Dec 2005

PNN Quarterly File—Fourth Quarter 2005

PNN Pharmacotherapy Line
Oct. 3, 2005 Vol. 12, No. 191
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
Early-online release article from the Lancet (www.thelancet.com; 2005; 366).

Prolonged Statin Treatment: “Prolonged statin treatment with substantial LDL cholesterol reductions” is beneficial “in all patients at high risk of any type of major vascular event,” according to a prospective meta-analysis of 90,056 participants in 14 randomized trials of the drugs (DOI: 10.1016/S0140-6736(05)67394-1). “There was a 12% proportional reduction in all-cause mortality per mmol/L reduction in LDL cholesterol (rate ratio [RR] 0.88, 95% CI 0·84–0.91; p < 0·0001),” write the authors. “This reflected a 19% reduction in coronary mortality (0.81, 0.76–0.85; p < 0.0001), and non-significant reductions in non-coronary vascular mortality (0.93, 0.83–1.03; p=0.2) and non-vascular mortality (0.95, 0.90–1.01; p = 0.1). There were corresponding reductions in myocardial infarction or coronary death (0.77, 0.74–0.80; p < 0.0001), in the need for coronary revascularisation (0.76, 0.73–0.80; p < 0.0001), in fatal or non-fatal stroke (0.83, 0.78–0.88; p < 0.0001), and, combining these, of 21% in any such major vascular event (0.79, 0.77–0.81; p < 0.0001). The proportional reduction in major vascular events differed significantly (p < 0.0001) according to the absolute reduction in LDL cholesterol achieved, but not otherwise. These benefits were significant within the first year, but were greater in subsequent years. Taking all years together, the overall reduction of about one fifth per mmol/L LDL cholesterol reduction translated into 48 (95% CI 39–57) fewer participants having major vascular events per 1000 among those with pre-existing CHD at baseline, compared with 25 (19–31) per 1000 among participants with no such history.” (Clinical Trial Service Unit and Epidemiological Studies Unit, Oxford, U.K.; ctt@ctsu.ox.ac.uk)

>>>BMJ Highlights
Source:
Oct. 1 issue of BMJ (www.bmj.org; 2005; 331).

ARBs & MIs: The possibility that angiotensin II receptor blockers increase the risk of myocardial infarction—suggested in the results of a recent trial—is not supported by a systematic review of 19 studies with 31,569 participants (DOI: 10.1136/bmj.38595.518542.3A). The researchers report: “Two studies investigated the use of angiotensin receptor blockers in hypertensive patients, four studies in patients with diabetes and nephropathy, 10 studies in patients with heart failure, and three in patients with recent myocardial infarction or ischaemic syndrome. 11 studies of 21,062 patients allowed for comparison between angiotensin receptor blockers and placebo; nine studies of 10,625 patients allowed for comparison between angiotensin receptor blockers and ACE inhibitors. Use of angiotensin receptor blockers was not associated with increased risk of myocardial infarction compared with placebo (odds ratio 0.94, 95% confidence interval 0.75 to 1.16) nor with increased risk of myocardial infarction compared with ACE inhibitors (1.01, 0.87 to 1.16).” (R. T. Tsuyuki; ross.tsuyuki@ualberta.ca)

>>>PNN JournalWatch
* Beta-2-Adrenergic Receptor Genotype and Survival Among Patients Receiving Beta-Blocker Therapy After an Acute Coronary Syndrome, in JAMA, 2005; 294: 1526–33. Reprints: www.jama.com; H. L. McLeod, Washington U., St . Louis; hmcleod@im.wustl.edu

* Effect of Sublingual Misoprostol on Severe Postpartum Haemorrhage in a Primary Health Centre in Guinea-Bissau: Randomised Double Blind Clinical Trial, in
BMJ, 2005; 331: 723 ff. Reprints: bmj.bmjjournals.com/cgi/content/abstract/331/7519/723; L Høj, Aarhus University Hosp., Aarhus N, Denmark; lars.hoj@dadlnet.dk

* Nosocomial Infections Due to Multidrug-Resistant
Pseudomonas aeruginosa: Epidemiology and Treatment Options, in Pharmacotherapy, 2005; 25: 1353–64. Reprints: www.pharmacotherapy.org; R. Jung, rose.jung@uchcs.edu

* Effects of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors on High-Sensitivity C-Reactive Protein Levels, in
Pharmacotherapy, 2005; 25: 1365–77. Reprints: www.pharmacotherapy.org; K. M. Field, U. Tex., Austin.

* Effect of Initial Corticosteroid Therapy on Coronary Artery Aneurysm Formation in Kawasaki Disease: A Meta-analysis of 862 Children, in
Pediatrics, 2005; 116: 989–95. Reprints: www.pediatrics.org; A. C. Wooditch, Temple U., 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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Oct. 4, 2005 Vol. 12, No. 192
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Oct. 4 issue of the Annals of Internal Medicine (www.annals.org; 2005; 143).

Obesity Risks: An individual’s long-term risks of overweight or obesity exceed 50% and 25%, respectively, according to data from the Framingham Heart Study (pp. 473-80). Assessing the experiences of 4,117 white participants, 51.9% of whom were women, in this prospective cohort study conducted between 1971 and 2001, the investigators report, “The observed 4-year rates of developing overweight varied from 14% to 19% in women and 26% to 30% in men. Four-year rates of developing obesity ranged from 5% to 7% in women and 7% to 9% in men. The long-term (30-year) risk estimates were similar for the 2 sexes generally; varied somewhat with age (in men, being lower for those 50 years of age); and, overall, exceeded 1 in 2 persons for overweight or more, 1 in 4 individuals for obesity, and 1 in 10 people for stage II obesity (BMI ≥ 35 kg/m2) across different age groups. The 30-year estimates correspond to the residual lifetime risk for overweight or more or obesity for participants 50 years of age.” (R. S. Vasan, Boston U., vasan@bu.edu)

MIs in December: For unknown reasons, 30-day mortality rates are higher for patients hospitalized with myocardial infarction during December than during other months (pp. 481-5). Investigators analyzed retrospectively data from the Cooperative Cardiovascular Project for 127,959 Medicare beneficiaries who were hospitalized for MI in 1994–96. While use of evidence-based therapies was similar across the months, the 30-day mortality rate in December was 21.7%, significantly higher than the 20.1% observed during other months (adjusted odds ratio, 1.07; 95% CI, 1.02–1.12). (T. J. Meine, Duke U., Greenville, S.C.)

Adult Vaccines:
Clinical utility of vaccines against herpes zoster and pertussis in adults is reviewed (pp. 539-41). Noting that a shingles vaccine is pending licensure at FDA and an acellular pertussis vaccine was recently licensed for use in adults, the editorialist explores these barriers to better care: “For a variety of reasons (for example, fear, ignorance, laissez-faire attitudes toward perceived ‘nuisance’ diseases, the antivaccine movement, vaccine cost, and poor medical systems and procedures for recognizing underimmunization), all currently licensed and routinely recommended vaccines—without exception—are underutilized in adults. This partially stems from a ‘collusion of ignorance’ between patients and providers. Providers (for example, physicians, nurses, and pharmacists) have substantial misperceptions and fears about vaccine efficacy and safety and an inadequate knowledge base about vaccine-preventable diseases. Few practices have highly developed systems for identifying and immunizing those who need vaccines. This results in low adult immunization rates, leading to tens of thousands of preventable deaths in American adults each year.” (G. A. Poland, Mayo Clinic and Foundation, Rochester, Minn.)

>>>PNN NewsWatch
* Five cases of Guillain-Barré syndrome reported in 17- and 18-year-olds following immunization with meningococcal conjugate vaccine A, C, Y, and W135 (Menactra, Sanofi Pasteur) prompted an alert from FDA and CDC. More than 2.5 million doses of Menactra have been administered or are now in distribution, making this number of reported cases well within the natural annual incidence of the disease
(1 in 100,000 people). To further assess any potential link between the vaccine and the syndrome, FDA and CDC asked health professionals and consumers to report any possible cases to the Vaccine Adverse Event Reporting System by phone at 800-822-7967 or on the Web at www.vaers.hhs.gov.

*
Phthalates—ingredients in cosmetics, medical devices, and medications—may affect sexual development of fetuses in utero and in people throughout life, according to a front-page story in this morning’s Wall Street Journal. Studies attribute a number of problems to exposure to phthalates, including demasculinized traits, lower testosterone levels, increased rates of testicular cancer, and structural anomalies in genitalia of newborn boys.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Oct. 5, 2005 Vol. 12, No. 193
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Oct. 5 of JAMA (www.jama.com; 2005; 294).

Treatment of Juvenile Idiopathic Arthritis: Evidence is lacking for treatment of several subtypes of juvenile idiopathic arthritis, according to authors of a Clinician’s Corner review article (pp. 1671-84). Noting that treatment plans need to be individualized based on JIA subtypes, the authors make these recommendations based on data from 34 controlled studies: “Nonsteroidal anti-inflammatory drugs are effective only for a minority of patients, mainly those with oligoarthritis. Intra-articular corticosteroid injections are very effective for oligoarthritis. Methotrexate is effective for the treatment of extended oligoarthritis and polyarthritis and less effective for systemic arthritis. Sulfasalazine and leflunomide may be alternatives to methotrexate. Antitumor necrosis factor medications are highly effective for polyarticular course JIA not responsive to methotrexate but are less effective in systemic arthritis. There is a lack of evidence for the optimal treatment of systemic and enthesitis-related arthritis.” (P. J. Hashkes, Cleveland Clinic Foundation, Cleveland; hashkep@ccf.org)

>>>Geriatrics Report
Source:
Oct. issue of the Journal of the American Geriatrics Society (www.blackwell-synergy.com/toc/jgs/52/10; 2005; 52).

HF Risk with Alpha-Blockers: Among 5,888 community-dwelling patients older than 65 years, risk of incident congestive heart failure was 2 to 3 times greater among those with hypertension who were taking peripheral alpha-1 antagonists, an effect partly explainable by the hypotensive effects of these agents (pp. 1648-54). “The 3,105 participants with treated hypertension were at risk for CHF; 22% of men and 8% of women took alpha antagonists during follow-up,” write the authors. “The age-adjusted risk of CHF in those receiving monotherapy treated with alpha antagonists was 1.90 (95% confidence interval = 1.033.50) compared with thiazides. In subjects without CVD at baseline receiving monotherapy, women taking an alpha antagonist had a 3.6 times greater age-adjusted risk of CHF, whereas men had no difference in risk. Adjustment for systolic blood pressure attenuated statistical differences in risk. There were 930 men without hypertension at risk for CHF; 5% used alpha antagonists [for prostatitis] during follow-up, with no observed increase in CHF risk.” (C. L. Bryson, cbryson@u.washington.edu)

Polypharmacy, Weight Loss, & Impaired Balance: Clinicians need to “consider the adverse effects of total drug use and not merely the benefits or risks of individual medications for specific diseases” when making prescribing decisions, according to authors who conducted a cross-sectional and longitudinal cohort study of 885 community-dwelling residents aged 72 years and older (pp. 1719-23). Looking for weight loss at least 10 pounds and/or indications of balance problems, the investigators report, “Participants took a mean ± standard deviation of 2.2 ± 1.9 medications (range 0–15). After adjustment for age, depressive symptoms, cognitive impairment, vision and hearing impairments, number of chronic diseases, and number of hospitalizations in the previous year, the adjusted odds ratio (OR) for weight loss was 1.48 (95% confidence interval (CI) = 0.85–2.59) for those taking one to two medications, 1.96 (95% CI = 1.08–3.54) for three to four medications, and 2.78 (95% CI = 1.38–5.60) for five or more medications. For impaired balance, adjusted ORs were 1.44 (95% CI = 0.94–2.19), 1.72 (95% CI = 1.09–2.71), and 1.80 (95% CI = 1.02–3.19), respectively.” (J. V. Agostini, joseph.agostini@yale.edu)

Antipsychotic Drug Withdrawal: Activity and sleep efficiency are altered and should be monitored following discontinuation of antipsychotic drugs, according to a study of 30 nursing home residents (pp. 1737-43). “Increases in total activity and impaired sleep quality after drug discontinuation should be monitored, because the long-term effect of these changes is not known,” the group concludes. “The [Neuropsychiatric Inventory Questionnaire] and actigraphy are feasible tools that disclose relevant changes occurring during antipsychotic withdrawal in NH patients with dementia.” (S. Ruths, U. Bergen, Bergen, Norway; sabine.ruths@isf.uib.no)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Oct. 6, 2005 Vol. 12, No. 194
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Oct. 6 issue of the New England Journal of Medicine (content.nejm.org; 2005; 353).

Medicare & CEA: The application of cost-effectiveness analysis by the U.S. Medicare program is badly needed to achieve greater efficiency, note authors of a Sounding Board article (pp. 1516-22). Noting that such analyses are used routinely to assess new medical interventions, the authors advise, “The problem posed by rising Medicare spending is not abating and is liable to worsen, with expenditures increasing faster than the growth of the gross domestic product and taking an ever greater share of federal revenues and national income. Medicare's policy of paying for any medical advance that has positive benefits, regardless of its costs, is unsustainable. Recent decisions to pay for therapies such as lung-volume–reduction surgery, implantable cardioverter–defibrillators, left ventricular assist devices, and positron-emission tomography to treat Alzheimer's disease could add billions per year to Medicare spending.” (P. J. Neumann, Harvard School of Public Health, Boston)

>>>Pediatrics Report
Source:
Oct. issue of Pediatrics (www.pediatrics.org; 2005; 116).

Emergency Contraception: Nonprescription availability of emergency contraception “has tremendous potential to reduce unintended pregnancy rates in teens and adults,” according to a policy statement issued by the American Academy of Pediatrics (pp. 1026-35). The position, prepared by the group’s Committee on Adolescence, notes, “A rather common concern about emergency contraception is that teens will repeatedly use this method of birth control rather than more reliable methods. A longitudinal study of teens and young women in the United Kingdom found that only 4% of emergency-contraception users reported taking emergency contraception more than twice within 1 year, suggesting that repeated use of emergency contraception within this group was not common.

“Several states currently allow patients to access emergency contraception via a pharmacist rather than a medical provider. In addition, over-the-counter emergency contraception has been encouraged by many professional organizations, including the AAP. The AAP was 1 of more than 60 medical and citizen groups signing a petition to the FDA stating that emergency contraception was safe, efficacious, and easy to administer, all 3 factors required by the FDA for over-the-counter medications.”

Parental Education & Antibiotic Use: Better parental education reduces the frequency of injudicious antibiotic prescribing, concludes a retrospective analysis of data on children of physicians, nurses, pharmacists, and nonhealth personnel in Taiwan in 2000 (pp. 826-32). Based on 53,733 care visits, the investigators note, “The study found that, after adjusting for characteristics of the children (demographic, socioeconomic, and health status) and the treating physicians (demographic, practice style, and setting), children with a physician (odds ratio [OR]: 0.50; 95% confidence interval [CI]: 0.36–0.68) or a pharmacist (OR: 0.69; 95% CI: 0.52–0.91) as a parent were significantly less likely than other children to receive antibiotic prescriptions. The likelihood of receiving an antibiotic for the children of nurses (OR: 0.91; 95% CI: 0.77–1.09) was similar to that for children in the comparison group.” (N. Huang, Natl. Yang Ming U., Taipei, Taiwan)

Web-Based Smoking Cessation: GottaQuit.com, a smoking cessation Web site, can help teen smokers kick the habit, according to telephone surveys conducted before and after a countywide media campaign (pp. 950-6). “Most teen smokers reported that they wanted to quit smoking,” the authors report. “Almost all teens reported exposure to GottaQuit.com ads and accurately identified GottaQuit.com as a Web site that offers cessation help for youths. Nearly 1 in 4 smokers who were trying to quit had visited GottaQuit.com or another Web site for cessation assistance.” (J. D. Klein)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Oct. 7, 2005 Vol. 12, No. 195
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Oct. issue of Pharmacotherapy (www.pharmacotherapy.org; 2005; 25).

INR Accuracy During LMWH, Warfarin Therapy:
International normalized ratios measured by a point-of-care device may be inaccurate when patients are receiving both warfarin and a low molecular weight heparin, according to a retrospective study that included 91 outpatients (pp. 1341-7). Comparing INR determinations made using capillary blood and the point-of-care testing device and venous blood analyzed in a standard reference laboratory, the investigators found, “In ... patients receiving only warfarin and ... warfarin plus LMWH, the mean INR as determined by the point-of-care testing device was statistically significantly higher than the mean INR determined by the laboratory. Although the differences were statistically significant in both groups, the clinical significance of this difference was accentuated in the patients receiving warfarin plus LMWH. The measure of divergence between the point-of-care and laboratory methods was greater in the group receiving warfarin plus LMWH than in the warfarin-only group, with a mean ± SD percent change between the INR values of 24.19 ± 27.54% in the warfarin plus LMWH group and 7.21 ± 17.73% in the warfarin-only group. In assessing the clinical impact of such variability, a greater degree of discordance in dosing adjustment decisions was noted for patients receiving warfarin plus LMWH. In this group, a 25% rate of discordance was noted compared with 8% in the warfarin-only group. Such discrepancy in dosing decisions based on the point-of-care INR would have resulted in discontinuation of LMWH therapy before the patient acquired a true therapeutic INR, with use of the laboratory measurement.” (E. M. Phillips, University Health Care, Syracuse, N.Y.)

Adverse Effects of Propofol: In intensive-care patients receiving the sedative agent propofol, hypertriglyceridemia and a related pancreatitis occur frequently, making monitoring necessary, concludes a retrospective study. (pp. 1348-52). The patients, all of whom had been receiving the sedative for more than 24 hours, showed these changes: “Of the 159 patients, 29 (18%) developed hypertriglyceridemia; six (21%) of the 29 had a serum triglyceride concentration of 1000 mg/dl or greater. The median maximum serum triglyceride concentration was 696 mg/dl (range 403–1737 mg/dl). At the time when hypertriglyceridemia was detected, the median infusion rate of propofol was 50 µg/kg/minute (range 5–110 µg/kg/min). The median time from the start of propofol therapy to identification of hypertriglyceridemia was 54 hours (range 14–319 hrs). Propofol was discontinued within 24 hours of detecting the hypertriglyceridemia 84% of the time. Compared with those who did not develop hypertriglyceridemia, patients who developed hypertriglyceridemia were older, had a longer intensive care unit stay, and received propofol for a longer duration; they were also more likely to be admitted to the medical versus the surgical intensive care unit. Pancreatitis developed in three (10%) of the 29 patients with hypertriglyceridemia.” (J. W. Devlin, Northeastern U., Boston, j.devlin@neu.edu)

>>>PNN NewsWatch
* “Stick with the Guidelines—Coronary Artery Disease” is a new pilot project of the APhA Foundation aimed at combating the effects heart disease has on America’s workforce. Funded under a grant from the American Heart Association’s Pharmaceutical Roundtable, the program will engage employers and health care providers in Columbus, Ohio, and Asheville, N.C., in an effort to educate and motivate employees at risk for or with heart disease to better manage their condition.

*
Nurse practitioners are staffing clinics being set up by outside contractors in the nation’s chain pharmacies, according to an article in Wednesday’s Wall Street Journal. A Pennsylvania company, Take Care Health Systems LLC, is driving the rapid spread, signing contracts with Rite Aid Corp., Brooks Eckerd Pharmacy, and Osco Drug and in talks with Walgreen, the article explains. In addition, CVS and Target are working with MinuteClinic to open clinics in Minneapolis, Baltimore, and Nashville, and Wal-Mart is partnering with InterFit Health and other companies in Oklahoma, Arkansas, Florida, and other states.

*
PNN will not be published on Mon., Oct. 10, Columbus 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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Oct. 11, 2005 Vol. 12, No. 196
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
Early-release articles from the Lancet and Lancet Oncology (www.thelancet.com).

Predicting Chemotherapy-Induced Anemia: Development and use of a model for predicting patients’ risk of chemotherapy-induced anemia are presented based on a study of 331 patients receiving adjuvant chemotherapy for breast cancer (DOI:10.1016/S1470-2045(05)70394-6). “The risk of anaemia increased as the pretreatment haemoglobin concentration decreased and was reduced with successive chemotherapy cycles,” the authors note. “Risk was also predicted by a platelet count of 200 X 109 cells/L or less before chemotherapy, age 65 years or older, type of adjuvant chemotherapy, and use of prophylactic antibiotics.” (G. Dranitsaris, Sunnybrook Regional Cancer Ctr., Toronto; gdranit@ca.inter.net)

NSAIDs & Oral Cancer Risk: Long-term use of NSAIDs is associated with a lower risk of oral cancer but an increased chance of cardiovascular death, according to a nested case–control study that analyzed prospectively obtained health data in the Cohort of Norway (DOI:10.1016/S0140-6736(05)67488-0). “We identified and analysed 454 (5%) people with oral cancer (279 men, 175 women, mean [SD] age at diagnosis 63.3 [13.2] years) and 454 matched controls (n = 908); 263 (29%) had used NSAIDs, 83 (9%) had used paracetamol (for a minimum of 6 months), and 562 (62%) had used neither drug. NSAID use (but not paracetamol use) was associated with a reduced risk of oral cancer (including in active smokers; hazard ratio 0.47, 95% CI 0.37–0.60, p < 0·0001). Smoking cessation also lowered the risk of oral cancer (0.41, 0.32–0.52, p < 0.0001). Additionally, long-term use of NSAIDs (but not paracetamol) was associated with an increased risk of cardiovascular-disease-related death (2.06, 1.34–3.18, p = 0·001). NSAID use did not significantly reduce overall mortality (p = 0.17).” (J. Sudbø, Norwegian Radium Hosp., Oslo; jon.sudbo@rh.uio.no)

>>>BMJ Highlights
Source:
Early-release articles from BMJ (www.bmj.org).

Self-Management of Anticoagulation: Patients can safely and reliably self-manage their oral anticoagulation treatment using a point-of-care testing device and simple dosing chart, conclude authors of a study of 617 adults (doi:10.1136/bmj.38618.580903.AE). With 57% of those randomized to routine care completing the 12-month intervention, the investigators report, “No significant differences were found in percentage of time in the therapeutic range between self management and routine care (70% v 68%). Self managed patients with poor control before the study showed an improvement in control that was not seen in the routine care group. Nine patients (2.8/100 patient years) had serious adverse events in the self managed group, compared with seven (2.7/100 patient years) in the routine care arm (chi square (df=1) = 0.02, P = 0.89).” (D. A. Fitzmaurice, U. Birmingham, Birmingham, U.K.; d.a.fitzmaurice@bham.ac.uk)

Beta-Blockers for Elective Surgery in Elderly: The longer duration of atenolol action proved beneficial in a comparison with short-acting metoprolol conducted in 37,151 elective surgical patients who were older than 65 years (doi:10.1136/bmj.38603.746944.3A). “1038 patients experienced a myocardial infarction or died, a rate that was significantly lower for patients receiving atenolol than for those receiving metoprolol (2.5% v 3.2%, P < 0.001),” write the researchers. “The decreased risk with atenolol persisted after adjustment for measured demographic, medical, and surgical factors; extended to comparisons of other long acting and short acting beta blockers; was accentuated in analyses that focused on patients with the clearest evidence of beta blocker treatment; and reflected the immediate postoperative interval.” (D. Redelmeier, Sunnybrook and Women's College Health Sci. Ctr., Toronto; AR@ICES.ON.CA">DAR@ICES.ON.CA)

>>>PNN JournalWatch
* Preventing Chronic Diseases: How Many Lives Can We Save?, in Lancet, DOI:10.1016/S0140-6736(05)67341-2. Reprints: www.thelancet.com/journals/lancet/article/PIIS0140673605673412/abstract; K. Strong, WHO, Geneva, Switzerland; strongk@who.in

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Oct. 12, 2005 Vol. 12, No. 197
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Oct. 12 issue of JAMA (www.jama.com; 2005; 294).

Drugs & Lipid Levels: Total and LDL cholesterol levels declined during several decades of the late 20th century and continued this trend in the 1999 through 2002 period, according to an analysis of data from five cross-sectional surveys of Americans conducted between 1960 and 2002 (pp. 1773-81). The improvements are probably the result of increased use of lipid-lowering medications, the authors surmised, adding, “Between 1988–1994 and 1999–2002, total serum cholesterol level of adults aged 20 years or older decreased from 206 mg/dL (5.34 mmol/L) to 203 mg/dL (5.26 mmol/L) (P = .009) and LDL cholesterol levels decreased from 129 mg/dL (3.34 mmol/L) to 123 mg/dL (3.19 mmol/L) (P < .001). Greater and significant decreases were observed in men 60 years or older and in women 50 years or older. The percentage of adults with a total cholesterol level of at least 240 mg/dL (6.22 mmol/L) decreased from 20% during 1988–1994 to 17% during 1999-2002 (P < .001). There was no change in mean HDL cholesterol levels and a nonsignificant increase in geometric mean serum triglyceride levels (P = .06).” (M. D. Carroll, mdc3@cdc.gov)

Candesartan for HF: Angiotensin II receptor blockers reduces the risk of cardiovascular death and nonfatal myocardial infarction in patients with heart failure, providing benefits similar to those of ACE inhibitors, concludes the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) program (pp. 1794-8). Comparing placebo with a target dose of candesartan 32 mg once daily, the investigators found, “During the median follow-up of 37.7 months, the primary outcome of cardiovascular death or nonfatal MI was significantly reduced in the candesartan group (775 patients [20.4%]) vs the placebo group (868 [22.9%]) (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.79–0.96; P = .004; number needed to treat [NNT], 40). Nonfatal MI alone was also significantly reduced in the candesartan group (116 [3.1%]) vs the placebo group (148 [3.9%]) (HR, 0.77; 95% CI, 0.60–0.98; P = .03; NNT, 118). The secondary outcome of fatal MI, sudden death, or nonfatal MI was significantly reduced with candesartan (459 [12.1%]) vs placebo (522 [13.8%]) (HR, 0.86; 95% CI, 0.75–0.97; P = .02; NNT, 59). Risk reductions in cardiovascular death or nonfatal MI were similar across predetermined subgroups and the component CHARM trials. There was no impact on hospitalizations for unstable angina or coronary revascularization procedures with candesartan.” (S. Yusuf, yusuf@ccc.mcmaster.ca)

Palliative Sedation in End-of-Life Care: In dying patients, palliative sedation is a last resort, one that can be appropriate when all other measures fail to relieve pain, according to authors of a Clinician’s Corner contribution (pp. 1810-6). “A patient with metastatic breast cancer, receiving high doses of opioids administered to relieve pain, developed myoclonus,” they write. “After other approaches proved ineffective, palliative sedation was an option of last resort. The doctrine of double effect, the traditional justification for palliative sedation, permits physicians to provide high doses of opioids and sedatives to relieve suffering, provided that the intention is not to cause the patient’s death and that certain other conditions are met. Such high doses are permissible even if the risk of hastening death is foreseen. Because intention plays a key role in this doctrine, clinicians must understand and document which actions are consistent with an intention to relieve symptoms rather than to hasten death. The patient or family should agree with plans for palliative sedation. The attending physician needs to explain to them, as well as to the medical and nursing staff, the details of care and the justification for palliative sedation. Because cases involving palliative sedation are emotionally stressful, the patient, family, and health care workers can all benefit from talking about the complex medical, ethical, and emotional issues they raise.” (B. Lo, bernie@medicine.ucsf.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Oct. 13, 2005 Vol. 12, No. 198
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Oct. 13 issue of the New England Journal of Medicine (content.nejm.org; 2005; 353).

Pertussis Vaccine in Adolescents, Adults: A tricomponent acellular pertussis vaccine “was protective among adolescents and adults, and its routine use might reduce the overall disease burden and transmission to children,” concludes a study of 2,781 healthy participants (pp. 1555-63). Those assigned to the control group (n = 1,390) received a hepatitis A vaccine, while intervention group (n = 1,391) participants a formulation that contained approximately one third of the pertussis-antigen component present in the children’s vaccine Infanrix (GlaxoSmithKline). “The groups had similar ages and demographic characteristics, and the median duration of follow-up was 22 months,” the investigators explain. “The acellular pertussis vaccine was safe and immunogenic. There were 2672 prolonged illnesses with cough, but the incidence of this nonspecific outcome did not vary between the groups, even when stratified according to age, season, and duration of cough. On the basis of the primary pertussis case definition, vaccine protection was 92 percent (95 percent confidence interval, 32 to 99 percent). Among unimmunized controls with illness, 0.7 percent to 5.7 percent had B. pertussis infection, and the percentage increased with the duration of cough. On the basis of other case definitions, the incidence of pertussis in the controls ranged from 370 to 450 cases per 100,000 person-years.” (J. I. Ward, UCLA, Torrance, Calif.)

An editorialist takes this position on how the recently approved Tetanus Toxoid (T), Reduced Diphtheria Toxoid (d), and Acellular Pertussis Vaccine (ap), Adsorbed (Adacel, Sanofi Pasteur) should be used (pp. 1615-7): “On the basis of the safety, the immunogenicity, and the now-demonstrated efficacy of these vaccines and the demonstrated burden of pertussis in adolescents and adults, dTap vaccines should be widely used in place of the Td vaccine. All adolescents should receive a dose of dTap, and consideration should be given to the use of dTap for any adult for whom Td vaccine is being considered. However, there are still gaps in our knowledge that need to be filled through continued research. The true burden of pertussis will be identified only if the diagnosis of pertussis is considered by health care providers caring for adults with prolonged illness with cough. The availability of better tools for the laboratory diagnosis of pertussis is essential to facilitate a better understanding of the epidemiology of the disease. The burden of pertussis in the elderly is not well defined, and the safety and immunogenicity of dTap vaccine in the elderly need to be determined. Finally, study is needed of the use of dTap vaccine during pregnancy and the effect of its use (and widespread use in other adults) on the epidemiology of pertussis in infants who are too young to have completed immunization.” (S. A. Halperin, Dalhousie U., Halifax, N.S., Canada)

TB Vaccine Development: An improved vaccine that protects against tuberculosis is under development, notes a brief article that describes animal research into the vaccine’s efficacy (pp. 1624-5). Describing progress toward a better BCG (Mycobacterium bovis bacille Calmette–Guérin) vaccine, the author writes, “The authors tested the vaccine's safety and efficacy in a mouse vaccination-and-challenge model.1 After vaccination, animals were challenged by infection with one of the most virulent clinical isolates of M. tuberculosis described to date.3 This pathogen, known as the W-Beijing strain, has spread throughout Southeast Asia, eastern Europe, and southern Africa. The new recombinant BCG vaccine provided better protection against infection by H37Rv, a laboratory strain of M. tuberculosis commonly used in such challenges, and a clinically derived W-Beijing strain. In contrast to many previous studies of tuberculosis vaccine that used a mouse model of infection, in this study protection was monitored for more than 200 days to ensure that the immune response was robust and long-lasting.” (G. Kaplan, International Center for Public Health, Newark, N.J.)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Oct. 14, 2005 Vol. 12, No. 199
Providing news and information about medications and their proper use

>>>Allergy/Immunology Update
Source:
Oct. issue of the Journal of Allergy and Clinical Immunology (www.jacionline.org; 2005; 116).

APAP & Allergic Symptoms: Already suggested in developed countries, an association between acetaminophen use and increased risk of asthma is supported by a study from Ethiopia of self-reported allergic symptoms (pp. 863-8). Based on a surveys of 7,649 adults and children, the researchers report, “Allergic symptoms increased significantly with frequency of acetaminophen use, with odds ratios in those using >3 tablets in the past month relative to none 1.89 (95% CI, 1.51–2.36) for wheeze, 2.14 (1.72–2.67) for nocturnal shortness of breath, 2.52 (1.99–3.20) for rhinitis, and 1.90 (1.39–2.61) for eczema. Cockroach sensitization was also more common in the highest acetaminophen category (odds ratio, 1.40; 95% CI, 1.10–1.79), but to [Dermatophagoides] pteronyssinus sensitization was not. Less than 1% of participants with asthma or wheeze in our nested study reported avoidance of aspirin because of asthma symptoms. None volunteered using acetaminophen to treat allergic symptoms.” Based on these results, the authors conclude, “There is a dose-related association between acetaminophen use and self-reported allergic symptoms in this population that is not a result of aspirin avoidance, reverse causation, or other bias. Acetaminophen may therefore be involved in the etiology of asthma and allergic disease.” (G. Davey, Ababa U., Addis Ababa, Ethiopia; nerurkar@ethionet.et)

Emergence of Biologic Agents for Allergic Conditions: Two reviews explore progress in development of monoclonal antibodies, fusion proteins, and other therapeutic antibodies.

“Humanized antibodies and decoy receptors have been introduced in clinical practice to treat malignancies and systemic autoimmune disease because they ablate specific cells or disrupt pathogenic processes at distinct points,” note the authors of the first review (pp. 721-9). “Reported clinical responses offer hope to treatment-resistant patients, particularly those with lymphomas and rheumatic diseases. Side effects from the use of biologic agents include lymphokine release syndrome, reactivation of tuberculosis, and immunosuppression. Further insights are needed regarding limitation of adverse effects, correct use in conjunction with existing drugs, and treatment of patients in whom resistance develops.” (S-N C. Liossis, Patras U. Hosp., Patras, Greece;
sliossis@med.upatras.gr)

In the second article, an author notes, “[Monoclonal antibodies] account for an increasing portion of marketed human biological therapeutics. As a consequence, the importance of optimal selection, design, and engineering of these not only has expanded in the past 2 decades but also is now coming into play as a competitive factor. This review delineates the 4 basic areas for optimal therapeutic antibody selection and provides examples of the increasing number of considerations necessary for, and options available for, antibody design. Though some of the advances in antibody technology (eg, antibodies derived from phage-display libraries) have already made it to market, other more recent advances, such as engineering antibodies for enhanced effector functions, may not be far behind, especially given the increasing competition for therapeutic antibodies to the same target (eg, anti-CD20 and anti–TNF-alpha).” (L. G. Presta, Schering-Plough Biopharma, Palo Alto, Calif.;
leonard.presta@spcorp.com)

Montelukast/Desloratadine Attenuation of Asthmatic Responses: In 10 adults with mild or moderate atopic asthma, early response to allergen challenge was inhibited more by the combination of montelukast and desloratadine than with either agent alone, suggesting the need for larger studies (pp. 768-72). Using the concentration of allergen that resulted in a 20% decrease in forced expiratory volume in 1 second as a measure, the investigators found montelukast alone to be no different than placebo, a 4.8-fold increase with montelukast, and an 8.9-fold increase with the two drugs together. (D. W. Cockcroft, U. Saskatchewan, Saskatoon; cockcroft@sask.usask.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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Oct. 17, 2005 Vol. 12, No. 200
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
Early-release articles from and the Oct. 15 issue of Lancet (www.thelancet.com; 2005; 366).

Infliximab for Psoriasis: The infliximab proved an effective treatment for psoriasis in patients with moderate or severe cases (pp. 1367-74). Comparing the tumor necrosis factor alpha inhibitor with placebo in 378 patients, investigators in the EXPRESS study found, “At week 10, 80% (242/301) of patients treated with infliximab achieved at least a 75% improvement from their baseline [psoriasis area and severity index] (PASI 75) and 57% (172/301) achieved at least a 90% improvement (PASI 90), compared with 3% and 1% in the placebo group, respectively (p < 0.0001). At week 24, PASI 75 (82% for infliximab vs 4% for placebo) and PASI 90 (58% vs 1%) were maintained (p < 0.0001). At week 50, 61% achieved PASI 75 and 45% achieved PASI 90 in the infliximab group. Infliximab was generally well tolerated in most patients.” (C. E. M. Griffiths, Hope Hosp., Manchester, U.K.; Christopher.griffiths@manchester.ac.uk)

BCG Vaccination in Children: Use of the Mycobacterium bovis bacille Calmette–Guerin (BCG) vaccine protected against both tuberculosis infection and disease in a study of 979 children, providing evidence that the vaccine confers more benefits than previously known (DOI:10.1016/S0140-6736(05)67534-4). The study took advantage of the availability of ELISpot, a T-cell–based enzyme-linked immunospot assay to assess infection among household contacts of 414 adult index patients with sputum smear-positive pulmonary tuberculosis: “Amount of tuberculosis exposure within the household and age (a marker of tuberculosis exposure outside the household) were strongly associated with likelihood of infection as measured by both [tuberculin skin test] and ELISpot. ELISpot also identified absence of BCG scar as an independent risk factor for infection in tuberculosis-exposed children; BCG-vaccinated children had an odds ratio of 0.60 (95% CI 0.43–0.83, p = 0.003) for tuberculosis infection, compared with unvaccinated children.” (A. Lalvani, Marmara U., Istanbul, Turkey; ajit.lalvani@ndm.ox.ac.uk)

Editorialists caution that this study fails to provide a definitive answer (DOI:10.1016/S0140-6736(05)67535-6): “Vaccination studies in animals indicate that successful vaccination can greatly reduce the level of [antigenic] responsiveness, without necessarily preventing infection. So we are left with the same quandary: it appears from [this] report that BCG vaccination might reduce the intensity of infection, but can it indeed prevent infection? Only large-scale longitudinal studies will provide more definitive answers.” (C. Lienhardt, Institut de Recherche pour le Déve-loppement, Dakar, Sénégal;
lienhardt@ird.sn)

>>>BMJ Highlights
Source:
Oct. 15 issue of BMJ (www.bmj.org; 2005; 331).

Cost-Effectiveness of Complementary Treatments: Spinal manipulation and acupuncture add to health expenditures but at favorable costs per quality-adjusted life-years, according to a systematic review of five randomized controlled trials (pp. 880-1). However, the benefits of these interventions in patients with chronic headache and back pain may not be that important, the authors write: “For spinal manipulation the health benefits were small to moderate and are of questionable clinical significance. Measurement of costs was incomplete in all studies and omitted follow-on costs. Standard modelling methods were not used. Absence of blinding and sham control treatments may have increased non-specific treatment effects. Estimates of cost effectiveness may be less favourable in situations for which the complementary treatment is offered routinely rather than in the novel situation of a clinical trial.” (P. H. Canter, Universities of Exeter and Plymouth, Exeter, U.K.; peter.canter@pms.ac.uk)

>>>PNN JournalWatch
* Early and Late Benefits of High-Dose Atorvastatin in Patients with Acute Coronary Syndromes: Results From the PROVE IT-TIMI 22 Trial, in Journal of the American College of Cardiology, 2005; 46: 1405–10. Reprints: content.onlinejacc.org; C. P. Cannon, TIMI Study Group, Boston;
cpcannon@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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Oct. 18, 2005 Vol. 12, No. 201
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Oct. 18 issue of the Annals of Internal Medicine (www.annals.org; 2005; 143).

Inhaled Insulin for Type 2 Diabetes: Overall glycemic control was improved among 309 patients with type 2 diabetes when inhaled insulin (Exubera, Pfizer) was added to oral combination regimens consisting of an insulin secretagogue and sensitizer (pp. 549-58). In this open-label trial conducted at 48 outpatient centers in the U.S., patients with baseline glycosylated hemoglobin levels of 8% to 11% had these results: “Reductions in hemoglobin A1c level were greater with inhaled insulin. Adjusted treatment group differences for inhaled insulin plus oral agents and inhaled insulin alone compared with continued oral agent therapy were –1.67 percentage points (95% CI, –1.90 to –1.44 percentage points; P < 0.001) and –1.18 percentage points (CI, –1.41 to –0.95 percentage point; P < 0.001), respectively. Hemoglobin A1c level less than 7% was achieved by 32% (inhaled insulin plus oral agents) and by 1% (oral agent therapy) of patients (adjusted odds ratio, 44.7 [CI, 6.0 to 335.2]). Hypoglycemia, mild weight gain, mild cough, and insulin antibodies were more frequent with inhaled insulin than with oral agent therapy alone. Pulmonary function was similar in all groups.” (J. Rosenstock, Dallas Diabetes and Endocrine Ctr., Dallas, TX 75230; juliorosenstock@dallasdiabetes.com)

Exenatide Versus Insulin Glargine in Type 2 Diabetes: In an open-label trial of 551 patients with type 2 diabetes and inadequate glycemic control, exenatide and insulin glargine produced similar improvements in glycosylated hemoglobin (pp. 559-69). The study, involving 82 outpatient study centers in 13 countries, used doses of exenatide of 10 mcg twice daily and insulin glargine titrated to keep blood glucose levels below 100 mg/dL. “Baseline mean hemoglobin A1c level was 8.2% for patients receiving exenatide and 8.3% for those receiving insulin glargine,” report the authors. “At week 26, both exenatide and insulin glargine reduced hemoglobin A1c levels by 1.11% (difference, 0.017 percentage point [95% CI, –0.123 to 0.157 percentage point]). Exenatide reduced postprandial glucose excursions more than insulin glargine, while insulin glargine reduced fasting glucose concentrations more than exenatide. Body weight decreased 2.3 kg with exenatide and increased 1.8 kg with insulin glargine (difference, –4.1 kg [CI, –4.6 to –3.5 kg]). Rates of symptomatic hypoglycemia were similar, but nocturnal hypoglycemia occurred less frequently with exenatide (0.9 event/patient–year versus 2.4 events/patient–year; difference, –1.6 events/patient–year [CI, –2.3 to –0.9 event/patient–year]). Gastrointestinal symptoms were more common in the exenatide group than in the insulin glargine group, including nausea (57.1% vs. 8.6%), vomiting (17.4% vs. 3.7%) and diarrhea (8.5% vs. 3.0%).” (R. J. Heine, VU U. Med. Ctr., Amsterdam, the Netherlands)

Commenting on both this and the above study on inhaled insulin, an editorialist notes the importance of these advances (pp. 609-10): “Until the discovery of precise molecular targets that are intrinsic to the pathophysiology of type 2 diabetes, increasing exercise and reducing weight will be the cornerstone of management. The mainstays of treatment in the later stages of type 2 diabetes—thiazolidinediones and insulins—cause weight gain and undo the hard-won effects of lifestyle change. The results of the studies in these 2 papers suggest a real advance in managing the later stages of diabetes: achieving glucose control without concomitant weight gain (exenatide) and a real choice for patients who dislike the prospect of injections (inhaled vs. injected insulin).” (R. J. Comi, Dartmouth Hitchcock Med. Ctr., Lebanon, N.H.)

>>>PNN NewsWatch
* Chiron yesterday began shipping its Fluvirin product to the U.S., completing a 2,000-step remediation process that satisfied British and American drug regulators. Still, the company said in a Webcast, the delays brought on by numerous and extensive inspections of its Liverpool vaccine plant mean that it will be able to produce less than the 18–24 million doses of influenza vaccine previously anticipated.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Oct. 19, 2005 Vol. 12, No. 202
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Oct. 19 issue of JAMA (www.jama.com; 2005; 294).

Mortality with Atypical Antipsychotic Drugs for Dementia: A small increase in risk of death is associated with use of atypical antipsychotic medications for treatment of dementia, according to a meta-analysis of available randomized controlled trials (pp. 1934-43). Compared with placebo, the authors found, “Fifteen trials (9 unpublished), generally 10 to 12 weeks in duration, including 16 contrasts of atypical antipsychotic drugs with placebo met criteria (aripiprazole [n = 3], olanzapine [n = 5], quetiapine [n = 3], risperidone [n = 5]). A total of 3353 patients were randomized to study drug and 1757 were randomized to placebo. Outcomes were assessed using standard methods (with random- or fixed-effects models) to calculate odds ratios (ORs) and risk differences based on patients randomized and relative risks based on total exposure to treatment. There were no differences in dropouts. Death occurred more often among patients randomized to drugs (118 [3.5%] vs 40 [2.3%]. The OR by meta-analysis was 1.54; 95% confidence interval [CI], 1.06–2.23; P = .02; and risk difference was 0.01; 95% CI, 0.004–0.02; P = .01). Sensitivity analyses did not show evidence for differential risks for individual drugs, severity, sample selection, or diagnosis.” (L. S. Schneider, lschneid@usc.edu)

Editorialists provide this reaction to this article (pp. 1963-5): “So what should a clinician do when caring for a patient with dementia who develops psychotic symptoms or aggression? First, etiologies other than dementia need to be considered. Delirium, untreated or undertreated medical illnesses, overmedication, environmental triggers, lack of engaging activities, and misinterpretation of disease symptoms are among the potential etiologies of such behaviors and symptoms. Because all have specific therapies, they should be considered when such symptoms first develop. Second, clinicians should consider the risk/benefit ratio for each patient. For example, patients with hallucinations and delusions that are neither distressing nor placing them or others at risk or harm should not be treated with antipsychotic drugs. Third, once antipsychotic drugs have been prescribed, careful assessment and documentation of the need for continued care is necessary. The Omnibus Budget Reconciliation Act (OBRA) regulations of 1987 require such a reassessment in long-term care, but the need for medication continuation should be regularly reassessed and justified for all individuals. Given the high rates of dementia in assisted living homes, similar practices should be instituted in those settings as well.” (C. G. Lyketsos, Johns Hopkins Med. Inst., Baltimore; kostas@jhmi.edu)

Surgery for Obesity: Three articles and a related editorial in this issue of JAMA explore risks and trends in bariatric surgeries. In the lead article (pp. 1903-8), a retrospective cohort study, the rates of 30-day, 90-day, and 1-year postsurgical all-cause mortality were high: 2.0%, 2.8%, and 4.6%. Increased risk of mortality was associated with advanced age, male gender, and lower surgeon volume of bariatric procedures. (D.R. Flum, daveflum@u.washington.edu)

>>>PNN NewsWatch
* Reacting to nine cardiovascular-related deaths among patients in pivotal clinical trials, FDA yesterday asked for more safety data on muraglitazar (Pargluva; Bristol-Myers Squibb, Merck), the first of a new class of dual-action drugs that lower both blood glucose levels and optimize lipoprotein subfractions. The action delays marketing of the drug but means that it could be approved for use in type 2 diabetes and hypercholesterolemia more quickly if the sponsors come up with the requisite safety data.

* Postmarketing reports of hepatic injury—including hepatitis and cholestatic jaundice—suggest that patients with preexisting liver disease who take
duloxetine (Cymbalta, Lilly) may have an increased risk for further liver damage. New labeling required by FDA extends a precaution against using duloxetine in patients with substantial alcohol use to include those patients with chronic liver disease. Duloxetine should not be administered to patients with any hepatic insufficiency, the labeling now recommends.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Oct. 20, 2005 Vol. 12, No. 203
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Oct. 20 issue of the New England Journal of Medicine (content.nejm.org; 2005; 353).

Trastuzumab in HER2-Positive Breast Cancer: Four articles discuss the utility of trastuzumab in women with HER2-positive breast cancer.

Reviewing the role of the
HER2/neu gene, the author of a Perspective article describes four classes of breast cancer: HER2-positive tumors; HER2-negative, hormone-receptor–positive tumors, which can be divided into two classes, favorable and unfavorable, on the basis of genomic and pathobiologic features; and basal-like tumors that express neither HER2 nor hormone receptors (pp. 1652-4). “The growing appreciation of the biologic diversity of breast cancer is forcing treatment into patterns that reflect the underlying biologic features of the tumor, and it challenges us to redefine principles of therapy for each distinctive class of breast cancer,” the writer explains. (H. J. Burstein, Dana–Farber Cancer Inst., Boston)

One trial compared 1 or 2 years of trastuzumab given every 3 weeks in 5,081 patients with HER2-positive and node-negative or node-positive breast cancer who had completed locoregional therapy and at least four cycles of neoadjuvant or adjuvant chemotherapy (pp. 1659-72). Reporting for the Herceptin Adjuvant (HERA) Trial Study Team, the authors provide these results for the 1-year and control groups: “At the first planned interim analysis (median follow-up of one year), 347 events (recurrence of breast cancer, contralateral breast cancer, second nonbreast malignant disease, or death) were observed: 127 events in the trastuzumab group and 220 in the observation group. The unadjusted hazard ratio for an event in the trastuzumab group, as compared with the observation group, was 0.54 (95 percent confidence interval, 0.43 to 0.67; P < 0.0001 by the log-rank test, crossing the interim analysis boundary), representing an absolute benefit in terms of disease-free survival at two years of 8.4 percentage points. Overall survival in the two groups was not significantly different (29 deaths with trastuzumab vs. 37 with observation). Severe cardiotoxicity developed in 0.5 percent of the women who were treated with trastuzumab.” (M. J. Piccart-Gebhart, Jules Bordet Inst., Brussels, Belgium;
martine.piccart@bordet.be)

Among women with surgically removed HER2-positive breast cancer in the National Surgical Adjuvant Breast and Bowel Project trial B-31 or the North Central Cancer Treatment Group trial N9831, outcomes were improved when trastuzumab was combined with paclitaxel after doxorubicin and cyclophosphamide chemotherapy (pp. 1673-84). “By March 15, 2005, 394 events (recurrent, second primary cancer, or death before recurrence) had been reported, triggering the first scheduled interim analysis,” the researchers report. “Of these, 133 were in the trastuzumab group and 261 in the control group (hazard ratio, 0.48; P < 0.0001). This result crossed the early stopping boundary. The absolute difference in disease-free survival between the trastuzumab group and the control group was 12 percent at three years. Trastuzumab therapy was associated with a 33 percent reduction in the risk of death (P = 0.015). The three-year cumulative incidence of class III or IV congestive heart failure or death from cardiac causes in the trastuzumab group was 4.1 percent in trial B-31 and 2.9 percent in trial N9831.” (C. E. Geyer, Jr., Allegheny Cancer Ctr., Pittsburgh;
cgeyer@wpahs.org)

An editorialist notes subtle yet key differences between these two similar reports (pp. 1734-6): “One third of patients included in the HERA trial had lymph-node–negative breast cancer. This would indicate a better overall prognosis for this patient population. However, the disease-free survival curves of the two reports indicate that both the control group and the trastuzumab group of the combined North American report fared better than the corresponding groups in the HERA trial. It is tempting to hypothesize that this difference is partly explained by differences in the schedule of administration and in the adjuvant chemotherapy regimens used: only 26 percent of the patients in the HERA trial received a taxane, whereas all patients in the combined analysis received paclitaxel.” (G. N. Hortobagyi, U. Texas M.D. Anderson Cancer Ctr., 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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Oct. 21, 2005 Vol. 12, No. 204
Providing news and information about medications and their proper use

>>>Chest Highlights
Source
: Oct. issue of Chest (www.chestjournal.org; 2005; 128).

Drug Effects in Comorbid Rhinitis, Asthma: Fluticasone propionate/salmeterol (FPS) was just as effective in treatment of persistent asthma as when fluticasone propionate aqueous nasal spray (FPANS) or montelukast was added, but the latter agents provided greater benefits in relieving symptoms of seasonal allergic rhinitis (pp. 1910-20). That conclusion comes from a 4-week study of 863 adult and adolescent patients with both conditions: “FPANS added to FSC resulted in superior outcomes for daytime total nasal symptom scores (D-TNSS) and individual daytime nasal specific symptoms (congestion, rhinorrhea, sneezing, and itching) compared with montelukast plus FSC and placebo plus FSC (p < 0.001). Montelukast plus FSC was superior to placebo plus FSC only for D-TNSS and itching and sneezing. Morning [peak expiratory flow], asthma symptoms, and rescue albuterol use improved significantly (p < 0.001) in all treatment groups, but improvements were comparable across the treatment groups.” (R. A. Nathan, Asthma and Allergy Associates, Colorado Springs, Colo.; drrnathan@aol.com)

Addition of Montelukast to Antiasthma Regimens: Some patients with asthma treated with inhaled corticosteroids can benefit from addition of montelukast to their regimens, according to a study that assessed suppression of inflammation (pp. 1958-63). Using exhaled cysteinyl-leukotriene and leukotriene B4 as markers for incomplete suppression, the authors found, “We detected cys-LTs in exhaled breath condensate in 25 of 50 patients; however, in the normal nonasthmatic subjects, cys-LTs were below the limit of detection. After treatment with montelukast, there was a fall in cys-LT concentrations from 14.6 ± 3.3 to 8.5 ± 2.6 pg/mL after 2 weeks (p > 0.05) and to 3.9 ± 1.3 pg/mL after 4 weeks (p < 0.01). Exhaled LTB4 levels were also elevated. After treatment with montelukast, LTB4 levels fell from 33.0 ± 3.9 to 20.4 ± 2.5 pg/mL after 2 weeks of treatment (p < 0.05), and to 17.0 ± 2.2 pg/mL after 4 weeks of treatment (p < 0.01). These changes in exhaled cys-LT and LTB4 were associated with significant improvements in [asthma quality of life] scores.” (P. J. Barnes, Imperial Coll., London; p.j.barnes@imperial.ac.uk)

Heroin, Cocaine Use Among Urban Asthmatics: Adults presenting to urban emergency departments with asthmatic exacerbations may need to be screened for presence of heroin and cocaine, conclude authors of study showing that such use is common and associated with a need for intubation (pp. 1951-7). In a retrospective chart review, users were those admitting to use of either drug within 24 hours of symptom onset or who had a positive drug screen. “27.6% (42 of 152 patients) used cocaine with or without heroin and were classified as cocaine users, while 30.9% (47 of 152 patients) used heroin with or without cocaine and were classified as heroin users,” write the researchers. “Cocaine users had longer mean lengths of hospital stay than nonusers (3.4 days vs 2.5 days; p < 0.049). Intubation and ICU admission were more common among cocaine users than nonusers (21.4% vs 2.3%, respectively [p = 0.0006]; 31.0% vs 11.5%, respectively [p = 0.0068]). Heroin users were also intubated more frequently than nonusers (17.0% vs 2.3%, respectively; p = 0.0036). Neither the length of hospital stay nor the percentage of ICU admissions was significantly different between heroin users and nonusers.” (M. Levine, mdlevine@partners.org)

Length of Antibiotic Therapy for AECB: For treating acute exacerbations of chronic bronchitis, 5 days of telithromycin is just as effective and well tolerated as 10 days of clarithromycin, and health resource use is lower, according to a study of 456 patients at 105 centers in 14 countries (pp. 1980-8). Clinical cure rates and bacteriologic outcomes were statistically similar with the two drugs, and those on telithromycin had significantly fewer hospitalizations for respiratory conditions, AECB-related emergency department visits, and unscheduled outpatient visits. (C. Fogarty, Spartanburg Pharmaceutical Research, Spartanburg, S.C.; cmf@bonetesting.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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Oct. 24, 2005 Vol. 12, No. 205
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Early-release articles from JAMA (www.jama.com; 2005; 294).

Safety of Muraglitazar: The investigational agent muraglitazar, a dual-action agent that lowers both glucose and lipids, increases patients’ risk of death, major cardiovascular events (myocardial infarction, stroke, or transient ischemic attacks), and congestive heart failure, according to an analysis of company data provided last month to an FDA advisory panel (doi:10.1001/jama.294.20.joc50147). Despite the panel’s near-unanimous recommendation that the agent be approved, FDA last week called for more safety data on the drug (see PNN, Oct. 19, Aug. 23). Among the problems identified in this study were the following: “In the muraglitazar-treated patients, death, MI, or stroke occurred in 35 of 2374 (1.47%) patients compared with 9 of 1351 (0.67%) patients in the combined placebo and pioglitazone treatment groups (controls) (relative risk [RR], 2.23; 95% confidence interval [CI], 1.07–4.66; P = .03). For the more comprehensive outcome measure that included TIA and CHF, the incidence was 50 of 2374 (2.11%) for muraglitazar compared with 11 of 1351 (0.81%) for controls (RR, 2.62; 95% CI, 1.36–5.05; P = .004). Relative risks for each of the individual components of the composite end point exceeded 2.1 but were not statistically significant. Incidence of adjudicated CHF was 13 of 2374 (0.55%) muraglitazar-treated patients and 1 of 1351 controls (0.07%) (RR, 7.43; 95% CI, 0.97–56.8; P = .053).” (S. E. Nissen, Cleveland Clinic Foundation, Cleveland; nissens@ccf.org)

An editorialist provides this perspective on muraglitazar (doi:10.1001/jama.294.20.jed50074): “What future studies are now required to allay these safety concerns? The sponsor has proposed a pharmacovigilance (observational) study of muraglitazar compared with conventional type 2 diabetes treatments in 15,000 patients with annual questionnaires during 5-year follow-up. While well-performed observational studies may provide useful information on drug safety, residual concerns will generally remain due to possible selection or channeling biases. A large premarketing safety trial as proposed by Nissen et al will provide more secure evidence and has an additional advantage of limiting risk only to study participants while safety concerns are being assessed.” (J. M. Brophy,
james.brophy@mcgill.ca)

>>>Lancet Report
Source:
Early-release articles from Lancet (www.thelancet.com; 2005; 366).

Beta-Blockers & Hypertension: Used as first-line therapies for hypertension, beta-blockers have “less than optimum” effects, according to a meta-analysis of 13 randomized controlled trials (DOI:10.1016/S0140-6736(05)67573-3). “The relative risk of stroke was 16% higher for beta-blockers (95% CI 4–30%) than for other drugs” write the authors. “There was no difference for myocardial infarction. When the effect of beta-blockers was compared with that of placebo or no treatment, the relative risk of stroke was reduced by 19% for all beta-blockers (7–29%), about half that expected from previous hypertension trials. There was no difference for myocardial infarction or mortality.” (L. H. Lindholm, Umeå U. Hosp., Umeå, Sweden; Larsh.lindholm@fammed.umu.se)

>>>PNN JournalWatch
* The Psychological Impact of Alopecia, in BMJ, 2005; 331: 951–3. Reprints: www.bmj.org; N. Hunt, U. Nottingham, Nottingham, U.K.

* Renal Failure Secondary to Acute Tubular Necrosis: Epidemiology, Diagnosis, and Management, in
Chest, 2005; 128: 2847–63. Reprints: www.chestjournal.org; N. Gill, Cleveland Clinic Foundation, Cleveland; gilln1@ccf.org

* Adjuvant Chemotherapy for Early-Stage Non-small Cell Lung Cancer, in
Chest, 2005; 128: 2933–43. Reprints: www.chestjournal.org; N. B. Leighl, Toronto; Natasha.Leighl@uhn.on.ca

* COPD: A Dust-Induced Disease?, in
Chest, 2005; 128: 3055–64. Reprints: www.chestjournal.org; C. E. Girod, carlos.girod@utsouthwestern.edu

* The Potential Use of Type-5 Phosphodiesterase Inhibitors in Coronary Artery Bypass Graft Surgery, in
Chest, 2005; 128: 3065–73. Reprints: www.chestjournal.org; A. A. Arifi, Chinese U. Hong Kong, Hong Kong; arifi64@surgery.cuhk.edu.hk

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Oct. 25, 2005 Vol. 12, No. 206
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Oct. 24 issue of Archives of Internal Medicine (www.archinternmed.com; 2005; 165).

Ribavirin, Interferon, & Hepatitis C Infection: Mortality and morbidity are reduced by 54% by the addition of ribavirin to interferon treatment of chronic hepatitis C infection, according to a systematic review and meta-analysis of 72 trials involving 9,991 patients (pp. 2206-12). “Treatment with ribavirin plus interferon [also] significantly improved sustained viral clearance in treatment-naive patients (risk ratio, 0.72; 95% CI, 0.68–0.76), relapsers (risk ratio, 0.63; 95% CI, 0.54–0.73), and nonresponders (risk ratio, 0.89; 95% CI, 0.84–0.94). Combination therapy also significantly improved liver histologic response. The effects on quality of life are unclear. However, combination therapy significantly increased the risk of hematological, dermatological, gastrointestinal, and several other types of adverse events.” (J. Brok, Cochrane Hepato-Biliary Group, Copenhagen, Denmark; jbrok@ctu.rh.dk)

Statins, Lipids, & Breast Cancer: Lowering of serum cholesterol levels and use of lipid-lowering drugs, including statins, are not associated with either increases or decreases in women’s risk of breast cancer, concludes an analysis of data from the Nurses Health Study (pp. 2264-71). Based on up to 12 years of follow-up for 79,994 women initially aged 42–69 years, the researchers report, “Overall, we documented 3177 incident cases of invasive breast cancer. Compared with nonusers, current lipid-lowering drug users experienced similar breast cancer risk (multivariate relative risk [RR], 0.99; 95% confidence interval [CI], 0.86–1.13). Current use of statins also was not significantly associated with breast cancer risk (RR, 0.91; 95% CI, 0.76–1.08). Associations by duration of current use were similarly null. Self-reported serum cholesterol levels were not associated with breast cancer risk in postmenopausal women with levels of 240 mg/dL or higher (6.22 mmol/L) compared with less than 180 mg/dL (<4.66 mmol/L) (RR, 1.04; 95% CI, 0.91–1.17).” (A. H. Eliassen, heather.eliassen@channing.harvard.edu)

Hemoglobin Levels & Mortality: Both low and high concentrations of hemoglobin are associated with increased mortality, report authors who studied 5,888 community-dwelling elderly men and women for a mean of 11.2 years (pp. 2214-20). The investigators note: “A reverse J-shaped relationship with mortality was observed; age-, sex-, and race-adjusted hazard ratios (95% confidence interval [CI]) in the first and fifth quintiles, compared with the fourth quintile, were 1.42 (95% CI, 1.25–1.62) and 1.24 (95% CI, 1.09–1.42). After multivariate adjustment, these hazard ratios were 1.33 (95% CI, 1.15–1.54) and 1.17 (95% CI, 1.01–1.36). The demographic- and fully-adjusted hazard ratios of anemia for mortality were 1.57 (95% CI, 1.38–1.78) and 1.38 (95% CI, 1.19–1.54). Adjustment for causes and consequences of anemia (renal function, inflammation, or frailty) did not reduce associations.” (M. Cushman, U. Vermont, Colchester; mary.cushman@uvm.edu)

>>>PNN NewsWatch
* A 10-city effort by the APhA Foundation and GlaxoSmithKline to improve diabetes care is highlighted in this morning’s Wall Street Journal. “Specially trained pharmacists are to be matched with patients and help manage their diabetes,” the article notes. “Employers could expect to pay $350 to $450 per patient for the coaching by pharmacists in the first year, a figure that would drop later, the project spokeswoman said. The project is expected to begin in January.” The effort builds on the success of the Asheville Project, the Journal explains, and the Pittsburgh Business Group on Health and the Northwest Georgia Healthcare Partnership have already inked deals to participate in the new project.

* Use of
pemoline products should be discontinued and patients transitioned to other medications for attention-deficit/hyperactivity syndrome, FDA warned yesterday. The overall risk of hepatotoxicity with this drug outweighs its benefits, the agency has concluded. Abbott had stopped sales and marketing of Cylert in May of this year, but the new warning extends to distributors of generic products.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Oct. 26, 2005 Vol. 12, No. 207
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Oct. 26 issue of JAMA (www.jama.com; 2005; 294).

Impact of Pediatric Pneumococcal Vaccine on Infections in Older Adults: Use of the 7-valent conjugate pneumococcal vaccine in young children is benefiting adults older than 50 through reductions in carriage and transmission of Streptococcus pneumoniae, concludes a population-based study (pp. 2043-51). Considering eight surveillance areas across the U.S., the investigators determined, “Incidence of invasive pneumococcal disease among adults aged 50 years or older declined 28% (95% confidence interval [CI], –31% to –24%), from 40.8 cases/100,000 in 1998–1999 to 29.4 in 2002–2003. Among those aged 65 years or older, the 2002–2003 rate (41.7 cases/100,000) was lower than the Healthy People 2010 goal (42 cases/100,000). Among adults aged 50 years or older, incidence of disease caused by the 7 conjugate vaccine serotypes declined 55% (95% CI, –58% to –51%) from 22.4 to 10.2 cases/100,000. In contrast, disease caused by any of the 16 serotypes only in polysaccharide vaccine did not change, and disease caused by serotypes not in either vaccine increased somewhat, from 6.0 to 6.8 cases/100 000 (13%; 95% CI, 1% to 27%). Between 1998–1999 and 2002–2003, the proportion of case-patients with human immunodeficiency virus infection increased from 1.7% (47/2737) to 5.6% (124/2231) (P < .001), and those with any comorbid condition that is an indication for pneumococcal polysaccharide vaccination increased from 62.3% (1842/2955) to 72.0% (1721/2390) (P < .001).”

Based on these results, the authors conclude, “Healthy adults may be benefiting more than chronically ill adults from the introduction of PCV-7 for children. The relative frequency of several comorbid conditions, including diabetes and immunocompromising conditions, increased among patients with invasive pneumococcal disease over the reporting period. Most notably, the proportion of those aged 50 through 64 years with HIV infection increased more than 2-fold, from 4.9% in 1998–1999 to 13.5% in 2002–2003.... Persons with immunocompromising conditions or other comorbid conditions may be more susceptible to invasive disease caused by certain serotypes in comparison with healthier individuals. In the conjugate vaccine era, targeting persons with chronic conditions for receipt of polysaccharide vaccine remains a useful strategy for reaching those at highest risk for invasive disease.” (C. A. Lexau, Minn. Dept. of Health, St. Paul;
catherine.lexau@health.state.mn.us)

Patents-Based Pharmaceutical Development: The rationale of, problems with, and potential reforms for patents-based development of pharmaceuticals are reviewed (pp. 2075-82): “Six major problems with the patent system are (1) recovery of research costs by patent monopoly reduces access to drugs; (2) market demand rather than health needs determines research priorities; (3) resources between research and marketing are misallocated; (4) the market for drugs has inherent market failures; (5) overall investment in drug research and development is too low, compared with profits; and (6) the existing system discriminates against US patients. Potential solutions fall into 3 categories: change in drug pricing through either price controls or tiered pricing; change in drug industry structure through a "buy-out" pricing system or with the public sector acting as exclusive research funder; and change in development incentives through a disease burden incentive system, orphan drug approaches, or requiring new drugs to demonstrate improvement over existing products prior to US Food and Drug Administration approval. We recommend 4 complementary reforms: (1) having no requirement to test new drug products against existing products prior to approval but requiring rigorous comparative postapproval testing; (2) international tiered pricing and systematic safeguards to prevent flow-back; (3) increased government-funded research and buy-out for select conditions; and (4) targeted experiments using other approaches for health conditions in which there has been little progress and innovation over the last few decades.” (E. J. Emanuel, eemanuel@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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Oct. 27, 2005 Vol. 12, No. 208
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Oct. 27 issue of the New England Journal of Medicine (content.nejm.org; 2005; 353).

Impact of Screening vs. Therapy on Breast Cancer: Improved screening mammography—resulting in earlier detection—and better adjuvant therapy contributed to a 24% decrease in mortality rate from breast cancer between 1990 and 2000, according to an analysis of data from seven clinical sites that use difference screening/treatment models (pp. 1784-92). “The proportion of the total reduction in the rate of death from breast cancer attributed to screening varied in the seven models from 28 to 65 percent (median, 46 percent), with adjuvant treatment contributing the rest,” the authors write. “The variability across models in the absolute contribution of screening was larger than it was for treatment, reflecting the greater uncertainty associated with estimating the benefit of screening.” (D. A. Berry, dberry@mdanderson.org)

An editorialist, commenting on a related research article on the differences between digital and film mammography (pp. 1773-83), made these observations (pp. 1846-7): “The availability of high-quality images and skilled interpretation and the screening of all women who are eligible for it will yield optimal benefits. Although digital mammography can detect cancers that might be missed by film mammography, the opposite will be true for some women. All women of the appropriate age should be screened. When both types of equipment are available, the decision to use digital or film equipment should be tailored to the individual woman. If only one type of equipment is available, women should recognize that most of the benefit of mammographic screening is derived from the test itself and not from the way the image is stored.” (D. D. Dershaw, Memorial Sloan Kettering, New York)

Treatment of Depression: In a review of medical management of depression, an author provides these insights into investigational drug research (pp. 1819-34): “New antidepressive treatments currently being evaluated include vagal-nerve stimulation, rapid transcranial magnetic stimulation, mifepristone (a glucocorticoid antagonist for treatment of delusional depression), and substance P antagonists. Other targets for future agents include neuropeptide Y, vasopressin V1b, N-methyl-d-aspartate, nicotinic cholinergic, delta-opiate, cannabinoid, dopamine D1, cytokine, and corticotropin-releasing factor 1 receptors, as well as GABA, intracellular messenger systems, and transcription, neuroprotective, and neurogenic factors.” (J. J. Mann, N. Y. State Psychiatric Inst., New York City; jjm@columbia.edu)

Physician Brain Drain: Immigration of physicians from less-developed countries to the U.S. and other industrialized nations is reducing the availability of medical care in lower-income countries, concludes an author who analyzed WHO data to report these emigration factors (pp. 1810-8): “International medical graduates constitute between 23 and 28 percent of physicians in the United States, the United Kingdom, Canada, and Australia, and lower-income countries supply between 40 and 75 percent of these international medical graduates. India, the Philippines, and Pakistan are the leading sources of international medical graduates. The United Kingdom, Canada, and Australia draw a substantial number of physicians from South Africa, and the United States draws very heavily from the Philippines. Nine of the 20 countries with the highest emigration factors are in sub-Saharan Africa or the Caribbean.” (F. Mullan, George Washington U., Washington; fmullan@gwu.edu)

>>>PNN NewsWatch
* Abbott Diabetes Care blood glucose meters can be unintentionally switched among units of measure, leading to consumer error in interpretation, FDA is warning.

* Citing 13 reports of liver failure resulting in liver transplant or death,
FDA this week called on health professionals to transition any patients still taking pemoline to other therapies for attention-deficit/hyperactivity disorder. Abbott discontinued sales and marketing of Cylert in May, and all generic manufacturers of the drug have now done likewise.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Oct. 28, 2005 Vol. 12, No. 209
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Nov. issue of Diabetes Care (care.diabetesjournals.org; 2005; 28).

Resistance to Insulin Therapy: Resistance to insulin therapy among patients and providers was substantial in a survey of 2,061 patients with type 2 diabetes who were not taking insulin, 1,109 nurses, and 2,681 physicians on four continents (pp. 2673-9). This reluctance to use insulin should be the focus of interventions targeted at several factors, the authors conclude after noting these survey findings: “Patient and provider attitudes differ significantly across countries, controlling for individual characteristics. Patients rate the clinical efficacy of insulin as low and would blame themselves if they had to start insulin therapy. Self-blame is significantly lower among those who have better diet and exercise adherence and less diabetes-related distress. Patients who are not managing their diabetes well (poor perceived control, more complications, and diabetes-related distress) are significantly more likely to see insulin therapy as potentially beneficial. Most nurses and general practitioners (50–55%) delay insulin therapy until absolutely necessary, but specialists and opinion leaders are less likely to do so. Delay of insulin therapy is significantly less likely when physicians and nurses see their patients as more adherent to medication or appointment regimens, view insulin as more efficacious, and when they are less likely to delay oral diabetes medications.” (M. Peyrot, Loyola Coll., Baltimore; mpeyrot@loyola.edu)

Ruboxistaurin for Diabetic Nephropathy: In a 1-year study of 123 patients with type 2 diabetes and nephropathy, ruboxistaurin reduced albuminuria and the estimated glomerular filtration rates (pp. 2686-90). The agent, which selectively inhibits protein kinase C-beta and ameliorates kidney disease in animal models of diabetes, provided these improvements in albumin-to-creatinine ratio: “At baseline, urinary ACR was 764 ± 427 mg/g (means ± SD), and eGFR was 70 ± 24 ml/min per 1.73 m2. Systolic and diastolic blood pressures were 135 ± 14 and 75 ± 9 mmHg, respectively. HbA1c was 8.0 ± 1.2%. After 1 year, urinary ACR decreased significantly (–24 ± 9%) in participants treated with ruboxistaurin (P = 0.020) and nonsignificantly (–9 ± 11%) in the placebo group (P = 0.430). The ACR-lowering effect of ruboxistaurin appeared by 1 month. eGFR did not decline significantly in the ruboxistaurin group (–2.5 ± 1.9 ml/min per 1.73 m2) (P = 0.185), whereas the placebo group lost significant eGFR over 1 year (–4.8 ± 1.8 ml/min per 1.73 m2) (P = 0.009). Between-group differences for changes in ACR and eGFR were not statistically significant, but this pilot study was underpowered to determine such differences.” (K. R. Tuttle, The Heart Inst. and Sacred Heart Med. Ctr., Spokane, Wash.; ktuttle@this.org)

Pitavastatin Therapy in Early Nephropathy: Among 58 patients with type 2 diabetes and 20 healthy, age-matched controls, pitavastatin appeared to ameliorate the tubulointerstitial damage of early diabetic nephropathy (pp. 2728-32). Over a 1-year period, those patients with pre-existing microalbuminuria and taking pitavastatin had significant improvements in urinary albumin excretion and urinary liver-type fatty acid–binding protein. (H. Koide, Koto Hosp., Tokyo; hkoide@koto-hospital.or.jp)

Lifestyle Education: Lifestyle education in high-risk individuals is an effective means of reducing both 2-hour plasma glucose and relative risk for type 2 diabetes and may be a useful tool in preventing diabetes, according to a meta-analysis of eight randomized controlled trials (pp. 2780-6). “Lifestyle education intervention reduced 2-h plasma glucose by 0.84 mmol/l (95% CI 0.39–1.29) compared with the control group,” note the authors. “The 1-year incidence of diabetes was reduced by 50% (RR 0.55, 95% CI 0.44–0.69) compared with the control group. Results were stable and little changed if data were analyzed by subgroups or other statistical models. Funnel plots revealed no selection bias.” (K. Yamaoka, Natl. Inst. of Public Health, Wako, Saitama, Japan; yamaoka@niph.go.jp)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Oct. 31, 2005 Vol. 12, No. 210
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
Early-release articles from and the Oct. 29 issue of Lancet (www.thelancet.com; 2005; 366).

Gefitinib for NSCLC: In a Phase III trial in 1,692 patients with locally advanced or metastatic nonsmall-cell lung cancer, gefitinib produced no significant improvement when used as a second- or third-line treatment (pp. 1527-37) Only patients who had never smoked and those of Asian origin showed evidence of benefit, the authors report, adding, “At median follow-up of 7.2 months, median survival did not differ significantly between the groups in the overall population (5.6 months for gefitinib and 5.1 months for placebo; hazard ratio 0.89 [95% CI 0.77–1.02], p = 0.087) or among the 812 patients with adenocarcinoma (6.3 months vs 5.4 months; 0.84 [0.68–1.03], p = 0.089). Preplanned subgroup analyses showed significantly longer survival in the gefitinib group than the placebo group for never-smokers (n = 375; 0.67 [0.49–0.92], p = 0.012; median survival 8.9 vs 6.1 months) and patients of Asian origin (n = 342; 0.66 [0.48–0.91], p = 0.01; median survival 9.5 vs 5.5 months). Gefitinib was well tolerated, as in previous studies.” (N. Thatcher, Christie Hosp., Manchester, U.K.; nick.thatcher@christie-tr.nwest.nhs.uk)

Fall Prevention in Elderly: Because of the aging population in developed and developing countries, fall prevention will be an increasingly important concern for elderly patients, advise authors of a review article (DOI:10.1016/S0140-6736(05)67604-0). “Many methods and programmes to prevent such injuries already exist, including regular exercise, vitamin D and calcium supplementation, withdrawal of psychotropic medication, cataract surgery, professional environment hazard assessment and modification, hip protectors, and multifactorial preventive programmes for simultaneous assessment and reduction of many of the predisposing and situational risk factors,” the investigators write. “To receive broader-scale effectiveness, these programmes will need systematic implementation. Care must be taken, however, to rigorously select the right actions for those people most likely to benefit, such as vitamin D and calcium supplementation and hip protectors for elderly people living in institutions.” (P. Kannus, U. K. K. Inst. for Health Promotion Research, Tampere, Finland; pekka.kannus@uta.fi)

>>>PNN NewsWatch
* FDA on Friday extended the deadlines for the iPledge program for both professionals and patients. Wholesalers and pharmacies wishing to obtain generic isotretinoin or brandname Accutane must now be registered and activated in the www.ipledge.com Web site by Dec. 30, and prescribers must sign up by Mar. 1, 2006. Patient registration, which was to have begun on Nov. 1, will now begin on Dec. 30, and their deadline for registration is now Mar. 1, 2006.

>>>PNN JournalWatch
* Effect of Incorporating a 10 Minute Point of Care Test for Salivary Nicotine Metabolites into a General Practice Based Smoking Cessation Programme: Randomised Controlled Trial, in BMJ, 2005; 331: 999 ff. Reprints: www.bmj.org; I. L.. Chapple, U. Birmingham, Birmingham, U.K.; I.L.C.Chapple@bham.ac.uk

* Impediments to Timely Diagnosis of Alzheimer's Disease in African Americans, in
Journal of the American Geriatrics Society, 2005; 53: 2012 ff. Reprints: www.blackwell-synergy.com; P. C. Clark, pcclark@emory.edu

* Practice Guidelines for the Diagnosis and Management of Skin and Soft-Tissue Infections, in
Clinical Infectious Diseases, 2005; 41: 1373–406. Reprints: www.journals.uchicago.edu/CID; D. L.. Stevens, VA Med. Ctr., Boise, Idaho; dlsteven@mindspring.com

* Hepatitis B and Liver Transplantation, in
Clinical Infectious Diseases, 2005; 41: 1461–6. Reprints: www.journals.uchicago.edu/CID; K. V. Kowdley, kkowdley@u.washington.edu

* Lithium in the Prevention of Suicidal Behavior and All-Cause Mortality in Patients with Mood Disorders: A Systematic Review of Randomized Trials, in
American Journal of Psychiatry, 2005; 162: 1805–19. Reprints: ajp.psychiatryonline.org; A. Cipriani.

* National Adherence to Evidence-Based Guidelines for the Prescription of Nonsteroidal Anti-Inflammatory Drugs, in
Gastroenterology, 2005; 129: 1171–8. Reprints: www.gastrojournal.org; N. S. Abraham, VA Med. Ctr., Houston; nabraham@bcm.tmc.edu

* Molecular Regulation of Platelet-Dependent Thrombosis, in
Circulation, 2005; 112: 2725–34. Reprints: circ.ahajournals.org; J. E. Freedman, Boston U., Boston; freedmaj@bu.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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Nov. 1, 2005 Vol. 12, No. 211
Providing news and information about medications and their proper use

>>>Nelarabine Approved for Refractory T-ALL, T-LBL
Nelarabine, a water-soluble prodrug of the nucleoside analogue ara-G, has been approved by FDA for marketing as Arranon (GlaxoSmithKline). The orphan drug is indicated for treatment of the small population of children and adults with T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) that does not respond to or has relapsed following treatment with at least two chemotherapy regimens. Of the 1,600 patients newly diagnosed annually with T-ALL or T-LBL in the United States, an estimated 500 are candidates for nelarabine treatment, including some 200 children.

Nelarabine received an accelerated approval from FDA based on its induction of complete responses in those taking the drug in two clinical trials conducted by the National Cancer Institute. Among 28 adults and 39 children who had multiple relapses following, or were refractory to, at least two prior induction regimens, 21% of adults and 23% of children achieved a complete response or a complete response without full hematologic recovery when nelarabine was given as a single agent. Remissions were generally long enough to allow for stem cell transplant procedure, often the intent following successful induction of remission. Following nelarabine, adults and children had median overall survivals of 21 and 13 weeks, respectively.

Hematologic toxicity was the most common Grade 3 (moderate) or 4 (severe) adverse event in clinical studies. Consistent with various other cytotoxic agents, nelarabine is also associated with neurologic events, some considered severe. Close monitoring for neurologic events is strongly recommended, and dosing of nelarabine should be discontinued for neurologic events of Grade 2 or greater. Other adverse events included fatigue, nausea, vomiting, and diarrhea.

>>>Internal Medicine Report
Source:
Nov. 1 issue of the Annals of Internal Medicine (www.annals.org; 2005; 143).

Relapse/Resistance in ANCA Small-Vessel Vasculitis: Among 350 patients newly diagnosed with antineutrophil cytoplasmic antibody–associated small-vessel vasculitis, women, blacks, and those with severe kidney disease proved more resistant to initial induction therapy with glucocorticoids and cyclophosphamide (pp. 621-31). This information comes from a longitudinal study conducted between 1985 and 2003, with patients followed for a median of 49 months. “Treatment resistance affected 23% of 334 treated patients and was associated with female sex, black ethnicity, and presentation with severe kidney disease (odds ratio per serum creatinine elevation of 100 µmol/L [1.13 mg/dL], 1.28 [95% CI, 1.16 to 1.39]),” write the authors. “The following factors were associated with relapse in 258 (77%) patients who attained remission: seropositivity for anti-PR3 antibodies (hazard ratio, 1.87 [CI, 1.11 to 3.14]) and disease of the lung (hazard ratio, 1.71 [CI, 1.04 to 2.81]) or upper respiratory tract (hazard ratio, 1.73 [CI, 1.04 to 2.88]). Relapses occurred in 26% of patients with no risk factors versus 73% of patients with all 3 risk factors (hazard ratio, 3.7 [CI, 1.4 to 9.7]). Among 143 patients attaining remission who subsequently stopped all immunosuppressant therapy, relapse rates were similar for those who had received cyclophosphamide therapy for 6 months or less (34%) compared with those treated for a longer duration (35%), even after adjusting for risk factors for relapse (hazard ratio, 1.41 [CI, 0.80 to 2.50]).” (S. L. Hogan, slh@med.unc.edu)

In a second study that focused specifically on patients with Churg–Strauss syndrome, ANCA phenotypic positivity at diagnosis was associated with renal involvement, peripheral neuropathy, and biopsy-proven vasculitis, whereas negative ANCA status was associated with heart disease and fever (pp. 632-8). These data suggest that ANCA-positive and ANCA-negative Churg–Strauss syndrome may differ, with positivity indicating “inflammation and necrosis of small vessels” that reflect “a predominantly vasculitic pattern,” the authors note. (L. Guillevin, Hôpital Cochin, Université Paris 5–René Descartes, Paris;
loic.guillevin@cch.ap-hop-paris.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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Nov. 2, 2005 Vol. 12, No. 212
Providing news and information about medications and their proper use

>>>Geriatrics Highlights
Source:
Nov. issue of the Journal of the American Geriatrics Society (www.blackwell-synergy.com/toc/jgs/53/11; 2005; 53).

Pharmacist-Led Antithrombotic Therapy: In an Australian teaching hospital, a pharmacist-coordinated multidisciplinary review process successfully increased the use of antithrombotic therapy among 218 patients with atrial fibrillation and a mean age of 85.2 years (pp. 1912 ff). Using evidence-based algorithms to address known barriers and limitations to warfarin use, the researchers achieved these results: “As a result of the intervention, 78 patients (35.8%) required changes to their existing antithrombotic therapy. Of these changes, 60 (76.9%) were ‘upgrades’ to more-effective treatment options (e.g., from no therapy to any agent or from aspirin to warfarin). The remaining 18 (23.1%) changes were ‘downgrades’ to less-effective, albeit safer, options. Despite a significant increase in anti thrombotic use overall (59.6% vs 81.2%, P < .001), fewer patients received warfarin postintervention, after having been assessed as inappropriate candidates (20.7% vs 17.4%, P = .39).” (B. V. Bajorek, U. Sydney, Sydney; beatab@pharm.usyd.edu.au)

Vitamin D for Fall Prevention: Even among older patients who are not deficient, vitamin D supplements administered for 2 years can reduce their incidence of falls, according to a randomized trial conducted in 60 assisted-living facilities and 89 nursing homes in Australia (pp. 1881 ff). Among 625 study participants, the investigators found these results: “In intention-to-treat analysis, the incident rate ratio for falling was 0.73 (95% confidence interval (CI) = 0.57–0.95). The odds ratio for ever falling was 0.82 (95% CI = 0.59–1.12) and for ever fracturing was 0.69 (95% C I= 0.40–1.18). An a priori subgroup analysis of subjects who took at least half the prescribed capsules (n = 540), demonstrated an incident rate ratio for falls of 0.63 (95% CI = 0.48–0.82), an odds ratio (OR) for ever falling of 0.70 (95% CI = 0.50–0.99), and an OR for ever fracturing of 0.68 (95% CI = 0.38–1.22).” (L. Flicker, U. Western Australia, Royal Perth Hosp., Perth, Australia; leonflic@cyllene.uwa.edu.au)

Adjuvant Tamoxifen in Breast Cancer: An evidence-based approach to tamoxifen use in 496 women with breast cancer was evident in treatment recommendation forms completed by physicians at community and academic hospitals in four states between 1996 and 1998 (pp. 1889 ff). The authors conclude, “Estrogen receptor status most strongly influenced physicians’ assessments of tamoxifen’s effectiveness in individual patients; this effectiveness was not found to be associated with advancing patient age.” (T. L. Lash, Boston U. Med. Ctr., Boston; tlash@bu.edu)

>>>PNN NewsWatch
* In a speech delivered at NIH in Bethesda, Md., President George W. Bush yesterday called on Congress to appropriate $7.1 billion to fund a three-pronged strategy aimed at preparing the United States for a possible pandemic of H5N1 (avian) influenza. The President’s plan is based on detection of influenza outbreaks anywhere in the world, stockpiling of vaccines and antiviral medications and improving the nation’s vaccine-production capacity, and being ready to respond at federal, state, and local levels if a pandemic reaches America.

* An article in today’s
JAMA (2005; 294: 2188–94) supports a recent Advisory Committee on Immunization Practices decision to recommend influenza vaccine for children with neurologic and neuromuscular disease. Assessing a retrospective cohort of patients younger than 21 hospitalized for community-acquired, laboratory-confirmed influenza, the investigators found, “Of 745 children hospitalized with community-acquired laboratory-confirmed influenza, 322 (43%) had 1 or more ACIP-designated high-risk chronic medical conditions. Neurological and neuromuscular disease, [gastroesophageal reflux disease], and history of prematurity were present in 12%, 14%, and 3%, of children, respectively. Thirty-two children (4.3%) developed respiratory failure.” (R. Keren, Children’s Hosp., Philadelphia; keren@email.chop.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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Nov. 3, 2005 Vol. 12, No. 213
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Nov. 3 issue of the New England Journal of Medicine (content.nejm.org; 2005; 353).

Natalizumab for Crohn's Disease: Use of natalizumab in patients with Crohn’s disease is associated with small but nonsignificant benefits that will “need to be weighed against the risk of serious adverse events, including progressive multifocal leukoencephalopathy,” concludes a report of results of two trials (pp. 1912-25). Noting that the controversial agent produced significant responses in a subgroup of responders when continued every 4 weeks, the investigators report, “In the first trial, the natalizumab and placebo groups had similar rates of response (56 percent and 49 percent, respectively; P = 0.05) and remission (37 percent and 30 percent, respectively; P = 0.12) at 10 weeks. Continuing natalizumab in the second trial resulted in higher rates of sustained response (61 percent vs. 28 percent, P < 0.001) and remission (44 percent vs. 26 percent, P = 0.003) through week 36 than did switching to placebo. Serious adverse events occurred in 7 percent of each group in the first trial and in 10 percent of the placebo group and 8 percent of the natalizumab group in the second trial. In an open-label extension study, a patient treated with natalizumab died from progressive multifocal leukoencephalopathy, associated with the JC virus, a human polyomavirus.” (W. J. Sandborn, sandborn.william@mayo.edu)

Using Janus, the god of doors usually depicted with two faces looking in opposite directions, to represent the risks and benefits of natalizumab, an editorialist notes (pp. 1965-8): “For natalizumab, the first anti-[selective adhesion molecules] therapy, to add a new dimension to the treatment of inflammatory bowel disease, it must have an acceptable risk of adverse events. [These] studies found a relatively low rate of immunogenicity or loss of responsiveness. More germane is the apparent unintended consequence of immunodeficiency. Indeed, virtually every agent currently used in the treatment of inflammatory bowel disease creates an iatrogenic form of immunodeficiency and a risk of opportunistic infection. No doubt, the deleterious effects on immune defenses represent the other Janus-like face of the mechanism that confers therapeutic benefit. Some opportunistic infections seem to be selectively associated with individual treatments, presumably illuminating mechanisms important in specific immune defense; for example, the reactivation of latent tuberculosis after the administration of anti–TNF-alpha therapy represents a clinical experiment that illuminated the key role played by TNF-alpha in the control of mycobacteria and other intracellular pathogens.” (D. K. Podolsky, Mass. Genl. Hosp., Boston)

Treatment of Allergic Rhinitis: In a Clinical Practice case report, a writer updates physicians on current concepts in treatment of allergic rhinitis, including the place in therapy of second-generation antihistamines, immunotherapy, and emerging pharmacologic agents (pp. 1934-44): “Mild symptoms of allergic rhinitis are easily ameliorated with either an oral antihistamine or a nasal corticosteroid alone. For patients with moderate-to-severe symptoms of allergic rhinitis with nasal congestion as a predominant finding, such as the student in the vignette, therapy should generally be started with the daily use of a nasal corticosteroid, which would reasonably be combined with a second-generation oral antihistamine.... Therapy should be started before the anticipated appearance of allergens and continue during the time of likely exposure. In the case described, this would mean starting before the appearance of tree pollen in the Baltimore area (usually in early March) and continuing through the peak of the grass-pollen season in May and June. If eye symptoms persist, an ocular antihistamine could be added. If symptom relief is incomplete, if there is a need for a high inhaled dose of a corticosteroid or a systemic corticosteroid, or if rhinitis is complicated by asthma or sinusitis, the initiation of immunotherapy (on the basis of the patient's history and allergy testing) before the next season of symptoms should be considered.” (M. Plaut, mplaut@niaid.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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Nov. 4, 2005 Vol. 12, No. 214
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Nov. issue of Pharmacotherapy (www.pharmacotherapy.org; 2005; 25).

Methadone & QT Intervals: QTc intervals and QT dispersion are both increased modestly among patients taking methadone, according to results of a 118-patient study (pp. 1523-9). QT dispersion—which is interlead variation between QT intervals as measured with a surface ECG—generally “reflects heterogeneous cardiac repolarization and occurs with nonantiarrhythmic agents, such as synthetic opioids,” the authors note. “However, the magnitude of this effect appears to be substantially less with methadone than with antiarrhythmic drugs.” Comparing baseline values and those measured after 6 months of methadone treatment, the study’s results showed, “Mean ± SD baseline QT dispersion was 32.9 ± 12 msec, which increased to 42.4 ± 15 msec (+9.5 ± 18.6 msec, p < 0.0001) after 6 months of therapy. The QTc increased by a similar magnitude (+14.1 msec, p < 0.0001). No QT dispersion value exceeded 100 msec. The only variable associated with a greater increase in QT dispersion was antidepressant therapy (20 vs 8.5 msec, p = 0.04).” (M. J. Krantz, Denver Health Med. Ctr., Denver; Mkrantz@dhha.org)

‘Ensuring’ Gatifloxacin Bioavailability: Peak concentrations and area under the serum concentration–time curve (0 to infinity) for gatifloxacin are reduced when the drug is administered with the nutritional supplement Ensure, concludes an oral bioavailability study conducted in 12 healthy volunteers (pp. 1530-5). Following every-30-minute consumption of five servings of 120 mL of water or Ensure in crossover fashion and gatifloxacin 400 mg with the second serving, study participants had these fluoroquinolone levels: “Comparison of parameters for gatifloxacin administered with water versus those with Ensure showed that Cmax (4.35 ± 0.90 vs 2.41 ± 0.58 mcg/ml, p < 0.0001) and AUC (42.4 ± 10.1 vs 31.3 ± 8.3 mg•hr/L, p < 0.0001) were significantly decreased with Ensure, and bioequivalence was not achieved for either parameter. The geometric least squares mean ratio was 0.553 (90% confidence interval [CI] 0.501–0.611) for Cmax and 0.730 (90% CI 0.664–0.802) for AUC. The median time to reach Cmax was significantly prolonged when gatifloxacin was administered with Ensure versus that with water (2.5 hrs vs 1.0 hr, p = 0.006).” (M. B. Kays, Purdue U., Indianapolis, mkays@iupui.edu)

Predicting Atomoxetine Therapy: Children and adolescents with psychiatric comorbidities, contraindications to stimulants, or relatively heavy use of behavioral health care are most likely to be initially placed on atomoxetine therapy, based on analysis of a managed care claims database with records on 45,144 patients treated with medications for attention-deficit/hyperactivity disorder (pp. 1541-9). “Patients with a claim of ADHD with hyperactivity were 1.50 times more likely to begin therapy with atomoxetine than with any stimulant (95% confidence interval [CI] 1.42–1.58),” the authors explain. “Patients with a history of tics (odds ratio [OR] 3.11, 95% CI 2.54–3.82), anxiety (OR 1.35, 95% CI 1.24–1.48), pervasive developmental disorders (OR 2.00, 95% CI 1.69–2.37), or frequent use of behavioral care services (OR 1.34, 95% CI 1.21–1.48) were predisposed to starting treatment with atomoxetine relative to any stimulant, but patients with obesity were not (OR 0.68, 95% CI 0.53–0.87). A short-acting stimulant was specifically preferred for patients with narcolepsy or hypersomnolence (OR 0.33, 95% CI 0.20–0.56). Alcohol dependence, but not drug dependence or drug abuse, was predictive of the selection of atomoxetine over a short-acting stimulant (OR 2.98, 95% CI 1.25–7.09).” (D. L. Van Brunt, Eli Lilly and Company, Indianapolis)

Beta-Blockers for Asthma, COPD: Atenolol and other beta-blockers, when clinically indicated, should be considered for use in patients with asthma or chronic obstructive pulmonary disorders, concludes a study of 8,390 veterans in Iowa and Nebraska (pp. 1550-9). Assessing resource use in 2000–01, the investigators found no significantly different rates of hospital admission or lengths of stay, but clinic visits were fewer when asthma or COPD was treated with beta-blockers, and hospital admission rates were lower with atenolol. (P. J. Kaboli, peter-kaboli@uiowa.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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Nov. 7, 2005 Vol. 12, No. 215
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
Nov. 5 issue of Lancet (www.thelancet.com; 2005; 366).

Post-MI Clopidogrel + Aspirin: Routine addition of clopidogrel 75 mg daily to aspirin therapy should be considered following acute myocardial infarction, according to results of COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial; also Second Chinese Cardiac Study [CCS-2]; pp. 1607-21). Among 45,852 patients admitted to 1,250 hospitals within 24 hours of suspected acute MI onset, the investigators found, “Allocation to clopidogrel produced a highly significant 9% (95% CI 3–14) proportional reduction in death, reinfarction, or stroke (2121 [9.2%] clopidogrel vs 2310 [10.1%] placebo; p = 0.002), corresponding to nine (SE 3) fewer events per 1000 patients treated for about 2 weeks. There was also a significant 7% (1–13) proportional reduction in any death (1726 [7.5%] vs 1845 [8.1%]; p = 0.03). These effects on death, reinfarction, and stroke seemed consistent across a wide range of patients and independent of other treatments being used. Considering all fatal, transfused, or cerebral bleeds together, no significant excess risk was noted with clopidogrel, either overall (134 [0.58%] vs 125 [0.55%]; p = 0.59), or in patients aged older than 70 years or in those given fibrinolytic therapy.” (Z. Chen, Oxford, U.K.; zhengming.chen@ctsu.ox.ac.uk)

Early Metoprolol After MI: In a second COMMIT analysis, use of early post-MI beta-blocker therapy reduced the risk of reinfarction and ventricular fibrillation but increased the risk of cardiogenic shock (pp. 1622-32). Because the excess risk of cardiogenic shock was particularly evident within the first day after admission, the authors advise starting beta-blocker therapy only after hemodynamics have stabilized. The report notes: “For death, reinfarction, or cardiac arrest, 2166 (9.4%) patients allocated metoprolol had at least one such event compared with 2261 (9.9%) allocated placebo (odds ratio [OR] 0.96, 95% CI 0.90–1.01; p = 0.1). For death alone, there were 1774 (7.7%) deaths in the metoprolol group versus 1797 (7.8%) in the placebo group (OR 0.99, 0.92–1.05; p = 0.69). Allocation to metoprolol was associated with five fewer people having reinfarction (464 [2.0%] metoprolol vs 568 [2.5%] placebo; OR 0.82, 0.72–0.92; p = 0.001) and five fewer having ventricular fibrillation (581 [2.5%] vs 698 [3.0%]; OR 0.83, 0.75–0.93; p = 0.001) per 1000 treated. Overall, these reductions were counterbalanced by 11 more per 1000 developing cardiogenic shock (1141 [5.0%] vs 885 [3.9%]; OR 1.30, 1.19–1.41; p < 0.00001).” (Z. Chen, Oxford, U.K.; zhengming.chen@ctsu.ox.ac.uk)

>>>BMJ Highlights
Source:
Nov. 5 issue of BMJ (www.bmj.org; 2005; 331).

Self-Management of Anticoagulation: Patients on oral anticoagulation can safely and reliably manage their own treatment, a 617-patient study shows, with self-managed patients spending slightly more time in the therapeutic range than did those in a routine-care group (pp. 1057 ff). “No significant differences were found in percentage of time in the therapeutic range between self management and routine care (70% v 68%),” write the authors. “Self managed patients with poor control before the study showed an improvement in control that was not seen in the routine care group. Nine patients (2.8/100 patient years) had serious adverse events in the self managed group, compared with seven (2.7/100 patient years) in the routine care arm (2(df = 1) = 0.02, P = 0.89).” (D. A. Fitzmaurice, U. Birmingham, Birmingham; d.a.fitzmaurice@bham.ac.uk)

>>>PNN JournalWatch
* Meta-Analysis: Secondary Prevention Programs for Patients with Coronary Artery Disease, in Annals of Internal Medicine, 2005; 143: 659–72. Reprints: www.annals.org; F. A. McAlister, Finlay.McAlister@ualberta.ca

* Influenza Vaccine Confusion: A Call for an Alternative Evidence-Based Approach, in
Pediatrics, 2005; 116: 1214–5. Reprints: www.pediatrics.org; R. Yogev.

* Effects of Perioperative Antiinflammatory and Immunomodulating Therapy on Surgical Wound Healing, in
Pharmacotherapy, 2005; 25: 1566–91. Reprints: www.pharmacotherapy.org; A. J. Busti, anthony.busti@ttuhsc.edu

* Antiplatelet Drug Resistance: Not Ready for Prime Time, in
Pharmacotherapy, 2005; 25: 1621–8. Reprints: www.pharmacotherapy.org; D. E. Hilleman, hilleman@creighton.edu

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Nov. 8, 2005 Vol. 12, No. 216
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
Nov. 1 issue of the Journal of the American College of Cardiology (www.cardiosource.com; 2005; 46).

Personalized Cardiovascular Medicine: The prospects for a paradigm shift to genomic medicine is analyzed in a review article on personalized cardiovascular medicine (pp. 1615-27): “Pharmacogenomic approaches are emerging across broad classes of cardiovascular therapeutics to assist practitioners in making more precise decisions about which drugs to give to which patients to optimize the benefit-to-risk ratio. Molecular imaging is developing chemical and biological probes that can sense molecular pathway mechanisms that will allow us to monitor health and disease. Together, these tools will enable a paradigm shift from genetic medicine—on the basis of the study of individual inherited characteristics, most often single genes—to genomic medicine, which by its nature is comprehensive and focuses on the functions and interactions of multiple genes and gene products, among themselves and with their environment. The information gained from such analyses, in combination with clinical data, is now allowing us to assess individual risks and guide clinical management and decision-making, all of which form the basis for cardiovascular genomic medicine.” (G. S. Ginsburg, geoffrey.ginsburg@duke.edu)

Estimating Aspirin Resistance:
Nonadherence to aspirin therapy was more commonly the reason for lack of response to aspirin therapy than was true aspirin resistance in a 223-patient study (pp. 1705-9). At issue is the method used to measure aspirin resistance, the authors explain. In analyzing platelet function in six healthy participants, 203 patients undergoing percutaneous interventions, and 20 patients with histories of stent thrombosis, they found that platelet aspirin resistance was overestimated by thrombelastograph platelet mapping. Instead, they argue, a method that directly indicates inhibition of cyclooxygenase is needed. When using such a method—arachidonic acid-induced light-transmittance platelet aggregation—the investigators determined that seven PCI patients were nonadherent to aspirin therapy and only 1 patient had true aspirin resistance. (P. A. Gurbel, Sinai Center for Thrombosis Research, Baltimore; pgurbel@lifebridgehealth.org)

Dyslipidemia Understudied, Undertreated in Women: Even though coronary heart disease continues to be the leading cause of death among women and differences are recognized between both men and women and younger and older women, CHD in women remains understudied and also undertreated, concludes an author of a state-of-the-art paper (pp. 1628-35). “Differences in lipoprotein levels and lipid fractions play an important role in CHD risk,” the author writes. “Hormonal influences on lipoprotein levels in women are complex, change throughout the life span, and are influenced by the administration of oral contraceptives and hormone replacement therapy. Women with obesity, metabolic syndrome, or diabetes have lipid profiles that adversely affect CHD risk. To date, no randomized trials testing the impact of lifestyle changes on lipoprotein levels and subsequent CHD events in non-institutionalized women have been performed, and women have not been well represented in clinical end point trials of pharmacologic lipid-lowering therapy. Available evidence suggests that lipid-lowering therapy with statins does provide benefit in reducing the risk of coronary events in women; however, women remain undertreated, and more data are needed to determine optimal cardiovascular prevention and treatment in this population.” (V. Bittner, U. Alabama, Birmingham; vbittner@uab.edu)

>>>PNN NewsWatch
* Morphine release is increased when Avinza capsules are exposed to ethanol, FDA and Ligand Pharmaceuticals are warning consumers and health professionals. Labeling for the extended-release morphine sulfate product has been strengthened through inclusion of a black box warning that cautions against use of beverages, prescription medications, and nonprescription drug products that contain ethanol.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Nov. 9, 2005 Vol. 12, No. 217
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Nov. 9 issue of JAMA (www.jama.com; 2005; 294).

Clinical Decision Support & Antimicrobial Prescribing: In rural practice settings, implementation of clinical decision support systems improved antimicrobial prescribing and reduced overall use of antibiotics (pp. 2305-14). In a cluster randomized trial of 407,460 inhabitants and 334 primary care clinicians in 12 Utah and Idaho communities, CDSS was targeted toward clinicians in six of the communities, while primary care providers in the other six municipalities received only a community intervention. Based on data obtained from community pharmacies in these 12 communities plus another 6 control towns, the investigators found, “Within CDSS communities, 71% of primary care clinicians participated in the use of CDSS. The prescribing rate decreased from 84.1 to 75.3 per 100 person-years in the CDSS arm vs 84.3 to 85.2 in community intervention alone, and remained stable in the other communities (P = .03). A total of 13,081 acute respiratory tract infection visits were abstracted. The relative decrease in antimicrobial prescribing for visits in the antibiotics ‘never-indicated’ category during the post-intervention period was 32% in CDSS communities and 5% in community intervention-alone communities (P = .03). Use of macrolides decreased significantly in CDSS communities but not in community intervention–alone communities.” (M. H. Samore, matthew.samore@hsc.utah.edu)

Antibiotic Treatment of Sore Throat: While on the decline, the rate of antibiotic prescriptions for children with sore throats still far exceeds the expected rate of infection with group A beta-hemolytic streptococci, according to a national analysis of pediatric visits to physicians, ambulatory care clinics, and emergency departments (pp. 2315-22). “Physicians prescribed antibiotics in 53% (95% confidence interval [CI], 49%–56%) of an estimated 7.3 million annual visits for sore throat and nonrecommended antibiotics to 27% (95% CI, 24%–31%) of children who received an antibiotic,” the authors note. “Antibiotic prescribing decreased from 66% of visits in 1995 to 54% of visits in 2003 (P = .01 for trend). This decrease was attributable to a decrease in the prescribing of recommended antibiotics (49% to 38%; P = .002). Physicians performed a GABHS test in 53% (95% CI, 48%–57%) of visits and in 51% (95% CI, 45%–57%) of visits at which an antibiotic was prescribed. GABHS testing was not associated with a lower antibiotic prescribing rate overall (48% tested vs 51% not tested; P = .40), but testing was associated with a lower antibiotic prescribing rate for children with diagnosis codes for pharyngitis, tonsillitis, and streptococcal sore throat (57% tested vs 73% not tested; P < .001).” (J. A. Linder, jlinder@partners.org)

Commenting on this and the above trial, an editorialist calls for “a better prescription” for antimicrobial drugs, especially in view of the decreasing number of new antibiotics (pp. 2354-6): “All interventions for improving appropriate use of antimicrobial drugs must be introduced and promoted in the context of efforts to improve awareness among the public and to further educate prescribers. Additional interventions can include formulary restrictions, practice measures such as those currently used and planned for the Health Plan Employer Data and Information Set, clinical decision support systems, and other measures indirectly related to prescribing. These interventions, as well as algorithms and guidelines to improve antimicrobial use, must be transparently evidence-based. Such interventions that improve quality of care for individual patients save time, reduce prescribing errors, and reduce costs and are those most likely to be acceptable, effective, and sustainable. Increased use of an electronic health record may serve as the framework for some of these practice changes. The electronic health record also may help answer the need for better, more universal, readily available data for designing and evaluating interventions that include patient-linked microbiological testing and results, diagnoses, and prescriptions. Surveillance systems under development, such as the National Healthcare Safety Network, may also provide the data required for better study of antimicrobial use and resistance.” (J. T. Weber,
jtw5@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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Nov. 10, 2005 Vol. 12, No. 218
Providing news and information about medications and their proper use

>>>Deferasirox Approved
An oral iron chelator indicated for treatment of chronic iron overload due to multiple blood transfusions, deferasirox (Exjade, Novartis), has been approved by FDA. The orphan drug is the first orally administered medication with this indication. Because previously approved treatments required prolonged daily infusions lasting 8–12 hours, the availability of an orally administered agent is an important advance in therapy.

Clinical trials of deferasirox, which included more than 1,000 adults and children, were part of the largest prospective global clinical trials program ever implemented for an investigational iron chelator, Novartis noted in a news release. Liver iron concentration, an indicator for body iron content in patients receiving blood transfusions, is a measure of iron accumulation in the liver. The studies demonstrated that deferasirox 20–30 mg/kg/day led to the maintenance or reduction of iron burden in transfused patients with thalassemia and sickle cell disease as well as other rare anemias and myelodysplastic syndromes. In the clinical studies, deferasirox was generally well tolerated, with the most frequently reported adverse events being nausea, vomiting, diarrhea, abdominal pain, skin rash, and increases in serum creatinine. As with deferoxamine, cases of ocular and auditory disturbances have been reported.

Mild, nonprogressive increases in serum creatinine, mostly within the normal range, occur in about one-third of deferasirox-treated patients. These are dose-dependent, often resolve spontaneously and can sometimes be alleviated by reducing the dose. Serum creatinine should be assessed before initiating therapy and should be monitored monthly thereafter to determine if dose modification or discontinuation is necessary. Liver function should be monitored monthly and deferasirox should be interrupted or discontinued if an unexplained, persistent, or progressive increase in serum transaminase levels occurs.

>>>NEJM Highlights
Source:
Nov. 10 issue of the New England Journal of Medicine (content.nejm.org; 2005; 353).

CPAP for Apnea, HF: While administration of continuous positive airway pressure improved a variety of clinical indicators among patients with central sleep apnea and heart failure, survival was not significantly affected in a 2-year study (pp. 2025-33). Among 258 patients, the investigators noted these findings: “Three months after undergoing randomization, the CPAP group, as compared with the control group, had greater reductions in the frequency of episodes of apnea and hypopnea (–21 ± 16 vs. –2 ± 18 per hour, P < 0.001) and in norepinephrine levels (–1.03 ± 1.84 vs. 0.02 ± 0.99 nmol per liter, P = 0.009), and greater increases in the mean nocturnal oxygen saturation (1.6 ± 2.8 percent vs. 0.4 ± 2.5 percent, P < 0.001), ejection fraction (2.2 ± 5.4 percent vs. 0.4 ± 5.3 percent, P = 0.02), and the distance walked in six minutes (20.0 ± 55 vs. –0.8 ± 64.8 m, P = 0.016). There were no differences between the control group and the CPAP group in the number of hospitalizations, quality of life, or atrial natriuretic peptide levels. An early divergence in survival rates without heart transplantation favored the control group, but after 18 months the divergence favored the CPAP group, yet the overall event rates (death and heart transplantation) did not differ (32 vs. 32 events, respectively; P = 0.54).” (T. D. Bradley, douglas.bradley@utoronto.ca)

Dubbing sleep “a new cardiovascular frontier,” an editorialist writes (pp. 2070-3): “Treatment of obstructive sleep apnea often provides substantial symptomatic benefit and even tangible improvements in disease state. Certainly, successful treatment of obstructive sleep apnea in the overweight, somnolent, hypertensive truck driver is gratifying and of likely benefit not only to the patient but also to the spouse, the physician, and perhaps even society at large. However, although the use of CPAP in obstructive sleep apnea may lower blood pressure, sympathetic activity, and other surrogates of cardiovascular risk, there are no large-scale, randomized trials of cardiovascular events or survival with the treatment.” (V. K. Somers, Mayo Clinic, Rochester, Minn.)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Nov. 11, 2005 Vol. 12, No. 219
Providing news and information about medications and their proper use

>>>Psychiatry Highlights
Source:
Nov. issue of the American Journal of Psychiatry (ajp.psychiatryonline.org; 2005; 162).

Lithium vs. Divalproex for Rapid-Cycling Bipolar Disorder: “The hypothesis that divalproex is more effective than lithium in the long-term management of rapid-cycling bipolar disorder is not supported” by results of a 20-month trial (pp. 2152-61). During an open-label acute stabilization phase, a large number (76%) of 254 participants discontinued the study, primarily because of poor adherence (28%), nonresponse (26%), and adverse effects (19%). Remaining participants were stratified for bipolar I versus bipolar II disorder and randomly assigned to one of the study drugs, with these results: “Of the 60 patients (24%) randomly assigned to double-blind maintenance monotherapy, 53% relapsed (59% into depression and 41% into a hypomanic/manic/mixed episode), 22% completed the study, 10% had intolerable side effects, and 10% were poorly adherent. The rates of relapse into any mood episode for those given lithium versus divalproex were 56% and 50%, respectively; the rates were 34% and 29% for a depressive relapse and 19% and 22% for a hypomania/mania relapse. There were no significant differences in time to relapse. The proportion discontinuing prematurely because of side effects was 16% for lithium and 4% for divalproex.” (J. R. Calabrese)

>>>PNN NewsWatch
* The risk of adverse events is higher among women using Ortho-McNeil’s Ortho Evra transdermal patch, compared with those on low-dose oral contraceptives, the company warned yesterday. The product, which contains norelgestromin and ethinyl estradiol, yields serum estrogen AUC and peak concentrations about 60% higher than with oral doses of ethinyl estradiol 35 mcg. In language added to the Warnings section of Ortho Evra product labeling, FDA and the company provide this precaution: “In general, increased estrogen exposure may increase the risk of adverse events. However, it is not known if there are changes in the risk of serious adverse events based on the differences in pharmacokinetic profiles of EE in women using Ortho Evra compared with women using oral contraceptives containing 35 micrograms of EE.”

*
Alefacept (Amevive, Biogen Idec) should not be used in patients infected with HIV, FDA and the company are cautioning. The drug reduces CD4+ T lymphocyte counts, which might accelerate disease progression or increase complications of disease in these patients. In addition, FDA notes on its MedWatch Web site, other sections of the product labeling were revised to reflect additional safety information.

* Patients who have had infusions of products containing maltose or galactose, or who have consumed oral xylose, cannot rely on
blood glucose readings from systems that use the reagent glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ), FDA cautioned yesterday. Falsely elevated glucose readings can lead patients to take life-threatening amounts of insulin or fail to recognize potentially fatal episodes of true hypoglycemia. A preliminary list of products that may interfere with GDH-PQQ–based glucose monitoring system is posted on the FDA MedWatch Web site; it includes several immune globulin intravenous products, vaccinia immune globulin, d-xylose, and peritoneal dialysis solution from Baxter (Extraneal).

*
FDA announced yesterday that it has issued warning letters to 16 dietary supplement and hormone cream marketers who are making unproven claims that tout the benefits of their “alternative hormone therapy” products in treating or preventing serious diseases, including cancer, heart disease, and osteoporosis, and in affecting the structure or function of the body. The agency said these alternative therapies are often promoted as "natural" or "safer" treatments that can be used in place of approved hormone treatments. Marketers have 15 days to respond to FDA. As part of a joint effort, the Federal Trade Commission is also issuing letters to 34 Web sites promoting alternative hormone therapy products with claims similar to the dietary supplement products.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Nov. 14, 2005 Vol. 12, No. 220
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
Nov. 12 issue of Lancet and early-release articles from Lancet Oncology (www.thelancet.com; 2005; 366).

NSAIDs & Barrett’s Esophagus: The risk of progression of Barrett’s esophagus was reduced with NSAID use among a cohort of 350 patients who were followed for 20,770 person–months (Lancet Oncology; DOI:10.1016/S1470-2045(05)70431-9). “Median follow-up was 65.5 months (range 3.1–106.9),” the authors report. “Compared with never users, HR for oesophageal adenocarcinoma (n = 37 cases) in current NSAID users was 0.32 (95% CI 0.14–0.76), and in former users was 0.70 (0.31–1.58). 5-year cumulative incidence of oesophageal adenocarcinoma was 14.3% (95% CI 9.3–21.6) for never users, 9.7% (4.5–20.5) for former users, and 6.6% (3.1–13.6) for current NSAID users. When changes in NSAID use during follow up were taken into account, the associations were strengthened: HR for oesophageal adenocarcinoma for current users at baseline or afterwards was 0.20 (95% CI 0.10–0.41) compared with never users. Compared with never users, current NSAID users (at baseline and follow-up) had less aneuploidy (n=35 cases; 0.25 [0.12–0.54]) and tetraploidy (n = 45 cases; 0.44 [0.22–0.87]).” (T. L. Vaughan, tvaughan@u.washington.edu)

Antibiotics for Diabetic Foot Infections: The once-daily carbapenem antibiotic ertapenem was equivalent to every-6-hour piperacillin/tazobactam in a study of 586 adults with diabetes and a foot infection (pp. 1695-703). Among 445 patients available for evaluation at the end of a 5-day treatment period, the investigators found, “Both baseline characteristics and favourable clinical response rates were similar for the 226 who received ertapenem and the 219 who received piperacillin/tazobactam (94% vs 92%, respectively; between treatment difference 1.9%, 95% CI –2·9 to 6·9). Rates of favourable microbiological responses (eradication rates and clinical outcomes, by pathogen) and adverse events did not differ between groups.” (B. A. Lipsky, U. Washington, Seattle; Benjamin.Lipsky@med.va.gov)

>>>BMJ Highlights
Source:
Early-release article from BMJ (www.bmj.org; 2005; 331).

Treating Insomnia in Older Adults: Benefits of use of sedative drugs for treating insomnia in patients aged 60 years and older may not exceed their risks, conclude authors who conducted a meta-analysis of 24 studies involving 2,417 participants (doi:10.1136/bmj.38623.768588.47). “Sleep quality improved (effect size 0.14, P < 0.05), total sleep time increased (mean 25.2 minutes, P < 0.001), and the number of night time awakenings decreased (0.63, P < 0.001) with sedative use compared with placebo,” report the researchers. “Adverse events were more common with sedatives than with placebo: adverse cognitive events were 4.78 times more common (95% confidence interval 1.47 to 15.47, P < 0.01); adverse psychomotor events were 2.61 times more common (1.12 to 6.09, P > 0.05), and reports of daytime fatigue were 3.82 times more common (1.88 to 7.80, P < 0.001) in people using any sedative compared with placebo.” (U. E. Busto, Ctr. for Addiction and Mental Health, Toronto; usoa_busto@camh.net)

>>>PNN JournalWatch
* Treatment for Diabetic Foot Ulcers, in Lancet, 2005; 366: 1725–35. Reprints: www.thelancet.com; P. R. Cavanagh, Cleveland Clinic Foundation, Cleveland; cavanap@ccf.org

* Metabolic Syndrome as a Precursor of Cardiovascular Disease and Type 2 Diabetes Mellitus, in
Circulation, 2005; doi:10.1161/CIRCULATIONAHA.105.539528; Reprints: P. W. F. Wilson, wilsonpw@musc.edu

* Severity Assessment in Asthma: An Evolving Concept, in
Journal of Allergy and Clinical Immunology, 2005; 116: 990–5. Reprints: www.jacionline.org; M. K.. Miller, Genentech, South San Francisco; mkmiller@gene.com

* Effect of Antiepileptic Medication on Bone Mineral Measures, in
Neurology, 2005; 65: 1358–65. Reprints: www.neurology.com; J. Wark, Royal Melbourne Hosp., Parkville, Victoria, Australia; jdwark@unimelb.edu.au

* High-Risk Localized Prostate Cancer: A Case for Early Chemotherapy, in
Journal of Clinical Oncology, 2005; 23: 8186–91. Reprints: www.jco.org; M. Gleave, U. British Columbia, Vancouver, gleave@interchange.ubc.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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Nov. 15, 2005 Vol. 12, No. 221
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Nov. 15 issue of the Annals of Internal Medicine (www.annals.org; 2005; 143).

Condom Use & HSV-2 Infection: Data gathered during a trial of an ineffective vaccine for herpes simplex virus type 2 show that consistent condom use can protect individuals from infection with HSV-2 (pp. 707-13). “Of 1843 participants, 118 (6.4%) became infected with HSV-2,” report authors of the observational analysis. “In multivariate analyses, participants reporting more frequent use of condoms were at lower risk for acquiring HSV-2 than participants who used condoms less frequently (hazard ratio, 0.74 [95% CI, 0.59 to 0.95]); categories of increasing condom use were 0% to 25%, 25% to 75%, and greater than 75% of sexual acts.” Noting that most transmission of HSV type 1 is through oral-genital conact for which barrier protection is typically not used, the authors add, “Nineteen (2.9%) of 659 participants at risk for infection with HSV-1 became infected. No statistically significant association between condom use and infection with HSV-1 was found (hazard ratio, 0.79 [CI, 0.48 to 1.31]).” (A. Wald, annawald@u.washington.edu)

An editorialist emphasizes the need for health professionals to promote condom use in an effort to prevent sexually transmitted diseases (pp. 751-2): “Proof that condoms help to reduce risk for acquisition of STDs provides clinicians with the weight of evidence behind their advice to use this tool for control of such diseases. Ongoing research and efforts to promote sexual abstinence, to reduce risk-taking behaviors, and to develop vaccines and topical microbicides for prevention of STDs should enhance efforts to control transmission and morbidity. For the present, however, condoms remain the best proven currently available means to reduce the risk for STDs in at-risk persons. Unfortunately, these individuals do not use condoms as much as they should. Clinicians should tell their at-risk patients that condoms can substantially reduce their risk for these diseases if they use them regularly. This simple message is our best weapon against STDs.” (E. W. Hook III, U. Ala., Birmingham;
ehook@uab.edu)

Early Adverse Effects of Efavirenz: Neurologic symptoms and bad dreams occur during the first week of efavirenz therapy but then subside, according to a study of 303 patients beginning antiretroviral therapy (pp. 714-21). “The efavirenz group experienced more neurologic symptoms at week 1 (P < 0.001) but not at weeks 4, 12, or 24,” the authors note. “A sleep index revealed that participants receiving efavirenz had more ’bad dreams’ during the first week of therapy (P = 0.038). No significant changes in anxiety or depressed mood were noted. Changes in efavirenz-associated neurologic symptoms were correlated to efavirenz plasma concentrations at week 1 but not at later time points. Twelve (6%) patients receiving efavirenz stopped taking the drug before the end of the study because of central nervous system symptoms.” (D. B. Clifford, Washington U., St. Louis)

>>>PNN NewsWatch
* The Scientific Sessions 2005 of the American Heart Association are underway this week in Dallas. Among the highlights thus far are a study showing that genetic variations in HMG-CoA reductase can reduce the effectiveness of statins in reducing LDL cholesterol, an epidemiologic analysis from Denmark indicating increased risk of death following myocardial infarctions when patients take NSAIDs or COX-2 inhibitors, and research showing that AHA’s Get With The Guidelines program has significantly improved care of coronary artery disease among 30,000 patients in U.S. hospitals.

* Another important medical convention, the
Annual Scientific Meeting of the American College of Rheumatology, began this past weekend in San Diego. Osteoarthritis researchers have reported positive results with glucosamine plus chondroitin in a large NIH-sponsored trial, superiority of the European glucosamine formulation over acetaminophen in a 318-patient trial, positive results with high doses of the antiosteoporotic agent risedronate, and reduction in symptoms when obese patients lost even modest amounts of weight.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Nov. 16, 2005 Vol. 12, No. 222
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Nov. 16 issue of JAMA (www.jama.com; 2005; 294).

High-Dose Atorvastatin: Results from the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) study, presented yesterday at the American Heart Association meeting in Dallas and published in this morning’s JAMA, show a reduction in cardiovascular events but not mortality with atorvastatin doses of 80 mg daily (pp. 2437-45). Compared with standard doses of simvastatin 20 mg/day, aggressive lowering of LDL cholesterol produced these outcomes: “During treatment, mean LDL-C levels were 104 (SE, 0.3) mg/dL in the simvastatin group and 81 (SE, 0.3) mg/dL in the atorvastatin group. A major coronary event occurred in 463 simvastatin patients (10.4%) and in 411 atorvastatin patients (9.3%) (hazard ratio [HR], 0.89; 95% CI, 0.78–1.01; P = .07). Nonfatal acute MI occurred in 321 (7.2%) and 267 (6.0%) in the 2 groups (HR, 0.83; 95% CI, 0.71–0.98; P = .02), but no differences were seen in the 2 other components of the primary end point. Major cardiovascular events occurred in 608 and 533 in the 2 groups, respectively (HR, 0.87; 95% CI, 0.77–0.98; P = .02). Occurrence of any coronary event was reported in 1059 simvastatin and 898 atorvastatin patients (HR, 0.84; 95% CI, 0.76–0.91; P < .001). Noncardiovascular death occurred in 156 (3.5%) and 143 (3.2%) in the 2 groups (HR, 0.92; 95% CI, 0.73–1.15; P = .47). Death from any cause occurred in 374 (8.4%) in the simvastatin group and 366 (8.2%) in the atorvastatin group (HR, 0.98; 95% CI, 0.85–1.13; P = .81). Patients in the atorvastatin group had higher rates of drug discontinuation due to nonserious adverse events; transaminase elevation resulted in 43 (1.0%) vs 5 (0.1%) withdrawals (P < .001). Serious myopathy and rhabdomyolysis were rare in both groups.” (T. R. Pedersen, Ullevål U. Hosp., Oslo, Norway; t.r.pedersen@medisin.uio.no)

An editorialist responds that the “ideal” cholesterol level needs to consider more than LDL-C values (pp. 2492-4): “The scientific community needs to continue to pursue new avenues of treatment, with approaches that may well be ‘beyond statins.’ Even with intensive statin therapy, the current best evidence-based treatment available, many patients still will have recurrent cardiovascular events. New strategies may include development of new agents to achieve even lower target LDL-C levels, substantially increase HDL-C levels, reduce triglycerides, reduce CRP and other components of inflammation, and modify many other identified components of vascular disease.” (C. P. Cannon,
cpcannon@partners.org)

Edifoligide in CABG: Edifoligide— an oligonucleotide decoy that binds to and inhibits E2F transcription factors—proved no more effective than placebo in preventing failure of one or more vein grafts within 12–18 months of coronary artery bypass graft surgery (pp. 2446-54). “A total of 1920 patients (80%) either died (n = 91) or underwent follow-up angiography (n = 1829),” the investigators note. “Edifoligide had no effect on the primary end point of per patient vein graft failure (436 [45.2%] of 965 patients in the edifoligide group vs 442 [46.3%] of 955 patients in the placebo group; odds ratio, 0.96 [95% confidence interval {CI}, 0.80–1.14]; P = .66), on any secondary angiographic end point, or on the incidence of major adverse cardiac events at 1 year (101 [6.7%] of 1508 patients in the edifoligide group vs 121 [8.1%] of 1506 patients in the placebo group; hazard ratio, 0.83 [95% CI, 0.64–1.08]; P = .16).” (J. H. Alexander, john.h.alexander@duke.edu)

A Strong FDA: Reflecting on the 1906 origins of FDA, a writer analyzed the current “disturbing episode of pharmacological crisis and medical mayhem in the United States” (pp. 2489-91): “Among the many reasons for founding the FDA a century ago was that industries and businesses that had profound effects on the nation’s health were placing profits over consumer safety. Sadly, that blind, and often careless, dash toward financial or political gains is again dominating the business–government nexus today. And all recent events suggest that the FDA—as it was originally conceived and allowed to develop—is needed more than ever.” (H. Markel, howard@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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Nov. 17, 2005 Vol. 12, No. 223
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Nov. 17 issue of the New England Journal of Medicine (content.nejm.org; 2005; 353).

Multipronged Interventions for Obesity: Combining drug therapy with group lifestyle modification results in significantly greater weight loss among obese adults than does either intervention alone, according to findings from a 224-patient study (pp. 2111-20). During the 1-year trial, participants received sibutramine 15 mg/day, which was delivered by a primary care provider during eight visits of 10–15 minutes each. Other interventions included lifestyle-modification counseling delivered in 30 group sessions; combined therapy using both of these interventions; or sibutramine plus brief counseling about lifestyle modification delivered by a primary care provider during eight visits of 10–15 minutes each.

The researchers found, “At one year, subjects who received combined therapy lost a mean (±SD) of 12.1 ± 9.8 kg, whereas those receiving sibutramine alone lost 5.0 ± 7.4 kg, those treated by lifestyle modification alone lost 6.7 ± 7.9 kg, and those receiving sibutramine plus brief therapy lost 7.5 ± 8.0 kg (P < 0.001). Those in the combined-therapy group who frequently recorded their food intake lost more weight than those who did so infrequently (18.1 ± 9.8 kg vs. 7.7 ± 7.5 kg, P = 0.04).” (T. A Wadden,
wadden@mail.med.upenn.edu)

Rimonabant for Obesity: The selective cannabinoid-1 receptor blocker rimonabant (see PNN, Apr. 18) significantly reduced weight and waist circumference and improved risk factors for metabolic syndrome among 1,036 overweight and obese patients with untreated dyslipidemia who participated in a 12-month trial (pp. 2121-34). The Rimonabant in Obesity–Lipids Study Group reports these results: “The rates of completion of the study were 62.6 percent, 60.3 percent, and 63.9 percent in the placebo group, the group receiving 5 mg of rimonabant, and the group receiving 20 mg of rimonabant, respectively. The most frequent adverse events resulting in discontinuation of the drug were depression, anxiety, and nausea. As compared with placebo, rimonabant at a dose of 20 mg was associated with a significant (P < 0.001) mean weight loss (repeated-measures method, –6.7 ± 0.5 kg, and last-observation-carried-forward analyses, –5.4 ± 0.4 kg), reduction in waist circumference (repeated-measures method, –5.8 ± 0.5 cm, and last-observation-carried-forward analyses, –4.7 ± 0.5 cm), increase in HDL cholesterol (repeated-measures method, +10.0 ± 1.6 percent, and last-observation-carried-forward analyses, +8.1 ± 1.5 percent), and reduction in triglycerides (repeated-measures method, –13.0 ± 3.5 percent, and last-observation-carried-forward analyses, –12.4 ± 3.2 percent). Rimonabant at a dose of 20 mg also resulted in an increase in plasma adiponectin levels (repeated-measures method, 57.7 percent, and last-observation-carried-forward analyses, 46.2 percent; P < 0.001), for a change that was partly independent of weight loss alone” (J-P Després, Laval Hosp. Res. Ctr., Ste.-Foy, Québec, Canada; jean-pierre.despres@crhl.ulaval.ca)

Commenting on both of the above studies, an editorialist writes of the “promise and uncertainty” of pharmacotherapy for obesity: “An improved armamentarium of therapeutic approaches is needed to promote and sustain weight loss safely and effectively in obese patients and to prevent or ameliorate many obesity-related conditions. Advances in our understanding of the complex systems regulating energy balance, the genetic determinants of obesity, and the environmental factors that promote obesity should lead to the development of more effective and targeted treatments in the future. Ultimately, our goal must be to use this understanding to develop more effective strategies not only for treatment, but also for the primary prevention of obesity.” (S. Z. Yanovski, NIH, Bethesda, Md.)

Sildenafil for PAH: In 278 patients with symptomatic pulmonary arterial hypertension, sildenafil significantly improved exercise capacity, WHO functional class, and hemodynamics, compared with placebo (pp. 2148-57). Flushing, dyspepsia, and diarrhea were the most common adverse effects associated with sildenafil doses of 20, 40, or 80 mg three times daily for 12 weeks. (N. Galiè, U. Bologna, Bologna, Italy;
n.galie@bo.nettuno.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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Nov. 18, 2005 Vol. 12, No. 224
Providing news and information about medications and their proper use

>>>Allergy/Immunology Update
Source:
Nov. issue of the Journal of Allergy and Clinical Immunology (www.jacionline.org; 2005; 116).

Asthma Severity & ASA Sensitivity: Through remodeling of both the upper and lower airways, aspirin sensitivity appears to be associated with increased asthma severity, according to a study of adults with severe or difficult-to-treat aspirin-exacerbated respiratory disease (pp. 970-5). Results of the Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study show, “Adult subjects (≥18 years) with AERD (n = 459) were compared with subjects with non–aspirin-sensitive asthma (n = 2848). Subjects with AERD had significantly lower mean postbronchodilator percent predicted FEV1 compared with subjects with non–aspirin-sensitive asthma (75.3% vs 79.9%, P < .001). Differences in spirometry between the 2 cohorts persisted after controlling for potential confounding variables. In addition, subjects with AERD were more likely to have severe asthma by means of physician assessment (66% vs 49%, P < .001), to have been intubated (20% vs 11%, P < .001), to have a steroid burst in the previous 3 months (56% vs 46%, P < .001), and to have required high-dose inhaled corticosteroids (34% vs 26%, P < .001).” (L. Borish, lb4m@virginia.edu)

Nasal Steroids & Glaucoma: In 24 eyes of 12 patients with glaucoma, discontinuation of intranasal corticosteroids significantly reduced intraocular pressure, according to a retrospective chart review (pp. 1042-7; K. M. Joos, Karen.joos@vanderbilt.edu)

>>>PNN NewsWatch
* A series of 12 deaths in Japanese pediatric patients receiving oseltamivir is being reviewed today by the FDA Pediatric Advisory Committee. Adverse event reports associated with oseltamivir therapy were primarily related to unusual neurologic or psychiatric events such as delirium, hallucinations, confusion, abnormal behavior, convulsions, and encephalitis, FDA noted in a Q&A posted yesterday on its Web site. These events were reported almost entirely in children from Japan who received oseltamivir according to Japanese treatment guidelines, which FDA described as being very similar but not identical to U.S. treatment guidelines. In many of the fatalities, a relationship to oseltamivir was difficult to assess because of the use of other medications, presence of other medical conditions, and/or lack of adequate detail in the reports, the federal agency added. FDA closed its posting by encouraging clinicians and caregivers to be sure that children from 6 months to 2 years of age and those with high-risk underlying medical conditions are vaccinated against influenza.

* Medications—especially ingredients in
nonprescription cough-and-cold products—were factors in 10 deaths of infants younger than 1 year over an 8-month period, according to a report posted this week on APhA’s www.pharmacist.com. Ephedrine, pseudoephedrine, dextromethorphan, diphenhydramine, chlorpheniramine, brompheniramine, ethanol, carbinoxamine, levorphanol, acetaminophen, and metoclopramide were detected in the infants during postmortem examinations. and allegedly either caused or contributed to their deaths. The report is based on an article in the October 2005 issue of the Journal of Analytical Toxicology by Laureen Marinetti and others from the Montgomery County Coroner’s Office in Dayton, Ohio.

* Novartis Nutrition Corporation is recalling 2,712 bottles of an
enteral feeding formula that was incorrectly labeled as Diabetisource AC 1.5 Liter bottles lot 2135L. The product, which was distributed only to health care facilities, contained in these bottles is actually Resource Diabetic TF, a tube feeding formulated for diabetes and containing sodium and calcium caseinate, components of milk. People with an allergy or severe sensitivity to milk run the risk of a serious or life threatening allergic reaction if they consume this product. Institutions that have received shipping cartons labeled Resource Diabetic TF lot number 2135L or bottles labeled Diabetisource AC 1.5 Liter bottles lot 2135L should contact Novartis 800-333-3785. Consumers who have questions can contact this same 800 number.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Nov. 21, 2005 Vol. 12, No. 225
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
Early-release articles from Lancet (www.thelancet.com; 2005; 366).

Long-term Fibrate Therapy: In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, 5 years’ fibrate treatment of 9,795 patients failed to reduce the frequency of coronary events, defined here as coronary heart deaths or nonfatal myocardial infarction (DOI: 10.1016/S0140-6736(05)67667-2). Study participants, all of whom had type 2 diabetes mellitus, included both those with (n = 2,131) and without (n = 7,664) previous cardiovascular disease. Elevations in total cholesterol, total cholesterol to HDL cholesterol ratios, and/or serum triglycerides responded to fenofibrate 200 mg daily or placebo as follows: “5.9% (n = 288) of patients on placebo and 5.2% (n = 256) of those on fenofibrate had a coronary event (relative reduction of 11%; hazard ratio [HR] 0.89, 95% CI 0.75–1.05; p = 0.16). This finding corresponds to a significant 24% reduction in non-fatal myocardial infarction (0.76, 0.62–0.94; p = 0.010) and a non-significant increase in coronary heart disease mortality (1.19, 0.90–1.57; p = 0.22). Total cardiovascular disease events were significantly reduced from 13.9% to 12.5% (0.89, 0.80–0.99; p = 0.035). This finding included a 21% reduction in coronary revascularisation (0.79, 0.68–0.93; p = 0.003). Total mortality was 6.6% in the placebo group and 7.3% in the fenofibrate group (p = 0.18). Fenofibrate was associated with less albuminuria progression (p = 0.002), and less retinopathy needing laser treatment (5.2% vs 3.6%, p = 0.0003). There was a slight increase in pancreatitis (0.5% vs 0.8%, p = 0.031) and pulmonary embolism (0.7% vs 1.1%, p = 0.022), but no other significant adverse effects.” (FIELD Study Investigators, U. Sydney, Sydney; FIELDTrial@ctc.usyd.edu.au)

Commenting on this study, an editorialist writes (DOI:10.1016/S0140-6736(05)67668-4): “Data on efficacy and safety of using a statin and a fibrate in combination will have to await the ACCORD trial due to report in 2010. Meanwhile, the FIELD investigators conclude that their study provides reassurance that combination therapy with statins and fenofibrate is safe. Given this conclusion, it would have been useful for the safety data for the subgroup of patients exposed to combination therapy to have been presented, and to know whether the combination therapy is limited to any particular statins. It should also be noted that, although non-fatal myocardial infarction was reduced by 24%, cardiac mortality showed a non-significant increase of 19%, largely reflecting an increase in sudden cardiac deaths in the fenofibrate group against a similar rate of fatal myocardial infarction....

“In summary the results from this well-executed trial do not warrant a recommendation for increased fenofibrate use in patients with diabetes, nor do they provide convincing evidence of the benefit of fenofibrate therapy in patients already at target serum LDL cholesterol.” (H. Colhoun, U. Coll., Dublin;
helen.colhoun@ucd.ie)

>>>PNN NewsWatch
* Severe asthma episodes and death can occur following use of long-acting beta-2 adrenergic agonists, FDA warned on Friday. The agency is calling on manufacturers of Advair Diskus (fluticasone and salmeterol), Foradil Aerolizer (formoterol), and Serevent Diskus (salmeterol) to update their existing product labels with new warnings and create a new Medication Guide for patients discussing this adverse effect. Even though LABAs decrease the frequency of asthma episodes, these medicines may make asthma episodes more severe when they occur, FDA noted in a public health advisory posted on its Web site.

>>>PNN JournalWatch
* Duration of Protection with RTS,S/AS02A Malaria Vaccine in Prevention of Plasmodium falciparum Disease in Mozambican Children: Single-Blind Extended Follow-up of a Randomised Controlled Trial, in Lancet, 2005; DOI:10.1016/S0140-6736(05)67669-6. Reprints: www.thelancet.com; P. L. Alonso, Universitat de Barcelona, Barcelona; palonso@clinic.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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Nov. 22, 2005 Vol. 12, No. 226
Providing news and information about medications and their proper use

>>>Circulation Highlights
Source:
Early-release articles from and the Nov. 22 issue of Circulation (circ.ahajournals.org; 2005; 112).

Route of Estrogen Administration: A multicenter case–control study provides further evidence that transdermal estrogen is safer than orally administered drug (doi:10.1161/CIRCULATIONAHA.105.565556). At seven clinical centers in France, 235 consecutive patients with a first documented episode of idiopathic venous thromboembolism were compared with 554 control patients, with these results: “Factor V Leiden was associated with a 3.4-fold-increased risk of VTE (95% confidence interval [CI], 2.0 to 5.8), and a prothrombin mutation was associated with a 4.8-fold-increased risk of VTE (95% CI, 2.5 to 9.4). Oral but not transdermal estrogen was associated with an increased risk of VTE (odds ratio [OR], 4.3; 95% CI, 2.6 to 7.2; and OR, 1.2; 95% CI, 0.8 to 1.7, respectively). After adjustment for potential confounding factors, the combination of either factor V Leiden or prothrombin G20210A mutation and oral estrogen gave a 25-fold-increased risk of VTE compared with nonusers without mutation (95% CI, 6.9 to 95.0). However, the risk for women with prothrombotic mutation using transdermal estrogen was similar to that of women with a mutation who were not using estrogen (OR, 4.4; 95% CI, 2.0 to 9.9; and OR, 4.1; 95% CI, 2.3 to 7.4, respectively).” (P-Y Scarabin, INSERM, Cardiovascular Epidemiology Unit, Villejuif, France; scarabin@vjf.inserm.fr)

Post-MI Care of the Elderly: Better therapies and increased use of aspirin, beta-blockers, and statins are needed among elderly patients who survive myocardial infarction, according to results of the Valsartan in Acute Myocardial Infarction Trial (VALIANT; doi:10.1161/CIRCULATIONAHA.105.551143). The study included 14,703 patients with heart failure and/or left ventricular ejection fraction of less than 40%, and these patients randomly received captopril, valsartan, or both. Assessing a composite end point of cardiovascular mortality, readmission for heart failure, reinfarction, stroke, and resuscitated cardiac arrest among those younger than 65 (n=6,988), 65 to 74 (n=4,555), 75 to 84 (n=2,777), and 85 or older (n=383), the investigators found, ”With increasing age, 3-year mortality almost quadrupled (13.4%, 26.3%, 36.0%, and 52.1%, respectively), composite end-point events more than doubled (25.2%, 41.0%, 52.3%, and 66.8%), and hospital admissions for heart failure almost tripled (12.0%, 23.1%, 31.3%, and 35.4%). Outcomes did not differ between the 3 study treatments in any age group. Adverse events associated with captopril and valsartan were more common in the elderly and in patients receiving combination therapy. With increasing age, use of aspirin, beta-blockers, and statins declined, and use of digoxin, calcium-channel blockers, and non-potassium–sparing diuretics increased. On 3-year multivariable analysis, each 10-year age increase was associated with a hazard ratio of 1.49 (95% CI, 1.426 to 1.557; P < 0.0001) for mortality and an odds ratio of 1.38 (95% CI, 1.31 to 1.46; P < 0.0001) for readmission with heart failure.” (H. D. White, Auckland City Hosp., Auckland, New Zealand; HarveyW@adhb.govt.nz)

Sudden Death & Linoleic Acid Intake: Dietary intake of alpha-linoleic acid may reduce the risk of sudden cardiac death but not other types of coronary heart disease, suggesting that this plant-derived n-3 fatty acid may have antiarrhythmic properties (pp. 3232-8). Based on 1984 food-frequency data from 76,763 women in the Nurses’ Health Study, researchers learned this during 18 years of follow-up, “We identified 206 SCDs, 641 other CHD deaths, and 1604 nonfatal [myocardial infarctions]. After controlling for coronary risk factors and other fatty acids, including long-chain n-3 fatty acids, the intake of alpha-linolenic acid was inversely associated with the risk of SCD (P for trend, 0.02) but not with the risk of other fatal CHD or nonfatal MI. Compared with women in the lowest quintile of alpha-linolenic acid intake, those in the highest 2 quintiles had a 38% to 40% lower SCD risk. This inverse relation with SCD risk was linear and remained significant even among women with high intakes of long-chain n-3 fatty acids.” (C. Albert, calbert@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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Nov. 23, 2005 Vol. 12, No. 227
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Nov. 23/30 issue of JAMA (www.jama.com; 2005; 294).

Enoxaparin Fails to Show “Synergy”: High-risk patients with non–ST-segment elevation acute coronary syndromes treated with an early revascularization strategy and enoxaparin or unfractionated heparin at the time of hospitalization for ACS had similar outcomes at 1 year, including remaining at substantial risk for adverse cardiovascular events, according to results of the Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial (pp. 2594-600). Considering rates of death, nonfatal myocardial infarction, revascularization procedures, stroke, and site-investigator–reported need for rehospitalization at 6 months and all-cause mortality at 1 year, the investigators found, “541 patients (5.4%) had died at 6 months and 739 (7.4%) at 1 year. Death or nonfatal MI at 6 months occurred in 872 patients receiving enoxaparin (17.6%) vs 884 receiving unfractionated heparin (17.8%) (hazard ratio [HR], 0.98; 95% confidence interval [CI], 0.89–1.07; P = .65). In the subgroup of patients receiving consistent therapy, ie, only enoxaparin or unfractionated heparin during the index hospitalization (n = 6138), a reduction in death or nonfatal MI with enoxaparin was maintained at 180 days (HR, 0.85; 95% CI, 0.75–0.95; P = .006). Rehospitalization within 180 days occurred in 858 patients receiving enoxaparin (17.9%) and 911 receiving unfractionated heparin (19.0%) (HR, 0.94; 95% CI, 0.85–1.03; P = .17). One-year all-cause death rates were similar in the 2 treatment groups (380/4974 [7.6%] for enoxaparin vs 359/4948 [7.3%] for unfractionated heparin; HR, 1.06; 95% CI, 0.92–1.22; P = .44). One-year death rates in patients receiving consistent therapy were also similar (251/3386 [7.4%] for enoxaparin vs 213/2720 [7.8%] for unfractionated heparin; HR, 0.95; 95% CI, 0.79–1.14; P = .55).” (K. W. Mahaffey, mahaf002@mc.duke.edu)

Determining the Value of Pharmaceuticals: Two articles provide details on pharmacoeconomic approaches used by the British National Health Service (pp. 2618-22; S. D. Pearson, Boston; spearson99@yahoo.com) and the Australian Pharmaceutical Benefits Scheme (pp. 2630-2; D. A. Henry, Newcastle Mater Misericordiae Hosp., Waratah, Australia; david.henry@newcastle.edu.au) to place a value on drug therapy.

Safety of Muraglitazar: The safety analysis of muraglitazar and accompanying editorial that were released early (see PNN, Oct. 24) are published in this issue of JAMA (pp. 2581-6; 2633-5).

>>>PNN NewsWatch
* Sterility concerns have prompted recall of five lots of Novartis Ophthalmics’ GenTeal Gel: Lot Z12468, 10 mL, expiration date 01/2006; Lot Z12912, 3.5 mL, expiration date 03/2006; Lot Z12900, 10 mL, expiration date 04/2006; Lot Z13161, 10 mL, expiration date 05/2006; and Lot Z13314, 3.5 mL, expiration date 06/2006. The five lots include about 142,500 tubes of the hydroxypropyl methylcellulose product distributed nationwide from Mar. to Nov. 2004. Also being recalled are two lots of GenTeal GelDrops: Lot 51139, 15 mL, expiration date 07/2007; and Lot 51283, 25 mL, expiration date 07/2007. The two lots include about 12,000 dropper bottles distributed nationwide in Oct. 2005.Consumers who have purchased products with any of these lot numbers should contact the company at 866-393-6336.

* Intraoperative floppy iris syndrome (IFIS) has been observed during phacoemulsification cataract surgery in some patients treated with
alpha-1 adrenergic antagonists, FDA and Boehringer Ingelheim are warning health professionals. Most of these reports were in patients taking the alpha-1 blocker when IFIS occurred, but in some cases alpha-1 blocker had been stopped before surgery. Men being considered for cataract surgery, as part of their medical history, be specifically questioned to determine whether they have taken tamsulosin (Flomax) or other alpha-1 blockers. If so, the patient's ophthalmologist should be prepared for possible modifications to their surgical technique that may that may be warranted should IFIS be observed during the procedure.

*
PNN will not be published on the following days during the holiday season: Nov. 24 and 25, Dec. 23 and 26, and Jan. 2.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Nov. 28, 2005 Vol. 12, No. 228
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
Nov. 26 issue of Lancet (www.thelancet.com; 2005; 366).

Zinc Supplements for HIV-Infected Children: No increase in plasma HIV-1 viral load was detected among HIV-infected children who received zinc supplementation for 6 months, according to a South African study, and the mineral did protect against watery diarrhea in at-risk children (pp. 1862-7). Mean HIV-1 loads were similar between zinc and placebo groups at 6 months, as were the mean percentage of CD4+ T lymphocytes and median hemoglobin concentrations, negating a potential concern about addition of zinc to the diet. “Children given zinc supplementation were less likely to get watery diarrhoea than those given placebo,” the authors report. “Watery diarrhoea was diagnosed at 30 (7.4%) of 407 clinic visits in the zinc-supplemented group versus 65 (14.5%) of 447 visits in the placebo group (p = 0·001).” (W. Moss, Johns Hopkins U., Baltimore; wmoss@jhsph.edu)

>>>BMJ Highlights
Source:
Early-release articles from BMJ (www.bmj.org; 2005; 331).

Vitamin A in Children: The dose of vitamin A recommended by WHO could be cut in half from a mortality viewpoint, but morbidity is minimized with the full dose, conclude investigators who studied 4,983 children aged 6 months to 5 years in Guinea-Bissau, Africa (DOI: 10.1136/bmj.38670.639340.55). As part of a combined oral polio vaccine and vitamin A supplementation campaign, the researchers noted these results: “Mortality was lower in the children who took half the recommended dose of vitamin A compared with the full dose at both six months (mortality rate ratio 0.69, 95% confidence interval 0.36 to 1.35) and nine months (0.62, 0.36 to 1.06) of follow-up. There was a significant interaction between sex and dose, the lower dose being associated with significantly reduced mortality in girls (0.19, 0.06 to 0.66) but not in boys (1.98, 0.74 to 5.29). The lower dose of vitamin A was consistently associated with lower hospital case fatality in girls (0.19, 0.02 to 1.45). Paradoxically, in children aged 6–18 months, the low dose was associated with slightly higher morbidity.” (C. S. Benn, Statens Serum Inst., Copenhagen, Denmark; cb@ssi.dk)

Cost-Effectiveness of Antiretroviral Strategies: Compared with interventions such as mass media campaigns and education of sex workers, antiretroviral therapy is “at least as cost effective,” according to an analysis performed for sub-Saharan Africa and southeastern Asia (DOI: 10.1136/bmj.38643.368692.68). Considering the costs per disability-adjusted life-year in 2000 international dollars, the investigators found, “In both regions interventions focused on mass media, education and treatment of sexually transmitted infections for female sex workers, and treatment of sexually transmitted infections in the general population cost <$Int150 per DALY averted. Voluntary counselling and testing costs <$Int350 per DALY averted in both regions, while prevention of mother to child transmission costs <$Int50 per DALY averted in [Africa] but around $Int850 per DALY in [Asia]. School based education strategies and various antiretroviral treatment strategies cost between $Int500 and $Int5000 per DALY averted.”
(J. A. Salomon,
jsalomon@hsph.harvard.edu)

>>>PNN JournalWatch
* Randomised Controlled Trial of Animal Facilitated Therapy with Dolphins in the Treatment of Depression, in BMJ, 2005; 331: 1231 ff. Reprints: bmj.bmjjournals.com/cgi/content/abstract/331/7527/1231; M. A. Reveley, U. Leicester, Leicester, U.K.; rev@le.ac.uk

* In-Hospital Initiation of Statin Therapy in Acute Coronary Syndromes, in
Chest, 2005; 128: 3641–51. Reprints: www.chestjournal.org/cgi/content/abstract/128/5/3641; G. C. Fonarow, gfonarow@mednet.ucla.edu

* Macrolides: A Treatment Alternative for Bronchiolitis Obliterans Organizing Pneumonia?, in
Chest, 2005; 128: 3611–7. Reprints: www.chestjournal.org/cgi/content/abstract/128/5/3611; D. E. Stover, Memorial Sloan-Kettering Cancer Ctr., New York; stoverd@mskcc.org

* Lifestyle Modification Counseling of Patients with Dyslipidemias by Pharmacists and Other Health Professionals, in
Journal of the American Pharmacists Assoc., 2005; 45: 709–13. Reprints: www.japha.org; T. L. Lenz, tlenz@creighton.edu

* Availability of and Attitudes Toward Resources on Alternative Medicine Products in the Community Pharmacy Setting, in
Journal of the American Pharmacists Assoc., 2005; 45: 734–9. Reprints: www.japha.org; J. P. Nathan, joseph.nathan@liu.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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Nov. 29, 2005 Vol. 12, No. 229
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Nov. 28 issue of Archives of Internal Medicine (www.archinternmed.com; 2005; 165).

Depression & Adherence: Two studies address problems related to medication adherence among patients with depression.

Patients with coronary heart disease were more likely not to take medications for the heart problems when they had comorbid depression, according to self-reports of 940 outpatients (pp. 2508-13). “A total of 204 participants (22%) had major depression,” write the authors. “Twenty-eight (14%) of 204 depressed participants reported not taking their medications as prescribed compared with 40 (5%) of 736 nondepressed participants (odds ratio [OR], 2.8; 95% confidence interval [CI], 1.7–4.7; P < .001). Twice as many depressed participants as nondepressed participants (18% vs 9%) reported forgetting to take their medications (OR, 2.4; 95% CI, 1.6–3.8; P < .001). Nine percent of depressed participants and 4% of nondepressed participants reported deciding to skip their medications (OR, 2.2; 95% CI, 1.2–4.2; P = .01). The relationship between depression and nonadherence persisted after adjustment for potential confounding variables, including age, ethnicity, education, social support, and measures of cardiac disease severity (OR, 2.2; 95% CI, 1.2–3.9; P = .009 for not taking medications as prescribed).” (M. A. Whooley,
mary.whooley@med.va.gov)

Looking at medication possession ratios over a 6- to 12-month period, researchers showed that medication adherence for both antidepressants and drugs for comorbid conditions reduces total medical costs for coronary artery disease, dyslipidemia, and/or diabetes mellitus (pp. 2497-503). Using retrospectively collected data, the second study showed, “Of 8040 patients meeting the study criteria, those adherent to antidepressant medication were more likely to be adherent to comorbid therapy vs those nonadherent to antidepressant drug therapy (CAD/dyslipidemia: odds ratio [OR], 2.13; DM: OR, 1.82; and CAD/dyslipidemia/DM: OR, 1.45; P < .001 for all). Patients adherent to antidepressant drug therapy also had significantly lower disease-specific charges vs nonadherent patients (17% lower in CAD/dyslipidemia, P = .02; 8% lower in DM, P = .39; and 14% lower in CAD/dyslipidemia/DM, P = .38). These patients also incurred lower total medical charges (6.4% lower in CAD/dyslipidemia, P = .048; 11.8% lower in DM, P = .04; and 19.8% lower in CAD/dyslipidemia/DM, P = .03).” (E. Chiao, Applied Health Outcomes, Palm Harbor, Fla.;
echiao@applied-outcomes.com)

Subclinical Hypothyroidism & Cardiovascular Disease: Two articles (pp. 2460-6; 2467-72) and an editorial (pp. 2451-2) indicate that “treatment of subjects with mild [subclinical hypothyroidism] or high-normal TSH levels would probably not be beneficial in the prevention of [cardiovascular disease].”

Clinical Research & the Pharmaceutical Industry: Medical specialists with research relationships with the pharmaceutical industry are significantly more likely to have multiple ties to the industry, according to a survey of Australian physicians (pp. 2493-6). Concluding that such “ties that bind” should be discouraged by institutional review, the authors provide these survey results, “A questionnaire was mailed to 2120 medical specialists; 823 (39%) responded. Of these, 338 (41%) reported involvement in industry-sponsored research in the previous year. They were more likely than others to have been offered industry-sponsored items or activities valued at more than AU $500 (>US $382; odds ratio [OR], 3.5; 95% confidence interval [CI], 2.6-4.7) and support for attending international conferences (OR, 5.4; 95% CI, 3.9-7.4). The strongest associations were seen for acting as a paid consultant to industry (OR, 9.0; 95% CI, 3.9-20.4) and for membership on advisory boards (OR, 6.9; 95% CI, 5.1-9.6). There was a strong relationship between research collaboration and accumulation of industry ties. For 1 additional tie the OR was 2.2 (95% CI, 1.2-3.8) and rose to 6.3 (95% CI, 3.5-11.1) with 3 ties and 41.8 (95% CI, 14.5-143.4) with 6 or more ties.” (D. Henry, Newcastle Mater Hosp., Waratah, New South Wales, Australia; david.henry@newcastle.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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Nov. 30, 2005 Vol. 12, No. 230
Providing news and information about medications and their proper use

>>>JAPhA Highlights
Source:
Nov/Dec issue of the Journal of the American Pharmacists Assoc. (www.japha.org; 2005; 45).

Lifestyle Counseling by Pharmacists: “Despite being well positioned to assist patients with elevated serum cholesterol concentrations, pharmacists offer less patient counseling about therapeutic lifestyle modifications compared with physicians and nurses,” concludes an article reporting results of a survey of 234 patients taking lipid-lowering medications (pp. 709-13). Conducted in two midwestern cities, the survey explored lifestyle counseling offered to the patients, with these results: “Nearly three quarters (73.9%) of participants received information about lowering their serum lipids through lifestyle modifications when they were first diagnosed with elevated serum cholesterol concentrations. Of these, most (83.8%) said that the information came from their physician. Fewer than one half (48.3%) of all participants said that they continued to receive this type of information. Those who received lifestyle modification information at their original diagnosis and who continued to receive this type of information were more likely to be actively trying to lower their serum lipid levels through diet (93.1%) and exercise (71.6%). Participants visited their pharmacy more often than their physician’s office each year, yet they recalled pharmacists offering less patient counseling on lifestyle modifications than did physicians and nurses.” (T. L. Lenz, tlenz@creighton.edu)

Rural Pharmacy Services: Two research studies explore pharmacy closings in rural Minnesota and possible solutions to an emerging access problem in these areas (pp. 684-93; 694-9). The first study, a survey of pharmacy owners and managers in 126 towns with 5,000 or fewer residents and only one community pharmacy in the summer of 2003, explored factors contributing to the possible loss of pharmacy services, including shrinking populations, lack of community support, aging owners who will soon be ready to sell their pharmacies, the difficulties in hiring pharmacist–employees, and lack of access to primary care in the community. The second study presented 177 upper-level student pharmacists with a nontraditional practice model that included professional opportunities more closely associated with the practice desires of individuals currently entering the profession. “Many of the respondents (62.7%), enrolled in the three schools of pharmacy at which the majority of rural pharmacists in Minnesota have traditionally been trained, expressed interest in practicing in rural settings,” the authors report. “Considerations cited in respondents’ choice of first position indicated that professional goals were of primary concern, followed by geographic location. Only 26.6% of student pharmacists expressed interest in pharmacy ownership, while 66% were interested in pursuing staff positions. Many respondents (63%) expressed interest in a nontraditional rural pharmacy practice model proposed in the survey.” (T. D. Sorensen, soren042@umn.edu)

Pharmacists & Hurricane Katrina: Pharmacists’ roles in relief efforts following Hurricane Katrina and disaster impact on pharmacies are covered in two feature articles (pp. 654-8; 659-62), a research study (pp. 670-5), and an editorial (p. 629). The feature articles, written by Jef Bratberg, PharmD, BCPS, of the U. Rhode Island (jefbratberg@yahoo.com), and Elaine Lust, PharmD, of Creighton U. (elainel@creighton.edu, detail these pharmacists’ respective involvements with Disaster and Veterinary Medical Assistance Teams that were deployed to Louisiana.

>>>PNN NewsWatch
* MBI Distributing, Inc., also known as Molecular Biologics, an OTC drug manufacturer of eye drops and other products, has signed a consent decree that requires it to cease manufacturing and distributing drugs until it corrects manufacturing deficiencies and other violations at its Benicia, Calif,. facility, FDA announced yesterday.

*
FDA also yesterday rescinded a generic drug approval it issued on Nov. 18. The agency explained that a U.S. district court had found that the ANDA for Kali Laboratories’ ondansetron orally disintegrating tablets infringes on an unexpired patent on the drug held by GlaxoSmithKline.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Dec. 1, 2005 Vol. 12, No. 231
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Dec. 1 issue of the New England Journal of Medicine (content.nejm.org; 2005; 353).

HAART in Developing Countries: The feasibility of treating large numbers of HIV-infected patients with highly active antiretroviral therapy is demonstrated in a study conducted in Haiti (pp. 2325-34). The investigators write: “During a 14-month period, three-drug antiretroviral therapy was initiated in 1004 patients, including 94 children under 13 years of age. At enrollment, the median CD4 T-cell count in adults and adolescents was 131 per cubic millimeter (interquartile range, 55 to 211 per cubic millimeter); in children, a median of 13 percent of T cells were CD4-positive (interquartile range, 8 to 20 percent). According to a Kaplan–Meier survival analysis, 87 percent of adults and adolescents and 98 percent of children were alive one year after beginning treatment. In a subgroup of 100 adult and adolescent patients who were followed for 48 to 56 weeks, 76 patients had fewer than 400 copies of human immunodeficiency virus RNA per milliliter. In adults and adolescents, the median increase in the CD4 T-cell count from baseline to 12 months was 163 per cubic millimeter (interquartile range, 77 to 251 per cubic millimeter). In children, the median percentage of CD4 T cells rose from 13 percent at baseline to 26 percent (interquartile range, 22 to 36 percent) at 12 months. Treatment-limiting toxic effects occurred in 102 of the 910 adults and adolescents (11 percent) and 5 of the 94 children (5 percent).” (D. W. Fitzgerald, Weill Medical College of Cornell U., New York; dfitzgerald@gheskio.org)

Editorialists support “scaling up treatment” of people with HIV in developing countries (pp. 2392-4): “Certainly, significant challenges remain. Some skeptics doubt that a high standard of care can be provided by nurses and community health workers (rather than scarce highly trained physicians), although this approach is now being used successfully in many countries. But we who have worked in developing countries know that in many settings that are poor in resources, adoption of a decentralized model of care is essential if health systems are to overcome serious human-resource constraints and move toward the goal of monitoring and supporting patients for life. Innovative strategies to support adherence may be required, but so far, adherence rates in even the most impoverished settings compare favorably with those of patients in the United States. Drug-supply links are fragile in many countries, but concerted efforts are now being made to strengthen them, with potentially great benefits for the provision of other essential medicines. It is now clear that responding aggressively to HIV and AIDS is critical to reinforcing health systems as a whole and to achieving broader development objectives in the coming decade.” (J. Y. Kim, WHO, Geneva)

Mortality Risk with Antipsychotic Agents: The risk of death is at least as high with conventional (typical or first generation) antipsychotic agents as with the newer atypical agents, according to a retrospective cohort study of 22,890 patients aged 65 years or younger (pp. 2335-41). FDA had recently warned of an increased risk of death with newer agents, but these authors conclude, “Conventional drugs should not be used to replace atypical agents discontinued in response to the FDA warning.” The risk of death was significantly elevated among those on conventional antipsychotic agents, compared with atypical agents, by 27% to 56% for various time periods studied. (P. S. Wang, pwang@rics.bwh.harvard.edu)

TSS After Medical Abortion: Four deaths caused by endometritis and toxic shock syndrome associated with Clostridium sordelli and occurring within 1 week of medical abortion are described in a brief report (pp. 2352-60). The women had all been given oral mifepristone 200 mg followed by vaginal misoprostol 800 mcg. The similarity of adverse effects of misoprostol (vomiting, diarrhea, and abdominal cramping) and initial symptoms of TSS caused by C. sordelli complicate recognition of the syndrome, the authors explain, adding, “Clinicians should be aware of the distinctive features of this potentially fatal entity, including tachycardia, hypotension, edema, hemoconcentration, profound leukocytosis, and absence of fever.” (M. Fischer, mfischer@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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Dec. 2, 2005 Vol. 12, No. 232
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Dec. Diabetes Care (care.diabetesjournals.org; 2005; 28).

Intensive Therapy & Retinopathy: Among patients with type 2 diabetes with no evidence of retinopathy, the risk of this complication can be significantly reduced through a relatively short period of case management, according to results from the California Medi-Cal Type 2 Diabetes Study (pp. 2819-22). Conducted among low income ethnic minority populations in southern California, study participants received either traditional treatment or diabetes case management. Based on two retinal photographs obtained for 149 patients, the investigators recorded results indicative of the rapid development of retinopathy in this patient population, “Progression of retinopathy in the intervention group was not significantly less than in the control group (P = 0.226). However, those in the intervention group with no evidence of retinopathy at baseline were less likely to develop diabetic retinal changes (5/48) during a mean follow-up of 23.1 months than those in the control group (10/34, chi square = 4.805, P = 0.028). This difference remained significant in a logistic regression model that controlled for potential confounders (odds ratio 5.35 [95% CI 1.14–25.12]).” (L. Jovanovic, Sansum Diabetes Res. Inst., Santa Barbara, Calif.; ljovanovic@sansum.org)

Exercise Capacity & Rosiglitazone: Possibly because of improvements in insulin sensitivity or endothelial function, rosiglitazone treatment improved exercise function among 20 patients with type 2 diabetes (pp. 2877-83). Compared with placebo, rosiglitazone 4 mg/day for 4 months significantly enhanced measures of maximal oxygen consumption, insulin sensitivity, and endothelial function. (J. G. Regensteiner, U. Colorado Health Sci. Ctr., Denver; judy.regensteiner@uchsc.edu)

Alcohol Consumption & Risk of Diabetes: Moderate alcohol consumption significantly reduced the risk of type 2 diabetes among 16,330 women aged 49–70 years, Dutch Prospect-EPIC (European Prospective Study Into Cancer and Nutrition) researchers report (pp. 2933-8). These results emerged during a mean of 6.2 years of monitoring: “760 cases of type 2 diabetes were documented. A linear inverse association (P = 0.007) between alcohol consumption and type 2 diabetes risk was observed, adjusting for potential confounders. Compared with abstainers, the hazard ratio for type 2 diabetes was 0.86 (95% CI 0.66–1.12) for women consuming 5–30 g alcohol per week, 0.66 (0.48–0.91) for 30–70 g per week, 0.91 (0.67–1.24) for 70–140 g per week, 0.64 (0.44–0.93) for 140–210 g per week, and 0.69 (0.47–1.02) for > 210 g alcohol per week. Beverage type did not influence this association. Lifetime alcohol consumption was associated with type 2 diabetes in a U-shaped fashion.” (M. L. Bots, U. Med. Ctr., Utrecht, the Netherlands; m.l.bots@umcutrecht.nl)

>>>PNN NewsWatch
* Cytokine stimulation of erythropoiesis can produce pure red cell aplasia and severe anemia, with or without other cytopenias, Amgen, Ortho Biotech, and FDA are cautioning health professionals. Based on reports in patients with chronic renal failure, epoetin alfa (Epogen, Procrit) and darbepoetin alfa (Aranesp) can produce these dysplasias, which are associated with development of neutralizing antibodies to erythropoietin.

* Three patients in a clinical study of
alemtuzumab (Campath) for treatment of multiple sclerosis have developed severe idiopathic thrombocytopenic purpura, with one fatality, FDA and Berlex announced this week. This drug is not currently approved by FDA for this indication, and dosing in the clinical study has been suspended.

*
Taking Your Medicine is a new title available from the Pharmaceutical Products Press. Written by U. Georgia pharmacy professor Jack E. Fincham, PhD, the text describes for patients and caregivers the importance of medication regimens and adherence, with chapters on drug interactions and how to choose a pharmacist.

* Another title of interest is
Health Care Informatics: A Skills-Based Resource, by Auburn U.’s Bill G. Felkey and colleagues. Published by APhA, the text defines informatics and presents information on telehealth, point-of-care technology, literature retrieval and evaluation, e-commerce, and patient/professional education.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Dec. 5, 2005 Vol. 12, No. 233
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
Dec. 3 issue of Lancet (www.thelancet.com; 2005; 366).

Adjuvant Therapy for High-Risk Breast Cancer: Compared with a dose-dense conventional regimen, high-dose chemotherapy yielded significant improvements in event-free and overall survival in patients with at least nine positive nodes at diagnosis of breast cancer (pp. 1935-44). Study participants received either two courses of accelerated (2-week intervals, with filgrastim support), conventionally dosed epirubicin and cyclophosphamide followed by two courses of high-dose chemotherapy (epirubicin, cyclophosphamide, and thiotepa supported by peripheral-blood progenitors) or four identical cycles of epirubicin and cyclophosphamide followed by three cycles of accelerated cyclophosphamide, methotrexate, and fluorouracil. Noting that their positive findings are in contrast to other studies, the investigators provided these results, “403 patients were enrolled; 201 were assigned high-dose chemotherapy and 202 conventional treatment. The mean number of positive nodes was 17.6, and median follow-up was 48.6 months. 4-year event-free survival (intention-to-treat analysis) was 60% (95% CI 53–67) in the high-dose chemotherapy group and 44% (37–52) in the control group (p = 0·00069). The corresponding overall survival was 75% (69–82) versus 70% (64–77; p = 0.02). There were no treatment-related deaths.” (U. A. Nitz, U. Hosp., Düsseldorf, Germany; nitzu@uni-duesseldorf.de)

>>>BMJ Highlights
Source:
Early-release articles from and the Dec. 3 issue of BMJ (www.bmj.org; 2005; 331).

Cannabis Intoxication and Fatal Road Crashes: Nearly 1 in 10 at-fault drivers in France involved in fatal crashes had detectable cannabis levels, but the proportion of fatalities attributed to marijuana was much lower than those by those caused by alcohol-intoxicated drivers (doi: 10.1136/bmj.38648.617986.1F). Over a 2-year period, 8.8% of at-fault drivers were positive for cannabis, compared with 2.8% of drivers involved but not charged in fatal crashes. The odds ratio increased from 2.18 at low THC levels to 4.72 among those with high levels of this active ingredient of marijuana. But overall, only 2.5% of fatal crashes were attributable to cannabis, compared with 26.8% where alcohol was the likely cause. (B. Laumon, French National Inst. for Transport and Safety Research; bernard.laumon@inrets.fr)

COX-2 Inhibitors, NSAIDs, and & GI Toxicity: Measured by frequencies of gastrointestinal events, the safety of nonselective NSAIDs and COX-2–specific inhibitors were largely equivalent in a nested case–control study of adults in the U.K. with a first diagnosis of peptic ulcer or hematemesis (pp. 1310-6). “The incidence of adverse upper gastrointestinal events was 1.36 per 1000 person years (95% confidence interval 1.34 to 1.39),” the authors note. “We identified 9,407 incident cases and 88,867 matched controls. Increased risks of adverse gastrointestinal events were associated with current use of cyclo-oxygenase-2 inhibitors and with conventional non-steroidal anti-inflammatory drugs. Risks were reduced after adjustment for confounders but remained significantly increased for naproxen (adjusted odds ratio 2.12, 95% confidence interval 1.73 to 2.58), diclofenac (1.96, 1.78 to 2.15), and rofecoxib (1.56, 1.30 to 1.87) but not for current use of celecoxib (1.11, 0.87 to 1.41). We found clinically important interactions with current use of ulcer healing drugs that removed the increased risks for adverse gastrointestinal events for all groups of non-steroidal anti-inflammatory drugs except diclofenac, which still had an increased odds ratio (1.49, 1.26 to 1.76).” (J Hippisley-Cox, U. Nottingham, Nottingham, U.K.; julia.hippisley-cox@nottingham.ac.uk)

>>>PNN JournalWatch
* Anabolic Steroids and the Pediatric Community, in Pediatrics, 2005; 116: 1542 ff. Reprints: www.pediatrics.org; J. D. Metzl.

* Pharmacotherapy for Human Immunodeficiency Virus–Associated Nephropathy, in
Pharmacotherapy, 2005; 25: 1761–72. Reprints: www.pharmacotherapy.org; S. D. Pope, Carolinas Med. Ctr., Charlotte; scott.pope@carolinas.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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Dec. 6, 2005 Vol. 12, No. 234
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Dec. 6 issue of the Annals of Internal Medicine (www.annals.org; 2005; 143).

Stroke Incidence After MI: The risk for ischemic or hemorrhagic stroke is markedly increased after myocardial infarction, and this risk has not changed much over the past two decades, according to a community-based cohort study (pp. 785-92). Looking at those with incident MI between 1979 and 1998, the investigators observed, “A total of 2160 persons with incident MI were hospitalized between 1979 and 1998 and followed for a median of 5.6 years (range, 0 to 22.2 years). The rate of stroke was 22.6 per 1000 person-months (95% CI, 16.3 to 30.6 per 1000 person-months) during the first 30 days after MI, corresponding to a 44-fold increase (standardized morbidity ratio, 44 [95% CI, 32 to 59]) risk for stroke in the population of Rochester, Minnesota. The risk for stroke remained 2 to 3 times higher than expected during the first 3 years after MI. Older age, previous stroke, and diabetes increased the risk for stroke, which did not decline over the study period. Strokes were associated with a large increase in the risk for death after MI (hazard ratio, 2.89 [CI, 2.44 to 3.43]).” (V. L. Roger, Mayo Clinic, Rochester, Minn.)

Lateral Epicondylitis & Botulinum Toxin: Pain is relieved for a 3-month period following injection of botulinum toxin into individuals with lateral epicondylitis, notes a study of 60 such patients (pp. 793-7). But the relief of tennis elbow may come at the expense of digit paresis and weakness of finger extension, the investigators add, noting, “Mean [visual analogue scale] scores for the botulinum group at baseline and at 4 weeks were 65.5 mm and 25.3 mm, respectively; respective scores for the placebo group were 66.2 mm and 50.5 mm (between-group difference of changes, 24.4 mm [95% CI, 13.0 to 35.8 mm]; P < 0.001). At week 12, mean VAS scores were 23.5 mm for the botulinum group and 43.5 mm for the placebo group (between-group difference of changes, 19.3 mm [CI, 5.6 to 32.9 mm]; P = 0.006). Grip strength was not statistically significantly different between groups at any time. Mild paresis of the fingers occurred in 4 patients in the botulinum group at 4 weeks. One patient's symptoms persisted until week 12, whereas none of the patients receiving placebo had the same complaint. At 4 weeks, 10 patients in the botulinum group and 6 patients in the placebo group experienced weak finger extension on the same side as the injection site.” (S. M. Wong, PacifiCare, Hong Kong, China; jsmwong@hkstar.com)

>>>NEJM Highlights
Source:
Advance-release articles from the Dec. 8 issue of the New England Journal of Medicine (content.nejm.org; 2005; 353).

New Clostridium difficile Strain: Two large studies describe the emergence of a new, virulent strain of Clostridium difficile, and an accompanying editorial describes how fluoroquinolone use may be the evolutionary factor driving the shift.

“A previously uncommon strain of
C. difficile with variations in toxin genes has become more resistant to fluoroquinolones and has emerged as a cause of geographically dispersed outbreaks of C. difficile-associated disease” in the U.S., explains the first research study (pp. 2433-41). The article describes outbreaks of C. difficile-related disease at eight health care facilities in six states. Genetic typing showed presence of one unusual strain, and all current but no historical isolates of this strain were resistant to gatifloxacin and moxifloxacin. (L. F. McDonald, cmcdonald1@cdc.gov)

Cephalosporins and fluoroquinolones were more commonly received by patients with nosocomial
C. difficile-associated diarrhea in a study of 12 Quebec hospitals (pp. 2442-9). The virulent strain produced disease in 2.25% of patients admitted to the hospitals, and 6.9% of affected patients died within 30 days. (V. G. Loo, vivian.loo@muhc.mcgill.ca)

Control of the emerging strain “hinges on prevention, recognition of cases, and optimal management of disease,” advise the editorialists (pp. 2503-5), along with “antibiotic stewardship.” (J. G. Bartlett, 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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Dec. 7, 2005 Vol. 12, No. 235
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Dec. 7 issue of JAMA (www.jama.com; 2005; 294).

Adjuvant Chemotherapy for Colon Cancer: Between 1990 and 2002, increased use of adjuvant chemotherapy for stage III colon cancer produced a 16% jump in 5-year survival rates, but blacks appeared to not benefit from the therapy as much as other patients, and women and elderly were often treated less aggressively (pp. 2703-11). Those findings come from an analysis of the National Cancer Data Base, which includes reports from 560 hospital cancer registries. The investigators report: “Adjuvant chemotherapy use increased from 39% in 1991 to 64% in 2002 but was lower in black, female, and elderly patients. It improved 5-year survival from almost 8% in 1991 to more than 16% in 1997 compared with surgery alone. Adjuvant chemo-therapy increases survival in elderly patients as much as it does in younger patients. However, the benefit of adjuvant chemotherapy in blacks and those with high-grade cancers is not as great.” (J. M. Jessup, jessupj@mail.nih.gov)

Editorialists question just how much progress has been made in extending research findings into clinical practice (pp. 2758-60): “Even though causes for recommending or not recommending adjuvant chemotherapy are multifactorial, Jessup et al observed an increase in the use of adjuvant chemotherapy over time. It is not clear why it took so many years for a majority of patients to receive adjuvant treatment despite the clear demonstration of a survival benefit. Hopefully, further progress in the knowledge of adjuvant therapy will have a more rapid influence on clinical practice in the near future.” (E. Van Cutsem, U. Hosp. Gasthuisberg, Leuven, Belgium;
Eric.VanCutsem@uz.kuleuven.ac.be)

Adverse Reactions to Intranasal Influenza Vaccine: No unexpected serious risks of intranasal influenza vaccine were identified during the first two seasons of FluMist use, explain researchers who analyzed voluntary reports to FDA’s Vaccine Adverse Event Reporting System (pp. 2720-5). Reactions to the live, attenuated influenza vaccine occurred with these frequencies: “Approximately 2,500,000 persons received LAIV-T during the first 2 postlicensure seasons. As of August 16, 2005, VAERS received 460 adverse event reports for vaccinations received from August 2003 through July 2005. No fatalities were reported. There were 7 reports of possible anaphylaxis, 2 reports of Guillain-Barré syndrome, 1 report of Bell palsy, and 8 reports of asthma exacerbation among individuals with a prior asthma history. Events in individuals for whom the vaccine was not indicated accounted for 73 reports (16%).” (H. S. Izurieta, hector.izurieta@fda.hhs.gov)

In an accompanying editorial, writers put the LAIV-T product in this perspective (pp. 2763-5): “In an era in which influenza vaccine delays and shortages have become the norm, LAIV represents an important option to increase vaccination rates among healthy persons for their own protection and for the protection of those with whom they have close contact. Currently, LAIV is licensed for healthy persons 5 to 49 years of age, although expanded indications may be forthcoming (based on the intent of the company to file for broader licensure). As with any licensed product, continued monitoring of the safety of LAIV will be important. However, the cumulative evidence, including the VAERS experience, should reassure clinicians and patients of the safety of both licensed influenza vaccines. Decisions regarding which influenza vaccine to choose in the healthy 5- to 49-year-old age group should be based on availability, patient preference, and cost.” (K. M. Neuzil, PATH, Seattle;
kneuzil@path.org)

Adverse Events with Smallpox Vaccine: Two research studies explore the rates of reaction to smallpox vaccine. Among 38,885 recipients of the smallpox vaccine in 2003, 822 individuals reported adverse events, including 21 serious sequelae (pp. 2734-43; Christine G. Casey; ccasey@cdc.gov). Detailing neurologic events associated with smallpox vaccination in 2002–2004, a second set of investigators found most of 214 problems mild and self-limiting (pp. 2744-50; James J. Sejvar, zea3@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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Dec. 8, 2005 Vol. 12, No. 236
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Dec. 8 issue of the New England Journal of Medicine (content.nejm.org; 2005; 353).

Febuxostat for Gout: An investigational, orally administered, nonpurine analogue inhibitor of xanthine oxidase proved more effective than allopurinol for lowering serum urate concentrations among 762 patients with gout (pp. 2450-61). Comparing febuxostat 80 and 120 mg daily with allopurinol 300 mg daily for 52 weeks based on lowering of serum uric acid levels to below 6.0 mg/dL, the investigators found, “The primary end point was reached in 53 percent of patients receiving 80 mg of febuxostat, 62 percent of those receiving 120 mg of febuxostat, and 21 percent of those receiving allopurinol (P < 0.001 for the comparison of each febuxostat group with the allopurinol group). Although the incidence of gout flares diminished with continued treatment, the overall incidence during weeks 9 through 52 was similar in all groups: 64 percent of patients receiving 80 mg of febuxostat, 70 percent of those receiving 120 mg of febuxostat, and 64 percent of those receiving allopurinol (P = 0.99 for 80 mg of febuxostat vs. allopurinol; P = 0.23 for 120 mg of febuxostat vs. allopurinol). The median reduction in tophus area was 83 percent in patients receiving 80 mg of febuxostat and 66 percent in those receiving 120 mg of febuxostat, as compared with 50 percent in those receiving allopurinol (P = 0.08 for 80 mg of febuxostat vs. allopurinol; P = 0.16 for 120 mg of febuxostat vs. allopurinol). More patients in the high-dose febuxostat group than in the allopurinol group (P = 0.003) or the low-dose febuxostat group discontinued the study. Four of the 507 patients in the two febuxostat groups (0.8 percent) and none of the 253 patients in the allopurinol group died; all deaths were from causes that the investigators (while still blinded to treatment) judged to be unrelated to the study drugs (P = 0.31 for the comparison between the combined febuxostat groups and the allopurinol group).” (M. A. Becker, mbecker@medicine.bsd.uchicago.edu)

An editorialist adds these cautions about febuxostat (pp. 2505-7): “Other studies will be needed to define better the long-term safety profile of febuxostat, especially when it is administered in patients with renal insufficiency, in those with other coexisting conditions, or in those receiving medications that may cause hepatotoxicity. The general indications for allopurinol therapy are failure of uricosuric drugs or contraindications to their use, tophaceous gout, frequent attacks of gouty arthritis (three or more per year), nephrolithiasis, decreased creatinine clearance, and overproduction of urate. Indications for the use of febuxostat will probably be the same as those for allopurinol. The relative costs of allopurinol and febuxostat may influence the decision to use one or the other.” (L. W. Moreland, U. Alabama, Birmingham)

Infliximab for Ulcerative Colitis: Compared with placebo, three doses of infliximab produced significantly greater clinical responses in 364 patients with mild-to-moderate ulcerative colitis (pp. 2462-76). In the Active Ulcerative Colitis Trials 1 and 2, induction and maintenance therapy was assessed using doses of placebo or infliximab 5 or 10 mg at weeks 0, 2, and 6. Results showed the following: “In ACT 1, 69 percent of patients who received 5 mg of infliximab and 61 percent of those who received 10 mg had a clinical response at week 8, as compared with 37 percent of those who received placebo (P < 0.001 for both comparisons with placebo). A response was defined as a decrease in the Mayo score of at least 3 points and at least 30 percent, with an accompanying decrease in the subscore for rectal bleeding of at least 1 point or an absolute rectal-bleeding subscore of 0 or 1. In ACT 2, 64 percent of patients who received 5 mg of infliximab and 69 percent of those who received 10 mg had a clinical response at week 8, as compared with 29 percent of those who received placebo (P < 0.001 for both comparisons with placebo). In both studies, patients who received infliximab were more likely to have a clinical response at week 30 (P ≤ 0.002 for all comparisons). In ACT 1, more patients who received 5 mg or 10 mg of infliximab had a clinical response at week 54 (45 percent and 44 percent, respectively) than did those who received placebo (20 percent, P < 0.001 for both comparisons).” (W. J. Sandborn, sandborn.william@mayo.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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Dec. 9, 2005 Vol. 12, No. 237
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Dec. issue of Pharmacotherapy (www.pharmacotherapy.org; 2005;25).

Bone Disease in Chronic Kidney Disease: An overview of recent National Kidney Foundation guidelines concerning bone aberration in patients with chronic kidney disease is presented (pp. 1687-707). “These guidelines provide, for the first time, a standard approach to the detection and management of alterations in calcium, phosphorus, and parathyroid hormone metabolism,” the authors note. “The problems and sequelae of soft-tissue calcification are discussed, and recommendations are provided for reducing the associated morbidity and mortality.” (G. R. Bailie, bailieg@acp.edu)

Absence of Heart Problems with Tiotropium: In 196 patients with chronic obstructive pulmonary disease, tiotropium therapy produced no adverse cardiac effects during electrocardiographic monitoring (pp. 1708-18). Compared with placebo, tiotropium 18 mcg once daily provided these results at 8 and 12 weeks of treatment: “Mean baseline forced expiratory volume in 1 second (FEV1) was 1.03 L. Mean changes in heart rate from baseline were similar in both groups. No differences were noted in the percentage of patients developing rhythm or conduction abnormalities detected with electrocardiography or Holter monitoring. Frequency of premature beats and mean maximal changes in PR, QRS, QT, QTcB, and QTcF intervals were similar in both groups. No patients developed new-onset QT or QTc intervals greater than 500 msec, and no differences were noted in the percentage of patients developing new QT prolongation less than 30 msec, 30–60 msec, or greater than 60 msec. At 12 weeks, predose and postdose improvements in FEV1 were 184 and 265 ml, respectively, with tiotropium versus placebo (p < 0.001). Physician and patient global COPD ratings and the [EuroQol Health Questionnaire] visual analog scale scores were improved with tiotropium (p < 0.05); as-needed albuterol was reduced by 25% relative to placebo (p < 0.05).” (H. Covelli, Pulmonary Consultants of North Idaho, Coeur d’Alene, Idaho; hdomc@imbris.net)

High-Dose Vitamin C & Microsomal Activity: Baseline activity of cytochrome P450 3A4 activity and patient gender appear to influence effects of high-dose vitamin C on 3A4 activity, according to a study of 14 volunteers (pp. 1725-8). “In men, mean activity increased by 21.9% (95% confidence interval –3.88–47.6%),” the author note. “The effect in women was not consistent.” (R. P. G. van Heeswijk, Tibotec BVBA, Mechelen, Belgium; rvheeswl@tibbe.jnj.com)

>>>PNN NewsWatch
* The early results of two studies showed that women who took paroxetine during the first 3 months of pregnancy were 1.5–2 times as likely to have a baby with a heart defect as women who received other antidepressants or women in the general population, FDA announced yesterday. Because of the problems, product labeling is being updated from changes made in Sept. of this year, and the pregnancy category of the drug is being downgraded from C to D. Most of the heart defects reported in these studies were atrial and ventricular septal defects. In general, these types of defects range in severity from those that are minor and may resolve without treatment to those that cause serious symptoms and may need to be repaired surgically.

* Three patients were omitted from the published analysis of the
VIGOR (Vioxx Gastrointestinal Outcomes Research) trial, the editors of the New England Journal of Medicine have announced. Posting a Dec. 29 editorial in advance on the NEJM Web site, the staff members noted, “Lack of inclusion of the three events resulted in an understatement of the difference in risk of myocardial infarction between the rofecoxib and naproxen groups (presented in the article as a reduction in the risk with naproxen but [actually] an increase in the risk with rofecoxib). It also resulted in the misleading conclusion that there was a difference in the risk of myocardial infarction between the aspirin indicated and aspirin not indicated groups.”

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Dec. 12, 2005 Vol. 12, No. 238
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
Early-release articles from and the Dec. 10 issue of Lancet (www.thelancet.com; 2005; 366).

ACE & Renoprotection: The assumption that ACE inhibitors and angiotensin II receptor blockers have renoprotective effects is challenged by results of a systematic review and meta-analysis (pp. 2026-33). Questioning whether the drugs have beneficial effects on the kidneys beyond reduction of blood pressure, the authors write, “Comparisons of ACE inhibitors or ARBs with other antihypertensive drugs yielded a relative risk of 0.71 (95% CI 0.49–1.04) for doubling of creatinine and a small benefit on end-stage renal disease (relative risk 0.87, 0.75–0.99). Analyses of the results by study size showed a smaller benefit in large studies. In patients with diabetic nephropathy, no benefit was seen in comparative trials of ACE inhibitors or ARBs on the doubling of creatinine (1.09, 0.55–2.15), end-stage renal disease (0.89, 0.74–1.07), glomerular filtration rate, or creatinine amounts. Placebo-controlled trials of ACE inhibitors or ARBs showed greater benefits than comparative trials on all renal outcomes, but were accompanied by substantial reductions in blood pressure in favour of ACE inhibitors or ARBs.” (J. P. Casas, U. College, London; juan.pablo-casas@lshtm.ac.uk)

Adherence as Marker of Healthy Behaviors: Based on improved outcomes among patients taking placebo in the CHARM (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity) study, researchers conclude that adherent patients are more likely to adopt other healthy recommendations and interventions (pp. 2005-11). Among 7,599 patients with congestive heart failure, the investigators found, “In the time-dependent Cox regression model, after adjustment for predictive factors (demographics, physiological and severity-of-illness variables, smoking history, and number of concomitant medications), good adherence was associated with lower all-cause mortality in all patients (hazard ratio [HR] 0.65, 95% CI 0.57–0.75, p < 0.0001). The adjusted HR for good adherence was similar in the candesartan (0.66, 0.55–0.81, p < 0.0001) and placebo (0.64, 0.53–0.78, p < 0.0001) groups.” (B. B. Granger, grang004@mc.duke.edu)

>>>BMJ Highlights
Source:
Early-release articles from BMJ (www.bmj.org).

Clarithromycin & CVD: Significantly higher cardiovascular mortality was noted among patients with stable coronary heart disease who took short courses of clarithromycin, calling into question the safety of the drug in this patient population (doi:10.1136/bmj.38666.653600.55). In an intention-to-treat analysis of adults discharged with diagnoses of myocardial infarction or angina pectoris in 1993–99 who received 2 weeks of clarithromycin 500 mg/day or placebo, researchers noted these outcomes during 3 years’ follow-up, “2172 participants were randomised to clarithromycin and 2201 to placebo. We found no significant effects of clarithromycin on [all-cause mortality, myocardial infarction, or unstable angina pectoris] (hazard ratio 1.15, 95% confidence interval 0.99 to 1.34) or [a composite of cardiovascular mortality, myocardial infarction, or unstable angina pectoris] (1.17, 0.98 to 1.40). Mortality was significantly higher in the clarithromycin arm (1.27, 1.03 to 1.54; P = 0.03) as a result of significantly higher cardiovascular mortality (1.45, 1.09 to 1.92; P = 0.01).” (C. M. Jespersen, Copenhagen U. Hosp., Copenhagen; cmj01@bbh.hosp.dk)

>>>PNN JournalWatch
* The Use of Vaccines in Adult Patients with Renal Disease, in American Journal of Kidney Diseases, 2005; 46: 997–1011. Reprints: www.ajkd.org/article/PIIS0272638605013314/abstract; M. Dinits-Pensy, U. Maryland Med. Syst., Baltimore

* Working Group on Pandemic Influenza Preparedness: Joint Statement in Response to Department of Health and Human Services Pandemic Influenza Plan, in
Clinical Infectious Diseases, 2006; 42: 92–4. Reprints: www.journals.uchicago.edu/CID/journal/issues/v42n1/38576/38576.html; J. Levi, Trust for America's Health, Washington; jlevi@tfah.org

* Pathogenesis of Early Lung Disease in Cystic Fibrosis: A Window of Opportunity To Eradicate Bacteria, in
Annals of Internal Medicine, 2005; 143: 816–22. Reprints: www.annals.org/cgi/content/full/143/11/816; P. B. McCray Jr., or T. D. Starner, U. Iowa, Iowa 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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Dec. 13, 2005 Vol. 12, No. 239
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Dec. 12/26 Archives of Internal Medicine (www.archinternmed.com; 2005; 165).

Statin-Associated Myopathy: All of 45 patients with statin-associated myopathy recovered fully upon discontinuation of the offending drug, report authors who identified the patients from a total of 437 individuals with suggestive diagnoses over a 13-year period (pp. 2671-6). About 1 in 8 patients required hospitalization for rhabdomyolysis, and recurrent muscle pain was common on rechallenge. The authors added these details, “The mean (SD) duration of statin therapy before symptom onset was 6.3 (9.8) months. Resolution of muscle pain occurred a mean (SD) of 2.3 (3.0) months after discontinuation of statin therapy. Six patients (13%) were hospitalized for the management of rhabdomyolysis; 2 had reversible renal dysfunction, and 1 with preexisting renal insufficiency subsequently began lifelong dialysis. Hospitalized patients developed myopathy more quickly after initiating statin therapy (1.3 vs 7.1 months; P = .048) and were more likely to be taking concomitant medications known to increase the risk of statin-associated myopathy (P = .03). Thirty-seven patients received another statin after an episode of statin-associated myopathy; 21 (57%) reported recurrent muscle pain, whereas 16 (43%) tolerated other statins without recurrent symptoms.” (K. E. Hansen, keh@medicine.wisc.edu)

Cystatin C & Peripheral Arterial Disease: Elevated cystatin C levels are indicative of presence of peripheral arterial disease among community-dwelling elderly patients, concludes a trial of 4,025 participants in the Cardiovascular Health Study (pp. 2666-70). The serum marker for renal function is a cysteine protease inhibitor that is filtered by the glomerulus, and concentrations are viewed as a more sensitive indicator of mild renal dysfunction than serum creatinine concentrations. Increased levels have also been associated with higher risks for all-cause and cardiovascular mortality as well as myocardial infarction, stroke, and congestive heart failure. Investigators assessed need for bypass surgery, angioplasty, or amputation, finding, “The annualized risk of undergoing a procedure for PAD was 0.43% per year among participants in the highest cystatin C quintile (>1.27 mg/L) compared with 0.21% per year or less in all other quintiles. After multivariable adjustment for known risk factors for PAD, elevated cystatin C levels remained associated with the outcome (hazard ratio, 2.5 for highest vs lowest quintile of cystatin C, 95% confidence interval, 1.2–5.1). The highest quintiles of serum creatinine level and eGFR were not associated with future PAD events in either unadjusted or adjusted analyses.” (A. M. O’Hare, Ann.O’Hare@med.va.gov)

Antipsychotics & Venous Thromboembolism: Significant but small elevations in risk of venous thromboembolism are linked to treatment of elderly patients with first- and second-generation antipsychotic agents, according to a retrospective cohort study conducted in nursing homes (pp. 2677-82). “The rate of hospitalization for VTE was 0.91 per 100 person-years,” the authors wrote of 19,940 new users of antipsychotic agents and 112,078 nonusers. “Venous thrombosis accounted for 77.6% of events and 22.4% were pulmonary embolisms. Relative to nonusers, the rate of hospitalization for VTE was increased for users of atypical antipsychotic agents, including risperidone (adjusted hazard ratio [HR], 1.98; 95% confidence interval [CI], 1.40–2.78), olanzapine (adjusted HR, 1.87; 95% CI, 1.06–3.27), and clozapine and quetiapine fumarate (adjusted HR, 2.68; 95% CI, 1.15–6.28). No increased rate was associated with phenothiazines (adjusted HR, 1.03; 95% CI, 0.60–1.77) or other conventional agents (adjusted HR, 0.98; 95% CI, 0.52–1.87).” (R. Liperoti, Università Cattolica del Sacro Cuore Largo A. Gemelli, Rome; rossella_liperoti@rm.unicatt.it)

>>>PNN NewsWatch
* FDA yesterday approved a second brand of mecasermin rinfabate (Iplex, Insmed; see PNN, Sept. 2), an orphan drug indicated for treatment of growth failure in children with severe primary insulin-like growth factor-1 deficiency or with growth hormone gene deletion who have developed neutralizing antibodies to growth hormone.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Dec. 14, 2005 Vol. 12, No. 240
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Dec. 14 issue of JAMA (www.jama.com; 2005; 294).

Status of Patient Safety Systems: Hospital patient safety systems fail far short of recommendations made by the Institute of Medicine, conclude authors who note paltry adoption of computerized physician order entry systems (pp. 2858-65). Based on surveys of all acute care hospitals in Missouri and Utah in 2002 and 2004, the investigators report, “Development and implementation of patient safety systems is at best modest. Self-reported regression in patient safety systems was also found. While 74% of hospitals reported full implementation of a written patient safety plan, nearly 9% reported no plan. The area of surgery appears to have the greatest level of patient safety systems. Other areas, such as medications, with a long history of efforts in patient safety and error prevention, showed improvements, but the percentage of hospitals with various safety systems was already high at baseline for many systems. Some findings are surprising, given the overall trends; for example, while a substantial percentage of hospitals have medication safety systems, only 3% reported full implementation at survey 2 of computerized physician order entry systems for medications, despite the growth of computer technology in general and in hospital billing systems in particular.” (D. R. Longo, longod@health.missouri.edu)

In related editorial, writers note that identifying and eliminating constraints are key components of “creating a safer health care system” (pp. 2906-8): “To produce sustained change, it is essential to understand root causes of current problems, establish policies to induce and maintain change, create measurements at all levels that shape safer behaviors, and properly measure progress toward the goal of having a safer health care system. Longo et al provide data about the introduction of safety systems, but better measurement systems and better data are also needed about the incidence of adverse events.

“Rewarding safety will surely help. Some clinicians might consider being paid to perform as being unprofessional, but few could object to creating a safer and higher-quality health care system. Rather than labeling such initiatives as pay-for-performance programs, it may be preferable to think of them as paying for quality and paying for safety. The time has come to take bold action and to embrace change, but first it is time to understand the constraints to accomplishing that change. As Deming said, ‘Change is not necessary; survival is not mandatory.’” (S. G. Pauker,
spauker@tufts-nemc.org)

Dietary Fiber & Colorectal Cancer: While high intake of dietary fiber from whole plant foods can be recommended to patients for a variety of reasons, prevention of colorectal cancer may not be one of them, according to a pooled analysis of 13 prospective cohort studies (pp. 2849-57). Dietary fiber intake was inversely related to colorectal cancer risk, but the relationship was not linear and not significant after accounting for other dietary risk factors. (S. A. Smith-Warner, pooling@hsphsun2.harvard.edu)

>>>PNN NewsWatch
* FDA has issued warning letters to nine companies marketing products that are claimed to be effective for prevention or treatment of avian or other forms of influenza. The federal agency said that it is aware of no scientific evidence that demonstrates the safety or effectiveness of these products for treating or preventing avian influenza and that it is concerned that the use of these products could harm consumers or interfere with conventional treatments. The products involved make claims such as "prevents avian flu," "a natural virus shield," "kills the virus," and "treats the avian flu."

*
FDA and Bedford Laboratories announced a voluntary recall of one lot of Methotrexate for Injection (preservative free), USP 1 gram per vial (NDC 55390-143-01), Lot 859142, exp 09/07, because the active drug substance used to manufacture the lot contained low levels of ethylene glycol. Preservative-free methotrexate is the only formulation acceptable for intrathecal administration. Health care professionals and suppliers should not distribute these vials and should contact Bedford Laboratories for return instructions. Consumers who have received this product and have questions should contact their physicians.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Dec. 15, 2005 Vol. 12, No. 241
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Dec. 15 issue of the New England Journal of Medicine (content.nejm.org; 2005; 353).

Contraceptives in SLE: Two articles and an editorial conclude that clinicians’ reluctance to use hormonal contraceptives in women with systemic lupus erythematosus is unjustified.

Based on the Systemic Lupus Erythematosus Disease Activity Index as recorded in 162 women with SLE in a single-blind trial of a combination oral contraceptive, a progestin-only formulation, or a copper intrauterine device, researchers report (pp. 2539-49): “The mean (± SD) SLEDAI score was 6.1 ± 5.6 in the group assigned to combined oral contraceptives, 6.4 ± 4.6 in the group assigned to the progestin-only pill, and 5.0 ± 5.3 in the group assigned to the IUD (54 patients in each group) (P = 0.36). Disease activity remained mild and stable in all groups throughout the trial. There were no significant differences among the groups during the trial in global or maximum disease activity, incidence or probability of flares, or medication use. The median time to the first flare was three months in all groups. Thromboses occurred in four patients (two in each of the two groups receiving hormones), and severe infections were more frequent in the IUD group. One patient receiving combined oral contraceptives died from amoxicillin-related severe neutropenia.” (J. Sánchez-Guerrero, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City;
jsanchez@innsz.mx)

A second trial tested triphasic oral contraceptives in 183 women with inactive (76%) or active (24%) SLE (pp. 2550-8): “The primary end point, a severe lupus flare, occurred in 7 of 91 subjects receiving oral contraceptives (7.7 percent) as compared with 7 of 92 subjects receiving placebo (7.6 percent). The 12-month rates of severe flare were similar: 0.084 for the group receiving oral contraceptives and 0.087 for the placebo group (P = 0.95; upper limit of the one-sided 95 percent confidence interval for this difference, 0.069, which is within the prespecified 9 percent margin for noninferiority). Rates of mild or moderate flares were 1.40 flares per person-year for subjects receiving oral contraceptives and 1.44 flares per person-year for subjects receiving placebo (relative risk, 0.98; P = 0.86). In the group that was randomized to receive oral contraceptives, there was one deep venous thrombosis and one clotted graft; in the placebo group, there was one deep venous thrombosis, one ocular thrombosis, one superficial thrombophlebitis, and one death (after cessation of the trial).” (J. P. Buyon,
jill.buyon@nyumc.org)

An editorialist supports use of hormonal contraception in women with inactive or moderately active, stable disease, but with this cautionary note (pp. 2602-4): “Neither of these reports addresses the issue of the use of combined oral contraceptives in women with severe active systemic lupus erythematosus. Whether combined oral contraceptives can be used safely in this subgroup has yet to be determined. Furthermore, thrombotic events occurred in both trials. In the trial reported on by Sánchez-Guerrero et al., these events occurred only among patients receiving exogenous hormones who had low titers of antiphospholipid antibodies (anticardiolipin or anti–beta-2-glycoprotein I antibodies). These findings suggest that patients with lupus should be tested for the presence of antiphospholipid antibodies before oral contraceptives are started and that oral contraceptives should probably be avoided among those with these antibodies or other hypercoagulable states.” (B. L. Bermas, Brigham and Women's Hosp., Boston)

Influenza Deaths in Children: Nearly one half of 153 children who died of influenza in the U.S. during the 2003–04 season were previously healthy, according to an analysis of CDC records (pp. 2559-67). Mortality was highest among infants younger than 6 months of age (0.88 per 100,000 children). Bacterial coinfections were factors in 24% of 102 tested children, and 33% of patients had an underlying condition recognized as problematic in influenza. About one third of children died outside the hospital setting, and similar numbers died within 3 days of symptom onset. (N. Bhat, nbhat@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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Dec. 16, 2005 Vol. 12, No. 242
Providing news and information about medications and their proper use

>>>Infectious Disease Report
Source:
Jan. 15 issue of Clinical Infectious Diseases (www.journals.uchicago.edu/CID; 2006; 42).

Resistant Staphylococcus aureus Outbreak: Control of a large outbreak of glycopeptide-intermediate Staphylococcus aureus in an intensive-care unit is described (pp. 170-8): “Recognition of the outbreak was difficult. Infections, all of which were severe, were diagnosed in 11 of 21 patients. Patient isolation and barrier precautions failed when used alone. Addition of a stringent policy of restricted admissions, twice daily environmental cleaning, and implementation of hand decontamination with a hydroalcoholic solution led to outbreak termination. This was associated with increases in workload, despite a marked decrease in the number of admissions.” (A. de Lassence, Hôpital Louis Mourier, Colombes, France; arnaud.de-lassence@lmr.ap-hop-paris.fr)

The need for new approaches to control of
S. aureus is noted in an accompanying editorial (pp. 179-80): “Because times are a-changin' regarding the epidemiology of S. aureus, our response needs to change by adhering to established infection-control measures and staff education, while creating better prevention strategies. Protein-polysaccharide conjugate vaccines have been highly effective for control and prevention of disease due to other encapsulated pathogens, such as Haemophilus influenzae type b, Streptococcus pneumoniae, and Neisseria meningitidis, and initial studies of S. aureus conjugate vaccine containing capsular polysaccharide types V and VIII provided some protection against invasive disease for patients undergoing hemodialysis. These data underscore the need to improve vaccine efficacy for this population and to study immune response and protection in other high-risk populations. S. aureus has been dynamic and creative in meeting new challenges during the past 50 years. Therefore, we must be more dynamic and demonstrate similar creativity and persistence in our response.” (D. E. Craven, Lahey Clinic Med. Ctr., Burlington, Mass.; donald.e.craven@lahey.org)

In Vitro Penicillin Resistance & Pneumococcal Pneumonia: Despite the emergence of in vitro resistance of Streptococcus pneumoniae, beta-lactam antibiotics should continue to be the agents of first choice for pneumococcal pneumonia, argues an author of a viewpoint article (pp. 224-33). Based on a critical review of the published literature, the author writes: “There is only a single report of documented microbiologic failure of parenteral penicillin-class antibiotics in the treatment of pneumococcal pneumonia in patients with or without bacteremia, whereas there are numerous well-documented reports of treatment failure with quinolone-class (n ≥ 21) and macrolide-class (n ≥ 33) antibiotics in the treatment of pneumococcal pneumonia.” (L. R. Peterson, lancer@northwestern.edu)

An editorialist agrees with this position (pp. 234-7): “Given the decreasing rate at which newer antimicrobials are being developed and the increasing trend of antimicrobial resistance, it seems timely and essential to reexamine the value of penicillin in the treatment of pneumococcal pneumonia. Penicillin is still widely used throughout the world, including in New Zealand, Taiwan, South Africa, and Sweden.... When administered at adequate dosage and frequency, penicillin remains the drug of choice for the treatment of pneumococcal pneumonia, despite the increasing prevalence of penicillin-resistant
S. pneumoniae strains.” (C. C. Chiou, NIH, Bethesda, Md.; chenchia@yahoo.com)

Treating Disseminated Candidiasis: Fluconazole is the agent of choice for empiric treatment of most nonneutropenic, hemodynamically stable patients with disseminated candidiasis, according to authors of a review article (pp. 244-51). Treatment should be modified based on identification of the pathogen, the authors write, with echinoandins or high-dose polyenes preferred for treatment of infections with Candida glabrata or Candida krusei. (B. J. Spellberg, Harbor–UCLA Med. Ctr., Torrance, Calif.; bspellberg@labiomed.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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Dec. 19, 2005 Vol. 12, No. 243
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
Early-release articles from and the Dec. 17 issue of Lancet (www.thelancet.com; 2005; 366).

Psychologic Effects of Etanercept in Psoriasis:
Fatigue and symptoms of depression are relieved by etanercept therapy in patients with moderate to severe psoriasis, according to a study of 618 patients (DOI:10.1016/S0140-6736(05)67763-X). Impact of the drug on physical sequelae of the disease had substantial mental health benefits, the authors reported, noting, “47% (147 of 311) of patients achieved [psoriasis area and severity index score] 75 at week 12, compared with 5% (15 of 306) of those receiving placebo (p < 0.0001; difference 42%, 95% CI 36–48). Greater proportions of patients receiving etanercept had at least a 50% improvement in [the Hamilton rating scale for depression] or [the Beck depression inventory] at week 12 compared with the placebo group; patients treated with etanercept also had significant and clinically meaningful improvements in fatigue (mean FACIT-F improvement 5.0 vs 1.9; p < 0.0001, difference 3.0, 95% CI 1.6–4.5). Improvements in fatigue were correlated with decreasing joint pain, whereas improvements in symptoms of depression were less correlated with objective measures of skin clearance or joint pain.” (R. Krishnan, krish001@mc.duke.edu)

Genetics & Septic Survival:
Patients have twice the chance of surviving sepsis if their mitochondrial genetic make-up includes haplotype H, a relatively recent evolutionary addition to the human genome but one that has become very common among people of European ancestry (pp. 2118-21). “On admission to the intensive care unit, the frequency of mtDNA haplogroup H in study patients did not differ between [150] study patients admitted with severe sepsis and 542 age-matched controls from the northeast of England,” the investigators write. “MtDNA haplogroup H was a strong independent predictor of outcome during severe sepsis, conferring a 2·12-fold (95% CI 1.02–4.43) increased chance of survival at 180 days compared with individuals without the haplogroup H.” (P. F. Chinnery, Med. Sch., Newcastle upon Tyne, U.K.; p.f.chinnery@ncl.ac.uk)

>>>BMJ Highlights
Source:
Dec. 17 issue of BMJ (www.bmj.org; 2005; 331).

Antidepressant Overprescribing in Children: SSRI prescriptions for children in Ireland did not decline between 2001 and 2004 despite cautionary announcements and lack of licensing of products for use in this age group, according to an analysis of that country’s General Medical Services database (pp. 1451-2). Based on prescriptions provided to about 28% of all Irish children, the authors found, “The overall trend in antidepressant prescribing in children showed a significant reduction between January 2001 and August 2004 (rate ratio –0.45%, 95% confidence interval –0.60% to –0.30%, P < 0.001). A similar trend was noted for tricyclic antidepressants (–1.80%, –2.10% to –1.50%). However prescribing patterns for selective serotonin reuptake inhibitors in children did not show an overall downward trend (0.17%, –0.03% to 0.37%, P = 0.091). In contrast, the adult pattern showed a statistically significant upward trend (1.06%, 1.05% to 1.07%, P < 0.001).” (K. Bennett, St. James's Hosp., Dublin; bennettk@tcd.ie)

>>>PNN JournalWatch
* Exercise-Induced Bronchoconstriction in Athletes, in Chest, 2005; 128: 3966–74. Reprints: www.chestjournal.org/cgi/content/abstract/128/6/3966; J. P. Parsons, Johnathan.Parsons@osumc.edu

* Targeted Therapy for the Treatment of Advanced Non-small Cell Lung Cancer: A Review of the Epidermal Growth Factor Receptor Antagonists, in
Chest, 2005; 128: 3975–84. Reprints: www.chestjournal.org/cgi/content/abstract/128/6/3975; G. A. Silvestri, silvestri@musc.edu

* Nocturnal Asthma, in
Journal of Allergy and Clinical Immunology, 2005; 116: 1179–86. Reprints: www.jacionline.org/article/PIIS0091674905021147/abstract; E. R. Sutherland, National Jewish Medical and Research Ctr., Denver

* Perspectives in Asthma: Molecular Use of Microbial Products in Asthma Prevention and Treatment, in
Journal of Allergy and Clinical Immunology, 2005; 116: 1202–5. Reprints: www.jacionline.org/article/PIIS0091674905019408/fulltext - cor1; J. N. Kline, U. Iowa, Iowa City.

* Cost-Effectiveness of Fixed-Dose Combination of Isosorbide Dinitrate and Hydralazine Therapy for Blacks With Heart Failure, in
Circulation, 2005; 112: 3745–53. Reprints: circ.ahajournals.org/cgi/content/abstract/112/24/3745; D. C. Angus, angusdc@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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Dec. 20, 2005 Vol. 12, No. 244
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Dec. 20 issue of the Annals of Internal Medicine (www.annals.org; 2005; 143).

Empirical Anti-Candida Therapy in ICUs: The use of empirical fluconazole or caspofungin is cost-effective for patients in intensive-care units with symptoms of infection who do not respond to antibacterial agents, but only when their risks are high or, for caspofungin, fluconazole resistance is prevalent (pp. 857-69). Using a societal perspective in a cost-effectiveness decision model to assess discounted life-years, the authors note, “Ten percent of the target population will have invasive candidiasis. Empirical caspofungin therapy is the most effective strategy but is expensive ($295,115 per DLY saved). Empirical fluconazole therapy is the most reasonable strategy ($12,593 per DLY saved) and decreases mortality from 44.0% to 30.4% in patients with invasive candidiasis and from 22.4% to 21.0% in the overall target cohort.”

The group’s sensitivity analysis showed the following: “Empirical fluconazole therapy is reasonable for likelihoods of invasive candidiasis greater than 2.5% or fluconazole resistance less than 24.0%. For higher resistance levels, empirical caspofungin therapy is preferred. For low prevalences of invasive candidiasis, culture-based fluconazole is reasonable. For prevalences exceeding 60%, empirical caspofungin therapy is reasonable. For caspofungin to be reasonable at a prevalence of 10%, its cost must be reduced by 58%.” (Y. Golan,
ygolan@tufts-nemc.org)

Universal CMV Prophylaxis in Transplant Patients: For recipients of solid organ transplants, prevention of cytomegalovirus organ disease requires a universal prophylaxis strategy rather than a preemptive approach of monitoring and treatment upon viral detection, according to results of a meta-analysis of 17 trials (pp. 870-80). “Compared with placebo or no therapy, both universal prophylaxis (odds ratio [OR], 0.20 [95% CI, 0.13 to 0.31]) and preemptive strategies (OR, 0.28 [CI, 0.11 to 0.69]) reduced CMV organ disease,” write the authors. “However, only universal prophylaxis seemingly reduced CMV organ disease in subgroups of patients at highest risk (donors with positive CMV serostatus and recipients with negative CMV serostatus and induction with antibodies). Both strategies reduced the rate of allograft rejection. Only universal prophylaxis statistically significantly reduced bacterial and fungal infections (OR, 0.49 [CI, 0.36 to 0.67]) and death (OR, 0.62 [CI, 0.40 to 0.96]). Both acyclovir and ganciclovir statistically significantly prevented CMV organ disease in the universal prophylaxis trials.” (A. C. Kalil, akalil@unmc.edu)

Because most of the trials included in this meta-analysis were small and had wide confidence intervals, an editorialist maintains that more research is needed (pp. 913-4): “The troll of transplantation is a wily foe and sometimes still eludes our best efforts at containment. I believe that only formal comparative studies of universal prophylaxis and preemptive therapy with long-term follow-up will be able to shed sufficient light on the 2 strategies to move us beyond the current state of controversy.” (S. Dummer,
Stephen.dummer@vanderbilt.edu)

Yoga for Low Back Pain: Yoga—a combination of exercise with mental focus achieved through breathing—proved more effective than a self-care book in improving function and reducing symptoms among 101 patients with chronic low back pain (pp. 849-56). Testing the effects of 12-week sessions of yoga or conventional exercise or the self-care book, the investigators found yoga superior to both exercise and the book at week 12 and to the book at a 26-week follow-up. (K. J. Sherman, Group Health Cooperative, Seattle; Sherman.k@ghc.org)

>>>PNN NewsWatch
* Technetium Tc-99m fanolesomab (NeutroSpec, Palatin Technologies; Mallinckrodt) has been withdrawn from the U.S. market pending investigations into two patient deaths and other serious cardiopulmonary events, CNS reactions, and infusion reactions following closely after drug administration. While indicated for use in diagnosis of appendicitis in patients with equivocal symptoms, the drug produced adverse effects primarily when used for off-label indications.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Dec. 21, 2005 Vol. 12, No. 245
Providing news and information about medications and their proper use

>>>Sorafenib Approved for Renal Cell Carcinoma
Sorafenib (Nexavar, Bayer; Onyx Pharmaceuticals) was approved yesterday by FDA for treatment of advanced cases of renal cell carcinoma. In its pivotal trial, sorafenib doubled the length of progression-free survival (167 days, compared with 84 days with placebo).

Most patients in the clinical trial had previously been treated unsuccessfully with interleukin-2 or interferon. Some common temporary adverse effects reported with sorafenib are rash, diarrhea, increases in blood pressure, and redness, pain swelling, or blisters on the palms of the hands or soles of the feet.

Sorafenib is an orally administered, multikinase inhibitor that targets serine/threonine and receptor tyrosine kinases in both the tumor cell and tumor vasculature. It is in Phase III clinical trials for treatment of advanced hepatocellular carcinoma and metastatic melanoma. A Phase III clinical trial in non–small-cell lung cancer is planned for the first half of 2006.

>>>JAMA Highlights
Source:
Dec. 21 issue of JAMA (www.jama.com; 2005; 294).

Acid Suppressors, NSAIDs, & C. difficile Disease: Community-acquired Clostridium difficile is significantly more common among those taking acid-suppressive therapy, especially PPIs, and also among those using NSAIDs, according to results of two population-based, case–control studies (pp. 2989-95). Conducted using the United Kingdom General Practice Research Database, the studies included all 1,672 cases of C. difficile recorded between 1994 and 2004 among all patients registered for at least 2 years in each practice and then analyzed separately those who had not been hospitalized within the year before diagnosis. The investigators report, “The incidence of C difficile in patients diagnosed by their general practitioners in the General Practice Research Database increased from less than 1 case per 100 000 in 1994 to 22 per 100 000 in 2004. The adjusted rate ratio of C difficile–associated disease with current use of proton pump inhibitors was 2.9 (95% confidence interval [CI], 2.4–3.4) and with H2-receptor antagonists the rate ratio was 2.0 (95% CI, 1.6–2.7). An elevated rate was also found with the use of nonsteroidal anti-inflammatory drugs (rate ratio, 1.3; 95% CI, 1.2–1.5).” (S. Dial, sandra.dial@mcgill.ca)

Genotyping for Long QT Syndrome: Genetic mutations associated with long QT syndrome are identified in a study of 430 consecutive patients referred to an Italian center and 1,115 family members (pp. 2975-80). Focusing on six genes for cardiac ion channels and cardiac ankyrin known to cause Romano–Ward syndrome, an autosomal dominant cause of LQTS, the authors found, “We identified 235 different mutations, 138 of which were novel, in 310 (72%) of 430 probands (49% KCNQ1, 39% KCNH2, 10% SCN5A, 1.7% KCNE1, and 0.7% KCNE2). Fifty-eight percent of probands carried nonprivate mutations in 64 codons of KCNQ1, KCNH2, and SCN5A genes. A similar occurrence of mutations at these codons (52%) was confirmed in the prospective cohort of 75 probands and in previously published LQTS cohorts.” (S. G. Priori, U. Pavia, Pavia, Italy; spriori@fsm.it)

While acknowledging the importance of this study, an editorialist notes these impediments to application in clinical practice: (pp. 3027-8): “The problem with this approach, as the authors acknowledge, is evident from their own data set. That is, 4.5% of probands had 2 or more mutations. If genetic analysis had been terminated with discovery of the first abnormal mutation in one of these probands, their family members with a different mutation might have been given false reassurance that they were unaffected, did not require prophylactic beta-blocker treatment, and did not require that their children be followed up closely. Without genetic information, these individuals would be treated according to the clinician's best judgment. With inaccurate genetic information, these individuals (or their children) might be at risk of fatal arrhythmias due to lack of treatment. In this situation, no information arguably is better than inaccurate information.” (E. S. Kaufman, Case Western Reserve U., Cleveland;
ekaufman@metrohealth.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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Dec. 22, 2005 Vol. 12, No. 246
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Dec. 22 issue of the New England Journal of Medicine (content.nejm.org; 2005; 353).

Intensive Therapy for Diabetes: In a long-term follow-up to the Diabetes Control and Complications Trial (DCCT), 1,441 patients with type 1 diabetes treated originally with intensive therapy had a 42% reduction in risk of cardiovascular events during a mean of 17 years of monitoring (pp. 2643-53). The observational Epidemiology of Diabetes Interventions and Complications study followed DCCT patients who were treated with either intensive therapy or usual care for a mean of 6.5 years between 1983 and 1993.

Through Feb. 1 of this year, patients had these outcomes with respect to cardiovascular disease (nonfatal myocardial infarction, stroke, death from cardiovascular disease, confirmed angina, or need for coronary-artery revascularization): “46 cardiovascular disease events occurred in 31 patients who had received intensive treatment in the DCCT, as compared with 98 events in 52 patients who had received conventional treatment. Intensive treatment reduced the risk of any cardiovascular disease event by 42 percent (95 percent confidence interval, 9 to 63 percent; P = 0.02) and the risk of nonfatal myocardial infarction, stroke, or death from cardiovascular disease by 57 percent (95 percent confidence interval, 12 to 79 percent; P = 0.02). The decrease in glycosylated hemoglobin values during the DCCT was significantly associated with most of the positive effects of intensive treatment on the risk of cardiovascular disease. Microalbuminuria and albuminuria were associated with a significant increase in the risk of cardiovascular disease, but differences between treatment groups remained significant (P ≤ 0.05) after adjusting for these factors.” (DCCT/EDIC Research Group,
dnathan@partners.org)

Obstacles remain in treating patients with type 1 diabetes, an editorialist writes (pp. 2707-9): “The medical community needs better means, different strategies, and a different mind-set if we hope to improve and maintain glycemic control in patients with type 1 diabetes and minimize side effects. Until the latter issue is addressed by the availability of new therapies and innovative approaches, the translation of research findings from a landmark study such as the DCCT/EDIC trial may not alter clinical practice for many years. Given the complications and mortality attributed to cardiovascular disease among patients with type 1 diabetes, this delay would be most unfortunate.” (W. T. Cefalu, La. State U. System, Baton Rouge)

Oseltamivir Resistance & Deaths from Bird Flu: Two patients in Vietnam who died of avian influenza were infected with strains resistant to oseltamivir (pp. 2667-72). Comparing these patients with others who survived infection, the , investigators note: “The efficacy of oseltamivir is unlikely to be optimal when treatment is instituted late in the course of illness, as has been the case in most patients with influenza A (H5N1) virus infection reported to date. However, antiviral treatment could still be expected to be beneficial when there is evidence of ongoing viral replication. Such benefit is suggested by the rapid decline in the viral load to undetectable levels in all four survivors in the current series. In contrast, virus was still detectable at the end of treatment in three patients who died of the infection after receiving the full course of treatment, two of whom had oseltamivir-resistant virus isolated from throat specimens. Our observations suggest that at least in some patients with influenza A (H5N1) virus infection, treatment with the recommended dose of oseltamivir incompletely suppresses viral replication. Besides allowing the infection to proceed, such incomplete suppression provides opportunities for drug resistance to develop.... Strategies aimed at improving antiviral efficacy (e.g., the use of higher doses, longer durations of therapy, or combination therapy) may deserve further evaluation. In addition, antiviral agents to which oseltamivir-resistant influenza viruses remain susceptible should be included in treatment arsenals for influenza A (H5N1) virus infections.” (M. D. de Jong, Oxford U. Clin. Res. Unit, Ho Chi Minh City, Vietnam; mddejong@hcm.vnn.vn)

>>>PNN NewsWatch
* PNN will not be published on Fri. and Mon., Dec. 23 and 26, Christmas holidays.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Dec. 27, 2005 Vol. 12, No. 247
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from and the Dec. 24 issue of BMJ (www.bmj.org; 2005; 331).

Gender-Related Coronary Risks in Diabetes: Women have a 50% higher risk of fatal coronary heart disease in type 2 diabetes than do men, according to a meta-analysis of 37 studies that included 447,064 patients (doi: 10.1136/bmj.38678.389583.7C). “The rate of fatal coronary heart disease was higher in patients with diabetes than in those without (5.4 v 1.6%),” write the authors. “The overall summary relative risk for fatal coronary heart disease in patients with diabetes compared with no diabetes was significantly greater among women than it was among men: 3.50, 95% confidence interval 2.70 to 4.53 v 2.06, 1.81 to 2.34. After exclusion of the eight studies that had adjusted only for age, the difference in risk between the sexes was substantially reduced but still highly significant. The pooled ratio of the relative risks (women:men) from the 29 studies with multiple adjusted estimates was 1.46 (1.14 to 1.88).” (R. Huxley, U. Sydney, Sydney; rhuxley@thegeorgeinstitute.org)

Holiday “Cheer”: In its annual holiday issue, BMJ focuses on a number of entertaining themes. Several articles relate to alcohol, including this pair of articles:

* University students and bartenders with an average of 6 years’ experience tended to overpour a “shot” (1.5 ounces; 44.3 mL) of alcoholic beverages into short, wide glasses but were much more accurate with tall, slender containers (pp. 1512-4). “Practice reduced the tendency to overpour, but not for short, wide glasses,” note the investigators. “Despite an average of six years of experience, bartenders poured 20.5% more into short, wide glasses than tall, slender ones; paying careful attention reduced but did not eliminate the effect.” (B Wansink, Cornell U., Ithaca, N.Y.;
wansink@cornell.edu)

* No conventional or alternative therapy is consistently effective for preventing or treating alcohol hangover, conclude authors of a systematic review (pp. 1515-8). They report: “Eight randomised controlled trials assessing eight different interventions were reviewed. The agents tested were propranolol, tropisetron, tolfenamic acid, fructose or glucose, and the dietary supplements
Borago officinalis (borage), Cynara scolymus (artichoke), Opuntia ficus-indica (prickly pear), and a yeast based preparation. All studies were double blind. Significant intergroup differences for overall symptom scores and individual symptoms were reported only for tolfenamic acid, gamma-linolenic acid from B officinalis, and a yeast based preparation.” (M. H Pittler, U. Exeter and Plymouth, Exeter, U.K.; M.H.Pittler@exeter.ac.uk)

>>>Lancet Report
Source:
Early-release article from Lancet (www.thelancet.com).

Human Cases of Avian Influenza: The first confirmed case of avian influenza (H5N1) in mainland China is reported (DOI: 10.1016/S0140-6736(05)67894-4). A previously healthy 12-year-old girl developed symptoms and died 9 days later. Her 9-year-old brother also became ill but responded to treatment with amantadine, ribavirin, corticosteroids, and broad spectrum antibiotics. Despite the possibility of human-to-human transmission in this situation, the authors explain that both patients could have acquired the virus from diseased poultry: “Our investigation highlights the major public health challenges in the unique setting of backyard farming where infection control measures remain to be improved, and where access to diagnosis and treatment is often limited.” (W. Yang, Chinese CDC, Beijing; ywz126@vip.sina.com)

>>>PNN JournalWatch
* Inhaled Nitric Oxide Therapy in Adults, in New England Journal of Medicine, 2005; 353: 2683–95. Reprints: content.nejm.org/cgi/content/extract/353/25/2683; T. W. Evans, Imperial Coll., London; t.evans@rbh.nthames.nhs.uk

* What a Cardiologist Needs to Know About Patients with Human Immunodeficiency Virus Infection, in
Circulation, 2005; 112: 3947–57. Reprints: circ.ahajournals.org/cgi/content/abstract/112/25/3947; D. Waters, dwaters@medsfgh.ucsf.edu

* Adult Botulism Type F in the United States, 1981–2002, in
Neurology, 2005; 65: 1694–700. Reprints: www.neurology.org/cgi/content/abstract/65/11/1694; A. Gupta, Johns Hopkins U., Baltimore; agupta25@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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Dec. 28, 2005 Vol. 12, No. 248
Providing news and information about medications and their proper use

>>>Abatacept Approved for RA
Abatacept (Orencia, Bristol-Myers Squibb) the first selective modulator of a costimulatory signal required for full T-cell activation, has been approved by FDA for reducing the signs and symptoms of rheumatoid arthritis, inducing major clinical response, slowing the progression of structural damage, and improving physical function in adult patients with moderately to severely active RA who have had an inadequate response to one or more disease-modifying antirheumatic drugs, such as methotrexate or tumor necrosis factor antagonists. While abatacept can be used as monotherapy or in combination with most DMARDs, its use in patients receiving TNF antagonists is contraindicated.

In three Phase III clinical trials, abatacept produced significant improvements in RA symptoms by day 15, compared with placebo (as measured by a 20% improvement in American College of Rheumatology scores [ACR 20]). Health-related quality of life, measured using the Short Form 36, was significantly improved in all eight SF-36 domains.

A significant proportion of patients taking abatacept plus MTX achieved a major clinical response (maintaining an ACR 70 score for 6 consecutive months), compared with those treated with MTX alone in one study (14% versus 2%). Among those on the new drug, structural damage was slowed in the Abatacept in Inadequate responders to Methotrexate (AIM) study.

Because more and serious infections were observed in patients taking abatacept with TNF antagonists during the pivotal clinical trials, concomitant use of these agents is contraindicated. In addition to these adverse drug effects, no significant improvement in symptoms was noted when the concomitant therapy was attempted.

Other key points about abatacept therapy include the following:

* Use with caution in patients with history of infection or conditions that predispose them to infection

* Hypersensitivity reactions, hypotension, urticaria, and dyspnea occur rarely (less than 1% of patients) and usually within 24 hours of infusion

* Live vaccines should not be given during or within 3 months of abatacept therapy

* The drug should be used during pregnancy only if clearly needed (Pregnancy Category C)

* Serious infections and malignancies occurred in more patients on abatacept, compared with placebo (3% versus 1.9% of patients developed serious infections, respectively; 1.3% versus 1.1% of patients had malignancies, respectively)

* Common adverse events affecting 10% or more patients on abatacept include headache, upper respiratory tract infections, nasopharyngitis, and nausea

>>>JAMA Highlights
Source:
Dec. 28 issue of JAMA (www.jama.com; 2005; 294).

Oral Amiodarone Following Cardiac Surgery: In the Prophylactic Amiodarone for the Prevention of Arrhythmias that Begin Early After Revascularization, Valve Replacement, or Repair (PAPABEAR) trial, oral amiodarone proved effective and appeared to be safe both overall and in important patient subgroups (pp. 3093-100). Administered in 10 mg/kg/day doses for 6 days before and 6 days after surgery, amiodarone produced significantly fewer atrial tachyarrhythmias, compared with placebo, in all patients (hazard ratio, 0.52 [95% CI, 0.34–0.69]); patients younger than 65 years (HR, 0.51 [95% CI, 0.28–0.94]); patients aged 65 years or older (HR, 0.45 [95% CI, 0.27–0.75]); patients who had CABG surgery only (HR, 0.45 [95% CI, 0.26–0.79]); patients who had valve replacement/repair surgery with or without CABG surgery (HR, 0.51 [95% CI, 0.31–0.84); patients who received preoperative beta-blocker therapy (HR, 0.58 [95% CI, 0.34–0.99]); and patients who did not receive preoperative beta-blocker therapy (HR, 0.40 [95% CI, 0.22–0.71]). The authors add, “Postoperative sustained ventricular tachyarrhythmias occurred less frequently in amiodarone patients (1/299; 0.3%) than in placebo patients (8/302; 2.6%) (P = .04). Dosage reductions of blinded therapy were more common in amiodarone patients (34/299; 11.4%) than in placebo patients (16/302; 5.3%) (P = .008). There were no differences in serious postoperative complications, in-hospital mortality, or readmission to the hospital within 6 months of discharge or in 1-year mortality.” (L. B. Mitchell, brent.mitchell@calgaryhealthregion.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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Dec. 29, 2005 Vol. 12, No. 249
Providing news and information about medications and their proper use

>>>Thalidomide Analogue Approved for MDS Subtype
Lenalidomide (Revlimid, Celgene) has been approved by FDA for treatment of patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities. The drug, an analogue of the teratogen thalidomide, will be available only through a Revlimid Education and Prescribing Safety Program, RevAssist, via contracted pharmacies, and will be priced at about $4,500 per month.

Under RevAssist, only prescribers and pharmacists registered under the program may prescribe and dispense lenalidomide, and patients must agree to comply with informed-consent and, for women, pregnancy-monitoring requirements. Physicians must check pregnancy tests, limit prescriptions to 1-month supplies delivered by mail, and report any pregnancies to FDA.

Chromosomal abnormalities are detected in more than one-half of patients with MDS, a group of hematologic malignancies with mean survival rates of 6 months to 6 years. These are diagnosed in an estimated 10,000 to 20,000 Americans annually. The most common cytogenetic abnormalities in MDS are deletions in the long arm of chromosomes 5, 7, and 20. Another common abnormality is an extra copy of chromosome 8. The deletion targeted by lenalidomide—involving the 5q chromosome—may be involved in 20% to 30% of all MDS patients. The World Health Organization has also recently identified a unique subset of MDS patients with a "5q-syndrome" in which the only chromosomal abnormality is a specific portion of the 5q chromosome.

The labeling for Revlimid will include a black box warning and a medication guide regarding the prevention of fetal exposure. Additional black box warnings include the potential need to lower the dose due to suppressed blood counts and increased risk of blood clots. Common adverse effects reported with lenalidomide include thrombocytopenia, neutropenia, diarrhea, pruritus, rash, and fatigue.

>>>NEJM Highlights
Source:
Dec. 29 issue of the New England Journal of Medicine (content.nejm.org; 2005; 353).

Letrozole vs. Tamoxifen in Early Breast Cancer:
Especially at distant sites, letrozole significantly reduced the risk of recurrent breast cancer, compared with tamoxifen, in postmenopausal women with endocrine-responsive breast cancer, according to results of the Breast International Group (BIG) 1-98 study (pp. 2747-57). “A total of 8010 women with data that could be assessed were enrolled, 4003 in the letrozole group and 4007 in the tamoxifen group,” the authors write. “After a median follow-up of 25.8 months, 351 events had occurred in the letrozole group and 428 events in the tamoxifen group, with five-year disease-free survival estimates of 84.0 percent and 81.4 percent, respectively. As compared with tamoxifen, letrozole significantly reduced the risk of an event ending a period of disease-free survival (hazard ratio, 0.81; 95 percent confidence interval, 0.70 to 0.93; P = 0.003), especially the risk of distant recurrence (hazard ratio, 0.73; 95 percent confidence interval, 0.60 to 0.88; P = 0.001). Thromboembolism, endometrial cancer, and vaginal bleeding were more common in the tamoxifen group. Women given letrozole had a higher incidence of skeletal and cardiac events and of hyper-cholesterolemia.” (Intl. Breast Cancer Study Group Coordinating Center, Bern, Switzerland; ibcsg.big198@ibcsg.org)

Medicare Part D:
Four Perspective articles provide varying views on the Medicare drug benefit set to launch on Jan. 1. “Seniors who find a plan that covers their entire regimen, minimizes out-of-pocket costs, and permits a continuing relationship with their corner pharmacy will have cause to celebrate,” write authors of a “promise and perils” article (pp. 2735-9). “However, plans can change their formularies monthly, whereas most beneficiaries will be locked into their drug plan for the year. As a result, some patients will be forced to switch to alternative agents midyear or else pay more for the privilege of maintaining a stable regimen.” (R. L. Kravitz, U. Calif., Davis)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Dec. 30, 2005 Vol. 12, No. 250
Providing news and information about medications and their proper use

>>>PNN’s Top 10 for 2005
Hurricane Katrina leads many a Top 10 list for this year, and it was the big story for many pharmacists, both personally and professionally. But for the profession in general and pharmacotherapy in particular, here are the topics that dominated PNN.

1. Medicare Part D: The largest expansion in the Medicare program since its inception has kept politicians, health professionals, and benefits managers busy for 2 years now, and the fun really begins on Sunday. Pharmacists are ready with Medication Therapy Management Services (see PNN, Sept. 23) and pharmacist-coached patient self-management initiatives (Apr. 22), but MTM and its success may depend primarily on business models (Jul. 22).Particularly troublesome are chain pharmacy initiatives that place nurse practitioners in in-store clinics (July 7, Oct. 7).

2. Drug Safety: The fallout from the “house of coxibs” debacle continued in 2005, beginning with Topol’s critique in JAMA (Jan. 5). Muraglitazar was a rising star until a new standard for safety emerged this fall (Aug. 23, Oct. 24), but agents such as abatacept (Aug. 23, 26, Sept. 9, 15, Dec. 28), exenatide (Apr. 29, May 2), and pramlintide (Mar. 18) survived increased FDA scrutiny to reach the U.S. market.

3. FDA Approaches 100: As it prepared for its centennial celebration (Nov. 16), FDA was troubled by drug-safety controversies (Jan. 20), a prolonged approval process for an interim commissioner followed by a swift resignation a few weeks later (Feb. 16, Apr. 15, Aug. 29, Sept. 26), and a focus on whether the four-decade-old drug-approval process is viable in the 21st century.

4. EC & Rx-to-OTC Switches: Part of FDA’s political problems flowed from its failure to make a decision on the Rx-to-OTC switch for the emergency contraceptive product Plan B (Jan. 5, Apr. 15, June 7, Oct. 6). Highly publicized incidents of pharmacist refusals to dispense EC products—and in some case berating patients about their use—made difficult the creation of a third class of drugs similar to that in the U.K. (Apr. 4, 19). FDA did turn down a proposal to switch a statin to nonprescription status (Jan. 14, 18, Apr. 7), even as the U.K. debated pharmacist-only availability of triptans (Aug. 22).

5. Vaccinations: Many advances in immunizations created new opportunities for immunizing pharmacists. Deaths from influenza in infants and children (Dec. 15) created renewed emphasis on CDC guidelines for vaccination on at-risk patients in this age group, and availability of meningococcal vaccine (Jan. 19, Oct. 4) and pertussis-containing products (May 4, June 22, Aug. 3) for use in adolescents and young adults added to the patient population needing vaccines. For older individuals, varicella vaccines are in development (June 2, Aug. 17, Oct. 4).

6. Immunology/Oncology Advances: Treatment of rheumatoid arthritis benefited greatly from immunologic research, beginning with a study on use of infliximab (Jan. 14) and concluding with this week’s approval of abatacept (Dec. 28). Immunology also figured into advances in treatment of many cancers throughout the year (e.g., May 16, 19; June 30, July 14, Aug. 8, 19).

7. Psychiatric Problems: Revisionist thinking is in vogue in psychiatry, as the efficacy and safety of antidepressants cause many to reconsider their use in adolescents, (Jan. 19, Feb. 22, May 18), adults (July 5), and pregnant women (Sept. 28, Dec. 9).

8. Computers & Errors: Five years after publication of “To Err Is Human” (May 18) the search for a safer medication-use system continues (Apr. 19, May 15, 24). Computers will be a part of—but not the only—solution to today’s problems (Sept. 16, Nov. 9).

9. Obesity Problems & Treatments: The risks of obesity are many (Aug. 2, Oct. 4), and possible treatments range from lifestyle (July 25) to drugs (Apr. 5, 18, June 15, Aug. 18) to surgery (Oct. 19).

10. Alternative Medicines: As some alternative therapies provided evidence of efficacy (May 13, July 6, Dec. 20) and enjoyed approval of mainstream practitioners, FDA-mandated claims for functional foods emerged as confusing for consumers (Sept. 30).

>>>PNN NewsWatch
* Correction: In the Dec. 28 PNN summary of the amiodarone trial, the dose should have been 10 mg/kg/day, not 10 mg/day.

*
PNN will not be published on Mon., Jan. 2, New Year’s 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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.