapine group 0.03 kg. In the olanzapine group, BMI increased by an average of 1.3 kg/m2; in the quetiapine group, BMI decreased by 0.2 kg/m2. After controlling for baseline differences, significant between-group differences in weight and BMI change were noted. Change in BMI correlated significantly with baseline BMI in quetiapine-treated girls.” (M. L. Crismon, crismonl@mail.utexas.edu)

Antipsychotic ADRs & QOL: Quality of life was high in 33 hospitalized patients taking atypical antipsychotic agents, unless metabolic disturbances were present (pp. 843-7). Based on results of the long form of the
Quality of Life Enjoyment and Satisfaction Questionnaire, the investigators found, “The mean score on overall life satisfaction and contentment was 3.6 (fair to good). The corresponding value for the group without [weight gain, diabetes mellitus, and hyperlipidemia] was 4.538 (good to very good). Psychiatrists’ assessments of their patients’ quality of life were less positive than the patients’ own assessments, regardless of the existence of comorbid disease.” (S. C. Stoner, stoners@umkc.edu)

Drug Interactions with Alcohol Biomarker: Angiotensin II receptor blockers may affect levels of carbohydrate-deficient transferrin (CDT), a new alcohol biomarker, conclude authors who tested 20 drug classes likely to be used in chronic therapy of conditions such as diabetes, hypertension, and dyslipidemias (pp. 831-7). For 799 primary care patients, a regression analysis of %CDT levels, 30-day history of alcohol consumption, symptoms of alcohol abuse or dependence, health status, and prescribed drugs showed, “Factors associated with increased %CDT levels were alcohol consumption, female sex, and bupropion use. Two additional drug classes, the angiotensin II receptor blockers and the tricyclic antidepressants, were associated with lower %CDT levels. The effects of bupropion and tricyclic antidepressants on %CDT levels, however, appear to be confounded by alcohol intake.” (M. P. Mundt, U. Wisconsin, Madison)

Unreliable INRs with Lupus Anticoagulant: The lupus anticoagulant—present in some people who have had any of several thrombotic events—can produce falsely elevated international normalized ratios during warfarin therapy, according to results of a prospective case series (pp. 838-42). Based on results from 57 control patients and 68 adult outpatients positive for lupus anticoagulant, the authors conclude, “At least 10% of patients with lupus anticoagulant receiving long-term warfarin therapy may have falsely high INR values, which could lead to inappropriate warfarin dosage reduction. Monitoring warfarin therapy by chromogenic factor X activity in patients with lupus anticoagulant avoids this INR artifact.” (M. F. Shepherd, Abbott Northwestern Hosp., Minneapolis; shelley.shepherd@allina.com)

>>>PNN NewsWatch
* FDA has approved Technetium 99mTc Fanolesomab, NeutroSpec (murine monoclonal antibody to CD15) for scintigraphic imaging of patients with equivocal signs and symptoms of appendicitis who are 5 years of age or older.

*
Patient adherence is a growing issue—20% of new prescriptions go unfilled, while 85% are never refilled—according to a new report from Cutting Edge Information. “Pharmaceutical Patient Compliance and Disease Management” shows how pharmaceutical companies develop customer-focused programs for patients and other consumers (www.PharmaDiseaseManagement.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.


PNN Pharmacotherapy Line
July 12, 2004 Vol. 11, No. 132
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
July 10 issue of BMJ (www.bmj.org; 2004; 329).

Atypical Antipsychotics & Dementia: Use of atypical antipsychotics in patients with behavioral and psychological symptoms of dementia (BPSD) is common but poorly studied, according to a systematic review (pp. 75 ff). Only five randomized trials of 1,570 patients could be identified, and these included olanzapine and risperidone. “Most participants were in an institution (> 96%), elderly (weighted mean 82.3 years), and had Alzheimer’s disease (76.3%),” report the authors. “Trials lasted 6–12 weeks. Treatment with atypical antipsychotic drugs was superior to placebo for the primary end point in three of the five trials. Two trials comparing risperidone with haloperidol did not find any differences in the primary measures of efficacy. Adverse events were common and included extrapyramidal symptoms, somnolence, and abnormal gait.” (P. Lee, , Baycrest Centre for Geriatric Care, Toronto; pelee@providencehealth.bc.ca)

>>>JAMA Highlights
Source:
July 14 issue of JAMA, a special theme issue on HIV/AIDS (www.jama.com; 2004; 292).

2004 HIV/AIDS Recommendations: New guidelines from the International AIDS Society–USA Panel incorporate four recently marketed drugs and provide more definitive advice about therapy of HIV infections, particularly in their early stages (pp. 251-65). Advising initiation of therapy when CD4 cell counts reach 200–350 per microliter, the authors recommend, “Initial regimens must still be individualized, and the choice is influenced by several factors including comorbid conditions, the patient’s readiness to start therapy, and concomitant medications, but it is now possible to say that certain initial regimens are generally preferable to others based on data from controlled clinical trials. Since publication of the last article [in 2002], evaluations of regimens that contain nonnucleoside reverse transcriptase inhibitors, protease inhibitors, and triple-nucleoside (or nucleotide) reverse transcriptase inhibitors (NRTIs), and dual-NRTI backbones have been reported. Furthermore, several more convenient and tolerable formulations and fixed-dose combinations of drugs have become available. These formulations should improve adherence and ultimately improve therapeutic success, but there are no data from clinical trials demonstrating improved outcome for most of these formulations.” (P. G. Yeni, Hôpital Bichat-Claude Bernard, Paris; Patrick.Yeni@Bch.Ap-Hop-Paris.Fr)

Commenting on this and several other medication-related articles in this issue, editorialists note (pp. 266-8), “What makes these articles exciting is an appreciation of the progress in HIV therapy in the 8 years since the beginning of the HAART era: both emtricitabine- and tenofovir-containing regimens offer reduced pill burden, once-daily administration, sustained viral suppression, and possibly fewer minor or serious adverse reactions. Now, provided that adherence is maximized with once-daily dosing and the evolution of resistance mutations is reduced, clinicians can be assured that the therapy of treatment-naive patients will be effective and can focus on strategies that minimize long-term drug toxicities.” (M. A. Sande, (merle.sande@hsc.utah.edu)

>>>PNN JournalWatch
* Severe Acute Respiratory Syndrome and Its Impact on Professionalism: Qualitative Study of Physicians' Behaviour During an Emerging Healthcare Crisis, in BMJ, 2004; 329: 83 ff. Reprints: www.bmj.org; S. Straus, U. Health Network, Toronto; sharon.straus@utoronto.ca

* Chronic Diarrhea, in
Gastroenterology, 2004; 127: 287–94. Reprints: www2.gastrojournal.org; L. R. Schiller.

* Effect of Soy Protein Containing Isoflavones on Cognitive Function, Bone Mineral Density, and Plasma Lipids in Postmenopausal Women: A Randomized Controlled Trial, in
JAMA, 2004; 292: 65–74. Reprints: www.jama.com; Y. T. van der Schouw, U. Med. Ctr., Utrecht, the Netherlands; y.t.vanderschouw@umcutrecht.nl

* Meta-Analysis: The Effect of Steroids on Survival and Shock During Sepsis Depends on the Dose, in
Annals of Internal Medicine, 2004; 141: 47–56. Reprints: www.annals.org; P. C. Minneci, pminneci@mail.cc.nih.gov

* ALLHAT: Setting the Record Straight, in
Annals of Internal Medicine, 2004; 141: 39–46. Reprints: www.annals.org; B. R. Davis, U. Texas Health Science Ctr., Houston; bdavis@sph.uth.tmc.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 13, 2004 Vol. 11, No. 133
Providing news and information about medications and their proper use

>>>Circulation Highlights
Source:
July 13 Circulation (circ.ahajournals.org; 2004; 110).

ATP III Update Based on Recent Findings: Target LDL cholesterol levels of 70 mg/dL are supported for high-risk patients in a just-released update to the 2001 guidelines of the Adult Treatment Panel III of the National Cholesterol Education Program (pp. 227-39). The added recommendations, developed by a working group of the NCEP Coordinating Committee, are based on evidence from five major clinical statin trials published since 2001 and have been endorsed by the National Heart, Lung, and Blood Institute, American College of Cardiology Foundation, and American Heart Association.

“Therapeutic lifestyle changes (TLC) remain an essential modality in clinical management,” the group writes. “The trials confirm the benefit of cholesterol-lowering therapy in high-risk patients and support the ATP III treatment goal of LDL-C <100 mg/dL. They support the inclusion of patients with diabetes in the high-risk category and confirm the benefits of LDL-lowering therapy in these patients. They further confirm that older persons benefit from therapeutic lowering of LDL-C.”

The working group adds these footnotes to the ATP III treatment algorithm:

* In high-risk persons, the recommended LDL-C goal is less than 100 mg/dL, but when risk is very high, an LDL-C goal of less than 70 mg/dL is reasonable, even extending to those whose baseline LDL-C levels are between 70 and 100 mg/dL.

* For patients with high triglycerides or low HDL-C, fibrates or nicotinic acid can be added to statins and other LDL-lowering agents.

* For moderately high-risk persons (2 or more risk factors and a 10-year risk of 10% to 20%), the recommended LDL-C goal is <130 mg/dL, but an LDL-C goal <100 mg/dL is reasonable, again including patients with baseline levels of 100 to 129 mg/dL

* In high-risk or moderately high-risk persons, lipid-lowering therapy should be targeted at 30% to 40% reductions in LDL-C levels.

The group also reminds clinicians to prescribe therapeutic lifestyle changes for patients with lifestyle-related risk factors (obesity, physical inactivity, elevated triglycerides, low HDL-C, or metabolic syndrome) regardless of LDL-C levels. (S. M. Grundy; single reprints [no. 71-0292] available from the American Heart Association at 800/242-8721)

>>>Internal Medicine Report
Source:
July 12 issue of Archives of Internal Medicine (www.archinternmed.com; 2004; 164).

Statins & CHD: Mortality and morbidity are reduced by statin therapy in patients with coronary heart disease, even when pretreatment LDL cholesterol levels are as low as 100 mg/dL, according to a meta-analysis of 25 clinical trials of 69,511 patients (pp. 1427-36). “Statin therapy reduced CHD mortality or nonfatal myocardial infarction 25% (relative risk [RR], 0.75; 95% confidence interval [CI], 0.71– 0.79), all-cause mortality 16% (RR, 0.84; 95% CI, 0.79–0.89), and CHD mortality 23% (RR, 0.77; 95% CI, 0.71–0.83). Beneficial effects were seen in women and the elderly. There were no data to determine whether lowering the LDL-C level to less than 100 mg/dL (<2.59 mmol/L) was superior to lowering it to 100 to 130 mg/dL (2.59–3.36 mmol/L). Meta-regression analyses revealed risk reductions for CHD mortality or nonfatal myocardial infarction and major vascular events across available pretreatment LDL-C levels.” (T. J. Wilt, VA Ctr. for Chronic Disease Outcomes Research, Minneapolis; tim.wilt@med.va.gov)

Beta-Blockers & HF: Any remaining concerns clinicians have about using beta-blockers for heart failure are unwarranted, according to a quantitative overview of nine studies of 14,594 patients (pp. 1389-94). “Although beta-blocker therapy was associated with hypotension, dizziness, and bradycardia, the absolute increases in risk were small, and overall fewer patients were withdrawn from beta-blocker therapy than from placebo,” the investigators note, adding that all-cause mortality, HF hospitalizations, and worsening HF occurred significantly less often with beta-blockers. (H. M. Krumholz, harlan.krumholz@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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 14, 2004 Vol. 11, No. 134
Providing news and information about medications and their proper use

>>>Chest Highlights
Source:
July issue of Chest (www.chestjournal.org; 2004; 126).

Local Adverse Effects of Inhaled Steroids: A review article explores potential clinical problems that might result from poorly studied local effects of inhaled corticosteroids (pp. 213-9). The authors note, “The systemic complications of ICSs have been extensively studied and are well-documented in the literature. There are comparatively few studies reporting on the local complications of ICSs. Compared with systemic side effects, the local side effects of ICSs are considered to constitute infrequent and minor problems. However, while not usually serious, these local side effects are of clinical importance. They may hamper compliance with therapy and the symptoms produced may mimic more sinister pathology.” (N. J. Roland, U. Hosp. Aintree, Liverpool, U.K.; DrNJRoland@aol.com)

Beta-Agonist & Steroid Therapy of COPD: The benefits and limitations of concomitant treatment of chronic obstructive pulmonary disorder with long-acting beta-2 agonists and inhaled corticosteroids are detailed in an extensive review article (pp. 220-37). “The concomitant use of a LABA and an ICS can influence both airway obstruction (ie, smooth muscle contraction, increased cholinergic tone, and loss of elastic recoil), and airway inflammation (ie, increased numbers of neutrophils, macrophages, and CD8+ lymphocytes, elevated interleukin-8 and tumor necrosis factor-alpha levels, and protease/ antiprotease imbalance). They are also able to reduce the total number of bacteria adhering to the respiratory mucosa in a concentration-dependent manner without altering the bacterial tropism for mucosa, and to preserve ciliated cells. Several clinical trials support the concept of inhaled combination therapy with LABAs and corticosteroids in stable COPD patients. This type of therapy not only improves airflow obstruction but also provides clinical benefits, as manifested by sustained reduction in overall symptoms, improvements in health-related quality of life, and reductions in exacerbations. All of these effects are very important because, despite recent advances in our understanding of COPD and its treatment, therapy remains suboptimal for a considerable number of patients.” (M. Cazzola, Napoli, Italy; mcazzola@qubisoft.it)

Beta-2-Adrenergic Polymorphisms: In a study of 152 patients with positive responses to methacholine challenge testing and 391 control subjects, beta-2-adrengergic receptor polymorphisms were associated with differences in airways hyperresponsiveness, particularly among lifelong smokers (pp. 66-74). The researchers analyzed variations at codons 16 and 27 of the beta-2-AR gene and compared genotypes with phenotypic airways hyperresponsiveness. They found: “Adjusting for age, baseline FEV1, serum IgE level, and smoking status, the Gly16/Gln27 haplotype was negatively associated with airways hyperresponsiveness in the full complement of case patients and control subjects (score statistic, –2.43; p = 0.02). The effect of the beta-2-AR haplotypes was much stronger among lifelong nonsmokers, among whom the Gly16/Gln27 haplotype remained negatively associated with airways hyperresponsiveness (score statistic, –3.114; p = 0.002), whereas the Arg16/Gln27 haplotype was positively associated with airways hyperresponsiveness (score statistic, 3.142; p = 0.002). No effects were seen among ever-smokers.” (A. A. Litonjua, Channing Laboratory, Boston; augusto.litonjua@channing.harvard.edu)

Asthma as Risk Factor for COPD: While asthma and chronic obstructive pulmonary disorder have been viewed as distinct entities, researchers find that asthma may in fact be a risk factor for development of chronic bronchitis, emphysema, and COPD (pp. 59-65). Among 3,099 adults in a longitudinal study, the 192 patients with active asthma had a 10-fold greater risk of developing symptoms of bronchitis, a 17-fold greater risk of being diagnosed with emphysema, and a 12.5-times increased chance of fulfilling COPD criteria, even after data were adjusted for smoking and other potentially confounding factors. (D. L. Sherrill, duane@resp-sci.arizona.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 15, 2004 Vol. 11, No. 135
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
July 15 issue of the New England Journal of Medicine (content.nejm.org; 2004; 351).

Antiretroviral Therapy:
Two articles and an editorial present information on perinatal management of HIV infections.

With or without dosing for the infant, a single dose of nevirapine for the mother is a useful addition to zidovudine therapy in preventing maternal-to-infant HIV transmission, according to a study from Thailand (pp. 217-28). Three regimens were tested in a randomized, double-blind trial of 1,844 women who were receiving zidovudine during the third trimester of pregnancy: mothers and infants received a single dose of nevirapine; mothers received nevirapine but infants received placebo; or mothers and infants received placebo. After birth, infants received 1 week of zidovudine and were bottle-fed. Before the placebo–placebo arm was stopped at an interim data analysis point, the investigators found a 1.1% HIV transmission rate with nevirapine–nevirapine, compared with 6.3% in the placebo–placebo group. “The final per-protocol transmission rate in the nevirapine–nevirapine group, 1.9 percent (95 percent confidence interval, 0.9 to 3.0), was not significantly inferior to the rate in the nevirapine–placebo group (2.8 percent; 95 percent confidence interval, 1.5 to 4.1),” add the authors. “Nevirapine had an effect within subgroups defined by known risk factors such as viral load and CD4 count. No serious adverse effects were associated with nevirapine therapy.” (M. Lallemant, Institut de Recherche pour le Développement, Chiang Mai, Thailand; marc@phpt.org)

In a follow-up to the above study, the women who received intrapartum nevirapine had significantly poorer virologic suppression during the ensuing 6 months (pp. 229-40). HIV-1 RNA levels of less than 50 copies/mL were observed in only 49% of women who received nevirapine but 68% of mothers who did not take the drug. Blood samples taken 10 days postpartum showed that 32% of nevirapine-treated mothers had resistance mutations to nonnucleoside reverse-transcriptase inhibitors. (G. Jourdain, Institut de Recherche pour le Développement, Chiang Mai, Thailand; gonzague@phpt.org)

An editorialist discusses the challenges of perinatal prevention of HIV transmission, particularly in the developing world (pp. 289-92): “As Jourdain et al. themselves recognized, their results are not a reason to abandon single-dose nevirapine for the prevention of mother-to-child transmission of HIV-1. Single-dose nevirapine is a regimen of striking simplicity, efficacy, and affordability (reminiscent of that of oral poliovirus vaccine). Implementation of even this basic regimen has been hampered by failing health systems in many countries in Africa. Overcoming these barriers and choosing optimal antiretroviral regimens are therefore simultaneous priorities.

“Of the estimated 700,000 children who were infected with HIV in 2003, about 315,000 were infected through breast-feeding. The findings of [this] Group do not address this massive burden, and to ensure improvement in the overall rate of survival among children, the improved regimen will have to be adapted and used by the majority of HIV-infected women in developing countries who breast-feed.” (H. Coovadia, U. Kwazulu/Natal, Durban, South Africa)

Levothyroxine Doses During Pregnancy: Maternal euthyroidism is required for normal fetal development, and in pregnant women, a new study shows that levothyroxine requirements increase as early as the fifth week of gestation (pp. 241-9). During 20 pregnancies in 19 women that resulted in 17 full-term births, mean levothyroxine requirements increased 47% during the first half of pregnancy, with a median onset of increase at 8 weeks’ gestation. Increased doses were required for the remainder of pregnancy, although the need for increases in doses plateaued by week 16. The authors conclude, “We propose that women with hypothyroidism increase their levothyroxine dose by approximately 30 percent as soon as pregnancy is confirmed. Thereafter, serum thyrotropin levels should be monitored and the levothyroxine dose adjusted accordingly.” (E. K. Alexander, ekalexander@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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 16, 2004 Vol. 11, No. 136
Providing news and information about medications and their proper use

>>>Oncology Highlights
Source:
July 15 issue of the Journal of Clinical Oncology (www.jco.org; 2004; 22).

Treatment-Induced Diarrhea: Loperamide remains standard therapy for uncomplicated diarrhea associated with cancer treatments, but clinicians should monitor for a life-threatening gastrointestinal syndrome and respond aggressively if it occurs, according to an expert panel (pp. 2918-26). The syndrome was identified based on a review of early toxic deaths in trials of irinotecan plus high-dose fluorouracil and leucovorin for advanced colorectal cancer. The panel adds: “Revised guidelines reflect the need for recognition of the early warning signs of complicated cases of diarrhea and the need for early and aggressive management, including the addition of antibiotics. Management of radiation-induced diarrhea is similar but may not require hospitalization, and chronic low- to intermediate-grade symptoms can be managed with continued loperamide.” (A. B. Benson III, a-benson@northwestern.edu)

ASCO Recommendations for Prostate Cancer Therapy: Management of men with metastatic, recurrent, or progressive carcinoma of the prostate is presented in a clinical practice guideline approved by the American Society of Clinical Oncology (pp. 2927-41). Based on 10 randomized controlled trials, six systematic reviews, and one Markov model, an expert panel writes, “A full discussion between practitioner and patient should occur to determine which therapy is best for the patient. Bilateral orchiectomy or luteinizing hormone releasing hormone agonists are the recommended initial treatments. Nonsteroidal antiandrogen therapy may be discussed as an alternative, but steroidal antiandrogens should not be offered as monotherapy. Patients willing to accept the increased toxicity of combined androgen blockage for a small benefit in survival should be offered nonsteroidal antiandrogen in addition to castrate therapy. Until data from studies using modern medical diagnostic/biochemical tests and standardized follow-up schedules become available, no specific recommendations can be issued regarding the question of early versus deferred [androgen deprivation therapy]. A discussion about the pros and cons of early versus deferred [androgen deprivation therapy] should occur.” (ASCO, guidelines@asco.org)

Gabapentin for Neuropathic Cancer Pain: In 121 consecutive patients with neuropathic cancer pain that was partially controlled by opioids, gabapentin improved analgesia (pp. 2909-17). For 10 days in this placebo-controlled trial, gabapentin was added to stable opioid doses and titrated from 600 to 1,800 mg/day. Average daily pain scores, on a 0 to 10 scale were 4.6 with gabapentin and 5.4 with placebo, a significant difference. One of several secondary outcome measures, dysesthesia scores, was also significant, and adverse events occurred in 7.6% and 7.3% of gabapentin and placebo patients, respectively. (A. Caraceni, National Cancer Inst., Milan, Italy; augusto.caraceni@istitutotumori.mi.it)

Oncolytic Kinetics in Elderly: Recommended doses of docetaxel and cisplatin are different for patients aged 75 years or more, compared with younger people, but pharmacokinetic differences do not explain the varying needs (pp. 2901-8). Rather, older patients with non–small-cell lung cancer seem to be more sensitive to docetaxel exposure. (H. Minami, National Cancer Ctr. Hosp. East,Kashiwa, Japan; hminami@east.ncc.go.jp)

>>>PNN NewsWatch
* FDA has approved imiquimod topical cream (Aldara, 3M Pharmaceuticals) for treatment of superficial basal cell carcinoma. The new indication is based on results of two double-blind studies with 364 patients. In these studies, 75% of patients who had their sBCC treated with imiquimod had no evidence clinically or on repeat biopsy of their sBCC at 12 weeks after finishing treatment. In a separate long-term study involving 182 patients, 79% of patients had no evidence of their sBCC at 2 years after finishing treatment. The drug was previously approved for treatment of actinic keratosis and external genital warts.

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 19, 2004 Vol. 11, No. 137
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
July 17 issue and early-access Web site of BMJ (www.bmj.org; 2004; 329).

Home Blood Pressure Monitoring: Patients with essential hypertension whose blood pressures are monitored at home have better control than as demonstrated with clinic-only measurements, according to a meta-analysis of 18 trials of 1,359 patients (pp. 145 ff). Overall, mean blood pressures were 4.4 mm Hg lower among those monitored at home, with mean diastolic blood pressures lower by 2.4 mm Hg. Reasons for the differences are unclear, the authors note, adding, “The relative risk of blood pressure above predetermined targets was lower in people with home blood pressure monitoring (risk ratio 0.90, 0.80 to 1.00). When publication bias was allowed for, the differences were attenuated: 2.2 (–0.9 to 5.3) mm Hg for systolic blood pressure and 1.9 (0.6 to 3.2) mm Hg for diastolic blood pressure.” The authors conclude, “The white coat effect is important in the diagnosis and treatment of hypertension, even in a primary care setting, and is not a research artefact. Either repeated measurements by health professionals or ambulatory or home measurements may substantially improve estimates of blood pressure and management and control of hypertension. Home blood pressure measurements are the most acceptable method to patients and are preferred to either readings in the surgery or ambulatory monitoring.” (F. P. Cappuccio, St. George’s Hosp. Med. Sch., London; f.cappuccio@sghms.ac.uk)

Dronabinol for MS: A modest but clinically relevant impact of dronabinol is demonstrated in a randomized controlled trial of 24 patients with multiple sclerosis (published online in advance of print publication). For 3 weeks, the patients, aged 23 to 55 years, received either placebo or 10 mg of the orally administered cannabinoid agent daily. “Median spontaneous pain intensity was significantly lower during dronabinol treatment than during placebo treatment (4.0 (25th to 75th centiles 2.3 to 6.0) v 5.0 (4.0 to 6.4), P=0.02), and median pain relief score (numerical rating scale) was higher (3.0 (0 to 6.7) v 0 (0 to 2.3), P=0.035),” report the authors. “The number needed to treat for 50% pain relief was 3.5 (95% confidence interval 1.9 to 24.8). On the SF-36 quality of life scale, the two items bodily pain and mental health indicated benefits from active treatment compared with placebo. The number of patients with adverse events was higher during active treatment, especially in the first week of treatment. The functional ability of the multiple sclerosis patients did not change.” (K. B. Svendsen, U. Hosp., Aarhus, Denmark)

>>>Lancet Report
Source:
July 17 issue of Lancet (www.thelancet.com; 2004; 364).

Antimalarial Combinations: In a review of combinations of available antimalarial agents for drug-resistant strains, the ideal regimen is defined (pp. 285-94): “A regimen should be safe and well tolerated, efficacious and effective, orally, rectally, and parenterally applicable, stable, available as a single dose, effective against all stages of parasite development, not susceptible to parasite resistance, and cheap. The drugs contained in a regimen should have elimination half-times that match and no other clinically significant negative pharmacokinetic interactions, have independent modes of action, act synergistically in vivo, and be produced as a fixed-dose combination in a single formulation.... When combining drugs, the potential for harm, caused by bringing together adverse effects of more than one drug or by generating new risks through unpredictable drug interactions, should be weighed against perceived benefits.” (P. G. Kremsner, U. Tübingen, Tübingen, Germany; peter.kremsner@uni-tuebingen.de)

>>>PNN JournalWatch
* Worldwide Severity and Control of Asthma in Children and Adults: The Global Asthma Insights and Reality Surveys, in Journal of Allergy and Clinical Immunology, 2004; 114: 40–7. Reprints: www2.us.elsevierhealth.com; K. F. Rabe, Leiden U. Med. Ctr., Leiden, the Netherlands; k.f.rabe@lumc.nl

* Treatment of Deep-Vein Thrombosis, in
New England Journal of Medicine, 2004; 351: 268–77. Reprints: nejm.content.org; S. M. Bates, batesm@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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 20, 2004 Vol. 11, No. 138
Providing news and information about medications and their proper use

>>>Internal Medicine Update
Source:
July 20 issue of the Annals of Internal Medicine (www.annals.org; 2004; 141).

Doxycycline & Gulf War Veterans’ Illnesses: In a 12-month study limited by poor adherence to treatment, doxycycline 200 mg daily and placebo similarly improved physical functioning and symptoms among Gulf War veterans with unexplained illnesses (pp. 85-94). The antibiotic has been recommended for therapy based on the possibility that some symptoms might be the result of Mycoplasma infections. Among 491 deployed Gulf War veterans with illness and detectable Mycoplasma DNA in their blood, the investigators found no significant differences between the doxycycline and placebo groups in the proportions whose scores improved by more than 7 units on the Physical Component Summary portion of the Veterans Short Form-36 General Health Survey (18.1%, doxycycline; 17.3%, placebo). Secondary outcomes—pain, fatigue, and cognitive function and change in positivity for Mycoplasma species at 6, 12, and 18 months after randomization—also were not significantly different between the groups. (J. F. Collins, VA Maryland Healthcare System, Perry Point, Md.)

Editorialists, writing about “the long aftermath of the 1991 Gulf War,” note (pp. 155-6): “Symptomatic Gulf War veterans, at least in the United Kingdom, are not feeling any better, and the simple truth is we do not really know why nor what to do about it. It is now time to consider the problems of sick Gulf War veterans in the context of other unexplained or ill-defined syndromes that have arisen in the aftermath of other wars, in other times and other places. Indeed, Gulf War veterans’ illnesses overlap not only with previous postconflict syndromes, such as soldier’s heart or the effort syndrome, but also other unexplained and controversial diagnoses found in nonmilitary settings, such as the chronic fatigue syndrome, multiple chemical sensitivity, or fibromyalgia.” (S. Wessely, King’s College, London; s.wessely@iop.kcl.ac.uk)

Differing Mortality Effects of ACE Inhibitors: Ramipril appears to be superior to other ACE inhibitors in protecting patients older than 65 against mortality in the first year after a myocardial infarction, according to results of a study of 7,512 Québecois (pp. 102-12). At 109 hospitals in the Canadian province, a retrospective cohort study linked hospital discharge data with prescription drug use from 1996 to 2000, and this analysis focused on older patients who filled a prescription for an ACE inhibitor within 30 days of discharge for acute MI and continued to receive the same drug for at least 1 year. The investigators report, “Enalapril, fosinopril, captopril, quinapril, and lisinopril were associated with higher mortality than was ramipril; the adjusted hazard ratios and 95% CIs were 1.47 (95% CI, 1.14 to 1.89), 1.71 (CI, 1.29 to 2.25), 1.56 (CI, 1.13 to 2.15), 1.58 (CI, 1.10 to 2.82), and 1.28 (CI, 0.98 to 1.67), respectively. The adjusted hazard ratio associated with perindopril [which has not been tested after MI] was 0.98 (CI, 0.60 to 1.60).” (L. Pilote, Montréal Genl. Hosp., Montréal; louise.pilote@mcgill.ca)

Editorialists support use of evidence-based practices but question whether this study provides better guidance than the available prospective clinical trials (pp. 157-8): “How, then, should clinicians choose among ACE inhibitors with a demonstrated mortality benefit? Many ACE inhibitors reduce mortality in patients with heart disease. Because of the lack of head-to-head mortality trials, and the difficulty, for reasons discussed [in this editorial], in interpreting differences in relative risk reductions across ACE inhibitor trials, favoring one proven ACE inhibitor over another on the basis of survival benefit has little rationale. Although the potential importance of pharmacologic factors such as lipophilicity or affinity for tissue ACE has been raised, the clinical importance of these factors has not been shown. Therefore, it seems reasonable to base choices among proven ACE inhibitors on considerations such as dosing frequency, cost, and a clinician’s own familiarity with the agent.” (S. Hennessy, shenness@cceb.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 21, 2004 Vol. 11, No. 139
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
July 21 issue of JAMA (www.jama.com; 2004; 292).

Statins in Children: In 214 children with familial hypercholesterolemia, pravastatin therapy significantly reduced carotid atherosclerosis with no serious adverse effects, according to results of a 2-year study (pp. 331-7). The children, aged 8 to 18 years, randomly received either pravastatin 20–40 mg/day or placebo, and carotid intima-media thickness was monitored. “Compared with baseline, carotid IMT showed a trend toward regression with pravastatin (mean [SD], –0.010 [0.048] mm; P = .049), whereas a trend toward progression was observed in the placebo group (mean [SD], +0.005 [0.044] mm; P = .28). The mean (SD) change in IMT compared between the 2 groups (0.014 [0.046] mm) was significant (P = .02). Also, pravastatin significantly reduced mean low-density lipoprotein cholesterol levels compared with placebo (–24.1% vs +0.3%, respectively; P < .001). No differences were observed for growth, muscle or liver enzymes, endocrine function parameters, Tanner staging scores, onset of menses, or testicular volume between the 2 groups.” (J. J. P. Kastelein, Academic Med. Ctr., Amsterdam, the Netherlands; e.vandongen@amc.uva.nl)

Aggressive therapy of children with this disease is supported by an editorialist who commented on the study findings (pp. 377-8): “There are many issues at the heart of the debate of using pharmaceuticals in young patients. At what point does the potential risk of therapy outweigh the potential benefit? In the case of familial hypercholesterolemia, the promise of reducing future cardiovascular morbidity and mortality, as well as future demands on acute care and more expensive preventive approaches, would make aggressive treatment of high-risk young patients a worthwhile long-term initiative. Appropriate targeting of lifestyle and drug therapies will optimize primary prevention in this group at demonstrated risk for early coronary disease.” (A. M. Gotto, Jr., amg_editorial@med.cornell.edu)

Antidepressants & Suicide: No substantial difference in suicidal behavior was found in a case–control study of U. K. users of four antidepressants, and severity of depression may be an uncontrolled confounder in studies of this type, conclude investigators (pp. 338-43). The analysis included 555 cases who received at least one prescription for amitriptyline, fluoxetine, paroxetine, and/or dothiepin within 90 days before a recorded diagnosis of first-time nonfatal suicide behavior or suicide and 2,062 control patients, chosen from among 159,810 users of the drugs. The authors report, “The relative risks for newly diagnosed nonfatal suicidal behavior in 555 cases and 2062 controls were 0.83 (95% confidence interval, [CI] 0.61–1.13) for amitriptyline, 1.16 (95% CI, 0.90–1.50) for fluoxetine, and 1.29 (95% CI, 0.97–1.70) for paroxetine compared with those using dothiepin. The RR for suicidal behavior among patients first prescribed an antidepressant within 1 to 9 days before their index date was 4.07 (95% CI, 2.89– 5.74) compared with patients who were first prescribed an antidepressant 90 days or more before their index date. Time since first antidepressant prescription was not, however, a confounder of the relation between specific antidepressants and suicidal behavior since its relation to suicidal behavior was not materially different among users of the 4 study drugs. Similarly for fatal suicide, the RR among patients who were first prescribed an antidepressant within 1 to 9 days before their index date was 38.0 (95% CI, 6.2–231) compared with those who were first prescribed an antidepressant 90 days or more before their index date. There were no significant associations between the use of a particular study antidepressant and the risk of suicide.” (H. Jick, Boston Collaborative Drug Surveillance Program, Lexington, Mass.; hjick@bu.edu)

Editorialists note (pp. 379-81): “The findings from Jick et al provide useful data in what is still a somewhat messy situation. Public anxiety fueled by media reports has transferred itself to the already nervous regulatory authorities, and it is unlikely that this study alone will restore confidence.” (S. Wessely, Inst. of Psychiatry, London; s.wessely@iop.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 22, 2004 Vol. 11, No. 140
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
July 22 issue of the New England Journal of Medicine (content.nejm.org; 2004; 351).

Treatment of Metastatic Colorectal Cancer: Cetuximab—both alone and in combination therapy—is active against irinotecan-refractory colorectal cancer, according to a study of 329 patients with progressive stage IV disease (pp. 337-45). Providing data that support the monoclonal antibody’s recent FDA approval (see PNN, Feb. 13), the study included patients whose disease had progressed during or within 3 months of treatment with an irinotecan-based regimen. Subjects received either cetuximab plus irinotecan or cetuximab alone. The authors report, “The rate of response in the combination-therapy group was significantly higher than that in the monotherapy group (22.9 percent [95 percent confidence interval, 17.5 to 29.1 percent] vs. 10.8 percent [95 percent confidence interval, 5.7 to 18.1 percent], P=0.007). The median time to progression was significantly greater in the combination-therapy group (4.1 vs. 1.5 months, P < 0.001 by the log-rank test). The median survival time was 8.6 months in the combination-therapy group and 6.9 months in the monotherapy group (P = 0.48). Toxic effects were more frequent in the combination-therapy group, but their severity and incidence were similar to those that would be expected with irinotecan alone.” (D. Cunningham, Royal Marsden Hosp., Surrey, U. K.; david.cunningham@icr.ac.uk)

Discussing new treatment options for colorectal cancer, editorialists write (pp. 391-2): “For patients with metastatic colorectal cancer, the past year has seen multiple new and promising treatment options. The addition of cetuximab in the armamentarium of treatment options for this group of patients must be tempered by the small advances that it offers in terms of the time to progression and the response rate and its uncertain effect on survival in patients with irinotecan-refractory cancer. The development of fully humanized antibodies to [epidermal growth factor receptor], such as EMD72000 and ABX-EGF, holds the potential for further refinement of EGFR-targeted therapy. Finally, the addition of cetuximab to the initial treatment of metastatic colorectal cancer or in the adjuvant setting may increase its usefulness.” (C. Erlichman, Mayo Clinic, Rochester, Minn.)

Cost of Treatment of Metastatic Colorectal Cancer: In a Perspectives article, an author puts a price tag on the options presented in the above study (pp. 317-9): “In the United States, the [irinotecan plus cetuximab] regimen costs approximately $30,790 for an eight-week course. Assuming that an average patient continues to receive treatment until the median time to progression, 8 months of front-line therapy followed by 4.1 months of irinotecan–cetuximab therapy would cost $161,000. In 2004, 32,000 people in the United States will receive a diagnosis of stage IV colorectal cancer, and recurrent metastatic disease will develop in an additional 24,000. The drug costs for an eight-week course of initial treatment for these 56,000 patients will be approximately $666 million—or $1.2 billion with the addition of monoclonal-antibody therapy. Unfortunately, such costly treatment will not provide a cure; one can only speculate about the relative effect of directing these resources toward screening and prevention.” (D. Schrag, Memorial Sloan-Kettering Cancer Center, New York City)

Vestibular Neuritis: Methylprednisolone is effective in vestibular neuritis, but valacyclovir adds little to treatment, conclude investigators who studied 141 patients in a placebo-controlled comparison (pp. 354-61). Using the vestibular paresis formula to measure the extent of unilateral caloric paresis, the authors found significant improvement at 12 months with methylprednisolone only (mean, 62.4 percentage points, compared with 39.6 with placebo and 36.0 with valacyclovir only) and with methylprednisolone plus valacyclovir (59.2). “Analysis of variance showed a significant effect of methylprednisolone (P < 0.001) but not of valacyclovir (P = 0.43),” the researchers add. (M. Strupp, U. Munich, Munich, Germany; mstrupp@nefo.med.uni-muenchen.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 23, 2004 Vol. 11, No. 141
Providing news and information about medications and their proper use

>>>Infectious Diseases Update
Source: Aug. 1 issue of Clinical Infectious Diseases (www.journals.uchicago.edu/CID; 2004; 39).

Etanercept & TB: Like infliximab, etanercept may increase patient risk of developing tuberculosis, according to an evaluation of adverse event reports submitted to FDA (pp. 342-8). “The median interval between the receipt of the first dose of etanercept and the diagnosis of TB was 11.5 months,” report the authors. “Thirteen patients had extrapulmonary TB at the time of diagnosis. Diagnosis was made on the basis of culture results for 12 patients, biopsy findings for 9, and sputum staining for 4. There were 2 deaths, 1 of which was directly attributed to TB. The estimated number of TB cases reported to the FDA for each person-year of treatment with etanercept (i.e., the ‘reporting rate&rsquoWinking among patients with rheumatoid arthritis (RA) was 10 cases/100,000 patient-years of exposure. Clinicians considering etanercept for patients with RA should be alert to the possibility of the occurrence of TB, sometimes with an unusual extrapulmonary presentation. It is unclear whether etanercept therapy increases the risk of TB beyond the elevated TB rates already documented for patients with RA.” (A. K. Mohan, mohan@cber.fda.gov)

Postexposure HIV Prophylaxis: Especially in areas of low antiretroviral resistance, a two-drug regimen is sufficient for postexposure prophylaxis following high-risk occupational HIV exposure (pp. 395-401). Using a mathematical model of prophylaxis, the authors found that a three-drug regimen would reduce transmission from 300 to 108 cases per 100,000 high-risk needlesticks. But omission of the protease inhibitor from the regimen was equally effective, with a transmission rate of 105 cases, and patients would not be at risk for the nausea, vomiting, fatigue, headache, and diarrhea that frequently produce poor adherence with the three-drug regimen. (I. V. Bassett, Mass. Genl. Hosp., Boston; ibassett@partners.org)

Niacin for HIV-Associated Dyslipidemia: A pilot study indicates possible effectiveness and safety of niacin in treatment of antiretroviral therapy-associated dyslipidemia (pp. 419-25). In an open trial of 14 HIV-infected individuals with dyslipidemia, administration of extended-release niacin for 14 weeks produced these results: “Significant reductions in serum levels of triglycerides (P = .02), total cholesterol (P = .005), and non-HDL cholesterol (P = .04) were seen after ER-niacin therapy. Seven of 11 subjects were glucose intolerant after ER-niacin therapy; for 3 of these subjects, this was a new finding. Beta-cell sensitivity to basal glucose levels increased significantly without concomitant increase in overall glucose disposition indices. The values for the homeostasis model of insulin resistance index increased significantly (P = .005).” (P. Tebas, pablo.tebas@uphs.upenn.edu)

>>>PNN NewsWatch
* Elderly Americans are more satisfied with the services of their pharmacies than are younger adults, according to a survey conducted by Wilson Health Information, a pharmacy satisfaction research firm. Among younger adults (aged 49 years and younger) and older adults (50–64 years of age), almost one half are highly satisfied with the pharmacy they use most often. In each of these two groups, 4% of customers are dissatisfied. Among senior customers, 56% are highly satisfied with their pharmacy and only 2% are dissatisfied. Customer satisfaction is critical for pharmacy, as nearly all highly satisfied customers intend to return to a pharmacy. A pharmacy with high satisfaction ratings loses $10,000 per month to customer defections, but a poorly rated pharmacy loses far more.

* Physicians using the
e-prescribing software of Allscripts Healthcare Solutions—TouchScript.NET—will soon have access to Wolters Kluwer Health products such as Facts & Comparisons, Clin-eguide, SKOLAR, and Medi-Span, thanks to an agreement announced this week. The partnership encourages the adoption of information technology tools at the point of care to improve patient safety and highlights the importance of high-quality medical knowledge in clinical technology solutions.

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 26, 2004 Vol. 11, No. 142
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
July 24 issue of Lancet (www.thelancet.com; 2004; 364).

Aspirin Plus Clopidogrel After Cerebrovascular Events: Adding aspirin to clopidogrel-based therapy following ischemic stroke or transient ischemic attack produces a significant increase in risk of life-threatening or major bleeding without significantly improving outcomes, according to results of the MATCH trial (pp. 331-7). In 7,599 high-risk patients with recent ischemic stroke or transient ischemic attack and at least one additional vascular risk factor who were already receiving clopidogrel 75 mg/day, investigators randomly added placebo or aspirin 75 mg/day. Based on a primary endpoint of ischemic stroke, myocardial infarction, vascular death, or rehospitalization for acute ischemia (including rehospitalization for transient ischemic attack, angina pectoris, or worsening of peripheral arterial disease) during the 18-month study, the researchers found: “596 (15.7%) patients reached the primary endpoint in the group receiving aspirin and clopidogrel compared with 636 (16.7%) in the clopidogrel alone group (relative risk reduction 6.4%, [95% CI –4.6 to 16.3]; absolute risk reduction 1% [–0.6 to 2.7]). Life-threatening bleedings were higher in the group receiving aspirin and clopidogrel versus clopidogrel alone (96 [2.6%] vs 49 [1.3%]; absolute risk increase 1.3% [95% CI 0.6 to 1.9]). Major bleedings were also increased in the group receiving aspirin and clopidogrel but no difference was recorded in mortality.” (H-C Diener, U. Essen, Essen, Germany; h.diener@uni-essen.de)

Effects of Darusentan on Cardiac Remodeling: Despite evidence of hemodynamic benefit of endothelin blockade in heart failure, darusentan failed to produce long-term improvements in cardiac remodeling or clinical symptoms or outcomes among 642 patients with chronic heart failure who were also treated with an ACE inhibitor, beta-blocker, or aldosterone antagonist (pp. 347-54). In the Endothelin-A Receptor Antagonist Trial in Heart Failure (EARTH), patients randomly received darusentan 10, 25, 50, 100, or 300 mg/day or placebo for 24 weeks. Patients assigned to the three higher doses were uptitrated over a 6-week period. In 485 patients who had paired magnetic resonance images showing change in left ventricular end-systolic volume, the authors observed: “The change in LVESV was not significantly different from that with placebo at any dose (mean difference from placebo 1.27 mL [95% CI –9.9 to 12.4] with 10 mg dose, –1.84 mL [–13.0 to 9.3] with 25 mg, –5.68 mL [–16.9 to 5.6] with 50 mg, –4.05 mL [–15.5 to 7.4] with 100 mg, and –4.34 mL [–15.7 to 7.0] with 300 mg). Heart failure worsened in 71 (11.1%) patients, and 30 (4.7%) died during the study with no difference between groups.” (T. F. Lüscher, U. Hosp., Zürich, Switzerland; cardiotfl@gmx.ch)

>>>PNN JournalWatch
* Effectiveness of Meningococcal Serogroup C Conjugate Vaccine 4 Years After Introduction, in Lancet, 2004; 364: 365–7. Reprints: www.thelancet.com; M. Ramsay, Health Protection Agency Meningococcal Reference Unit, Manchester, U.K.; mary.ramsay@hpa.org.uk

* Osteomyelitis, in
Lancet, 2004; 364: 369–79. Reprints: www.thelancet.com; D. P. Lew, Geneva U. Hosp., Geneva, Switzerland; Daniel.Lew@hcuge.ch

* Passive Smoking and Risk of Coronary Heart Disease and Stroke: Prospective Study with Cotinine Measurement, in
BMJ, 2004; 329: 200–5. Reprints: www.bmj.org; P. H. Whincup, St. George’s Hosp. Med. Sch., London; p.whincup@sghms.ac.uk

* Which Drugs Should Be Available Over the Counter?, in
BMJ, 2004; 329: 182–3. Reprints: www.bmj.org; R. R. Fenichel, Washington, D.C.; bob@fenichel.net

* Sex, Sun, Sea, and STIs: Sexually Transmitted Infections Acquired on Holiday, in
BMJ, 2004; 329: 214–7. Reprints: www.bmj.org; K. E. Rogstad, Royal Hallamshire Hosp., Sheffield, U.K.; Karen.Rogstad@sth.nhs.uk

* Management of Dyslipidemia in Patients with Metabolic Syndrome, in
Journal of the American Pharmacists Association, 2004; 44: 478–90. Reprints: www.japha.org; M. J. Cziraky, HealthCore Inc., Wilmington, Del.; MCziraky@healthcore.com

* Drug Use in Sports: A Veritable Arena for Pharmacists, in
Journal of the American Pharmacists Association, 2004; 44: 501–16. Reprints: www.japha.org; P. J. Ambrose, Mem. Med. Ctr., Long Beach, Calif; pambrose@memorialcare.org

* Fever after Immunization: Current Concepts and Improved Future Scientific Understanding, in
Clinical Infectious Diseases, 2004; 39: 389–94. Reprints: www.journals.uchicago.edu/CID; Brighton Collaboration Fever Working Group, http://brightoncollaboration.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 27, 2004 Vol. 11, No. 143
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
July 26 issue of Archives of Internal Medicine (www.archinternmed.com; 2004; 164).

Benzodiazepines & Elderly Hip Fractures: Short half-life benzodiazepines are no safer than those with longer half-lives in terms of risk of hip fracture in the elderly, according to a report that contradicts the prevailing wisdom (pp. 1567-72). Using data from the New Jersey Medicaid program that covered 42 months, the investigators found, “Cohort members (n = 125,203) contributed 194,071 person-years and had 2312 eligible hip fractures. After adjustment for age, sex, race, Medicaid nursing home residence, exposure to other psychoactive medications, including antiparkinsonian medications, diagnoses of epilepsy and dementia, and hospitalization in the previous 6 months, the incidence rate of hip fracture was significantly higher compared with no benzodiazepine use for exposure to any benzodiazepine (incidence rate ratio [IRR], 1.24; 95% confidence interval [CI], 1.06–1.44), to a short half-life, high-potency benzodiazepine (IRR, 1.27; 95% CI, 1.01–1.59), during the first 2 weeks after starting a benzodiazepine (IRR, 2.05; 95% CI, 1.28–3.28), during the second 2 weeks after starting a benzodiazepine (IRR, 1.88; 95% CI, 1.15–3.07), and for continued use (IRR, 1.18; 95% CI, 1.03–1.35).” (A. K. Wagner, Harvard Med. Sch., Boston)

Renal Function & Lifetime Analgesic Exposure: Higher total use of acetaminophen was associated with declines in renal function among 1,697 women in the Nurses’ Health Study, while no relationship was observed between aspirin or NSAID use and decline in glomerular filtration rate (pp. 1519-24). Participants provided blood samples in 1989 and 2000 and completed a 1999 mailed questionnaire about lifetime analgesic use. “The mean ± SD estimated GFR decreased from 88 ± 17 to 79 ± 17 mL/min per 1.73 m2. There were no substantial differences in the unadjusted or estimated GFR levels among the categories of lifetime intake for the 3 analgesic groups at baseline or after 11 years. Acetaminophen use was associated with an increased risk of a GFR decline of at least 30 mL/min per 1.73 m2 (P trend = .01) and a GFR decline of 30% or greater (P trend < .001), but aspirin and NSAID use were not. Compared with women consuming less than 100 g of acetaminophen, multivariate-adjusted odds ratio (95% confidence intervals) for a decline in GFR of at least 30 mL/min per 1.73 m2 for women consuming more than 3000 g was 2.04 (1.28– 3.24).” (G. C. Curhan, Brigham and Women’s Hosp., Boston)

Tea Consumption & Hypertension: Habitual consumption of moderate-strength green or oolong tea significantly reduces risk of developing hypertension among Taiwanese people, according to a study of 1,507 subjects (pp. 1534-40). Compared with nonhabitual tea drinkers, those consuming 120–599 mL/day for at least 1 year had a 46% reduction in risk of developing hypertension. The risk was even lower, 65%, among those consuming 600 mL/day or more. (Yi-Ching Yang, National Cheng Kung U., Tainan, Taiwan)

Vitamin E & Cardiovascular Disease: Six of seven large-scale, randomized trials of vitamin E show no significant effect on prevention or treatment of cardiovascular disease (pp. 1552-6). “The use of agents of proven lack of benefit, especially those easily available over the counter, may contribute to underuse of agents of proven benefit and failure to adopt healthy lifestyles,” the authors caution. (R. S. Eidelman, Agatston Research Institute, Miami Beach)

Excessive Anticoagulation: Among 101 consecutive patients with major bleeding during administration of warfarin, heparin, or low-molecular weight heparins, those with excessive anticoagulation had a mortality rate of 26%, compared with 10% in those with nonexcessive anticoagulation (pp. 1557-60). “Excessive anticoagulation was also a significant predictor of the combined nonfatal end point of stroke, myocardial infarction, hypotension, critical anemia, and surgical or angiographic intervention at 30 days,” the authors add. (S. Koo, 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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 28, 2004 Vol. 11, No. 144
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
July 28 issue of JAMA (www.jama.com; 2004; 292).

Treatment of NSCLC: Compared with monotherapy, use of two drugs improved both tumor response and survival rate among patients with non–small-cell lung cancer, but addition of a third drug had a weaker effect, according to an analysis of 65 trials involving 13,601 patients (pp. 470-84). Assessing pooled odds ratios and median ratios reported in studies performed between 1980 and 2001, the investigators note, “In the trials comparing a doublet regimen with a single-agent regimen, a significant increase was observed in tumor response (OR, 0.42; 95% confidence interval [CI], 0.37–0.47; P < .001) and 1-year survival (OR, 0.80; 95% CI, 0.70– 0.91; P < .001) in favor of the doublet regimen. The median survival ratio was 0.83 (95% CI, 0.79–0.89; P < .001). An increase also was observed in the tumor response rate (OR, 0.66; 95% CI, 0.58–0.75; P < .001) in favor of the triplet regimen, but not for 1-year survival (OR, 1.01; 95% CI, 0.85–1.21; P = .88). The median survival ratio was 1.00 (95% CI, 0.94–1.06; P = .97).” (C. Delbaldo, Institut Gustave-Roussy, Villejuif Cedex, France)

Functional Decline, Symptoms, & PAD:
Baseline ankle brachial index and leg symptoms proved useful predictors of functional decline in patients with peripheral arterial disease (pp. 453-61). Researchers measured annual changes in 6-minute walk performance and in usual-paced and fast-paced 4-meter walking velocity, adjusted for age, sex, race, prior-year functioning, coexisting diseases, body mass index, cigarette smoking, and patterns of missing data. “Among 676 men and women age 55 years and older, participants with low ABI levels at baseline had significantly greater decline in walking endurance at 2-year follow-up, compared with those with normal baseline ABI levels,” the authors write. “Participants with ABIs less than 0.50 at baseline had a nearly 13-fold increased risk of becoming unable to walk for 6 minutes continuously 2 years later, relative to participants with ABIs of 1.10 to 1.50.” Baseline leg symptoms among participants with PAD also predicted rates of functional decline. “Participants with PAD having leg pain on exertion and rest experienced greater declines in walking endurance and walking speed than did individuals without PAD,” the authors explain. “Participants with asymptomatic PAD had significantly greater declines in 6-minute walk performance than did participants without PAD.” (M. M. McDermott, Northwestern U., Chicago)

>>>Nephrology Highlights
Source:
Aug. issue of the American Journal of Kidney Diseases (www2.ajkd.org; 2004; 44).

Monitoring LMWHs with Thrombin Generation Time: In patients with end-stage renal disease who are receiving low molecular weight heparins, thrombin generation time may be a preferred anticoagulation monitoring tool, as a study demonstrates poorer predictions with antifactor Xa (pp. 270-7). Included in the analysis were 10 healthy controls, 10 patients with chronic kidney disease, and 10 patients with ESRD. The investigators found, “Subjects with ESRD had an approximately 50% greater anticoagulant effect, determined by thrombin generation time prolongation, than controls at antifactor Xa activity concentrations of 0.5 to 3.0 IU/mL. This may explain why subjects with ESRD with seemingly therapeutic antifactor Xa levels still experience adverse bleeding. There were no intergroup differences in platelet function, determined by platelet contractile force and clot elastic modulus” (D. F. Brophy, dbrophy@vcu.edu)

Vitamin Use During Dialysis: Exploring international differences in use of water-soluble vitamins among hemodialysis patients, researchers find that supplementation lowers risk of mortality by a significant 16% (pp. 293-9). Among 16,345 HD patients at 308 facilities, prevalence of vitamin use ranged from 3.7% in the U.K. to 71.9% in the U.S. While controlled trials of the practice are lacking, the authors conclude that the intervention has minimal risk and appears to produce better outcomes. (R. B. Fissell, rfissell@umich.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 29, 2004 Vol. 11, No. 145
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
July 29 issue of the New England Journal of Medicine (content.nejm.org; 2004; 351).

Treatment of Hepatitis C: Two articles and a perspectives manuscript discuss peginterferon alfa-2a treatment of chronic hepatitis C virus infection in patients with coinfections of HIV.

In 868 HIV/HCV-infected patients who had not previously been treated for HCV with interferon or ribavirin, the combination of peginterferon alfa-2a plus ribavirin proved significantly more effective than the pegylated interferon alone or interferon alfa-2a plus ribavirin (pp. 438-50). For 48 weeks plus an additional 24 weeks, patients received either peginterferon alfa-2a 180 mcg/week plus ribavirin 800 mg/day, peginterferon alfa-2a plus placebo, or interferon alfa-2a 3 million IU three times a week plus ribavirin. The authors report, “The overall rate of sustained virologic response was significantly higher among the recipients of peginterferon alfa-2a plus ribavirin than among those assigned to interferon alfa-2a plus ribavirin (40 percent vs. 12 percent, P < 0.001), or peginterferon alfa-2a plus placebo (40 percent vs. 20 percent, P < 0.001). Among patients infected with HCV genotype 1, the rates of sustained virologic response were 29 percent with peginterferon alfa-2a plus ribavirin, 14 percent with peginterferon alfa-2a plus placebo, and 7 percent with interferon alfa-2a plus ribavirin. The corresponding rates among patients infected with HCV genotype 2 or 3 were 62 percent, 36 percent, and 20 percent. Neutropenia and thrombocytopenia were more common among patients treated with regimens that contained peginterferon alfa-2a, and anemia was more common among patients treated with regimens containing ribavirin.” (F. J. Torriani, ftorriani@ucsd.edu.)

A second study, assessing the responses of 133 patients with HIV/HCV coinfection, provides similar conclusions as those reached in the above study (pp. 451-9). In addition to receiving ribavirin on a dose-escalation schedule, subjects randomly received of peginterferon alfa-2a 180 mcg weekly for 48 weeks or interferon alfa-2a 6 million IU three times weekly for 12 weeks followed by interferon alfa-2a 3 million IU three times weekly for 36 weeks. Liver biopsy was performed on those not responding by week 24. “Treatment with peginterferon and ribavirin was associated with a significantly higher rate of sustained virologic response (an HCV RNA level of less than 60 IU per milliliter 24 weeks after completion of therapy) than was treatment with interferon and ribavirin (27 percent vs. 12 percent, P=0.03),” note the researchers. “In the group given peginterferon and ribavirin, only 14 percent of subjects with HCV genotype 1 infection had a sustained virologic response (7 of 51), as compared with 73 percent of subjects with an HCV genotype other than 1 (11 of 15, P < 0.001). Histologic responses were observed in 35 percent of subjects with no virologic response who underwent liver biopsy.” (R. T. Chung, Mass. Genl. Hosp., Boston; rtchung@partners.org)

The Perspectives author predicts (pp. 422-3): “The availability of four classes of therapeutic interventions for HCV infection is foreseeable in the next 5 to 10 years: interferons, including new interferon molecules with enhanced activity and further improved pharmacologic properties; ribavirin and ribavirin-like molecules that mimic ribavirin’s effects but have a better tolerance profile; specific inhibitors of HCV replication, including HCV protease inhibitors, HCV polymerase inhibitors, HCV helicase inhibitors, and inhibitors of the HCV internal ribosome entry site; and immune therapies, such as new immune modulators and therapeutic vaccines. There is little doubt that the combination of several different approaches tailored to the individual patient and to the early virologic response to treatment will result in the clearance of HCV in a substantial proportion of the patients who are currently classified as difficult to treat. For patients in whom infection cannot be cleared and whose liver disease is likely to progress (such as those who are coinfected with HIV and HCV), ‘suppressive,’ noncurative therapy inducing a sustained and profound inhibition of HCV replication might remain the only therapeutic option.” (J-M Pawlotsky, Henri Mondor Hosp., U. Paris XII, Créteil, France)

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 30, 2004 Vol. 11, No. 146
Providing news and information about medications and their proper use

>>>Acamprosate Approved for Alcohol Dependence
FDA yesterday approved acamprosate calcium (Campral; Forest, Merck), delayed-release tablets indicated for maintenance of abstinence from alcohol in patients with alcohol dependence who are abstinent at treatment initiation. The drug, used in conjunction with comprehensive management programs that include psychosocial support, will be available around the end of this year.

The mechanism of action of acamprosate, a GABA analogue, in maintenance of alcohol abstinence is not completely understood. Chronic alcohol exposure alters the normal balance between neuronal excitation and inhibition. Acamprosate interacts with neurotransmitter systems and is hypothesized to restore the normal balance, thereby achieving an anticraving action different from other available medications, which block alcohol’s action or induce vomiting if alcohol is ingested.

FDA approval of acamprosate is based primarily on safety and efficacy data from four double-blind, placebo-controlled trials. In three of these trials, acamprosate increased abstinence rates when used as part of a multidisciplinary approach that included various types of psychosocial support. In a fourth study, the acamprosate-treated group failed to show a difference on the primary efficacy endpoint, cumulative abstinence duration. In this trial, patients were not required to be abstinent before randomization as required in the positive studies. In clinical trials, adverse effects with acamprosate were generally mild, with diarrhea the most frequently reported problem.

>>>JAPhA Highlights
Source:
July/Aug Journal of the American Pharmacists Association (www.japha.org; 2004; 44).

Medication Error Reporting: While 62% of 113 Vermont community pharmacists were aware of the USP Medication Errors Reporting Program, few (21%) had ever submitted a report, according to a telephone survey of pharmacists in all but 11 community pharmacies in the Green Mountain State (pp. 434-8). “Significantly more pharmacists employed by independent pharmacies had submitted a report, compared with pharmacists from other pharmacy types (chain, supermarket, mass merchandiser; P = .03),” the authors report. “Submitting reports through a corporate hierarchy or to a corporate program was the reason most frequently cited by pharmacists for not submitting reports directly to USP MER (37%). Whether corporate reports were forwarded to USP MER is unknown.” (A. G. Kennedy, U. Vermont, Burlington; amanda.kennedy@vtmednet.org)

In an accompanying editorial, a USP staff member calls for action by pharmacists (pp. 427-8): “National voluntary reporting of medication errors should be a fundamental, ongoing activity—a cornerstone of patient safety initiatives. Voluntary reporting systems go beyond simply measuring the status of current problems. Through sharing, these systems provide collective awareness and knowledge leading to the development of risk reduction strategies and improved patient care—a goal all the inhabitants of our ‘village’ share.” (J. P. Santell, USP Center for the Advancement of Patient Safety, Rockville, Md.)

Media Coverage of Controlled Substance Diversion: If media reports accurately reflect the frequency of diversion of controlled substances, robberies and thefts from pharmacies and distribution channels are overtaking inappropriate prescribing and dispensing as factors in diverting these products (pp. 439-44). A quantitative news search of LexisNexis Academic from 1993 through 2002 shows these percentage increases in media reports of different types of diversion: 200% for prescribers; 350% for dispensers; 133% for pharmacy robberies and thefts; and 1,800% for thefts from shipping channels. (D. B. Brushwood, brushwood@cop.ufl.edu)

Review Articles: Articles in this issue review dyslipidemia management in patients with metabolic syndrome (pp. 478-90; M. J. Cziraky, HealthCore, Wilmington, Del.; MCziraky@healthcore.com), risk-management strategies used for pharmaceuticals (pp. 491-500; E. Andrews, RTI Health Solutions, Research Triangle Park, N.C.; eandrews@rti.org), and pharmacists’ roles in informing athletes about drug use in sports (P. J. Ambrose, Long Beach Memorial Med. Ctr., Long Beach, Calif.; pambrose@memorialcare.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Aug. 2, 2004 Vol. 11, No. 147
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
July 31 issue of BMJ (www.bmj.org; 2004; 329).

Dronabinol for MS: A modest but clinically relevant impact of dronabinol is demonstrated in a randomized controlled trial of 24 patients with multiple sclerosis (pp. 253 ff; published early online and reported in PNN, July 19). For 3 weeks, the patients, aged 23 to 55 years, received either placebo or 10 mg of the orally administered cannabinoid agent daily. “Median spontaneous pain intensity was significantly lower during dronabinol treatment than during placebo treatment (4.0 (25th to 75th centiles 2.3 to 6.0) v 5.0 (4.0 to 6.4), P = 0.02), and median pain relief score (numerical rating scale) was higher (3.0 (0 to 6.7) v 0 (0 to 2.3), P = 0.035),” report the authors. “The number needed to treat for 50% pain relief was 3.5 (95% confidence interval 1.9 to 24.8). On the SF-36 quality of life scale, the two items bodily pain and mental health indicated benefits from active treatment compared with placebo. The number of patients with adverse events was higher during active treatment, especially in the first week of treatment. The functional ability of the multiple sclerosis patients did not change.” (K. B. Svendsen, U. Hosp., Aarhus, Denmark)

The prospects for success of cannabinoid research—at least from a scientific perspective—are discussed in an accompanying commentary (pp. 257-8): “The perception of pain is controlled by neurotransmitter systems within the central nervous system, but peripheral tissues also have mechanisms for relieving and preventing pain. Cannabinoids may therefore have two distinct roles in relation to pain. The evidence comes from animal experiments showing that cannabinoids lower the response of pain neurones in the spinal cord and also in parts of the thalamus in the brain. The possibility that cannabinoid receptor subtypes act synergistically hints at a potentially valuable strategy: the development of a new class of analgesic drug comprising a mixture of synthetic CB1 and CB2 agonists. Alternatively, devising agents to slow the breakdown of natural cannabinoids might potentiate their analgesic effects.” (G. Watts, BMJ, London; geoff@scileg.freeserve.co.uk)

Doxycycline-Associated Photo-onycholysis: Five cases of photo-onycholysis occurring during doxycycline prophylaxis for Lyme disease are presented (pp. 265 ff). Based on their observations and drug knowledge, the authors recommend that patients avoid exposure of the nail beds to sunlight shortly after using doxycycline. (A. Passier, Netherlands Pharmacovigilance Centre Lareb, Hertogenbosch, the Netherlands; A.Passier@Lareb.nl)

>>>Lancet Report
Source: July 31 issue of Lancet (www.thelancet.com; 2004; 364).

Recognizing Inhalational Anthrax: “Nausea, vomiting, pallor or cyanosis, diaphoresis, altered mental status, and raised haematocrit were more frequently recorded in ... inhalational anthrax cases than in either ... community-acquired pneumonia or influenza-like illness controls,” report authors who analyzed 47 historical cases of anthrax and 376 controls with similarly presenting conditions (pp. 449-52). “The most accurate predictor of anthrax was mediastinal widening or pleural effusion on a chest radiograph. This finding was 100% sensitive (95% CI 84.6– 100.0) for inhalational anthrax, 71.8% specific (64.8–78.1) compared with community-acquired pneumonia, and 95.6% specific (90.0–98.5) compared with influenza-like illness.” (D. N. Kyriacou, Northwestern U., Chicago; dkyriacou@aol.com)

>>>PNN JournalWatch
* Borderline Personality Disorder, in Lancet, 2004; 364: 453–61. Reprints: www.thelancet.com; K. Lieb, U. Freiburg, Freiburg, Germany; klaus_lieb@psyallg.ukl.uni-freiburg.de

* Bipolar Disorder, in
New England Journal of Medicine, 2004; 351: 476–86. Reprints: content.nejm.org; R. H. Belmaker, Beersheba Mental Health Center, Beersheba, Israel;belmaker@bgumail.bgu.ac.il

* Evaluation and Treatment of the Human Immunodeficiency Virus-1– Exposed Infant, in
Pediatrics, 2004; 114: 497–505. Reprints: pediatrics.aappublications.org; American Academy of Pediatrics Committee on Pediatric AIDS.

* Managing Acute Gastroenteritis Among Children: Oral Rehydration, Maintenance, and Nutritional Therapy, in
Pediatrics, 2004; 114: 507. Reprints: pediatrics.aappublications.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Aug. 3, 2004 Vol. 11, No. 148
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release article from and Aug. 3 issue of the Annals of Internal Medicine (www.annals.org; 2004; 141).

Medicare Prescription Drug Law: The political origins of the complexity of the new Medicare prescription drug law—and the resulting confusion among beneficiaries—are explored in an article that also discusses the impact on health of new private health plan options under the law (early-release article). The Medicare Modernization Act was “designed ... to attract enough votes from Democrats and moderate Republicans in the Senate without losing the support of too many Republican conservatives in the House of Representatives,” the author explains. This resulted in compromises in four critical areas: addition of choice of private plans led to complexity for beneficiaries, restriction of costs to $400 billion over 10 years produced a confusing cost-sharing structure, introduction of means testing departed from Medicare’s past philosophy of providing the same benefits at the same costs to all beneficiaries, and reliance on private insurers to negotiate discounts means that drug costs and formularies will vary for localities and individuals.

“Prescription drug costs will probably strain the federal government’s ability to fund the program while continuing to meet other urgent priorities,” the author concludes. “Faced with recent estimates from CMS that the legislation may cost as much as $530 billion over 10 years instead of the $400 billion estimated by the Congressional Budget Office, lawmakers are already talking about how to rein in costs. Voters should be asking how Congress will be able to meet its promises to current beneficiaries, fund other national priorities, and keep Medicare solvent for the baby-boomer generation. In this election year, few politicians are willing to raise these issues.”(R. B. Doherty, American College of Physicians, Philadelphia)

Sildenafil & Acute Mountain Sickness: In a study conducted in a hospital at low altitude and the base camp on Mount Everest (5,400 m above sea level), sildenafil reduced hypoxic pulmonary hypertension in 14 mountaineers and trekkers both at rest and with exercise (pp. 169-77). The effects of sildenafil 50 mg or placebo were assessed at high altitude and at low altitude while volunteers breathed a hypoxic gas mixture with 10% oxygen. The authors found, “Sildenafil ... significantly increased arterial oxygen saturation during exercise (P = 0.005) and reduced systolic pulmonary artery pressure at rest (P < 0.001) and during exercise (P = 0.031). Of note, sildenafil increased maximum workload (172.5 W [CI, 147.5 to 200.0 W]) vs. 130.6 W [CI, 108.8 to 150.0 W]); P < 0.001) and maximum cardiac output (P < 0.001) compared with placebo. At high altitude, sildenafil had no effect on arterial oxygen saturation at rest and during exercise compared with placebo. However, sildenafil reduced systolic pulmonary artery pressure at rest (P = 0.003) and during exercise (P = 0.021) and increased maximum workload (P = 0.002) and cardiac output (P = 0.015). At high altitude, sildenafil exacerbated existing headache in 2 participants.” (F. Grimminger, U. Hosp., Giessen, Germany; ardeschir.ghofrani@innere.med.uni-giessen.de.)

>>>PNN NewsWatch
* The possibility of OTC availability of statins is explored in two surveys conducted by the National Lipid Association. Physicians were cautiously open to the idea, with 73% believing that new approaches are needed to reach consumers at risk for heart disease who are not now being treated. More than one half of consumers at moderate risk for heart disease indicated they would be highly likely to use OTC statins if they were available; 83% of respondents said they would talk with their physician before beginning OTC statin therapy.

* Emergency department visits related to
“club drugs” remained stable or declined in 2002, notes a new report for the Substance Abuse and Mental Health Services Administration. Emergent visits associated with GHB declined by one third between 2000 and 2002; visits involving LSD fell rapidly between 1999 and 2002; visits involving Ecstasy remained at 2001 levels; and ketamine-related visits remained at the low levels seen since 1998.

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Aug. 4, 2004 Vol. 11, No. 149
Providing news and information about medications and their proper use

>>>Geriatrics Highlights
Source:
Aug. issue of the Journal of the American Geriatrics Society (www.blackwell-synergy.com; 2004; 52).

ADEs in Ambulatory Older Adults:
Older adults with multiple medical conditions or taking multiple medications, nonopioid analgesics, anticoagulants, diuretics, or antiseizure medications are prime candidates for efforts to prevent adverse drug events, according to authors who analyzed 30,397 person-years of care in a multispecialty group in New England (pp. 1349-54). ADEs occurred in 1,299 older adults during a 12-month period in 1999–2000. Based on demographic data on these Medicare beneficiaries, the authors report, “Independent risk factors included being female and aged 80 and older. There were dose-response associations with the Charlson Comorbidity Index and number of scheduled medications. Patients taking anticoagulants, antidepressants, antibiotics, cardiovascular drugs, diuretics, hormones, and corticosteroids were at increased risk. In the analysis of preventable ADEs, the dose–response relationship with comorbidity and number of medications remained. Patients taking nonopioid analgesics (predominantly nonsteroidal antiinflammatory drugs and acetaminophen), anticoagulants, diuretics, and anti-seizure medications were at increased risk.” (T. S. Field, Meyers Primary Care Inst., Worcester, Mass.; tfield@meyersprimary.org)

Nutritional Supplements & Dementia: Those patients with probable Alzheimer’s disease who are most likely to be targeted for nutritional therapies—those with low body weights—are least likely to benefit from the interventions because they reduce other intake, conclude authors who studied 34 institutionalized adults (pp. 1305-12). Midmorning nutritional supplements were provided between breakfast and lunch for 21 consecutive days, and body weight and other variables were compared with values obtained during 21 consecutive days of habitual intake. “Group mean analyses showed increased 24-hour energy, protein, and carbohydrate intake during the supplement phase, but five of 31 subjects who finished all study phases completely compensated for the energy provided by the supplement by reducing lunch intake, and 24-hour energy intake was enhanced in only 21 of 31 subjects,” the investigators write. “Compensation at lunch was more likely in subjects with lower body mass indices, increased aberrant motor behavior, poorer attention, and increased mental disorganization/confusion.(K. Young, karen.young@utoronto.ca)

Polymorphism & Dementia: A polymorphism in the promoter gene for tumor necrosis factor may play a role in protecting patients against age-related neurodegeneration, researchers report based on a study of Danish centenarians (pp. 1361-6). The study compared with 174 octogenarians and 47 young healthy control patients with 122 Danes who had reached age 100. The authors note, “The distribution of TNF 308 genotypes was not different across the three different age groups, but the GA genotype was associated with decreased prevalence of dementia in centenarians. The few centenarians with AA carrier status had higher mortality risk and tended to show higher plasma levels of TNF-alpha, but the significance was questionable due to a low number of subjects with this genotype.” (H. Bruunsgaard, Rigshospitalet, Copenhagen East, Denmark; hellebkemp@os.dk)

Hospices & Cost of End-of-Life Care: Missed savings may be the result of policies that limit access of Medicare skilled-nursing facility residents to Medicare hospice services, according to a retrospective cohort study conducted at 657 Florida nursing homes (pp. 1284-92). NH residents who had cancer, Alzheimer’s disease, dementia, and/or other diagnoses were studied; NH stays were grouped as short (90 days or less) or long. “Mean government expenditures in the last month of life were significantly less for hospice than nonhospice residents ($7,365; 95% confidence interval (CI) = $7,144–7586 vs $8,134; 95% CI = $7,896–8,372), but 1-month expenditures were only significantly lower for hospice residents with short NH stays, not for those with long NH stays,” the authors explain. (S. C. Miller, Susan_Miller@brown.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Aug. 5, 2004 Vol. 11, No. 150
Providing news and information about medications and their proper use

>>>Duloxetine Approved for Treating Major Depression
Duloxetine hydrochloride (Cymbalta, Lilly), a dual reuptake inhibitor active in both the serotonin and norepinephrine systems, has been approved by FDA for treatment of major depressive disorder in adults. The drug is also being studied for treatment of stress urinary incontinence and diabetic neuropathic pain, conditions believed to respond to treatment with central serotonin and norepinephrine enhancements.

Safety and efficacy of the new drug were established in placebo-controlled trials involving only adult patients. Duloxetine has not been studied for depression in children. Pharmacologic treatment of depression in younger patients remains controversial. Today’s Wall Street Journal, in a page 1 article, reports that a new analysis supports the views of an FDA staff member who found that 25 studies of nine drugs showed increased suicidality among children and teenagers. The staff member’s analysis was reportedly suppressed by FDA officials, and Congress is looking into the officials’ actions.

Depression, as a disease, can be associated with periods when the symptoms can worsen or thoughts of suicide can emerge, Lilly cautions in a news release. Patients and their families should monitor for and report to a physician suicidal symptoms as well as anxiety, agitation, panic, difficulty sleeping, irritability, hostility, aggressiveness, impulsivity, restlessness, or overexcitement, and hyperactivity, especially at the initiation of antidepressant drug therapy and during dose changes.

Duloxetine is contraindicated in patients hypersensitive to the drug or other ingredients in this product, those taking thioridazine, and patients who are taking or have recently taken MAO inhibitors. Precautions are needed in those with any hepatic insufficiency, end-stage renal disease, or uncontrolled narrow-angle glaucoma. Duloxetine ordinarily should not be prescribed to patients with substantial alcohol use, and the risk–benefit relationship should be considered before the drug is used in women who are pregnant. Nursing while taking duloxetine is not recommended.

In clinical studies, duloxetine’s most common adverse effects were nausea, dry mouth, constipation, decreased appetite, fatigue, sleepiness, and increased sweating.

>>>NEJM Highlights
Source:
Aug. 5 issue of the New England Journal of Medicine (content.nejm.org; 2004; 351).

Treatment-Resistant ALL: Differential expression of a relatively small number of genes determines drug resistance and treatment outcome in children with acute lymphoblastic leukemia, according to a study of leukemia cells from 173 children (pp. 533-42). “We identified sets of differentially expressed genes in B-lineage ALL that were sensitive or resistant to prednisolone (33 genes), vincristine (40 genes), asparaginase (35 genes), or daunorubicin (20 genes),” report the authors. “A combined gene-expression score of resistance to the four drugs, as compared with sensitivity to the four, was significantly and independently related to treatment outcome in a multivariate analysis (hazard ratio for relapse, 3.0; P = 0.027). Results were confirmed in an independent population of patients treated with the same medications (hazard ratio for relapse, 11.85; P = 0.019). Of the 124 genes identified, 121 have not previously been associated with resistance to the four drugs we tested.” (W. E. Evans, william.evans@stjude.org)

Spironolactone & Hyperkalemia: Publication of results from the Randomized Aldactone Evaluation Study (RALES) produced sustained increases in spironolactone use in patients with severe heart failure, and this led to an increase in hyperkalemia-associated morbidity and mortality without evidence of benefits, investigators report (pp. 543-51). In Ontario, hospitalizations for hyperkalemia quadrupled in the years after publication of RALES findings, and associated mortality jumped from 0.3 to 2.0 per 1,000 patients, accounting for an estimated 73 additional hospital deaths. But HF hospitalization rates and all-cause mortality did not decline. (D. N. Juurlink, Sunnybrook and Women’s College Health Sci. Ctr., Toronto; dnj@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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Aug. 6, 2004 Vol. 11, No. 151
Providing news and information about medications and their proper use

>>>Pharmacotherapy Update
Source:
Aug. Pharmacotherapy (www.accp.com; 2004; 24).

Inpatient Anticoagulation Management: Hospitals with pharmacist-provided heparin and warfarin management services have lower rates of all-cause mortality and morbidity as well as lower rates of bleeding-related morbidity, according to an analysis of Medicare hospitalizations in 1995 (pp. 953-63). Extending their previous studies on the impact of pharmacists’ services on inpatient deaths and adverse effects, Texas Tech researchers report these findings for the 717,396 Medicare patients who were treated in 955 hospitals: “In hospitals without pharmacist-provided heparin management, death rates were 11.41% higher (chi square(1) = 122.84, p < 0.0001), length of stay was 10.05% higher (Mann–Whitney U test = 40039529342, p < 0.0001), Medicare charges were 6.60% higher (U = 41004749266, p < 0.0001), bleeding complications were 3.1% higher (chi square(1) = 10.996, p = 0.0009) and the transfusion rate for bleeding complications was 5.47% higher (chi square(1) = 11.24, p = 0.0008) than in hospitals with pharmacist-provided heparin management. In hospitals without pharmacist-provided warfarin management, death rates were 6.20% higher (chi square(1) = 19.20, p < 0.0001), length of stay was 5.86% higher (U = 25730993838, p < 0.0001), Medicare charges were 2.16% higher (U = 259955112970, p < 0.0001), bleeding complications were 8.09% higher (chi square(1) = 49.259, p < 0.0001), and the transfusion rate for bleeding complications was 22.49% higher (chi square(1) = 78.68, p < 0.0001). Study hospitals without pharmacist-provided heparin management had 4664 more deaths, 494,855 more patient-days, 145 more patients with bleeding complications, and $651,274,844 more in patient charges; 9784 more units of whole blood were used in patients requiring transfusions for bleeding complications. Hospitals without pharmacist-provided warfarin management had 2786 more deaths, 316,589 more patient-days, 429 more patients with bleeding complications, and $234,275,490 more in patient charges; 8991 more units of whole blood were used in patients requiring transfusions for bleeding complications.” (C. A. Bond, cbond@ama.ttuhsc.edu)

Safety Warnings & Drug Use: For cisapride and troglitazone, numerous FDA-mandated safety warnings were required before drug use declined, especially for refills of prescriptions, conclude authors who studied Idaho Medicaid claims data from 1994 through July 2000 (pp. 978-86). Comparing the 5 months before each safety alert with the following 5 months, the investigators found, “Overall and new cisapride usage increased after the first alert, which occurred in February 1995 (p < 0.05). After the second alert, in September 1995, growth in new prescriptions ended but total prescriptions continued to grow (p < 0.05). After the third alert, in June 1998, growth in total use ended and the number of new prescriptions declined (p < 0.05). The final two alerts (June 1999 and January 2000) were met with significant declines (p < 0.05 for both). Troglitazone was the subject of two alerts in October and December 1997. After these, overall usage increased (p < 0.05), whereas the number of new prescriptions decreased (p < 0.05). The third alert, in July 1998, caused no change as total prescription use continued to grow (p < 0.05), whereas the number of new prescriptions decreased (p < 0.05). A fourth alert, in June 1999, resulted in a decrease of overall usage and new prescriptions (p < 0.05 for both).” (J. J. Wilkinson, jjwilkinson@southuniversity.edu)

Atomoxetine Review: The norepinephrine transport inhibitor atomoxetine “appears to be effective” in controlling the symptoms of attention-deficit/hyperactivity disorder with a sound safety and efficacy profile but without the controlled-substance restrictions of methylphenidate (pp. 1020-36). Authors write, “Clinical trials to evaluate the short-term effects of atomoxetine in children and adults have shown that atomoxetine is effective in maintaining control of ADHD. Likewise, long-term trials have determined that atomoxetine is effective in preventing relapse of ADHD symptoms without an increase in adverse effects.... Additional long-term studies are needed to determine its continued efficacy for those who require lifelong treatment....” (A. K. Christman, Med. U. of S.C., Charleston)

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Aug. 9, 2004 Vol. 11, No. 152
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
Aug. 7 issue of Lancet (www.thelancet.com; 2004; 364).

Comparison of Transplant Drugs: In transplant patients receiving cyclosporine, mycophenolate mofetil offers no advantage over the less-expensive azathioprine, according to a study of 336 recipients of cadaver kidneys (pp. 503-12). Acute rejections and adverse events were monitored over 6 months of treatment with one of the study drugs, cyclosporine, and steroids (phase A) and for 15 additional months on the same regimens without steroids (phase B). Equivalent percentages of patients had clinical rejections during phases A and B (34% and 35% on mycophenolate mofetil and azathioprine, respectively, during phase A, and 16% and 12% on the two respective drugs during phase B). Costs were significantly higher with mycophenolate mofetil (2,665 euros versus 184 euros during phase A and 5,095 euros versus 322 euros during phase B). “Standard immunosuppression regimens for transplantation should perhaps include azathioprine rather than mycophenolate mofetil, at least for kidney grafts,” the authors conclude. (P. Ruggenenti, Negri Bergamo Laboratories, Bergamo, Italy; manuelap@marionegri.it)

>>>BMJ Highlights
Source:
Aug. 7 issue of BMJ (www.bmj.org; 2004; 329).

Topical NSAIDs for OA: A meta-analysis of trials of topical NSAIDs used for treating patients with osteoarthritis finds little evidence of short-term benefits and no support for long-term use (pp. 324 ff). Based on findings of 18 randomized controlled trials, the authors report, “Topical NSAIDs were superior to placebo in relieving pain due to osteoarthritis only in the first two weeks of treatment. Effect sizes for weeks 1 and 2 were 0.41 (95% confidence interval, 0.16 to 0.66) and 0.40 (0.15 to 0.65), respectively. No benefit was observed over placebo in weeks 3 and 4. A similar pattern was observed for function, stiffness, and clinical response rate ratio and number needed to treat. Topical NSAIDs were inferior to oral NSAIDs in the first week of treatment and associated with more local side effects such as rash, itch, or burning (rate ratio 5.29, 1.14 to 24.51).” (W. Zhang, , U Nottingham, Nottingham, U.K.; weiya.zhang@nottingham.ac.uk)

>>>PNN JournalWatch
* Hospital at Home for Patients with Acute Exacerbations of Chronic Obstructive Pulmonary Disease: Systematic Review of Evidence, in BMJ, 2004; 329: 315 ff. Reprints: www.bmj.org; F. S. F. Ram, National Collaborating Centre for Women and Children’s Health, London; fsfram@yahoo.co.uk

* Managing Hyperkalemia Caused by Inhibitors of the Renin-Angiotensin-Aldosterone System,
in New England Journal of Medicine, 2004; 351: 585–92. Reprints: content.nejm.org; B. F. Palmer, U. Texas Southwestern Med. Sch., Dallas; biff.palmer@utsouthwestern.edu

* Attention-Deficit/Hyperactivity Disorder in Adults, in
JAMA, 2004; 292: 619–23. Reprints: www.jama.com; T. E. Wilens.

* Weight Management Through Lifestyle Modification for the Prevention and Management of Type 2 Diabetes: Rationale and Strategies, in
Diabetes Care, 2004; 27: 2067–73. Reprints: care.diabetesjournals.org; N. G. Clark, nclark@diabetes.org

* Approach to the Pathogenesis and Treatment of Nonalcoholic Steatohepatitis, in
Diabetes Care, 2004; 27: 2057–66. Reprints: care.diabetesjournals.org; R. Moreno-Otero, Hospital Universitario de la Princesa, Madrid, Spain; rmoreno.hlpr@salud.madrid.org

* High Prevalence of Adherent-Invasive Escherichia coli Associated with Ileal Mucosa in Crohn's Disease, in
Gastroenterology, 2004; 127: 412–21. Reprints: www2.gastrojournal.org; A. Darfeuille-Michaud, Centre Biomédical de Recherche et Valorisation, Clermont-Ferrand, France; arlette.darfeuille-michaud@u-clermont1.fr

* The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents, in
Pediatrics, 2004; 114: 555–76. Reprints: www.pediatrics.org; National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents.

* Evaluation and Treatment of the Human Immunodeficiency Virus-1-Exposed Infant, in
Pediatrics, 2004; 114: 497–505. Reprints: www.pediatrics.org; American Academy of Pediatrics Committee on Pediatric AIDS Infectious Diseases and Immunization Committee

* West Nile Virus and “Poliomyelitis,” in
Neurology, 2004; 63: 206–7. Reprints: www.neurology.org; J. J. Sejvar, zea3@cdc.gov

* Gender Differences in the Prescribing of Antipsychotic Drugs, in
American Journal of Psychiatry, 2004; 161: 1324–33. Reprints: ajp.psychiatryonline.org; M. V. Seeman.

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Aug. 10, 2004 Vol. 11, No. 153
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Aug. 9/23 issue of the Archives of Internal Medicine (www.archinternmed.com; 2004; 164).

Inappropriate Prescribing for the Elderly: In an analysis of outpatient prescription claims, one fifth of elderly patients were found to have had a prescription filled for a medication that should be avoided in older patients (pp. 1621-5). Using Beers’ criteria, researchers analyzed a PBM database, looking among 765,423 subjects for use of one or more medications that should be avoided those older than 65 years. They found, “A total of 162,370 subjects (21%) filled a prescription for 1 or more drugs of concern. Amitriptyline and doxepin accounted for 23% of all claims for Beers list drugs, and 51% of those claims were for drugs with the potential for severe adverse effects. More than 15% of subjects filled prescriptions for 2 drugs of concern, and 4% filled prescriptions for 3 or more of the drugs within the same year. The most commonly prescribed classes were psychotropic drugs and neuromuscular agents.” (K. A. Schulman, kevin.schulman@duke.edu)

An editorialist, calling for establishment of a system for reducing inappropriate prescribing, includes pharmacy as step 1 (pp. 1603-4): “One way to begin is to include pharmacists in the process of prescription writing in a more meaningful way. Since they usually have information about patients’ age, pharmacists could be required to question the use of certain drugs or dosages in the elderly. A physician might tire of receiving phone calls regarding prescriptions from patients, and patients might suspect that their physician was less than up to date if this happened repeatedly....

“Perhaps not all physicians should be able to prescribe all drugs. It does not seem the least unreasonable for those of us who are not oncologists to be prohibited from prescribing most drugs used by this group of physicians. Certainly, in the hospital setting I have limitations on what I can do. I am prohibited from delivering anesthetic agents, and I am not allowed to go to the neonatology unit and order medicines for a premature infant. Another approach would be to restrict some drugs from use in older persons just as they are in infants. Some sleeping pills, for example, should simply never be used in the elderly.” (K. Steel, Hackensack U. Med. Ctr., Hackensack, N.J.; 103106.1164@compuserve.com)

Short-Term Hormonal Therapy: Survival suffers when menopausal women use hormonal therapy, but quality-adjusted life expectancy (QALE) is improved in selected women whose symptoms are helped sufficiently by the drugs (pp. 1634-40). Using a Markov model to simulate the effects of 2 years of estrogen/progestin hormonal therapy, the researchers looked at life expectancy and QALE among hypothetical 50-year-old women with intact uteri. “Among asymptomatic women, short-term HT was associated with net losses in life expectancy and QALE of 1 to 3 months, depending on [cardiovascular disease (CVD)] risk,” the authors write. “Women with mild or severe menopausal symptoms gained 3 to 4 months or 7 to 8 months of QALE, respectively. Among women at low risk for CVD, HT extended QALE if menopausal symptoms lowered QOL by as little as 4%. Among women at elevated CVD risk, HT extended QALE only if symptoms lowered QOL by at least 12%.” (N. Col, Rhode Island Hosp., Providence; ncol@lifespan.org)

Length of Cellulitis Treatment: For patients with uncomplicated cellulitis, 5 days of levofloxacin 500 mg is just as effective as 10 days of the drug, according to an 87-patient study (pp. 1669-74). All patients received 5 days of therapy and were then randomized to either placebo or an additional 5 days of active treatment. Patients were excluded if they had worsening cellulitis, persistent nidus of infection, lack of any clinical improvement, or abscess formation within the first 5 days of therapy. A total of 98% of patients in each group responded, with resolution of cellulitis at 14 days and absence of relapse at 28 days. (M. J. Hepburn, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Md.; matthew.hepburn@det.amedd.army.mil)

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Aug. 11, 2004 Vol. 11, No. 154
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Aug. 11 issue of JAMA (www.jama.com; 2004; 292).

Bivalirudin & Gp IIb/IIIa Blockade During PCI: Long-term mortality was similar among 6,010 patients who received bivalirudin plus provisional glycoprotein IIb/IIIa blockade versus heparin plus planned Gp IIb/IIIa inhibition during percutaneous coronary interventions (pp. 696-703). During the PCI, patients received i.v. bivalirudin 0.75 mg/kg bolus followed by 1.75 mg/kg/hr plus provisional Gp IIb/IIIa inhibition or heparin 65 U/kg bolus with planned Gp IIb/IIIa inhibition (abciximab or eptifibatide). For 30 days after the PCI, all patients took a daily aspirin and a thienopyridine, and the researchers assessed outcomes at 6 and 12 months. “At 6 months, death occurred in 1.4% of patients in the heparin plus Gp IIb/IIIa group and in 1.0% of patients in the bivalirudin group (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.43–1.14; P = .15). Myocardial infarction occurred in 7.4% and 8.2% of patients, respectively (HR, 1.12; 95% CI, 0.93–1.34; P = .24), and repeat revascularization was required in 11.4% and 12.1% of patients, respectively (HR, 1.06; 95% CI, 0.91–1.23; P = .45). By 1 year, death occurred in 2.46% of patients treated with heparin plus Gp IIb/IIIa blockade and in 1.89% of patients treated with bivalirudin (HR, 0.78; 95% CI, 0.55–1.11; P = .16). Nonsignificant trends toward lower 1-year mortality with bivalirudin were present in all patient subgroups analyzed and were of greatest magnitude among high-risk patients.” (A. M. Lincoff, Cleveland Clinic Foundation, Cleveland; lincofa@ccf.org)

Varicella Contagiousness After Vaccination: The contagiousness of varicella-vaccinated patients is about one half that among unvaccinated people who have the infection, conclude researchers who studied 6,316 varicella cases (pp. 704-8). In Los Angeles County between 1997 and 2001, analysis of the varicella secondary attack rate and effectiveness of the varicella vaccine showed, “Among children and adolescents aged 1 to 14 years, secondary attack rates varied according to age and by disease and vaccination status of the primary case and exposed household contacts. Among contacts aged 1 to 14 years exposed to unvaccinated cases, the secondary attack rate was 71.5% if they were unvaccinated and 15.1% if they were vaccinated (risk ratio [RR], 0.21; 95% confidence interval [CI], 0.15–0.30). Overall, vaccinated cases were half as contagious as unvaccinated cases. However, vaccinated cases with 50 lesions or more were similarly contagious as unvaccinated cases whereas those with fewer than 50 lesions were only one third as contagious (secondary attack rate, 23.4%; RR, 0.32 [95% CI, 0.19– 0.53]). Vaccine effectiveness for prevention of all disease was 78.9% (95% CI, 69.7%–85.3%); moderate disease, 92% (50–500 lesions) and 100% (clinician visit); and severe disease, 100%.” (J. F. Seward, jseward@cdc.gov)

Streptococcal Vaccine Evaluation: Preliminary evaluation in 28 healthy volunteers of a recombinant fusion peptide group A streptococcal vaccine containing N-terminal M protein fragments from serotypes 1, 3, 5, 6, 19, and 24 provides encouraging evidence of immunogenicity without cross-reactivity with host tissues (pp. 709-15). Among the adults, sequential intramuscular doses of 50, 100, or 200 mcg were well tolerated during 1 year of intensive follow-up. “There was no evidence of tissue cross-reactive antibodies or immunological complications. At the highest (200 µg) dose, vaccination elicited significant increases in geometric mean antibody levels to all 6 component M antigens by ELISA (all P < .01) and to 5 of 6 M types in the opsonophagocytosis assay (all P < .05). In addition, postvaccination increases in serum bactericidal activity of at least 30% were observed in 31 (55%) of 56 assays.” (K. L. Kotloff, kkotloff@medicine.umaryland.edu)

Acne Therapy: Combination therapy is often needed for adequate management of acne vulgaris, according to authors of a review article (pp. 726-35). They conclude, “Patients may require adjustment of therapies depending on their degree of improvement and level of tolerance to the treatments.” (J. C. Shaw, Toronto Western Hosp., Toronto; james.shaw@uhn.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Aug. 12, 2004 Vol. 11, No. 155
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Aug. 12 issue of the New England Journal of Medicine (content.nejm.org; 2004; 351).

Insect-Sting Allergy: The idea that children “outgrow” allergic reactions to insect stings is not correct, according to a research study that included 1,033 patients who were initially diagnosed between 1978 and 1985 (pp. 668-74). But venom immunotherapy in 356 patients was beneficial, with decreased risk of systemic reaction to stings persisting for at least 10–20 years after treatment ended, the authors note. “Of the 1033 patients, 512 patients (50 percent) responded [to telephone and mailed surveys in 1997–2000], with a mean follow-up period of 18 years, a mean duration of venom immunotherapy of 3.5 years in treated patients, and an incidence of stings of 43 percent. Systemic reactions occurred less frequently in patients who had received venom immunotherapy (2 of 64 patients, or 3 percent) than in untreated patients (19 of 111 patients, or 17 percent; P = 0.007). Patients with a history of moderate-to-severe reactions had a higher rate of reaction if they had not been treated (7 of 22 patients, or 32 percent) than if they had received venom immunotherapy (2 of 43 patients, or 5 percent; P = 0.007). In patients who had been treated and who had a history of mild (cutaneous) systemic reaction (i.e., one with only cutaneous manifestations), none of the 21 subjects who received stings had a systemic reaction.”(D. B. K. Golden, Johns Hopkins Asthma and Allergy Ctr., Baltimore; dgolden1@jhmi.edu)

An editorialist, explaining that children have often not received immunotherapy because of the idea that they would outgrow insect-sting allergies, proposes a new standard of care (pp. 707-9): “For most children who have systemic allergic reactions to insect stings—that is, those with dermatologic manifestations only—venom immunotherapy is not warranted. However, for the small percentage of children who have more severe sting-induced systemic allergic reactions, there is a high likelihood that they will have similar severe reactions if they receive subsequent stings. It is to be hoped that now, with hard data provided, physicians will be able to move beyond misconceptions and support the use of venom immunotherapy for the children most at risk.” (R. S. Gruchalla, U. Texas Southwestern Med. Ctr., Dallas)

Generalized Anxiety Disorder: In a clinical practice article, an author describes emergence of SSRIs and venlafaxine as first-line agents in management of patients with generalized anxiety disorder and anxiety as a component of depression (pp. 675-82): “In patients who present with anxiety as a symptom, medical causes, such as hyperthyroidism, require consideration, as do common coexisting illnesses such as major depression, panic disorder, and substance abuse. For generalized anxiety alone or anxiety that is associated with depression, a reasonable first-line approach is to administer an SSRI or extended-release venlafaxine on the basis of the demonstrated efficacy of these drugs and their generally favorable side-effect profiles. To minimize side effects, particularly restlessness, one would start with a low dose and then increase it during the next three weeks or so until the target dose is reached....

“A four-to-five-week course of a benzodiazepine (e.g., clonazepam, given at a dose of 0.25 to 0.5 mg twice daily) may also be useful in reducing restlessness related to antidepressant therapy and in rapidly controlling anxiety. One would taper this dose during the next two to four weeks. Patients who prefer a nonpharmacologic approach should be referred for cognitive behavioral therapy and relaxation training. These therapies may also be useful in patients who take medication, although data are limited.” (G. Fricchione, Mass. Genl. Hosp., Boston)

von Willebrand’s Disease: Drugs for von Willebrand’s disease are detailed in a review article (pp. 683-94): “Desmopressin and plasma concentrates are effective in controlling bleeding in most patients with the disease. Even though virus-inactivated products appear to have an acceptable level of safety, it is hoped that the von Willebrand factor that is produced by recombinant DNA techniques will soon undergo clinical trials and become available for replacement therapy.” (P. M. Mannucci, U. Milan, Milan, piermannuccio.mannucci@unimi.it)

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Aug. 13, 2004 Vol. 11, No. 156
Providing news and information about medications and their proper use

>>>Pediatrics Highlights
Source:
Aug. issue of Pediatrics (www.pediatrics.org; 2004; 114).

Treating Otitis Media:
Assessment of local resistance patterns among Streptococcus pneumoniae can enable pediatricians in some areas to use standard doses of amoxicillin for treating acute otitis media, conclude authors of a study conducted in St. Louis (pp. 342-7). By collecting nasal swabs from children younger than 7 years who had AOM and were seen by seven community pediatricians, the researchers determined the cross-sectional prevalence S. pneumoniae that were nonsusceptible to penicillin (NSSP; strains with a minimum inhibitory concentration of 0.12 mcg/mL) and nonsusceptible to standard-dose amoxicillin (NSSP-A; penicillin MIC >2 mcg/mL). After finding higher prevalence of NSSP-A only among child care attendees, the authors conclude, “In our community, although the prevalence of NSSP among isolates of S pneumoniae identified from the nasopharynx of symptomatic children is high (48%), the probability of NSSP-A infection among symptomatic children is <5%. Our data support a recommendation to treat most children who have uncomplicated AOM with standard-dose amoxicillin. Children who attend child care or have recently received an antibiotic may require treatment with high-dose amoxicillin. Other communities may benefit from a similar assessment of the prevalence of NSSP and NSSP-A.” (J. Garbutt, Washington U., St. Louis)

Fracture Risk with Inhaled Steroids:
Children and adolescents on long-term inhaled corticosteroids do not have an increased risk of fracture, according to an analysis of the U.K.’s General Practice Research Database (pp. 469-73). Among 3,744 cases (patients with fractures) and 21,757 matched control subjects aged 5 to 17 years, the authors found, “Current exposure to inhaled steroids did not reveal a substantially altered fracture risk compared with nonusers, even in individuals with current longer term exposure (ie, 20 prescriptions; adjusted odds ratio 1.15; 95% confidence interval: 0.89– 1.48). In individuals with current or previous exposure to oral steroids, the adjusted odds ratio for current long-term inhaled steroid use compared with nonusers was 1.21 (95% confidence interval: 0.99– 1.49).” (R. G. Schlienger, U. Hosp. Basel, Switzerland)

CEA of Nitric Oxide in Neonates: For treating persistent pulmonary hypertension of the newborn, inhaled nitric oxide is cost effective but not cost saving, according to a decision-analysis model used to evaluate incremental cost-effectiveness ratios (pp. 417-26). Using 2001 dollars and a societal perspective, the investigators calculated, “The addition of iNO to the treatment regimen of PPHN increased the cost of treating an infant by an average of $1,141, primarily from an increased number of mechanical ventilation days. Use of iNO led to 3.4% more lives saved and a 6% increase in the average utility gained per infant. The incremental cost-effectiveness ratio was $33,234 per life saved and $19,022 per quality-adjusted life year gained.” In a probabilistic sensitivity analysis, 3.6% of trials found iNO more expensive with a worse outcome than conventional therapy, compared with 35.7% of trials that found lower expenses and better outcomes with iNO. (S. A. Lorch, Children’s Hosp., Philadelphia)

>>>PNN NewsWatch
* The pharmacist shortage has lessened considerably in supermarket pharmacies, reports the Food Marketing Institute in its Report from the 2004 Supermarket Pharmacy Survey. Only 13% of food retail companies reported the need to reduce pharmacy hours due to a lack of pharmacist staffing in 2003, down 33.3% from the year before. Survey respondents attributed the decline to improved recruiting and training, enhanced compensation packages and an increase in the number of graduates (www.fmi.org/pub).

*
Traces of Prozac have been found in the British water supply, sparking concerns among the public about “pharmacy residues in ... drinking water,” according to lay media reports. Reuters reported that “experts say that Prozac finds its way into rivers and water systems from treated sewage water, and some believe the drugs could affect reproductive ability.”

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Aug. 16, 2004 Vol. 11, No. 157
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Advance online publications and Aug. 14 issue of BMJ (www.bmj.org; 2004; 329).

MAO Type B Inhibitors for PD: Disability, need for levodopa, and incidence of motor fluctuations are reduced in patients with Parkinson’s disease through treatment with monoamine oxidase type B inhibitors, according to a meta-analysis of 17 clinical trials (published early online). “Patients randomised to MAOBIs had significantly better total scores, motor scores, and activities of daily living scores on the unified Parkinson's disease rating scale at three months compared with patients taking placebo; they were also less likely to need additional levodopa (0.57, 0.48 to 0.67; P < 0.00001) or to develop motor fluctuations (0.75, 0.59 to 0.95; P = 0.02),” the authors write. “No difference existed between the two groups in the incidence of side effects or withdrawal of patients.” Despite the positive findings, larger and longer comparative trials are needed, the article concludes. (N. J. Ives, U. Birmingham, Birmingham, U.K.)

Mortality Reduction by Influenza Vaccine:
A prospective cohort study provides “robust evidence” of reduced mortality among elderly patients vaccinated against influenza during periods of high circulation of the virus (published early online). Among 24,535 British patients older than 75 years, the authors found, “In unvaccinated members of the cohort daily all cause mortality was strongly associated with an index of influenza circulating in the population (mortality ratio 1.16, 95% confidence interval 1.04 to 1.29 at 90th centile of circulating influenza). The association was strongest for respiratory deaths but was also present for cardiovascular deaths. In contrast, in vaccinated people mortality from any cause was not associated with circulating influenza. The difference in patterns between vaccinated and unvaccinated people could not easily be due to chance (P = 0.02, all causes).” (B. G. Armstrong, London School of Hygiene and Tropical Medicine, London)

Adverse Events in Hospitals: Some 2.2% of all hospital episodes mention an adverse event, totaling 4,000 misadventures annually, according to statistics from the U.K. over a 4-year period (pp. 369 ff). “Events were more likely to occur in men, in elderly people, and in emergency admissions,” the investigators report. “The differences may be due in part to the severity of underlying disease in the different groups and the length of time people are in hospital. ” (P. Aylin, Imperial Coll., London)

>>>Lancet Report
Source:
Aug. 14 issue of Lancet (www.thelancet.com; 2004; 364).

Drug-Eluting Stents: Continuing uncertainty about drug-eluting stents is evident in a Bayesian meta-analysis of 11 controlled comparisons of the new devices with bare-metal stents (pp. 583-91). “Sirolimus-eluting and polymeric paclitaxel-eluting stents are effective at decreasing rates of angiographic restenosis and major adverse cardiac events compared with BMS,” the authors conclude. “However, there is no evidence that they affect mortality or myocardial-infarction rates. They also appear to be safe in the short to medium term, although definitive conclusions are not possible. Larger studies with longer follow-up are needed to define better the role of these new devices.” (M. J Eisenberg, Jewish General Hosp./McGill U., Montreal; marke@epid.jgh.mcgill.ca )

>>>PNN JournalWatch
* Challenges in the Design of Antibiotic Equivalency Studies: The Multicenter Equivalency Study of Oral Amoxicillin versus Injectable Penicillin in Children Aged 359 Months with Severe Pneumoni, in Clinical Infectious Diseases, 2004; 39: 526–31. Reprints: www.journals.uchicago.edu/CID; P. L. Hibberd, Tufts–New England Med. Ctr., Boston.

* Sexually Transmitted Infections in Travelers: Implications for Prevention and Control ,
in Clinical Infectious Diseases, 2004; 39: 533–8. Reprints: www.journals.uchicago.edu/CID; A.S.M. Abdullah, U. Hong Kong, Pokfulam, Hong Kong.

* High Prevalence of Adherent-Invasive
Escherichia coli Associated with Ileal Mucosa in Crohn's Disease, in Gastroenterology, 2004; 127: 412–21. Reprints: www2.gastrojournal.org; A. Darfeuille-Michaud, Centre Biomédical de Recherche et Valorisation, Clermont-Ferrand, France; arlette.darfeuille-michaud
@u-clermont1.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Aug. 17, 2004 Vol. 11, No. 158
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Aug. 17 issue of the Annals of Internal Medicine (www.annals.org; 2004; 141).

Stockings for DVT: In 180 patients with first episodes of symptomatic proximal deep-vein thrombosis who were on anticoagulants, addition of below-knee compression elastic stockings reduced the rate of post-thrombotic sequelae by 50%, investigators report (pp. 249-56). In a university hospital, patients were randomly assigned to unblinded use of full-strength stockings (30–40 mm Hg at the ankle) or no stockings for 2 years, and follow-up continued for 5 years. “Post-thrombotic sequelae developed in 44 of 90 controls (severe in 10) and in 23 of 90 patients wearing elastic stockings (severe in 3),” the research group notes. “All but 1 event developed in the first 2 years. The cumulative incidence of the post-thrombotic syndrome in the control group versus the elastic stockings group was 40.0% (95% CI, 29.9% to 50.1%) versus 21.1% (CI, 12.7% to 29.5%) after 6 months, 46.7% (CI, 36.4% to 57.0%) versus 22.2% (CI, 13.8% to 30.7%) after 1 year, and 49.1% (CI, 38.7% to 59.4%) versus 24.5% (CI, 15.6% to 33.4%) after 2 years. After adjustment for baseline characteristics, the hazard ratio for the post-thrombotic syndrome in the elastic stockings group compared with controls was 0.49 (CI, 0.29 to 0.84; P = 0.011).” (P. Prandoni, U. Hosp., Padua, Italy; paoloprandoni@tin.it)

In an accompanying article, an editorialist suggests use of full-strength stockings like those used in this study primarily in patients whose symptoms persist or worsen or when ulceration seems imminent (pp. 314-5). “However, if symptoms subside and the patient remains asymptomatic or has only trivial persistent signs or symptoms with little or no effect on quality of life (for example, venous ectasia or mild ankle swelling at the end of the day), stockings can be avoided and the patient can be followed for clinically important signs and symptoms of the post-thrombotic syndrome,” the writer concludes. ( J. S. Ginsberg, McMaster U., Hamilton, Ontario, Canada)

Diabetes Care in the VA: Care of patients with diabetes was significantly better at 5 Veterans Affairs medical centers than in a 8 comparable commercial managed care organizations, according to a cross-sectional patient survey and retrospective review of medical records (pp. 272-81). Among 1,285 VA patients and 6,920 commercial managed-care patients, researchers found: “Patients in the VA system had better scores than patients in commercial managed care on all process measures (for example, 93% vs. 83% for annual hemoglobin A1c; P = 0.006; 91% vs. 75% for annual eye examination; P < 0.001). Blood pressure control was poor in both groups (52% to 53% of persons had blood pressure < 140/90 mm Hg), but patients in the VA system had better control of low-density lipoprotein cholesterol and hemoglobin A1c (for example, 86% vs. 72% for low-density lipoprotein cholesterol level < 3.37 mmol/L [<130 mg/dL]; P = 0.002). Satisfaction was similar in the 2 groups.” (E. A. Kerr, ekerr@umich.edu)

“The progress made by the VA, other closed health care systems, and the quality assessment community reflects a steady evolution toward optimal management of chronic diseases,” an editorialist observes (pp. 316-8). “In these settings, determined leadership, focused interventions to improve care and programs to advance evaluation science, systematically applied uniform performance standards, and incentives to improve care produced measurable and meaningful benefits for patients. Can the broader, less organized U.S. health care delivery system learn from the experience of these organizations? Extending these ‘mega-system’ quality improvement programs into the microenvironments of solo and small group practices, where most chronic disease care in the United States occurs, is a more serious challenge..... Meeting these challenges will bring us closer to the goal that John Eisenberg so eloquently advocated—to translate scientific research into the everyday practice of medicine in ways that improve and support quality care for all patients in every U.S. health care setting.” (S. Greenfield, U. California, Irvine)

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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Aug. 18, 2004 Vol. 11, No. 159
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Aug. 18 issue of JAMA (www.jama.com; 2004; 292).

Treatment of Adolescent Depression: For adolescents with major depressive disorder, combined therapy with fluoxetine and cognitive-behavioral therapy was the best of four options, according to the 12-week Treatment for Adolescents with Depression Study (TADS) of 439 patients (pp. 807-20). At 13 U.S. academic and community clinics in 2000–03, volunteers aged 12–17 years were randomly assigned to receive 12 weeks of fluoxetine 10–40 mg/day, CBT alone, CBT plus fluoxetine, or placebo. “Compared with placebo, the combination of fluoxetine with CBT was statistically significant (P = .001) on the Children's Depression Rating Scale-Revised,” the authors report. “Compared with fluoxetine alone (P = .02) and CBT alone (P = .01), treatment of fluoxetine with CBT was superior. Fluoxetine alone is a superior treatment to CBT alone (P = .01). Rates of response for fluoxetine with CBT were 71.0% (95% confidence interval [CI], 62%–80%); fluoxetine alone, 60.6% (95% CI, 51%–70%); CBT alone, 43.2% (95% CI, 34%–52%); and placebo, 34.8% (95% CI, 26%–44%). On the Clinical Global Impressions improvement responder analysis, the 2 fluoxetine-containing conditions were statistically superior to CBT and to placebo. Clinically significant suicidal thinking, which was present in 29% of the sample at baseline, improved significantly in all 4 treatment groups. Fluoxetine with CBT showed the greatest reduction (P = .02). Seven (1.6%) of 439 patients attempted suicide; there were no completed suicides.” (J. S. March, jsmarch@acpub.duke.edu)

A journal editor comments on these findings (pp. 861-3): “Probably the most important message from TADS is that carefully assessed, empirically validated treatments are available for adolescents with major depression. A corollary of that message is that depressive illness is a major public health problem with substantial morbidity and mortality for adolescents as well as for adults. The results from this major new trial demonstrate that although treatment of a depressive illness is often successful and gratifying for patients and clinicians, such success typically requires more than a brief visit for prescription of medication. Rather, it requires careful assessment and monitoring in the context of an ongoing patient-physician relationship. Furthermore, the current evidence suggests that the likelihood of a good outcome is enhanced by the combination of appropriate and carefully monitored drug treatment with an empirically validated psychotherapy.” (R. M. Glass, richard_glass@jama-archives.org)

Treatment of Prostate Cancer: Six months of androgen suppression therapy might be enough to provide an added survival benefit to radiation therapy in men with localized prostate cancer, conclude investigators who tested the possibility of avoiding 3 years of AST and its associated adverse effects (pp. 821-7). Comparing 3-dimensional conformal radiation therapy alone or in combination with 6 months of AST, the researchers found: “After a median follow-up of 4.52 years, patients randomized to receive 3D-CRT plus AST had a significantly higher survival (P = .04), lower prostate cancer-specific mortality (P = .02), and higher survival free of salvage AST (P = .002). Kaplan–Meier estimates of 5-year survival rates were 88% (95% confidence interval [CI], 80%–95%) in the 3D-CRT plus AST group vs 78% (95% CI, 68%–88%) in the 3D-CRT group. Rates of survival free of salvage AST at 5 years were 82% (95% CI, 73%–90%) in the 3D-CRT plus AST group vs 57% (95% CI, 46%–69%) in the 3D-CRT group.” (A. V. D’Amico,
adamico@lroc.harvard.edu)

Vitamin E & Respiratory Tract Infections: In 451 nursing home residents, vitamin E 200 IU/day supplements had no effect on incidence of lower respiratory tract infections, but upper RT infections, especially the common cold, were reduced in frequency (pp. 828-36). Compared with placebo over the 2-year trial, vitamin E reduced the risk of acquiring one or more RT infections by 12% and the incidence of common colds by 17%. The authors recommend more study of the effects of vitamin E on upper RT infections. (S. N. Meydani, simin.meydani@tufts.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Aug. 19, 2004 Vol. 11, No. 160
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Aug. 18 issue of Diabetes Care (care.diabetesjournals.org; 2004; 27).

Treating DKA with Insulin Aspart: In 45 patients with uncomplicated diabetic ketoacidosis, subcutaneous doses of insulin aspart given every 1 or 2 hours were as effective and safe as intravenous infusions of regular insulin (pp. 1873-8). Based on duration of treatment until resolution of hyperglycemia and ketoacidosis, the researchers report: “Admission biochemical parameters in patients treated with [insulin aspart] SC-1h (glucose: 44 ± 21 mmol/l [means ± SD], bicarbonate: 7.1 ± 3 mmol/l, pH: 7.14 ± 0.09) were similar to those treated with [insulin aspart] SC-2h (glucose: 42 ± 21 mmol/l, bicarbonate: 7.6 ± 4 mmol/l, pH: 7.15 ± 0.12) and IV regular insulin (glucose: 40 ± 13 mmol/l, bicarbonate 7.1 ± 4 mmol/l, pH: 7.11 ± 0.17). There were no statistical differences in the mean duration of treatment until correction of hyperglycemia (6.9 ± 4, 6.1 ± 4, and 7.1 ± 5 h) or until resolution of ketoacidosis (10 ± 3, 10.7 ± 3, and 11 ± 3 h) among patients treated with SC-1h and SC-2h or with IV insulin, respectively (NS). There was no mortality and no differences in the length of hospital stay, total amount of insulin administration until resolution of hyperglycemia or ketoacidosis, or the number of hypoglycemic events among treatment groups.” (G. Umpierrez, geumpie@emory.edu)

Early Sartan Therapy: In patients with type 2 diabetes, hypertension, and renal disease, early supplementation of standard care with irbesartan can improve life expectancy and reduce costs, according to a Markov-model simulation (pp. 1897-903). Assuming a progression from microalbuminuria to overt nephropathy, doubling of serum creatinine, end-stage renal disease, and death in hypertensive patients with type 2 diabetes, the authors compared early irbesartan 300 mg daily (initiated with microalbuminuria) and late irbesartan (initiated with overt nephropathy). They found, “Compared with control, early and late irbesartan treatment in 1,000 patients were projected to save (mean ± SD) $11.9 ± 3.3 million and $3.3 ± 2.7 million, respectively. Early use of irbesartan added 1,550 ± 270 undiscounted life–years (discounted 960 ± 180), whereas late irbesartan added 71 ± 40 life–years (discounted 48 ± 27) in 1,000 patients. Early irbesartan treatment was superior under a wide-range of plausible assumptions.” (A. J. Palmer, CORE-Ctr. for Outcomes Research, Binningen/Basel, Switzerland; ap@thecenter.ch)

Accuracy of Continuous Glucose Sensors: Continuous monitoring of glucose levels in patients with diabetes provides important information that is not captured by traditional self-monitoring approaches, according to a study that introduces continuous glucose-error grid analysis (CG-EGA) as a method of evaluating the accuracy of continuous glucose-monitoring sensors (pp. 1922-8). Testing the TheraSense Freestyle Navigator, the investigators note, “CG-EGA revealed that the accuracy of the Navigator, measured as a percentage of accurate readings plus benign errors, was significantly different at hypoglycemia (73.5%), euglycemia (99%), and hyperglycemia (95.4%). Failure to detect hypoglycemia was the most common error. The point accuracy of the Navigator was relatively stable over a wide range of BG rates of change, and its rate accuracy decreased significantly at high BG levels.” (B. Kovatchev, boris@virginia.edu)

Lipoprotein Predictors in Diabetes: Non-HDL cholesterol and apoB levels are better predictors of cardiovascular disease in men with diabetes than is the more commonly used LDL cholesterol, conclude investigators in the Health Professionals’ Follow-up Study (pp. 1991-7). In 746 diabetic men who were aged 46–81 years and free of CVD or cancer in 1993–94, “The ratio of total to HDL cholesterol is the best predictor of CVD in this cohort of diabetic men,” the authors state. “After adjustment for age, BMI, and other lifestyle risk factors, the multivariate [relative risk] of CVD (the highest versus the lowest quartile) was 2.34 (95% CI 1.26-4.32) for non-HDL cholesterol, 2.31 (1.23-4.35) for apoB, and 1.74 (0.99-3.06) for LDL cholesterol.” (R. Jiang, rjiang@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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Aug. 20, 2004 Vol. 11, No. 161
Providing news and information about medications and their proper use

>>>Psychiatry Highlights
Source:
Aug. issue of the American Journal of Psychiatry (ajp.psychiatryonline.org; 2004; 161).

Gender Differences in Antipsychotic Prescribing: Maintenance dosage regimens of antipsychotic agents need to be customized based on gender, argues an author who reviewed recent literature (pp. 1324-33). “The pharmacokinetics and pharmacodynamics of antipsychotic drugs differ in women and men and are influenced by gender-specific factors such as body build, diet, smoking, concurrent medication, exercise, substance use, and hormonal transitions,” she explains. “In general, and for some drugs in particular, women require lower doses in order to stay well. Because preliminary drug testing is not done in pregnant women, the issue of effective dosing during pregnancy is unstudied, and safety for fetuses and nursing infants may not become evident until a drug is widely used. Specific adverse effects on issues crucial to women (e.g., parenting) have not been well studied, but some side effects, such as weight gain, passivity, hypotension, and hyperprolactinemia, are reported to be particularly problematic for women. Some serious side effects are more often seen among women than among men.” (V. Seeman)

Psychotropic Medication Use & 9/11: While most of the nation did not increase usage of psychotropic medications in the wake of the September 11 terrorist attacks, doses of these medications were increased for a statistically significant but modest proportion of residents of New York City (pp. 1377-83). Data from two large pharmacy databases were analyzed for use of antidepressant, antipsychotic, anxiolytic, and hypnotic medications in the 12 weeks before and after Sept. 11, 2001, compared with the same weeks during 2000. The investigators found, “Nationally and in Washington, D.C., there was no evidence of an increase in overall prescriptions, new prescriptions, or daily doses for psychotropic medications. In New York City, there was an increase in the proportion of existing users with psychotropic dose increases in the weeks after the attacks (16.9% in 2001 versus 13.6% in 2000) but no significant increase in the rate of new psychotropic prescriptions.” (B. G. Druss)

ACTH, Dexamethasone, & PTSD: Enhanced cortisol negative feedback inhibition of the pituitary gland resulting in decreased adrenal secretion of adrenocorticopic hormone appears to be the mechanism for paradoxical observations in patients with posttraumatic stress disorder (pp. 1394-403). Medical researchers have wondered why PSTD patients have increased release of corticotropin-releasing factor but low cortisol levels. In 15 men and 4 women with PTSD and 14 men and 5 women with no psychiatric disorders, ACTH and cortisol responses to dexamethasone 0.5 mg were assessed. “The ACTH-to-cortisol ratio did not differ between groups before or after dexamethasone, but the subjects with PTSD showed greater suppression of ACTH (as well as cortisol) in response to dexamethasone,” the authors report. “The data support the hypothesis of enhanced cortisol negative feedback inhibition of ACTH secretion at the level of the pituitary in PTSD. Pituitary glucocorticoid receptor binding, rather than low adrenal output, is implicated as a likely mechanism for this effect.” (R. Yehuda)

>>>PNN NewsWatch
* Approved in Feb. for treatment of mesothelioma, pemetrexed disodium (Alimta, Lilly) has received FDA’s OK for an additional indication, treatment of locally advanced or metastatic nonsmall-cell lung cancer in previously treated patients. The drug is an antifolate agent that simultaneously blocks three separate enzyme targets in cancer cells. It is administered with folic acid and vitamin B12 supplements.

* FDA is working on more specific warnings for
labels of antidepressant medications that will focus on increased suicidality risks in children and adolescents, the Wall Street Journal reports this morning. An advisory committee meeting next month will consider language that goes beyond the warnings developed in March for all 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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Aug. 23, 2004 Vol. 11, No. 162
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
Aug. 21 issue of Lancet (www.thelancet.com; 2004; 364).

COX-2 Inhibitors & GI Events: Compared with ibuprofen or naproxen, lumiracoxib reduced ulcer complications by 3- to 4-fold among 18,325 patients with osteoarthritis (pp. 665-74). In the 52-week Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), patients aged 50 years and older who were free of serious cardiovascular disease took lumiracoxib 400 mg once daily, naproxen 500 mg twice daily, or ibuprofen 800 mg three times daily. The authors report, “In patients not taking aspirin, the cumulative 1-year incidence of ulcer complications was 1.09% (95% CI 0.82–1.36) with non-steroidal anti-inflammatory drugs (64 events) versus 0.25% (95% CI 0.12–0.39) with lumiracoxib (14 events; hazard ratio 0.21 [95% CI 0.12–0.37], p < 0.0001). Reductions in ulcer complications were also significant in the overall population (0.34 [0.22–0.52], p < 0.0001) but not in those taking aspirin (0.79 [0.40–1.55], p = 0.4876). In the overall population, 0.55% (50/9127) of those on non-steroidal anti-inflammatory drugs and 0.65% (59/9117) of those on lumiracoxib reached the cardiovascular endpoint (1.14 [0.78–1.66], p = 0.5074).” (C. J. Hawkey, U. Hosp., Nottingham, U.K.; cj.hawkey@nottingham.ac.uk)

In a safety analysis of data from this study, the investigators found that the incidence of myocardial infarction and other cardiovascular events did not differ between the COX-2 and nonselective NSAID arms of the study (pp. 675-84). Rates of of nonfatal and silent myocardial infarction, stroke, or cardiovascular death were statistically similar among patients assigned to lumiracoxib, naproxen, and ibuprofen, regardless of low-dose aspirin use. (M. E. Farkouh, michael.farkouh@med.nyu.edu)

However, editorialists maintain that the overall picture for coxibs remains unclear because of a lack of data on patients with cardiac problems (pp. 639-40): “The US regulatory agency [FDA] has been remiss in not requiring coxib manufacturers to undertake dedicated trials in patients with established cardiovascular disease—a public health problem of great magnitude—for which there are theoretical coxib anti-inflammatory benefits or harms. The continued commercial availability of rofecoxib without a black-box warning for cardiovascular patients is indeed troubling. The coxib debate will not go away until safety and efficacy questions are answered; if only a small fraction of the direct-to-consumer advertising costs or revenue were appropriately channeled for clinical trials, we might be able to have an enhanced perspective and make sound recommendations for our patients.” (E. J. Topol, Cleveland Clinic Foundation, Cleveland; topole@ccf.org)

Atorvastatin & DM: In patients with diabetes mellitus type 2 but no pre-existing cardiovascular disease, atorvastatin 10 mg daily reduces the incidence of stroke and other cardiovascular events, compared with placebo (pp. 685-96). The 2,838 patients in the study had LDL-cholesterol levels of 160 mg/dL or lower, fasting triglyceride levels of 600 mg/dL or less, and histories of at least one of the following: retinopathy, albuminuria, current smoking, or hypertension. During a median follow-up period of 3.9 years, rates of acute coronary heart disease events, coronary revascularisation, or stroke were 2.46 and 1.54 per 100 person–years among those on placebo and atorvastatin, respectively. Overall, 37 major cardiovascular events would be prevented by atorvastatin, and the mortality rate reduced by 27%. (H. M. Colhoun, U. Coll., Dublin; helen.colhoun@ucd.ie)

>>>PNN JournalWatch
* Using the NO TEARS Tool for Medication Review, in BMJ, 2004; 329: 434 ff. Reprints: www.bmj.org; T. Lewis, Carreg Wen Surgery, Torfaen, U.K.; Tessa.Lewis@gp-w93015.wales.nhs.uk

* Effectiveness of a Multiple Intervention To Reduce Antibiotic Prescribing for Respiratory Tract Symptoms in Primary Care, in
BMJ, 2004; 329: 431 ff. Reprints: www.bmj.org; I. Welschen, U. Med. Ctr., Utrecht, the Netherlands; i.welschen@med.uu.nl

* Update on Statins: 2003, in
Circulation, 2004; 110: 886–92. Reprints: circ.ahajournals.org; C. J. Vaughan.

* Primary Care Guidelines for the Management of Persons Infected with Human Immunodeficiency Virus: Recommendations of the HIV Medicine Association of the Infectious Diseases Society of America, in
Clinical Infectious Diseases, 2004; 39: 609–29. Reprints: www.journals.uchicago.edu/ CID; J. A. Aberg, judith.aberg@med.nyu.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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Aug. 24, 2004 Vol. 11, No. 163
Providing news and information about medications and their proper use

>>>Neurology Highlights
Source:
Aug. 24 Neurology (www.neurology.org; 2004; 63).

Economics of Donepezil in AD: In 290 patients with moderate or severe Alzheimer’s disease, addition of donepezil 5–10 mg/day provided economic benefits, largely as a result of less use of residential care and less caregiver time for activities of daily living (pp. 644-50). In a cost-consequence analysis that compared active and placebo therapy over 24 weeks, investigators found, “After adjusting for baseline total cost per patient, the mean total societal cost per patient for the 24-week period was donepezil, Can $9,904 (US $6,686) and placebo, Can $10,236 (US $6,910). This net cost saving of Can $332 (US $224) included the average 24-week cost of donepezil treatment.” (H. Feldman, UBC Hosp., Vancouver; hfeldman@interchange.ubc.ca)

Donepezil for Mild Cognitive Impairment: In 270 patients with mild cognitive impairment, 24 weeks of treatment with donepezil failed to affect primary outcome measures but did improve some secondary outcomes (pp. 651-7). Patients received placebo or donepezil 5 mg/day for 42 days followed by forced dose escalation to 10 mg/day. “More donepezil-treated patients showed improvements in [modified Alzheimer’s Disease Assessment Scale–cognitive subscale] total scores, in tests of attention and psychomotor speed, and in [Patient Global Assessment] scores,” write the authors. “More donepezil-treated than placebo-treated patients experienced adverse events, most of which were mild to moderate and transient.” (S. Salloway, Butler Hosp., Providence, R.I.; SSalloway@Butler.org)

>>>Infectious Disease Update
Source:
Sept. 1 issue of Clinical Infectious Diseases (www.journals.uchicago.edu/CID; 2004; 39).

Herd Immunity with PCV: Widespread vaccination of infants with 7-valent pneumococcal conjugate vaccine has quickly resulted in decreases in rates of invasive pneumococcal disease among older family members, according to a 2-year analysis of Tennessee data (pp. 641-8). Investigators report: “Among children younger than 2 years, IPD rates peaked at 235 cases per 100,000 in 1999 before decreasing, after PCV licensure, to 46 cases per 100,000 in 2002 (P < .001). The proportion of penicillin-nonsusceptible IPD isolates from this age group declined from 59.8% in 1999 to 30.4% in 2002 (P < .01). After 2001, similar decreases in IPD rates and in the proportion of antibiotic-nonsusceptible isolates recovered were seen among persons aged 2 years and older (P < .01). Rates of IPD due to PCV-associated serotypes declined after PCV introduction in all age groups (P < .001), whereas the rate of IPD due to nonvaccine serotypes increased among persons aged 2 years and older.” (T. R. Talbot, tom.talbot@vanderbilt.edu)

Noting that Tennessee has had the highest rates of pneumococcal disease in the nation, an editorialist comments (pp. 649-51): “Vaccination with PCV is a novel approach to reduction of the burden of antibiotic resistance in the pneumococcus. The effect of the vaccine has extended beyond immunized children to reduce the carriage of resistant strains among family members and adults. Although capsular switching has not yet been documented as a consequence of immunization in a vaccinated child, surveillance is required to document the further evolution of antimicrobial resistance after the introduction of the vaccine. Lower levels of antimicrobial resistance may allow the reevaluation of the effectiveness of certain classes of antibiotics. The vaccine has also contributed to the reduction in antibiotic use, but continued restraint in antibiotic use—for example, in the proposed use of fluoroquinolones to treat children—is required to reduce the selective pressure for resistance among residual vaccine serotypes and nonvaccine-type pneumococcal strains.” (K. P. Klugman, kklugma@sph.emory.edu)

Interferon for Granulomatous Disease: Long-term interferon-gamma prophylaxis was effective and well tolerated among 76 patients with chronic granulomatous disease (pp. 692-9). During as much as 9 years of observation, the incidence of serious bacterial and fungal diseases was low, and adverse effects caused only 3 patients to withdraw from the trial. (S. M. Holland, smh@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 © 2004, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher (lmposey@mac.com). E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Aug. 25, 2004 Vol. 11, No. 164
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Aug. 25 issue of JAMA (www.jama.com; 2004; 292).

Gaps in Drug Benefits: Patients frequently decrease or stop their use of essential medications during gaps in their prescription drug coverage, according to a 2002 survey of Medicare beneficiaries who were under managed care plans (pp. 952-60). Responses from 665 individuals who exceeded $750 or $1,200 annual caps were compared with those of 643 patients who did not exceed $2,000 caps. The authors report, “A higher proportion of patients exceeding caps reported using less prescribed medication than controls (18% vs 10%, respectively; P < .001), but similar proportions reported stopping medications completely (8% for both, P = .86) and of not starting prescribed medications (6% vs 5%, P = .39). Patients exceeding caps more often called pharmacies to find the best price (46% vs 29%, P < .001), switched medications (15% vs 9%, P = .002), used samples (34% vs 27%, P = .006), and had difficulty paying for prescriptions (62% vs 37%, P < .001). Twelve of the 20 therapeutic classes most often affected by decreases in use of medication were for chronic health problems such as hypertension, hyperlipidemia, and emphysema or asthma.”

Since the new Medicare prescription drug benefit has a sizable gap before catastrophic coverage begins, the authors offer these observations, “Our results provide insight into how beneficiaries’ medication use may be affected if they fall into the ‘donut hole’ in the national Medicare drug benefit, ie, the gap in which no coverage is provided for total drug expenditures between $2250 and $5100. The $2250 cap may seem much more generous than the caps ($750, $1200, $2000) found in our Medicare + Choice population. However, the national prescription benefit will apply annual caps to total prescription costs rather than to only the health plan’s share of costs. In fact, two thirds of the beneficiaries in our study who exceeded their cap had average monthly total prescription costs of $187.50 or more ($2250/12) prior to exceeding the cap and would be at risk for having a gap in coverage under the national drug benefit. Although beneficiaries with low income and many health conditions are most likely to be affected, other design features such as premiums, deductibles, catastrophic coverage, and low-income subsidies wil