Jun 2005

PNN Quarterly File—Second Quarter 2005

PNN Pharmacotherapy Line
Apr. 1, 2005 Vol. 12, No. 63
Providing news and information about medications and their proper use

>>>Geriatrics Highlights
Source:
Apr. issue of the Journal of the American Geriatrics Society (www.blackwell-synergy.com; 2005; 53).

Warfarin & AF in Old Old Patients: While the rate of major hemorrhage was high in a retrospective observational cohort analysis of frail elderly patients older than 75 and five of the patients died from bleeding, warfarin provided effective prophylaxis against strokes, with no long-term sequelae identified in surviving patients (pp. 655-9). “Two hundred twenty-eight patients (42% men) with a mean age of 81.1 (range 7694) were included in the analysis,” the authors report. “Total follow-up on warfarin was 530 years (mean 28 months). There were 53 major hemorrhages, for an annual rate of 10.0%, including 24 (45.3%) life-threatening and five (9.4%) fatal bleeds. The annual stroke rate after initiation of warfarin was 2.6%.” (C. E. Johnson, Kingston Ctr., Cheltenham, Victoria, Australia; kwangchristina@iprimus.com.au)

Homebound Elderly Patients’ Difficulties with Prescription Drug Costs: Homebound elderly patients reported use of six different strategies for minimizing their out-of-pocket expenses for prescription drugs, according to a study conducted in conjunction with a home-delivered meals program in four North Carolina counties (pp. 666-74). Based on responses of 222 individuals aged 60 or older, the researchers found: “Forty-five (20.3%) participants used one or more behaviors that restricted medication use; another 47 (21.2%) used one or more strategies to reduce out-of-pocket medication cost. Using medication restriction to reduce medication expense was more likely in older people who had difficulty paying for medications (odds ratio (OR) = 8.2, 95% confidence interval (CI) = 1.4–50.3), or used a strategy to cope with out-of-pocket expenses (choose food or medications (OR = 5.1, 95% CI = 1.7–15.7) or borrowed money or had another person pay for medications (OR = 5.5, 95% CI = 2.6–11.6)). Income, drug coverage, and medication use (prescribed and over-the-counter) increased the likelihood of having increased difficulty paying for medications.” (J. R. Sharkey, Texas A&M Health Sci. Ctr., College Station, Tex.; sharkey@tamu.edu)

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

Donepezil & Hippocampal Atrophy:
In a study of 54 patients with Alzheimer’s disease being treated with donepezil and 93 control patients, the acetylcholinesterase inhibitor provided a neuroprotective effect, slowing the progression of atrophy of the hippocampus (pp. 676-82). Assessing the annual rate of hippocampal atrophy for each patient based on two MRI images taken within 1 year, the investigators found, “The mean annual rate of hippocampal volume loss among the treated patients (mean = 3.82%, SD = 2.84%) was significantly smaller than that among the control patients (mean = 5.04%, SD = 2.54%). Upon analysis of covariance, where those confounding variables (age, sex, disease duration, education, MRI interval, APOE genotype, and baseline Alzheimer’s Disease Assessment Scale score) were entered into the model as covariates, the effect of donepezil treatment on hippocampal atrophy remained significant.” (M. Hashimoto)

Raloxifene & Alzheimer’s Disease: In the Multiple Outcomes with Raloxifene Evaluation (MORE), higher doses of this selective estrogen receptor modulator reduced the risk of cognitive impairment among 5,386 postmenopausal women (pp. 683-90). The researchers report: “Compared to those taking placebo, women receiving 120 mg/day of raloxifene had a 33% lower risk of mild cognitive impairment (relative risk, 0.67; 95% confidence interval [CI], 0.46–0.98) and somewhat lower risks of Alzheimer’s disease (relative risk = 0.52, 95% CI = 0.22–1.21) and any cognitive impairment (relative risk = 0.73, 95% CI = 0.53–1.01). Risks of mild cognitive impairment, Alzheimer’s disease, and any impairment were not significantly different in the group taking 60 mg/day of raloxifene.” (K. Yaffe)

PNN Pharmacotherapy Line is published via e-mail each business day except 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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 4, 2005 Vol. 12, No. 64
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from and the Apr. 2 issue of BMJ (www.bmj.org; 2005; 330).

Vitamins, Minerals for Infection Prevention: In older people, the use of vitamin and mineral supplements for reducing the frequency and severity of infections is poorly supported by objective evidence, conclude authors of a systematic review and meta-analysis (early-release article; doi:10.1136/
bmj.38399.495648.8F). “Eight trials met our inclusion criteria,” write the authors. “Owing to inconsistency in the outcomes reported, only a proportion of the trials could be included in each meta-analysis. Multivitamins and mineral supplements were found to reduce the mean annual number of days spent with infection (three studies) by 17.5 (95% confidence interval 11 to 24, P < 0.001). The odds ratio for at least one infection in the study period (three studies) was 1.10 (0.81 to 1.50, P = 0.53). The infection rate ratio (four studies) was 0.89 (0.78 to 1.03, P = 0.11). Reporting of adverse events was poor.” (A. El-Kadiki, Royal Hallamshire Hosp., Sheffield, U.K.; alia@elkadiki.fsnet.co.uk)

Smoking Cessation: Smoking cessation services offered by the British National Health Service are reducing smoking prevalence among patients by no more than 0.1% to 0.3% annually, according to an analysis of available data (pp. 760 ff). In 2003–04, only 20,103 people used smoking cessation services, despite the presence of an estimated 333,000 smokers in a health district. Of these, 9,910 were abstinent at 4 weeks, and the author predicts that 3,500–4,000 patients would remain tobacco-free by the end of 1 year. “For each additional quitter at one year, [numbers needed to treat] are around 17 for nicotine replacement treatment (gum or patches in large trials) and eight for bupropion,” the writer adds. “For entrants to the services whose treatment was recorded, 91% received nicotine replacement and 6% bupropion. An assumed average NNT of 15 would yield 1350 additional quitters, an annual attributable prevalence fall of 0.12%.” (E. Milne, Northumberland Tyne and Wear Strategic Health Authority, Newcastle upon Tyne, U.K.; eugene.milne@nhs.net)

>>>PNN NewsWatch
* In two clinical trials on the use of galantamine hydrobromide (Reminyl, Ortho-McNeil) in patients with mild cognitive impairment, deaths occurred in 13 participants on active drug and 1 patient taking placebo. Information about this risk is being added to the Precautions section of the product’s labeling. The deaths were from causes that could be expected in patients of advanced age; about half were from vascular causes such as myocardial infarction and stroke or sudden death. The company noted that it is not seeking FDA approval for use of the Alzheimer’s agent in patients with mild cognitive impairment.

* The issue of
pharmacists’ refusal to fill oral and emergency contraceptives is flaring in the lay media. Commenting on recent developments—including an Illinois law enacted late last week that requires pharmacists to fill such prescriptions regardless of their own professional opinions or beliefs—New York Times editors wrote in Sunday’s issue, “Any pharmacist who cannot dispense medicines lawfully prescribed by a doctor should find another line of work.”

* A federal contract awarded to Sanofi Pasteur will enable the company to switch to a new, faster method of producing
influenza vaccine using Petri plates, reports this morning’s Wall Street Journal.

>>>PNN JournalWatch
* Use of Clinical Syndromes To Target Antibiotic Prescribing in Seriously Ill Children in Malaria Endemic Area: Observational Study, in BMJ, 2005; doi:10.1136/bmj.38408.471991.8F (early-release article). Reprints: www.bmj.org; J. A. Berkley, Ctr. for Geographic Medicine Research, Kilifi, Kenya; jberkley@kilifi.mimcom.net

* Improving Clinical Practice Using Clinical Decision Support Systems: A Systematic Review of Trials to Identify Features Critical to Success, in
BMJ, 2005; 330: 765 ff. Reprints: www.bmj.org; D. F. Lobach, david.lobach@duke.edu

* Recent Developments in Bisphosphonates for Patients with Metastatic Breast Cancer, in
BMJ, 2005; 330: 769–73. Reprints: www.bmj.org; M. Clemons, Sunnybrook/Women’s College Health Sci. Ctr., Toronto; Mark.Clemons@sw.ca

* Does DOTS Work in Populations with Drug-Resistant Tuberculosis? in
Lancet, 2005; 365: 1239–45. Reprints: www.thelancet.com; L. García-García, Instituto Nacional de Salud Pública, Cuernavaca, Mexico; garcigar@correo.insp.mx

PNN Pharmacotherapy Line is published via e-mail each business day except 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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 5, 2005 Vol. 12, No. 65
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Apr. 5 issue of the Annals of Internal Medicine (www.annals.org; 2005; 142).

Rofecoxib & MI: In a study released previously by Annals (see PNN, Feb. 1), higher doses of rofecoxib increased the risk of myocardial infarction among older patients with no history of MI (pp. 481-9). In a nested case–control analysis of Quebec administrative health databases, daily doses of aspirin mitigated the risks associated with use of lower drug doses in the 113,927 patients. The authors noted: “Compared with no use of NSAIDs in the year preceding the event, current use of rofecoxib was associated with an increased risk for an acute MI (rate ratio [RR], 1.24 [95% CI, 1.05 to 1.46]) that was more pronounced at higher doses (RR, 1.73 [CI, 1.09 to 2.76]). The concomitant use of aspirin appears to decrease the risk associated with low-dose rofecoxib (RR, 1.00 [CI, 0.77 to 1.28]) but not with high-dose rofecoxib (RR, 2.36 [CI, 1.27 to 4.39]). No increased risks were observed with celecoxib (RR, 0.99 [CI, 0.85 to 1.16]) or the other NSAIDs.” (J. Brophy, james.brophy@mcgill.ca)

Management of Obesity: A clinical practice guideline developed by the American College of Physicians is presented, along with meta-analyses on the use of medications and surgery in management of overweight and obesity.

Medications, while limited in their effectiveness, can be used to achieve modest weight loss (<5 kg in year 1) in obese patients (BMI of ≥30 kg/sq m), according to the clinical practice guideline (pp. 525-31). Among the document’s 5 recommendations are these (V. Snow, vincenza@acponline.org):

* For obese patients who choose to use adjunctive drug therapy, options include sibutramine, orlistat, phentermine, diethylpropion, fluoxetine, and bupropion. The choice of agent will depend on the side effects profile of each drug and the patient's tolerance of those side effects.

* Surgery should be considered as a treatment option for patients with a BMI of 40 kg/sq m or greater who instituted but failed an adequate exercise and diet program (with or without adjunctive drug therapy) and who present with obesity-related comorbid conditions, such as hypertension, impaired glucose tolerance, diabetes mellitus, hyperlipidemia, and obstructive sleep apnea. A doctor–patient discussion of surgical options should include the long-term side effects, such as possible need for reoperation, gall bladder disease, and malabsorption.

In the meta-analysis of drug therapy for obesity, authors conclude, “Sibutramine, orlistat, phentermine, probably diethylpropion, bupropion, probably fluoxetine, and topiramate promote modest weight loss when given along with recommendations for diet” (pp. 532-46). The authors also note, “All pooled weight loss values are reported relative to placebo. A meta-analysis of sibutramine reported a mean difference in weight loss of 4.45 kg (95% CI, 3.62 to 5.29 kg) at 12 months. In the meta-analysis of orlistat, the estimate of the mean weight loss for orlistat-treated patients was 2.89 kg (CI, 2.27 to 3.51 kg) at 12 months. A recent meta-analysis of phentermine and diethylpropion reported pooled mean differences in weight loss at 6 months of 3.6 kg (CI, 0.6 to 6.0 kg) for phentermine-treated patients and 3.0 kg (CI, –1.6 to 11.5 kg) for diethylpropion-treated patients. Weight loss in fluoxetine studies ranged from 14.5 kg of weight lost to 0.4 kg of weight gained at 12 or more months. For bupropion, 2.77 kg (CI, 1.1 to 4.5 kg) of weight was lost at 6 to 12 months. Weight loss due to topiramate at 6 months was 6.5% (CI, 4.8% to 8.3%) of pretreatment weight. With one exception, long-term studies of health outcomes were lacking. Significant side effects that varied by drug were reported.” (Z. Li, West LA VA Med. Ctr., Los Angeles)

For patients whose BMIs exceed 40 kg/sq m, surgery presents an option more effective than medications, add authors of an additional meta-analysis (pp. 547-59). Weight loss of 20–30 kg that is maintained for up to 10 years can be expected, along with improvements in some comorbid conditions. Lower-weight individuals can benefit from surgery, but more data are needed before its use can be recommended. (M. A. Maggard, mmaggard@mednet.ucla.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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 6, 2005 Vol. 12, No. 66
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Apr. 6 issue of JAMA (www.jama.com; 2005; 293).

Race & Treatment of Hypertension: Thiazide diuretics should be drugs of first choice for treatment of hypertension in both blacks and nonblacks, according to analysis of data from the ALLHAT study (pp. 1595-608). The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial included 33,357 patients aged 55 or older with hypertension, and antihypertensive regimens compared amlodipine or lisinopril with chlorthalidone. The authors report, “No significant difference was found between treatment groups for the primary CHD outcome in either racial subgroup. For amlodipine vs chlorthalidone only, [heart failure] was the only prespecified clinical outcome that differed significantly (overall: relative risk [RR], 1.37; 95% confidence interval [CI], 1.24–1.51; blacks: RR, 1.46; 95% CI, 1.24–1.73; nonblacks: RR, 1.32; 95% CI, 1.17–1.49; P < .001 for each comparison) with no difference in treatment effects by race (P = .38 for interaction). For lisinopril vs chlorthalidone, results differed by race for systolic BP (greater decrease in blacks with chlorthalidone), stroke, and combined CVD outcomes (P < .001, P = .01, and P = .04, respectively, for interactions). In blacks and nonblacks, respectively, the RRs for stroke were 1.40 (95% CI, 1.17–1.68) and 1.00 (95% CI, 0.85–1.17) and for combined CVD were 1.19 (95% CI, 1.09–1.30) and 1.06 (95% CI, 1.00–1.13). For HF, the RRs were 1.30 (95% CI, 1.10–1.54) and 1.13 (95% CI, 1.00–1.28), with no significant interaction by race. Time-dependent BP adjustment did not significantly alter differences in outcome for lisinopril vs chlorthalidone in blacks.” (J. T. Wright, Jr, Case Western Reserve U., Cleveland; jackson.wright@case.edu)

Commenting that “diuretics are color blind,” editorialists add (pp. 1663-6): “After many years of research, the ALLHAT study has shown that diuretic therapy is highly efficacious in reducing the risk of CVD among both blacks and nonblacks. It is notable that with respect to the black population, ALLHAT had more events than most trials had participants. It is now time to move beyond comparisons of diuretics with other classes of BP-lowering drugs—that issue has been settled. Determining how to lower BP to more optimal levels (eg, 120/80 mm Hg) in the most cost-effective manner and in the populations at risk is the new priority. More research is needed on nutritional hygienic approaches, such as those studied in the TOMHS and DASH trials, to prevent hypertension and to supplement antihypertensive drugs. Also, it is important to continually recognize that reducing the risk of vascular disease (especially CHD) involves control of multiple risk factors to achieve maximum success. The findings of this important study have provided many ideas for the design of the next generation of trials—the children of ALLHAT.” (J. D. Neaton, jim@ccbr.umn.edu)

Naltrexone for Alcohol Dependence: Long-acting naltrexone was effective for the treatment of alcohol dependence in a study of 624 adults who were actively drinking and alcohol dependent (pp. 1617-25). Comparing monthly injections of long-acting naltrexone 190 or 380 mg with placebo, the authors noted, “380 mg of long-acting naltrexone resulted in a 25% decrease in the event rate of heavy drinking days (P = .03) and 190 mg of naltrexone resulted in a 17% decrease (P = .07). Sex and pretreatment abstinence each showed significant interaction with the medication group on treatment outcome, with men and those with lead-in abstinence both exhibiting greater treatment effects. Discontinuation due to adverse events occurred in 14.1% in the 380-mg and 6.7% in the 190-mg group and 6.7% in the placebo group. Overall, rate and time to treatment discontinuation were similar among treatment groups.” The researchers conclude, “In addition to their utility for alcohol dependence, long-acting formulations [of naltrexone] may prove to be an important treatment strategy for a variety of addictive disorders.” (J. C. Garbutt, jc_garbutt@med.unc.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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 7, 2005 Vol. 12, No. 67
Providing news and information about medications and their proper use

>>>APhA2005 Highlights
Attracting nearly 7,000 pharmacists, student pharmacists, pharmacy technicians, and others to Orlando, APhA2005 convened on Apr. 1–5 for education, exhibits, and policy deliberations.

Setting an upbeat tone for the meeting at the opening general session, CMS Administrator Mark B. McClellan, MD, PhD, drew a standing ovation after sharing his vision for transforming Medicare into a program that provides “affordable, prevention-oriented, personalized, high-quality care that gives patients the information and support they need to be educated health care consumers.” In this effort, he added, “Pharmacists will play a central role.”

The world’s fastest swimmer in U.S. history, Gary Hall, Jr., spoke to student pharmacists at their opening session. Hall is a three-time Olympian, 10-time Olympic medalist, and type 1 diabetic. Hall’s motivational message included highlights of his Olympic career and the importance that his pharmacist has played in his athletic success.

Attendees provided one-on-one education and counseling for 162 Orlando-area seniors at a special session on Apr. 4. “America’s Pharmacists Helping America’s Seniors” featured 62 pharmacists and student pharmacists who talked about the new Medicare prescription drug benefit, conducted medication “check-ups,” demonstrated use of medication adherence tools, and measured blood pressure, cholesterol and glucose, and bone density for 160 patients.

In the APhA House of Delegates, policies were adopted on continuing professional development, patient safety, and state board of pharmacy regulation of student pharmacists’ practice experiences. New business items adopted by the delegates addressed public access to clinical trial data, compounding of specialized delivery systems, and preventing illegal trafficking of methamphetamine and methamphetamine precursors.

More details about APhA2005 can be accessed on APhA Web sites (www.aphanet.org, www.pharmacist.com).

>>>NEJM Highlights
Source:
Apr. 7 issue of the New England Journal of Medicine (content.nejm.org; 2005; 352).

Intensive Statin Therapy: A study (pp. 1425-35) and related editorial (pp. 1483-4) released in March to coincide with presentation at the American College of Cardiology meeting describe intensive therapy with atorvastatin 80 mg daily (see PNN, Mar. 9).

OTC Statins: Switching one or more statins to nonprescription status is not a good idea, argues an author of a Perspective article (pp. 1403-5): “Proponents of over-the-counter access for this class of drugs cite their dramatic efficacy, relative safety, and underuse, stating that many people in the United States would benefit from more aggressive efforts to lower levels of cholesterol. Moreover, serious illness is unlikely to be masked by this therapy, and there is precedent in the United Kingdom, where some statins are no longer restricted to prescription access.

“The experience in the United Kingdom, however, is largely irrelevant, since the drugs there are available not over the counter but, rather, ‘behind the counter’ (a third option that is not used in the United States), meaning that an intervention by a pharmacist is still required. More important, statins fail to meet many of the other criteria for a switch to over-the-counter status.” (B. L. Strom, U. Penn., Philadelphia)

Treatment of Acne: A case report and clinical review present current strategies for diagnosing, assessing, and treating acne with topical and systemic therapies (pp. 1463–72): “The management of acne depends on its severity. For the patient in the vignette, in whom moderately severe acne is present (based on the large number of papules and pustules, and their distribution), I would prescribe both topical and oral therapy. For the face, I would initially prescribe 0.025 percent tretinoin for nighttime use, in combination with 5 percent benzoyl peroxide, in an aqueous vehicle, in the morning. I would also prescribe 500 mg of tetracycline twice daily. I would see the patient in six to eight weeks to assess efficacy, irritation, and compliance and to adjust the regimen accordingly.” (W. D. James, U. Penn., 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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 7, 2005 Special Alert
Providing news and information about medications and their proper use

>>>PNN Special Alert
FDA announced this morning that it is asking Pfizer to withdraw valdecoxib (Bextra) from the U.S. market and to add a black-box warning to the labeling of celecoxib (Celebrex). The company has agreed to take both actions. In postings its Web site (www.fda.gov/bbs/topics/news/2005/NEW01171.html), FDA noted that it is asking the manufacturers of all nonprescription NSAIDs to revise their labels to include more specific information about the potential cardiovascular and gastrointestinal risks, and information to assist consumers in the safe use of the drugs. FDA is also asking manufacturers of nonprescription NSAIDs to include a warning about potential skin reactions similar to that already present in labeling of prescription NSAIDs.

More details about these FDA actions will be in tomorrow’s PNN.

PNN Pharmacotherapy Line is published via e-mail each business day except 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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 8, 2005 Vol. 12, No. 68
Providing news and information about medications and their proper use

>>>Class Effect, Skin Reactions: FDA Weighs Evidence, Makes NSAID Decisions
Surprising many, FDA yesterday forced valdecoxib (Bextra, Pfizer) off the U.S. market and standardized warnings about increased risks of cardiovascular, gastrointestinal, and dermatologic adverse effects in the labeling of all NSAIDs, including both COX-2–specific and nonselective agents. Acting contrary to the advice of advisory committees that in Feb. had narrowly recommended continued marketing of Bextra and a resurrection of rofecoxib (Vioxx, Merck), FDA sided with the cautious with respect to both long- and short-term concerns about these drugs.

FDA acted just 2 days after Pfizer had given an upbeat presentation to stock analysts, and the company reluctantly deferred to the agency, saying in a news release only that it was suspending sales and marketing of the drug “pending further discussions with FDA.” However, with the European Union taking a similar action on Thursday, the prospects for Bextra remaining on either key market appeared dim, and Pfizer advised “for now” that patients stop taking the drug and contact prescribers about alternatives. In assessing valdecoxib, FDA emphasized the drug’s lack of advantage over celecoxib and its association during short-term use with Stevens–Johnson syndrome and toxic epidermal necrolysis.

FDA did not directly address prospects for a return to market for Vioxx or either of two investigational COX-2–specific NSAIDs, saying only that it “will carefully review any proposal from Merck for resumption of marketing of Vioxx.” But the handwriting appears to be on the wall, short of new evidence of safety or a clinical advantage over alternative medicines. Rofecoxib is generally considered safest for patients at high risk for gastrointestinal adverse effects, but it also appears to have the greatest detrimental effects on the cardiovascular system.

Concluding that cardiovascular and gastrointestinal risks represent a class effect, FDA asked manufacturers of all prescription NSAIDs, including the COX-2–specific agent celecoxib (Celebrex, Pfizer), to add a black-box warning and Medication Guide to product labeling. “The boxed warning will highlight the potential for increased risk of cardiovascular events and the well-described, serious, and potentially life threatening gastrointestinal bleeding associated with these drugs,” FDA noted in a Q&A page posted to its Web site.

FDA also asked manufacturers of all nonprescription NSAIDs to revise product labels to include more specific information about the potential cardiovascular, gastrointestinal, and dermatologic risks, and information to assist consumers in the safe use of the drugs. Labeling of prescription NSAIDs already addresses potential skin reactions.

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

NSAIDs & MI: The risk of first-time acute myocardial infarction is not materially affected by current NSAID use, according to a retrospective case–control analysis of 8,688 case patients and 33,923 control subjects (pp. 503-10). “Exposure to NSAIDs was assessed, and 650 case patients and 2339 control subjects were found to be currently taking NSAIDs,” write the authors. “After adjusting for various risk factors for acute myocardial infarction (e.g., hypertension, hyperlipidemia, diabetes mellitus, ischemic heart disease, body mass index, smoking), the relative risk (odds ratio [OR]) of acute myocardial infarction was 1.07 (95% confidence interval [CI] 0.96–1.19) for subjects with current NSAID exposure compared with those not taking NSAIDs. The adjusted OR for current diclofenac use was 1.23 (95% CI 1.00–1.51), for current ibuprofen use 1.16 (95% CI 0.92–1.46), and for current naproxen use 0.96 (95% CI 0.66–1.38) compared with those not taking NSAIDs. Current aspirin use combined with current NSAID use was associated with a statistically significant risk reduction (adjusted OR 0.74, 95% CI 0.57–0.97), compared with nonuse of NSAIDs and aspirin. Current use of aspirin together with current use of ibuprofen yielded an adjusted OR of 0.69 (95% CI 0.42–1.15).” (C. R. Meier, U. Hosp., Basel, Switzerland; meierch@uhbs.ch)

PNN Pharmacotherapy Line is published via e-mail each business day except 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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 11, 2005 Vol. 12, No. 69
Providing news and information about medications and their proper use

>>>Pediatric Highlights
Source:
Apr. issue of Pediatrics (www.pediatrics.org; 2005; 115).

Helping Parents Stop Smoking: Pediatricians are missing opportunities to recommend or provide smoking cessation medications to parents, according to results of a national survey of parents conducted in late 2003 (pp. 1013-7) Researchers report: “Of 3990 eligible respondents contacted, 3010 (75%) completed surveys; 1027 (34%) of those were parents. Of those parents, 211 (21%) were self-identified smokers. One half would consider using a smoking cessation medication and, of those, 85% said that it would be acceptable if the child’s doctor prescribed or recommended it to them. In contrast, of the 143 smoking parents who accompanied their child to the doctor, only 15% had pharmacotherapy recommended and only 8% received a prescription for a smoking cessation medication.” (J. P. Winickoff, Mass. Genl. Hosp., Boston)

Treating Constipation: Undertreatment of childhood constipation is common among primary care physicians, with nearly 40% of 119 patients remaining constipated after 2 months of treatment, according to a study of children aged 2 to 7 years (pp. 873-7). Based on care provided by 15 pediatricians and 11 family physicians, investigators found, “In the majority (87%) of cases, physicians prescribed some form of laxative or stool softener. The most commonly prescribed laxatives were magnesium hydroxide (77%), senna syrup (23%), mineral oil (8%), and lactulose (8%). In nearly all cases, a specific fixed dose of laxative was recommended; in only 5% of cases were parents instructed clearly to adjust the dose of laxative up or down to get the desired effect. In approximately half of the cases, physicians recommended some sort of dietary intervention. Some form of behavioral intervention was mentioned in the office records of approximately one third of cases; however, in most cases, little detail was provided. In 45% of cases, physicians prescribed disimpaction using oral cathartics, enemas, or suppositories followed by daily laxatives. In 35% of cases, physicians prescribed daily laxatives without any disimpaction procedure. In the remainder, physicians prescribed only dietary changes (5%), the use of intermittent laxatives (9%), or no therapy (7%). Treatment success corresponded to how aggressively the child was treated. Specifically, children who underwent some form of colonic evacuation followed by daily laxative therapy were more likely to have responded to treatment than were those who were treated less aggressively. ” (S. M. Borowitz, U. Virginia, Charlottesville)

>>>PNN JournalWatch
* Type 2 Diabetes: Principles of Pathogenesis and Therapy, in Lancet, 2005; 365: 1333–46. Reprints: www.thelancet.com; T. W. van Haeften, U. Med. Ctr., Utrecht, the Netherlands; T.W.vanHaeften@azu.nl

* Mind, Brain, and Personality Disorders, in
American Journal of Psychiatry, 2005; 162: 648–55. Reprints: ajp.psychiatryonline.org; G. O. Gabbard.

* The Efficacy of Light Therapy in the Treatment of Mood Disorders: A Review and Meta-Analysis of the Evidence, in
American Journal of Psychiatry, 2005; 162: 656–62. Reprints: ajp.psychiatryonline.org; R. N. Golden.

* A Review of Evidence Supporting the American Academy of Pediatrics Recommendation for Prescribing Cephalosporin Antibiotics for Penicillin-Allergic Patients, in
Pediatrics, 2005; 115: 1048–57. Reprints: www.pediatrics.org; M. E. Pichichero, U. Rochester, Rochester, N. Y.

* Meta-Analysis: Low-Dose Dopamine Increases Urine Output but Does Not Prevent Renal Dysfunction or Death, in
Annals of Internal Medicine, 2005; 142: 510–24. Reprints: www.annals.org; J. O. Friedrich, j.friedrich@utoronto.ca

* Clinical Practice Guidelines in Nephrology: Evaluation, Classification, and Stratification of Chronic Kidney Disease, in
Pharmacotherapy, 2005; 25: 491–502. Reprints: www.pharmacotherapy.org; G. R. Bailie, bailieg@acp.edu

* Can the Renin-Angiotensin System Protect Against Stroke? A Focus on Angiotensin II Receptor Blockers, in
Pharmacotherapy, 2005; 25: 531–9. Reprints: www.pharmacotherapy.org; B. J. Epstein, epstein@chfm.ufl.edu

* Chemotherapy- and Radiotherapy-Induced Oral Mucositis: Review of Preventive Strategies and Treatment, in
Pharmacotherapy, 2005; 25: 540–54. Reprints: www.pharmacotherapy.org; C. E Saadeh, saadehc@ferris.edu

* Antiinflammatory Therapies for Cystic Fibrosis: Past, Present, and Future, in
Pharmacotherapy, 2005; 25: 555–73. Reprints: www.pharmacotherapy.org; W. A. Prescott, Jr., prescott@buffalo.edu

* Treatment of Postmenopausal Osteoporosis, in
Pharmacotherapy, 2005; 25: 574–84. Reprints: www.pharmacotherapy.org; D. Greenblatt, Deaconess Arthritis Ctr., Cincinnati.

PNN Pharmacotherapy Line is published via e-mail each business day except 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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 12, 2005 Vol. 12, No. 70
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Apr. 11 issue of Archives of Internal Medicine (www.archinternmed.com; 2005; 165).

LMWHs for DVT, PE: Outpatient treatment of deep-vein thrombosis or pulmonary embolism can be successfully treated with either tinzaparin and dalteparin, concludes a 254-patient study (pp. 733-8). Study participants, most of whom had active malignancy or idiopathic DVT/PE, were started on warfarin therapy for 90 days and received either subcutaneous tinzaparin sodium 175 IU/kg every 24 hours or subcutaneous dalteparin sodium 200 IU/kg every 24 hours for at least 5 days. The two low molecular weight heparins were equivalent, with recurrent thromboembolism occurring in 11 and 15 patients in the dalteparin and tinzaparin groups, respectively, and 9 and 10 episodes of bleeding in the two groups, with 2 and 5 major hemorrhages, respectively. The authors conclude, “Our finding of no differences between the LMWHs based on major clinical end points means that practical issues can be the deciding factor on which drug to use.” (P. S. Wells, Ottawa Hosp., Ottawa, Ont., Canada; pwells@ohri.ca)

Editorialists concur that LMWHs appear to be therapeutically equivalent for this indication but that more comparisons with other anticoagulants are needed (pp. 722-3). “A study similar in size and scope to the GUSTO trial..., while undoubtedly very time-consuming and expensive, could provide a wealth of relevant clinical- and laboratory-related correlative data, including information on short-term outcomes occurring prior to warfarin initiation, antifactor Xa–antifactor IIa activity ratios, and tissue plasma factor inhibitor measurements, and could be conducted in various settings, including the treatment of acute coronary syndromes. These studies may also be necessary to define the role of new anticoagulants, such as fondaparinux, in treatment algorithms. In the meantime, it is likely that clinicians will be left to wonder if alternative LMWH formulations are more similar than different.” (C. L. Bennett, cbenne@northwestern.edu)

Antilipidemic Agents, Diet, & Mortality: Statins and n-3 fatty acids should be preferred over fibrates for lipid lowering, conclude authors of a systematic review, as those two agents lower both overall and cardiac mortality, while fibrates’ beneficial effect on cardiac mortality “is offset by an increased risk of death from noncardiovascular causes” (pp. 725-30). “A total of 97 studies met eligibility criteria, with 137,140 individuals in intervention and 138,976 individuals in control groups,” write the authors. “Compared with control groups, risk ratios for overall mortality were 0.87 for statins (95% confidence interval [CI], 0.81–0.94), 1.00 for fibrates (95% CI, 0.91–1.11), 0.84 for resins (95% CI, 0.66–1.08), 0.96 for niacin (95% CI, 0.86–1.08), 0.77 for n-3 fatty acids (95% CI, 0.63–0.94), and 0.97 for diet (95% CI, 0.91–1.04). Compared with control groups, risk ratios for cardiac mortality indicated benefit from statins (0.78; 95% CI, 0.72–0.84), resins (0.70; 95% CI, 0.50–0.99) and n-3 fatty acids (0.68; 95% CI, 0.52–0.90). Risk ratios for noncardiovascular mortality of any intervention indicated no association when compared with control groups, with the exception of fibrates (risk ratio, 1.13; 95% CI, 1.01–1.27).” (H. C. Bucher, U. Hosp., Basel, Switzerland; hbucher@uhbs.ch)

Studies of Geriatric Patients: Three research articles focus on care of older patients:

* Used following acute myocardial infarction, antiplatelet and anticoagulant combinations produce modest increases in the risk of bleeding among elderly patients, according to a study of 21,443 patients who received combinations of aspirin, warfarin, and thienopyridines (pp. 784-9; L. Pilote, louise.pilote@mcgill.ca).

* Normal creatinine levels do not necessarily mean normal renal function in older hospitalized patients, and clinicians’ failure to recognize this increases patients’ risk of adverse reactions to water-soluble drugs, concludes a study of 11,687 patients (pp. 790-5; A. Corsonello, Istituto Nazionale di Ricovero e Cura per Anziani (INRCA), Cosenza, Italy; andrea_corsonello@tin.it).

* Cholinesterase inhibitors used for dementia increase patients’ risk of needing anticholinergic drugs for urinary incontinence, concludes a study of 44,884 Canadians (pp. 808-13; S. S. Gill, MD, St. Mary’s of the Lake Hosp., Kingston, Ont., Canada; gills@pccchealth.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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 13, 2005 Vol. 12, No. 71
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Apr. 13 issue of JAMA (www.jama.com; 2005; 293).

Fibrinolytic Dosing & Outcomes: Examining the Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT-2) trial database, investigators find that confounding factors better correlate with patient outcomes than does incorrect dosing of fibrinolytics (pp. 1746-50). “Incorrect dosing occurred in 4.9% of patients who received active alteplase and in 4.6% of patients who received alteplase placebo,” note the authors. “Patients receiving incorrect doses of alteplase or alteplase placebo were more likely to be older, female, black, shorter, have lower body weight and systolic blood pressure, and have a higher Killip class at presentation. Thirty-day mortality was higher in patients who received an overdose (9.8%) or underdose (19.5%) of alteplase compared with those who received a correct dose (5.4%). The same pattern was present in patients who received an alteplase placebo (10.0% for overdose, 23.5% for underdose, and 5.4% for correct dose). Similar patterns were seen for in-hospital intracranial hemorrhage and major bleeding. The higher rates of adverse outcomes with incorrect dosing were largely accounted for by adjusting for baseline characteristics.” The group concludes, “These data highlight the need for caution when ascribing a causal relationship to associations between incorrect dosing and adverse outcomes.” (C. B. Granger, grang001@mc.duke.edu)

Pneumococcal–Meningococcal Vaccine: A combination 9-valent pneumococcal–group C meningococcal conjugate candidate vaccine (Pnc9-MenC) has been safe and effective during testing as part of infants’ immunizations at 2, 3, and 4 months in the U.K., report authors of a 240-patient study (pp. 1751-8). Compared with monovalent group C meningococcal conjugate vaccine (MenC), the new combination product has produced these serum bactericidal titer results: “MenC component immunogenicity was reduced in the Pnc9-MenC vs the MenC group (geometric mean SBT, 179 [95% confidence interval {CI}, 133–243] vs 808 [95% CI, 630–1037], respectively; P < .001). The proportion with group C meningococcal SBT greater than 1:8 was lower in the Pnc9-MenC vs the MenC group (95% vs 100%, P = .05). The geometric mean concentration of antibodies to concomitantly administered [Haemophilus influenzae type b] vaccine was reduced in the Pnc9-MenC vs the MenC group (2.11 [95% CI, 1.57–2.84] µg/mL vs 3.36 [95% CI, 2.57–4.39] µg/mL; P = .02), as were antibodies against diphtheria (0.74 [95% CI, 0.63–0.87] µg/mL vs 1.47 [95% CI, 1.28–1.69] µg/mL; P < .001). Pnc9-MenC was immunogenic for each of 9 contained pneumococcal serotypes, with responses greater than 0.35 µg/mL observed in more than 88% of infants. Increased irritability and decreased activity were observed after the third dose in the Pnc9-MenC group.” (J. P. Buttery, Royal Children’s Hosp., Parkville, Victoria, Australia; jim.buttery@rch.org.au )

Abciximab in STEMI: According to a meta-analysis, abciximab therapy added to primary angioplasty in patients with ST-segment–elevation myocardial infarction yielded significant reductions in 30-day and long-term mortality but also a higher rate of major bleeding (pp. 1759-65). “Eleven trials were analyzed, involving 27,115 patients (12,602 [46.5%] in the abciximab group, 14,513 [53.5%] in the control group),” the authors report. “When compared with the control group, abciximab was associated with a significant reduction in short-term (30 days) mortality (2.4% vs 3.4%, P = .047) and long-term (6-12 months) mortality (4.4% vs 6.2%, P = .01) in patients undergoing primary angioplasty but not in those treated with fibrinolysis or in all trials combined. Abciximab was associated with a significant reduction in 30-day reinfarction, both in all trials combined (2.1% vs 3.3%, P < .001), in primary angioplasty (1.0% vs 1.9%, P = .03), and in fibrinolysis trials (2.3% vs 3.6%, P < .001). Abciximab did not result in an increased risk of intracranial bleeding (0.61% vs 0.62%, P = .62) but was associated with an increased risk of major bleeding complications when combined with fibrinolysis (5.2% vs 3.1%, P < .001) but not with primary angioplasty (4.7% vs 4.1%, P = .36).” (H. Suryapranata, Hospital De Weezenlanden, Zwolle, the Netherlands; h.suryapranata@diagram-zwolle.nl)

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

PNN Pharmacotherapy Line
Apr. 14, 2005 Vol. 12, No. 72
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Early-release articles and the Apr. 14 issue of the New England Journal of Medicine (content.nejm.org; 2005; 352).

Vitamin E, Donepezil for Cognitive Impairment: Among patients with mild cognitive impairment, progression to Alzheimer’s disease was significantly lower during the first of 3 years of therapy with donepezil, compared with placebo, but not during the entire time period, and vitamin E supplements showed no protective effects (10.1056/NEJMoa050151). In an article released early to coincide with presentation yesterday at the American Academy of Neurology annual meeting, researchers tested vitamin E 2000 IU daily and donepezil 10 mg daily, finding the following: “A total of 769 subjects were enrolled, and possible or probable Alzheimer’s disease developed in 212. The overall rate of progression from mild cognitive impairment to Alzheimer’s disease was 16 percent per year. As compared with the placebo group, there were no significant differences in the probability of progression to Alzheimer’s disease in the vitamin E group (hazard ratio, 1.02; 95 percent confidence interval, 0.74 to 1.41; P = 0.91) or the donepezil group (hazard ratio, 0.80; 95 percent confidence interval, 0.57 to 1.13; P = 0.42) during the three years of treatment. Prespecified analyses of the treatment effects at 6-month intervals showed that as compared with the placebo group, the donepezil group had a reduced likelihood of progression to Alzheimer’s disease during the first 12 months of the study (P = 0.04), a finding supported by the secondary outcome measures. Among carriers of one or more apolipoprotein E4 alleles, the benefit of donepezil was evident throughout the three-year follow-up. There were no significant differences in the rate of progression to Alzheimer’s disease between the vitamin E and placebo groups at any point, either among all patients or among apolipoprotein E4 carriers.” (R. C. Petersen, peter8@mayo.edu)

Listing lessons from the above study, an editorialist writes (10.1056/NEJMe058086): “First, symptoms of memory loss in older persons should be taken seriously, since they may represent the beginning of Alzheimer’s disease, and—once more effective early interventions are available—it will be critical to ask patients about these symptoms and learn to recognize them as early as possible. Second, at least one standard Alzheimer’s disease therapy, donepezil, may offer some benefit, but any such benefit is quite limited and apparently transient. Last and most important, this study puts to rest the hope that early intervention with vitamin E can delay the onset of Alzheimer’s disease, joining a group of recent trials of vitamin E with disappointing results.” (D. Blacker, Harvard Med. Sch., Boston)

Steroids for Mild Persistent Asthma: Short intermittent courses of inhaled or oral corticosteroids can perhaps replace daily treatment of mild persistent asthma, according to a 1-year study of 225 adults (pp. 1519-28). Participants received either inhaled budesonide or oral zafirlukast daily or intermittent short-course corticosteroid treatment guided by a symptom-based action plan. “The three treatments produced similar increases in morning [peak expiratory flow] (7.1 to 8.3 percent; approximately 32 liters per minute; P = 0.90) and similar rates of asthma exacerbations (P = 0.24), even though the intermittent-treatment group took budesonide, on average, for only 0.5 week of the year,” the authors explain. “As compared with intermittent therapy or daily zafirlukast therapy, daily budesonide therapy produced greater improvements in pre-bronchodilator [forced expiratory volume in 1 second (FEV1)] (P = 0.005), bronchial reactivity (P < 0.001), the percentage of eosinophils in sputum (P = 0.007), exhaled nitric oxide levels (P = 0.006), scores for asthma control (P < 0.001), and the number of symptom-free days (P = 0.03), but not in post-bronchodilator FEV1 (P = 0.29) or in the quality of life (P = 0.18). Daily zafirlukast therapy did not differ significantly from intermittent treatment in any outcome measured.” (H. A. Boushey, U. California, San Francisco)

PNN Pharmacotherapy Line is published via e-mail each business day except 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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 15, 2005 Vol. 12, No. 73
Providing news and information about medications and their proper use

>>>Chest Highlights
Source:
Apr. issue of Chest (www.chestjournal.org; 2005; 127).

GERD & Asthma: Gastroesophageal reflux disease is common among patients with difficult-to-manage cases of asthma, but GERD treatments do not seem to help much with asthmatic symptoms, according to a study of 68 patients (pp. 1227-31). “Esophageal probe data were available in 52 patients (76%) with difficult asthma,” write the investigators. “The prevalence of GERD/GERD-associated asthma symptoms was 75% (39 of 52 patients; 95% confidence interval [CI], 63 to 84.7%). The prevalence of GERD as evidenced by an abnormal pH profile at the distal esophageal probe was 55% (29 of 52 patients; 95% CI, 40 to 69%). The prevalence of GERD at the proximal probe was 34.6% (18 of 52 patients; 95% CI, 23.6 to 51%). The prevalence of GERD was similar in asthmatic subjects who responded to intervention and those who remained difficult to control (therapy resistant). Asymptomatic GERD was present in 9.6% (5 of 52 patients); 16% of cough episodes correlated with acid reflux.” (L. Heaney, Regional Respiratory Ctr., Belfast, U.K.; Liam.Heaney@bch.n-i.nhs.uk)

>>>PNN NewsWatch
* Ephedra Coming Back? Perhaps it’s fitting on Tax Day that we all are reminded of what the federal government does for us: Congress passes and the President signs laws, the regulatory agencies interpret and implement the laws, and the courts overturn everything and tell them all to start over. At least that’s where the U.S. may soon find itself with respect to regulation of dietary supplements. Striking at the heart of FDA’s interpretation of the Dietary Supplement Health and Education Act of 1994, a federal judge in Utah yesterday ruled that Congress did not mean for FDA to apply the type of risk-versus-benefit equation to dietary supplements that it does to drugs. While FDA presumably will appeal the decision, Congressional critics of DSHEA are quoted in today’s newspapers as saying that if the ruling stands, Congress will need to consider new laws to provide clearer direction about how FDA should regulate herbal and other alternative products that fall somewhere between foods and drugs. The judge’s ruling also forbids FDA from enforcing the ephedra ban with respect to a low “dose” ephedra product marketed by the plaintiff, Nutraceutical International Corp. If that aspect of the judge’s decision is not stayed during appeals, then that product could return to the market immediately, and other manufacturers would likely file similar suits to permit sales of their ephedra products.

* The
emergency contraceptive Plan B will be approved in a pharmacist-only, behind-the-counter category, the Pink Sheet reported yesterday. While such a decision has not been confirmed by either FDA or the product sponsor, Barr subsidiary Duramed, if it happens it would create a third category of drugs in the U.S. similar to that in the U.K. and other countries. FDA in the past has approved products for sale in certain types of retail environments—such as smoking cessation products that are limited to pharmacies—but this would be the agency’s first recognition that some products are appropriate for pharmacist-only status.

* With a decision on Plan B now months overdue, the Senate consideration of
Lester M. Crawford, DVM, PhD, as permanent FDA commissioner is being held up partially because of FDA’s inaction. News reports also indicate that a Senate committee has received a letter from an FDA employee making allegations concerning the acting commissioner that need to be cleared up before the nomination goes to the floor for a vote by the full Senate. The Republican chairman of the Health, Education, Labor and Pensions Committee said in a news release, “FDA’s mission to protect the public health has never been more important. It is critical that the Senate confirm a qualified nominee in an atmosphere free from political agendas.”

*
Lilly has successfully defended its patents for olanzapine (Zyprexa), with a federal judge yesterday ruling against three generic companies.

*
Kos and Barr this week ended litigation that had been pending between the companies and agreed that Kos and Duramed will begin copromoting Niaspan and Advicor products by mid-2005.

PNN Pharmacotherapy Line is published via e-mail each business day except 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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 18, 2005 Vol. 12, No. 74
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
Apr. 16 issue of Lancet (www.thelancet.com; 2005; 365).

Cannabinoid Receptors & Weight Loss: Significant improvements in weight, waist circumference, and cardiovascular risk factors resulted when patients were treated with a cannabinoid-1 receptor blocker (pp. 1389-97). In a study of 1,507 patients with obesity or overweight plus CV risk factors, placebo or rimonabant 5 or 20 mg daily were provided with a mildly hypocaloric diet (600 kcal/day deficit). The researchers found, “Weight loss at 1 year was significantly greater in patients treated with rimonabant 5 mg (mean –3.4 kg [SD 5.7]; p = 0.002 vs placebo) and 20 mg (–6.6 kg [7.2]; p < 0.001 vs placebo) compared with placebo (–1.8 kg [6.4]). Significantly more patients treated with rimonabant 20 mg than placebo achieved weight loss of 5% or greater (p < 0.001) and 10% or greater (p < 0.001). Rimonabant 20 mg produced significantly greater improvements than placebo in waist circumference, HDL-cholesterol, triglycerides, and insulin resistance, and prevalence of the metabolic syndrome. The effects of rimonabant 5 mg were of less clinical significance. Rimonabant was generally well tolerated with mild and transient side effects.” (L. F. Van Gaal, U. Hosp., Edegem-Antwerp, Belgium; luc.van.gaal@uza.be)

Anesthesia & Lethal Injection: Analysis of blood samples from 49 inmates executed by lethal injection in four states shows low concentrations of the anesthetic agent thiopental (pp. 1412-4). “Post-mortem concentrations of thiopental in the blood were lower than that required for surgery in 43 of 49 executed inmates (88%); 21 (43%) inmates had concentrations consistent with awareness,” the authors write. “Methods of lethal injection anaesthesia are flawed and some inmates might experience awareness and suffering during execution.” (L. G. Koniaris, LKoniaris@med.miami.edu)

“Capital punishment is not only an atrocity, but also a stain on the record of the world’s most powerful democracy,” Lancet editors write in an accompanying commentary (p. 1361). “Doctors should not be in the job of killing. Those who do participate in this barbaric act are shameful examples of how a profession has allowed its values to be corrupted by state violence.”

>>>BMJ Highlights
Source:
Apr. 16 issue of BMJ (www.bmj.org; 2005; 330).

Treatment of Agitation in Alzheimer’s Disease: Not only do quetiapine and rivastigmine fail to improve symptoms of agitation among institutionalized patients with Alzheimer’s disease or dementia, use of quetiapine is associated with increased cognitive decline, report authors of a study of 93 individuals (pp. 874 ff). “31 patients were randomised to each group, and 80 (86%) started treatment (25 rivastigmine, 26 quetiapine, 29 placebo), of whom 71 (89%) tolerated the maximum protocol dose (22 rivastigmine, 23 quetiapine, 26 placebo),” the authors note. “Compared with placebo, neither group showed significant differences in improvement on the agitation inventory either at six weeks or 26 weeks. Fifty six patients scored > 10 on the severe impairment battery at baseline, 46 (82%) of whom were included in the analysis at six week follow up (14 rivastigmine, 14 quetiapine, 18 placebo). For quetiapine the change in severe impairment battery score from baseline was estimated as an average of –14.6 points (95% confidence interval –25.3 to –4.0) lower (that is, worse) than in the placebo group at six weeks (P = 0.009) and –15.4 points (–27.0 to –3.8) lower at 26 weeks (P = 0.01). The corresponding changes with rivastigmine were –3.5 points (–13.1 to 6.2) lower at six weeks (P = 0.5) and –7.5 points (–21.0 to 6.0) lower at 26 weeks (P = 0.3).” (R. Jacoby, Oxford U., Oxford, U.K.; Robin.Jacoby@psych.ox.ac.uk)

>>>PNN JournalWatch
* Prevalence of the Metabolic Syndrome and Overweight Among Adults in China, in Lancet, 2005; 365: 1398–405. Reprints: www.thelancet.com; J. He, jhe@tulane.edu

* The Metabolic Syndrome, in
Lancet, 2005; 365: 1415–28. Reprints: www.thelancet.com; R. H. Eckel, U. Colorado, Aurora; Robert.Eckel@UCHSC.edu

* Open Access and Openly Accessible: A Study of Scientific Publications Shared via the Internet, in
BMJ, doi:10.1136/bmj.38422.611736. Reprints: www.bmj.org; J. D. Wren, U. Oklahoma, Norman.

PNN Pharmacotherapy Line is published via e-mail each business day except 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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 19, 2005 Vol. 12, No. 75
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Apr. 19 issue of the Annals of Internal Medicine (www.annals.org; 2005; 142).

Preventing Metabolic Syndrome: Lifestyle interventions plus pharmacotherapy with metformin decreased development of metabolic syndrome among participants in the Diabetes Prevention Program (pp. 611-9). All participants in the study had impaired glucose tolerance at baseline and fasting glucose levels of 95 mg/dL or more, and they received metformin 850 mg daily or intensive lifestyle interventions during a mean of 3.2 years of follow-up. “Fifty-three percent of participants (n = 1711) had the metabolic syndrome at baseline; incidence did not vary substantially by age,” the investigators write. “However, low levels of high-density lipoprotein cholesterol predominated in younger participants (age 25 to 44 years), and high blood pressure predominated in older participants (age 60 to 82 years). In life-table analyses (log-rank test), incidence of the metabolic syndrome was reduced by 41% in the lifestyle group (P < 0.001) and by 17% in the metformin group (P = 0.03) compared with placebo. Three-year cumulative incidences were 51%, 45%, and 34% in the placebo, metformin, and lifestyle groups, respectively. There was no significant heterogeneity by ethnic group.” (Diabetes Prevention Program Coordinating Ctr., Rockville, Md.)

Medical Errors: In a quality grand rounds article, authors explore why some organizations are error-prone (pp. 627-30). They note: “High performers know how to prevent problems from producing further consequences once they occur and how to prevent their recurrence. They do this by specifying how work is expected to proceed—who will do what for whom, with what purpose, when, where, and how—before work is actually done. Then, when anything contrary to expectations occurs, it is immediately identified as a problem....

“In contrast, error-prone organizations tolerate ambiguity, a prevailing lack of clarity over what is supposed to happen at any given time. Problems are thus hard to identify, and, even when recognized, they are worked around. People ‘get the job done,’ but don’t initiate efforts to learn from the problem or improve the process.” (S. J. Spear, Harvard Business Sch., Boston; sspear@hbs.edu)

>>>PNN NewsWatch
* FDA has approved a new antigingivitis mouthwash, Decapinol (delmopinol), indicated for use in nonpregnant patients 12 years of age and older. Because delmopinol acts by forming a surfactant barrier that prevents bacteria from sticking to tooth surfaces—in contrast to previously approved mouthwashes for gingivitis, which kill bacteria chemically—FDA approved Decapinol as a medical device rather than a drug.

* The fight over
emergency contraception in pharmacies makes page 1 of the New York Times this morning, with reporters detailing how pro-life and pro-choice forces are engaged in legislative battles in some 23 states that have passed or are considering “laws that would explicitly grant pharmacists the right to refuse to dispense drugs related to contraception or abortion on moral grounds” or “require pharmacies to fill any legal prescription for birth control.” The article notes, “While a few doctors and pharmacists have for years declined to prescribe or sell birth control pills for religious reasons, the objections of some to the morning-after pill are more vehement because they consider it to be more akin to abortion.... Abortion rights advocates and most physicians say the pill, unlike the French drug RU-486, is not an abortion drug because it does not destroy an embryo. Instead, the pill prevents ovulation or fertilization, or blocks a fertilized egg from becoming implanted in the uterus.” An APhA Web site, www.pharmacist.com, reports that a bill introduced into both houses of the U.S. Congress would require “pharmacies to make sure that prescriptions are filled without delay by another pharmacist employed by the pharmacy if a pharmacist refuses to fill a prescription.”

* Launched last week, the hypnotic agent
eszopiclone (Lunesta, Sepracor) achieved the fifth fastest recorded rate of uptake, reports today’s Wall Street Journal. With a total of 20,805 prescription orders recorded by IMS Health, this “strong demand” could be a sign that “the sleeping-pill business is waking up again.”

PNN Pharmacotherapy Line is published via e-mail each business day except 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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 20, 2005 Vol. 12, No. 76
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Apr. 20 issue of JAMA (www.jama.com; 2005; 293).

Mortality Risk with Nesiritide: Risk of death appears to be elevated when patients with acutely decompensated heart failure are treated with nesiritide, compared with noninotrope-based control therapy, according to a meta-analytic review article (pp. 1900-5). Data were obtained from three trials, FDA, and study sponsor Scios. The authors report, “In the 3 trials, 485 patients were randomized to nesiritide and 377 to control therapy. Death within 30 days tended to occur more often among patients randomized to nesiritide therapy (35 [7.2%] of 485 vs 15 [4.0%] of 377 patients; risk ratio from meta-analysis, 1.74; 95% confidence interval [CI], 0.97–3.12; P = .059; and hazard ratio after adjusting for study, 1.80; 95% CI, 0.98–3.31; P = .057).”

Second-line status for nesiritide should be considered, these authors conclude: “Nesiritide may be associated with an increased risk of death within the first month after its use for the treatment of decompensated heart failure when compared with noninotrope-based control therapies. As this is not an analysis based on an adequately powered prospective trial but rather an analysis pooling data from existing trials, our finding should be viewed as hypothesis generating rather than as conclusive evidence of harm. However, given the high mortality rate associated with heart failure, excluding an increased risk with nesiritide is imperative. An adequately powered, controlled randomized mortality trial comparing nesiritide with traditional diuretic and vasodilator drug therapy must be performed. Until then, it may be prudent to reserve use of this agent to situations in which a combination of diuretics and nitroglycerin has proven inadequate.” (J. D. Sackner-Bernstein, North Shore U. Hosp., Manhasset, N.Y.; jonathansb@yahoo.com)

Weight, Health, & Death: Two articles assess the relationships among patient weight, cardiovascular disease, and mortality.

While mortality rates are higher among patients who are underweight or obese, the impact of obesity on mortality has decreased over time, perhaps because of improved care of those with ischemic heart disease, report investigators who analyzed data from the three National Health and Nutrition Examination Surveys conducted in 1971–75; 1976–80, with follow-up through 1992; and 1988–94, with follow-up through 2000 (pp. 1861-7). “Relative to the normal weight category (BMI 18.5 to <25), obesity (BMI ≥30) was associated with 111,909 excess deaths (95% confidence interval [CI], 53,754–170,064) and underweight with 33,746 excess deaths (95% CI, 15,726–51,766). Overweight was not associated with excess mortality (–86,094 deaths; 95% CI, –161,223 to –10,966). The relative risks of mortality associated with obesity were lower in NHANES II and NHANES III than in NHANES I.” (K. M. Flegal, kflegal@cdc.gov)

The second study also finds that the level of risk associated with increased BMI has declined over the past 40 years (pp. 1868-74). Also using data from NHANES I, II, and III, the researchers report: “The prevalence of all risk factors except diabetes decreased over time across all BMI groups, with the greatest reductions observed among overweight and obese groups. Compared with obese persons in 1960–1962, obese persons in 1999–2000 had a 21-percentage-point lower prevalence of high cholesterol level (39% in 1960–1962 vs 18% in 1999–2000), an 18-percentage-point lower prevalence of high blood pressure (from 42% to 24%), and a 12-percentage-point lower smoking prevalence (from 32% to 20%). Survey x BMI group interaction terms indicated that compared with the first survey, the prevalence of high cholesterol in the fifth survey had fallen more in obese and overweight persons than in lean persons (P < .05). Survey x BMI changes in blood pressure and smoking were not statistically significant. Changes in risk factors were accompanied by increases in lipid-lowering and antihypertensive medication use, particularly among obese persons. Total diabetes prevalence was stable within BMI groups over time, as nonsignificant 1- to 2-percentage-point increases occurred between 1976–1980 and 1999–2000.” (E. W. Gregg, edg7@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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 21, 2005 Vol. 12, No. 77
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Apr. 21 issue of the New England Journal of Medicine (content.nejm.org; 2005; 352).

Antibiotics & Heart Disease: Two research articles, an editorial, and a review article explore the use of antibiotics in preventing coronary events.

Weekly doses of azithromycin failed to protect patients with stable coronary artery disease from cardiac events, according to investigators from the Azithromycin and Coronary Events Study (ACES; pp. 1637-45). Comparing weekly azithromycin 600 mg against placebo, ACES showed, “The primary end point, a composite of death due to coronary heart disease, nonfatal myocardial infarction, coronary revascularization, or hospitalization for unstable angina, occurred in 446 of the participants who had been randomly assigned to receive azithromycin and 449 of those who had been randomly assigned to receive placebo. There was no significant risk reduction in the azithromycin group as compared with the placebo group with regard to the primary end point (risk reduction, 1 percent [95 percent confidence interval, –13 to 13 percent]). There were also no significant risk reductions with regard to any of the components of the primary end point, death from any cause, or stroke. The results did not differ when the participants were stratified according to sex, age, smoking status, presence or absence of diabetes mellitus, or [
Chlamydia] pneumoniae serologic status at baseline.” (J. T. Grayston, U. Washington, Seattle)

Among 4,162 patients hospitalized for acute coronary syndrome, long-term treatment with gatifloxacin failed to reduce the rate of cardiovascular events, compared with placebo (pp. 1646-54). The Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 investigators report these findings about the primary end point (a composite of death from all causes, myocardial infarction, documented unstable angina requiring rehospitalization, revascularization performed at least 30 days after randomization, or stroke), “A Kaplan–Meier analysis revealed that the rates of primary-end-point events at two years were 23.7 percent in the gatifloxacin group and 25.1 percent in the placebo group (hazard ratio, 0.95; 95 percent confidence interval, 0.84 to 1.08; P = 0.41). No benefit was seen in any of the prespecified secondary end points or in any of the prespecified subgroups, including patients with elevated titers to
C. pneumoniae or C-reactive protein.” (C. P. Cannon, cpcannon@partners.org)

These studies mark the “end of the road” in some but not all ways, an editorialist maintains (pp. 1706-9): “A large body of negative clinical-trial results suggests that antibiotics effective for clinical
C. pneumoniae infection are not useful for secondary prevention.... The testing of these agents for the treatment of advanced coronary heart disease appears to be at the end of the road. On the other hand, evidence that infection can be a stimulus for atherothrombosis continues to mount. These positive observations suggest that we should rethink, revise, and reformulate hypotheses and research strategies—that is, that we should begin anew, rather than discard the possibility of infection as an etiologic factor. We should focus on expanding our limited knowledge base with regard to proatherogenic mechanisms (including viral vectors); we should include sophisticated preclinical models in our research plans; and, when appropriate, we should return to the clinical arena with trials that better select target patients (e.g., those at an earlier stage of atherosclerosis or those with better markers of latent or active infection or with a high total or viral burden) and interventions, including novel antiinfective agents and vaccines. Meanwhile, standard antibiotics do not work for the secondary prevention of cardiovascular heart disease.” (J. L. Anderson, U Utah, LDS Hospital, Salt Lake City)

The review article author notes that inflammation is better therapeutic target than infection per se (pp. 1685-95): “New knowledge about inflammation in CAD has provided surprising insights into its pathogenesis, has offered new opportunities for diagnosis and prediction, and may lead to new treatments for this life-threatening disease.” (G. K. Hansson, Karolinska U. Hosp., Stockholm, Sweden; goran.hansson@cmm.ki.se)

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

PNN Pharmacotherapy Line
Apr. 22, 2005 Vol. 12, No. 78
Providing news and information about medications and their proper use

>>>JAPhA Highlights
Source:
Mar/Apr issue of the Journal of the American Pharmacists Association (www.japha.org; 2005; 45).

Self-Management by Patients with Diabetes: Pharmacist-directed self-management in patients with diabetes produced improved clinical indicators, higher rates of self-management goal setting and achievement, and increased satisfaction with diabetes care, according to results of an APhA Foundation study involving 80 community pharmacy providers in five states (pp. 130-7). Employers experienced a decline in mean projected total direct medical costs, the authors noted, explaining, “Over the initial year of the program, participants’ mean A1C decreased from 7.9% at initial visit to 7.1%, mean LDL-C decreased from 113.4 mg/dL to 104.5 mg/dL, and mean systolic blood pressured decreased from 136.2 mm Hg to 131.4 mm Hg. During this time, influenza vaccination rate increased from 52% to 77%, the eye examination rate increased from 46% to 82%, and the foot examination rate increased from 38% to 80%. Patient satisfaction with overall diabetes care improved from 57% of responses in the highest range at baseline to 87% at this level after 6 months, and 95.7% of patients reported being very satisfied or satisfied with the diabetes care provided by their pharmacists. Total mean health care costs per patient were $918 lower than projections for the initial year of enrollment.” (D. G. Garrett, dgarrett@aphanet.org).

Pharmacist-Managed Nonprescription Drug Therapy: Civilian pharmacists successfully managed nonprescription drug benefits for members of the Canadian military who had no access to military pharmacies (pp. 170-8). Assessing the care provided by 65 community pharmacists to 583 members of the Canadian Forces, the investigators note, “Based on 563 transactions that occurred during the pilot study period, 96% of the CF members reported being very to somewhat satisfied with the service received under the new drug-management program, and a majority stated that desirable health outcomes were achieved. The one area of concern cited about the new program was the low percentage of members who recalled being instructed by civilian pharmacists to see a physician if their symptoms did not abate. The cost analysis showed the new program was more economical than a previous physician-based system.” (R. Kassam, U. British Columbia, Vancouver; rokassam@interchange.ubc.ca)

Pharmacists’ Involvement in Schools: Problems with medications in primary and secondary schools are common and of concern to community pharmacists, yet much more could be done to resolve them, according to a survey of 569 Illinois pharmacists (pp. 179-84). “Almost all respondents reported that they had dispensed medications for use in school; two thirds thought that taking medications at school creates the potential for special problems (e.g., missed dose, social stigma),” write the researchers. “Of nine interventions that could help minimize these problems, the respondents used a mean of 3.34 interventions. Providing additional labeled containers for use at school was the most common intervention reported. Respondents who thought that medication use in schools caused special problems provided significantly more interventions than those that did not share this concern.” (T. J. Reutzel, treutz@midwestern.edu)

Automation & Counseling by Pharmacists: Two research articles from the same group report that pharmacists did not increase their rate of counseling of patients after implementation of automation in community pharmacies and that changes in patient factors may be needed to improve the dynamics in the typical pharmacy (pp. 138-44; 145-50). Finding in one analysis that the “likelihood that a patient would receive counseling was not related to staffing levels, automation, or workload,” the investigators note in the second article, “Given the drastic increase in counseling offers but lack of effect on counseling rates, patient behavior and expectations with regard to counseling likely need to change to further improve dynamics in the community pharmacy.” (L. B. Angelo, langelo@butler.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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 25, 2005 Vol. 12, No. 79
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early online articles from BMJ (www.bmj.org; 2005; 330).

MMR Vaccine & Crohn’s Disease: No connection between the mumps–measles–rubella vaccine introduced in the U.K. in 1988 and Crohn’s disease was found in an analysis of hospital admissions in England in 1991–2002 (early online publication). “There were 4463 admissions for Crohn’s disease, 923 of which occurred in populations with a vaccination rate of ≥84% (those born in 1988–9 or later). Although the age specific rates increased over the study period, no obvious changes occurred that coincided with the introduction of MMR vaccine. The estimated rate ratio for the MMR vaccination programme (rates in populations with a vaccination rate of ≥84% compared with those with a rate of ≤7%) was 0.95 (95% confidence interval 0.84 to 1.08).” (V. Seagroatt, U. Oxford, Oxford OX3 7LF, U.K.; valerie.seagroatt@dphpc.ox.ac.uk)

Metformin & Cancer Risk: The risk of cancer may be reduced by metformin therapy in patients with type 2 diabetes, a possibility that is supported by a plausible biological mechanism, according to analysis of a Scottish database (early online publication). Among 11,876 people newly diagnosed with type 2 diabetes in 1993–2001, 923 patients were hospitalized with malignant cancer. Based on an observation that activation of a muscle enzyme by metformin plus exercise requires an upstream regulator that is also a tumor suppressor, the authors analyzed metformin exposure among these cancer cases, finding, “More than a third (336; 36.4%) of the cases had been given at least one prescription for metformin in the year before their index date compared with 732 (39.7%) of the controls. The unadjusted odds ratio was 0.86 (95% confidence interval 0.73 to 1.02). The unadjusted odds ratio for any exposure to metformin since 1993 was 0.79 (0.67 to 0.93).” (J. M. M. Evans, U. Dundee, Dundee, U.K. j.m.m.stansfield@dundee.ac.uk)

>>>Lancet Report
Source:
Early online article from Lancet (www.thelancet.com; 2005; 365).

Drug Treatment of Acromegaly: Combination treatment of acromegaly with pegvisomant and somatostatin analogues should be investigated further, according to an open-label, dose-finding study of 26 patients who had not responded to somatostatin monotherapy (early online publication). “Dose of pegvisomant was increased until [insulin-like growth factor I] concentration became normal or until a weekly dose of 80 mg was reached. IGF-I reached normal concentrations in 18 of 19 (95%) patients who completed 42 weeks of treatment, with a median weekly dose of 60 mg pegvisomant (range 40–80). No signs of pituitary tumour growth were noted, but mild increases in liver enzymes were observed in ten patients (38%). This combined treatment is effective, might increase compliance, and could greatly reduce the costs of medical treatment for acromegaly in some patients.” (A. J. van der Lely, Erasmus Med. Ctr., Rotterdam, the Netherlands; a.vanderlelij@erasmusmc.nl)

>>>PNN JournalWatch
* Malaria, in Lancet, 2005; 365: 1487–98. Reprints: www.thelancet.com; B. Greenwood, London School of Hygiene & Tropical Medicine, London; brian.greenwood@lshtm.ac.uk

* New Drugs of 2004, in
Journal of the American Pharmacists Association, 2005; 45: 185–218. Reprints: www.japha.org; D. A. Hussar, d.hussar@usip.edu

* Overweight in Children and Adolescents: Pathophysiology, Consequences, Prevention, and Treatment [AHA Scientific Statement], in
Circulation, 2005; 111: 1999–2012. Reprints: circ.ahajournals.org; S. R. Daniels.

* Adding Aspirin to Clopidogrel After TIA and Ischemic Stroke: Benefits Do Not Match Risks, in
Neurology, 2005; 64: 1117–21. Reprints: www.neurology.org; G. J. Hankey, Royal Perth Hosp., Perth, Australia; gjhankey@cyllene.uwa.edu.au

* A Randomized Controlled Crossover Trial of Aspirin for Fatigue in Multiple Sclerosis, in
Neurology, 2005; 64: 1267–9. Reprints: www.neurology.org; D. M. Wingerchuk, wingerchuk.dean@mayo.edu

* Heparin-Induced Thrombocytopenia in Neurologic Patients Treated with Low-Molecular-Weight Heparin, in
Neurology, 2005; 64: 1285–7. Reprints: www.neurology.org; U. Harbrecht, Inst. of Experimental Hematology and Transfusion Medicine, Bonn, Germany; ursula.harbrecht@ukb.uni-bonn.de

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

PNN Pharmacotherapy Line
Apr. 26, 2005 Vol. 12, No. 80
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Apr. 25 issue of Archives of Internal Medicine (www.archintermed.com; 2005; 165).

Healthy Lifestyles: Very few adult Americans have healthy lifestyles, according to an analysis of national 2000 data from the Behavioral Risk Factor Surveillance System (pp. 854-7). No patient subgroup has high numbers of people who meet four “healthy lifestyle characteristics” (nonsmoking, healthy weight [BMI of 18.5–25.0 kg/sq m], consuming 5 or more fruits and vegetables per day, and regular physical activity [30 minutes for 5 times per week]), the authors explain: “By using data from more than 153,000 adults, the prevalence (95% confidence interval) of the individual HLCs was as follows: nonsmoking, 76.0% (75.6%–76.4%); healthy weight, 40.1% (39.7%–40.5%); 5 fruits and vegetables per day, 23.3% (22.9%–23.7%); and regular physical activity, 22.2% (21.8%–22.6%). The overall prevalence of the healthy lifestyle indicator (ie, having all 4 HLCs) was only 3.0% (95% confidence interval, 2.8%-3.2%), with little variation among subgroups (range, 0.8%–5.7%).” (M. J. Reeves, Michigan State U., East Lansing; Reevesm@msu.edu)

ACE Inhibitors & Calcific Aortic Valves: Lower rates of aortic valve calcium were observed retrospectively in patients taking ACE inhibitors, supporting the need for a prospective evaluation of the drugs, conclude authors of a 123-patient study (pp. 858-62). All participants had undergone two serial electron beam computed tomographic scans, and the investigators found, “Unadjusted and adjusted median rates of AVC score change were significantly higher in the no-ACEI group than in the ACEI group (adjusted median AVC changes [95% confidence interval]: relative, 28.7%/y [18.9%–38.5%/y] vs 11.0%/y [–1.9% to 24.0%/y], P = .04; absolute: 25.1/y [19.7–30.5/y] vs 12.2/y [4.5–19.9/y], P = .02). The adjusted odds ratio (95% confidence interval) for definite AVC progression was significantly lower for patients who received ACEIs (0.29 [0.11–0.75], P = .01).” (K. D. O’Brien, cardiac@u.washington.edu)

Drug-Induced Agranulocytosis: A small number of medications are responsible for about two thirds of cases of drug-induced agranulocytosis, note authors who analyzed 78.73 million person-years of therapy (pp. 869-74). Comparing 177 community cases of agranulocytosis with 586 hospital-matched control subjects with similar medication use, the investigators report: “The annual incidence of community-acquired agranulocytosis was 3.46:1 million, and it increased with age. The fatality rate was 7.0%, and the mortality rate was 0.24:1 million. The drug most strongly associated with a risk of agranulocytosis was ticlopidine hydrochloride with an odds ratio (OR) of 103.23 (95% confidence interval [CI], 12.73–837.44), followed by calcium dobesilate (OR, 77.84 [95% CI, 4.50–1346.20]), antithyroid drugs (OR, 52.75 [95% CI, 5.82–478.03]), dipyrone (metamizole sodium and metamizole magnesium) (OR, 25.76 [95% CI, 8.39–179.12]), and spironolactone (OR, 19.97 [95% CI, 2.27–175.89]). Other drugs associated with a significant risk were pyrithyldione, cinepazide, aprindine hydrochloride, carbamazepine, sulfonamides, phenytoin and phenytoin sodium, beta-lactam antibiotics, erythromycin stearate and erythromycin ethylsuccinate, and diclofenac sodium. Individual attributable incidences for all these drugs, which collectively accounted for 68.6% of cases, were less than 1:1 million per year.” (J-R Laporte, Universitat Autònoma de Barcelona, Barcelona; jrl@icf.uab.es)

Thyrotoxicosis & Herbal Medicines: Two Chinese herbal products sold for weight reduction in Japan contain triiodothyronine and thyroxine, and their use is associated with changes in serum thyroid indicators and in 12 patients, factitious thyrotoxicosis (pp. 831-4). Based on observations made in the affected patients, two of the authors took servings of Dream Shape and Ever Youth—products available via the Internet to Americans—and their serum free triiodothyronine levels began rising within 2 hours and peaked at 8 hours. (H. Ohye, Kuma Hosp., Kobe, Japan; ohye@kuma-h.or.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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 27, 2005 Vol. 12, No. 81
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Apr. 27 issue of JAMA (www.jama.com; 2005; 293).

Patient Requests for Advertised Antidepressants: Physician prescribing for antidepressants is profoundly affected by patient requests like those that can be prompted by direct-to-consumer advertising, conclude authors who conducted a randomized trial using “standardized patients” (pp. 1995-2002). At the offices of family physicians and general internists in private practices and HMOs in California and New York, the SPs randomly made requests for one of three products (a specific brand, an antidepressant in general, or none) and portrayed one of two conditions (depression or adjustment disorder with depressed mood). The authors report: “Standardized patient role fidelity was excellent, and the suspicion rate that physicians had seen an SP was 13%. In major depression, rates of antidepressant prescribing were 53%, 76%, and 31% for SPs making brand-specific, general, and no requests, respectively (P < .001). In adjustment disorder, antidepressant prescribing rates were 55%, 39%, and 10%, respectively (P < .001). The results were confirmed in multivariate models. Minimally acceptable initial care (any combination of an antidepressant, mental health referral, or follow-up within 2 weeks) was offered to 98% of SPs in the major depression role making a general request, 90% of those making a brand-specific request, and 56% of those making no request (P < .001).”

The authors conclude, “The results of this trial sound a cautionary note for DTC advertising but also highlight opportunities for improving care of depression (and perhaps other chronic conditions) by using public media channels to expand patient involvement in care. Furthermore, physicians may require additional training to respond appropriately to patients’ requests in clinically ambiguous circumstances. Research in other clinical contexts is needed to confirm the results of this study and determine the relative effects of DTC advertising and noncommercial media on patient activation and outcomes.” (R. L. Kravitz, rlkravitz@ucdavis.edu)

Terming DTCA a “haphazard approach to health promotion,” an editorialist supports a new model under which public health is foremost in such promotions (pp. 2030-3): “Concise, coherent, evidence-based messages, delivered using the most sophisticated techniques of Madison Avenue, unbiased by the motivation to turn a profit, and funded by either a tax on DTCA or an alternative financing scheme will benefit the public’s health. These public service messages could supplement the haphazard approach to health promotion that relies on occasionally helpful and intermittently harmful advertisements that play to a patient’s vulnerability and appeal to the desire to assert control over a potential outcome—advertisements that, first and foremost, sell prescription drugs.

“If such a strategy proves untenable, then at a minimum, the FDA should expect that pharmaceutical companies improve the educational nature of DTCA by further developing and adhering to appropriate standards to facilitate regulatory efforts.” (M. F. Hollon, mfhollon@u.washington.edu)

Minocycline for HIV Encephalitis: A study in macaques indicates that the anti-inflammatory and neuroprotective properties of minocycline may be beneficial in HIV encephalitis (pp. 2003-11): “Minocycline-treated macaques had less severe encephalitis (P = .02), reduced CNS expression of neuroinflammatory markers (major histocompatibility complex class II, P = .03; macrophage marker CD68 , P = .07; T-cell intracytoplasmic antigen 1, P = .03; CSF monocyte chemoattractant protein 1, P = .001), reduced activation of p38 mitogen-activated protein kinase (P < .001), less axonal degeneration (-amyloid precursor protein, P = .03), and lower CNS virus replication (viral RNA, P = .04; viral antigen, P = .04). In in vitro analysis, minocycline suppression of HIV and SIV replication in cultured primary macrophages did not correlate with suppression of activation of p38-mitogen-activated protein kinase pathways, whereas suppression in primary lymphocytes correlated with suppression of p38 activation.” (M. C. Zink, Johns Hopkins U., Baltimore; mczink@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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 28, 2005 Vol. 12, No. 82
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Apr. 28 issue of the New England Journal of Medicine (content.nejm.org; 2005; 352).

RSV in Adults: Infections of respiratory syncytial virus, when they occur in the elderly and other adults at high risk because of chronic heart or lung problems, have a disease burden similar to that of nonpandemic influenza A, and a protective vaccine is needed, according to researchers who studied followed patients during four consecutive winters (pp. 1749-59). “A total of 608 healthy elderly patients and 540 high-risk adults were enrolled in prospective surveillance, and 1388 hospitalized patients were enrolled,” the authors report. “A total of 2514 illnesses were evaluated. RSV infection was identified in 102 patients in the prospective cohorts and 142 hospitalized patients, and influenza A was diagnosed in 44 patients in the prospective cohorts and 154 hospitalized patients. RSV infection developed annually in 3 to 7 percent of healthy elderly patients and in 4 to 10 percent of high-risk adults. Among healthy elderly patients, RSV infection generated fewer office visits than influenza; however, the use of health care services by high-risk adults was similar in the two groups. In the hospitalized cohort, RSV infection and influenza A resulted in similar lengths of stay, rates of use of intensive care (15 percent and 12 percent, respectively), and mortality (8 percent and 7 percent, respectively). On the basis of the diagnostic codes of the International Classification of Diseases, 9th Revision, Clinical Modification at discharge, RSV infection accounted for 10.6 percent of hospitalizations for pneumonia, 11.4 percent for chronic obstructive pulmonary disease, 5.4 percent for congestive heart failure, and 7.2 percent for asthma.” (A. R. Falsey, Rochester General Hosp., Rochester, N.Y.; ann.falsey@viahealth.org)

Explaining that RSV infection is “not for kids only,” two editorialists discuss prospects for a vaccine: “The World Health Organization has designated RSV as a high-priority pathogen for vaccine development. However, during the past decade, the enthusiasm for developing RSV vaccines has declined substantially among vaccine-development companies. A combination of the inherent scientific challenges, the high-risk nature of the target populations, and the enormous cost of vaccine development probably accounts for the lower priority given to RSV vaccine programs. Compounding the problem is a general lack of public awareness of RSV infection. Perhaps adults who have lost their parents or grandparents to RSV infection will form advocacy groups.” (S. Sethi, SUNY, Buffalo)

Genetics of Iron-Overload Screening: Racial and genetic differences are explored in a 99,711-participant study of serum ferritin levels and transferrin saturation (pp. 1769-78). Of the 299 individuals homozygous for the C282Y mutation of the HFE gene that confers susceptibility to iron overload, the authors report, “The estimated prevalence of C282Y homozygotes was higher in non-Hispanic whites (0.44 percent) than in Native Americans (0.11 percent), Hispanics (0.027 percent), blacks (0.014 percent), Pacific Islanders (0.012 percent), or Asians (0.000039 percent). Among participants who were homozygous for the C282Y mutation but in whom iron overload had not been diagnosed (227 participants), serum ferritin levels were greater than 300 µg per liter in 78 of 89 men (88 percent) and greater than 200 µg per liter in 79 of 138 women (57 percent). Pacific Islanders and Asians had the highest geometric mean levels of serum ferritin and mean transferrin saturation despite having the lowest prevalence of C282Y homozygotes. There were 364 participants in whom iron overload had not been diagnosed (29 C282Y homozygotes) who had a serum ferritin level greater than 1000 µg per liter. Among men, C282Y homozygotes and compound heterozygotes were more likely to report a history of liver disease than were participants without HFE mutations.” (P. C. Adams, London Health Sci. Ctr., London, Ont., Canada; padams@uwo.ca)

>>>PNN NewsWatch
* Paxil CR and Avandamet could be back on the U.S. market by the middle of this year, GlaxoSmithKline announced this morning. Millions of doses of the products were seized by FDA on Mar. 4, citing problems with recall procedures (see PNN, Mar. 7).

PNN Pharmacotherapy Line is published via e-mail each business day except 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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 29, 2005 Vol. 12, No. 83
Providing news and information about medications and their proper use

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

Adding Sulfonylureas to Metformin: The benefits of adding a sulfonylurea to metformin monotherapy for type 2 diabetes last only about 6 months, and the high proportion of patients who remain on the combination despite high A1C levels indicates the presence of “significant barriers to starting insulin or adding a third agent,” report authors of a 2,220-patient study (pp. 995-1000). Retrospectively analyzing patient records at U.K. primary care practices, the authors found these predictors of time to therapy intensification: “At 6 months post-SU initiation, median A1C resumed deteriorating at a somewhat comparable rate to that observed on MF monotherapy. Higher pre-SU A1C, younger age, female sex, shorter diabetes duration, higher serum creatinine, and being an ex-smoker predicted time until A1C ≥8.0% or glucose-lowering therapy was intensified in various analyses. Median A1C was 9.5% when therapy was intensified. A1C ≥8.0% was estimated to occur in 85% of patients 4 years after SU initiation and in 68% 4 years after initially achieving A1C <7% on MF plus SU therapy.” (M. N. Cook, michael_cook@merck.com)

Reeducating Hospital Staff Members About Sliding-Scale Insulin: Use of sliding-scale insulin can be eliminated among hospital personnel through direct ward-based teaching and wide dissemination of pocket guidelines, according to an analysis of a systematic reeducation program (pp. 1008-11). With all patients requiring insulin therapy during the study period being treated with basal and bolus insulin rather than sliding-scale doses, the authors note, ”During 8 weeks, 88 patients were identified and 16 house officers were instructed. The mean duration of diabetes was 10.4 years. Mean HbA1c level was 8.7%, and 48% of patients had HbA1c >8%. All patients with HbA1c >7% had diabetes therapy intensified. Overall 80% had their diabetes therapy changed by discharge. Compared with 98 historical control subjects, significantly fewer study patients had episodes of hyperglycemia, and a subgroup followed for 12 months showed a decrease in HbA1c from 10.1 to 8%.” (D. Baldwin, Rush U. Med. Ctr, Chicago; david_baldwin@rush.edu)

Cholesterol Challenges: About one fourth of patients with diabetes will require three or more medications to reach LDL cholesterol goals of 70 mg/dL, based on interviews of ambulatory patients (pp. 1029-34). “Of the entire cohort, 49.4% (321 of 650) had LDL <100 mg/dl,” write the authors. “According to the National Cholesterol Education Program, 29.4% (191 of 650) of patients were very high risk and have an optional LDL goal of <70 mg/dl. Only 15.7% (30 of 191) of very-high-risk patients had an LDL <70 mg/dl. Based on our analysis of high-risk patients, 17 of 459 (3.7%) would require more than two lipid-lowering drugs to achieve an LDL <100 mg/dl. In the very-high-risk group, we estimate that 26.2% (50 of 191) of patients will not reach LDL <70 mg/dl with two lipid-lowering medications.” (A. G. Kennedy, U. Vermont, Burlington; amanda.kennedy@vtmednet.org)

Exenatide Effectiveness: Two articles describe clinical studies of exenatide, an Amylin agent for which an FDA approval decision is due today.

In two 30-week trials of the incretin mimetic, significant reductions in A1C were achieved among patients with type 2 diabetes whose glycemic control was inadequate with metformin and for some patients sulfonylurea (pp. 1083-91, 1092-100). Changes from baseline A1C, percentage of patients with A1C levels of 7% or less, and weight loss were significantly improved among exenatide-treated patients, compared with placebo. Referring to the two tested doses of the drug, the authors add, “Exenatide-treated subjects displayed progressive dose-dependent weight loss (–2.8 ± 0.5 kg [10 µg], –1.6 ± 0.4 kg [5 µg]; P < 0.001 vs. placebo).

Nausea of mild or moderate severity was the most common adverse effect of exenatide. Hypoglycemia was less of a problem among patients who minimized their sulfonylurea doses while taking the drug. (A. D. Baron, abaron@amylin.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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 2, 2005 Vol. 12, No. 84
Providing news and information about medications and their proper use

>>>FDA Approves Exenatide For Type 2 Diabetes
FDA on Friday approved the application of Amylin Pharmaceuticals and Lilly to market exenatide (Byetta) as adjunctive therapy to improve blood glucose control in patients with type 2 diabetes who have not achieved adequate control on metformin and/or a sulfonylurea. The approval, which follows a March nod by FDA for Amylin’s first-ever approved product, pramlintide acetate (Symlin; see PNN, Mar. 18), provides a second injectable agent with indications for adjunctive treatment of type 2 diabetes between the first-line use of oral agents and the addition of insulin to regimens.

Amylin and Lilly noted in a news release that FDA has stated that exenatide, an incretin mimetic that has actions like those of glucagon-like peptide-1, is “approvable” for monotherapy of type 2 diabetes. Once new data are submitted to support this indication, FDA is expected to rule within 6 months.

Incretin mimetics work to mimic the glucose-lowering actions of human incretins. These actions include stimulating the body's ability to produce insulin in response to elevated levels of blood glucose, inhibiting the release of glucagon following meals, slowing the rate at which nutrients are absorbed into the bloodstream, and reducing food intake.

Exenatide is formulated in fixed-dose prefilled pen-injector devices suitable for self-administration of either 5 or 10 mcg before morning and evening meals. In three 30-week trials (two of which were described in Friday’s PNN), the most frequently reported adverse event was mild-to-moderate, dose-dependent nausea. With continued therapy in most patients who initially experienced nausea, the frequency and severity decreased over time. Exenatide in combination with a sulfonylurea produces an increased risk of hypoglycemia; to reduce this risk, reduction in the dose of the sulfonylurea should be considered.

Patients should be advised that treatment with exenatide may result in a reduction in appetite, food intake, and/or body weight but that no modification of the dosing regimen is needed if these occur.

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

Vitamin D/Calcium Supplementation: For elderly patients who were mobile at the time of a bone fracture, use of vitamin D3 and calcium failed to prevent subsequent fractures, according to results of a study of conducted at 21 U.K. hospitals. “698 (13%) of 5292 participants had a new low-trauma fracture, 183 (26%) of which were of the hip,” write the investigators. “The incidence of new, low-trauma fractures did not differ significantly between participants allocated calcium and those who were not (331 [12.6%] of 2617 vs 367 [13.7%] of 2675; hazard ratio (HR) 0.94 [95% CI 0.81–1.09]); between participants allocated vitamin D3 and those who were not (353 [13.3%] of 2649 vs 345 [13.1%] of 2643; 1.02 [0.88–1.19]); or between those allocated combination treatment and those assigned placebo (165 [12.6%] of 1306 vs 179 [13.4%] of 1332; HR for interaction term 1·01 [0.75–1.36]). The groups did not differ in the incidence of all-new fractures, fractures confirmed by radiography, hip fractures, death, number of falls, or quality of life. By 24 months, 2886 (54.5%) of 5292 were still taking tablets, 451 (8.5%) had died, 58 (1.1%) had withdrawn, and 1897 (35.8%) had stopped taking tablets but were still providing data for at least the main outcomes. Compliance with tablets containing calcium was significantly lower (difference: 9.4% [95% CI 6.6–12.2]), partly because of gastrointestinal symptoms. However, potentially serious adverse events were rare and did not differ between groups.” (RECORD Trial Group, A. M. Grant, U. Aberdeen, Aberdeen, U.K.; a.grant@abdn.ac.uk)

>>>PNN JournalWatch
* Continuous Glucose Monitoring: Roadmap for 21st Century Diabetes Therapy, in Diabetes Care, 2005; 28: 1231–9. Reprints: care.diabetesjournals.org; D. C. Klonoff.

* Endometrial Cancer and Hormone-Replacement Therapy in the Million Women Study, in
Lancet, 2005; 365: 1543–51. Reprints: www.thelancet.com; secretariat@millionwomenstudy.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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 3, 2005 Vol. 12, No. 85
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
May 3 issue of the Annals of Internal Medicine (www.annals.org; 2005; 142).

Alendronate & Osteopenia: Alendronate therapy in postmenopausal women with osteopenia is not cost-effective, conclude authors of a Markov-model analysis of eight health states (pp. 734-41). Taking the societal perspective, the authors compared 5 years of alendronate therapy with no drug treatment: “Alendronate therapy is not cost-effective for white, early postmenopausal women who have not had a fracture and do not have additional risks strongly predictive of fracture independent of BMD, assuming current estimates of alendronate costs in the United States and efficacy in this population and a societal willingness to pay of $50,000 per QALY gained. This conclusion should be reconsidered, however, if the cost of drug therapy is significantly lowered, if drug therapy is shown to reduce the risk for nonvertebral fractures in this population, or if fracture reduction benefit persists longer than 10 years after a 5-year treatment course.” (J. T. Schousboe, Park Nicollet Clinic, Minneapolis; schouj@parknicollet.com)

An editorialist argues that treating patients based on overall fracture risks is preferable to relying on labels such as “osteopenia” or treating T-scores (pp. 796-7): “The diagnostic category of osteopenia in individual patients does not serve the clinical community well. It is time to abandon the diagnosis of osteopenia based on BMD values and give the term back to radiologists to describe decreased bone mineralization on radiographs. Bone density measurement remains an important tool in assessing skeletal health, but the determinants of fracture are much more complex and interesting than simply the T-score. The objective of using osteoporosis drugs is to prevent fractures. This can be accomplished only by treating patients who are likely to have a fracture, not by simply treating T-scores.” (M. R. McClung, Oregon Osteoporosis Center, Portland; mmcclung@orost.com)

Barriers to Ultrasafe Health Care: “Five successive systemic barriers currently prevent health care from becoming an ultrasafe industrial system,” write authors who seek to compare the status quo with industries such as the airlines (pp. 765-64): the need to limit the discretion of workers, the need to reduce worker autonomy, the need to make the transition from a craftsmanship mindset to that of equivalent actors, the need for system-level (senior leadership) arbitration to optimize safety strategies, and the need for simplification. The writers add, “Health care must overcome 3 unique problems: a wide range of risk among medical specialties, difficulty in defining medical error, and various structural constraints (such as public demand, teaching role, and chronic shortage of staff.” (P. Barach, pbarach@med.miami.edu)

Exercise for Low Back Pain: Supervised exercise programs have the potential for improving pain and function in patients with chronic nonspecific low back pain, according to a systematic review of 43 trials (pp. 776-85). “Bayesian multivariable random-effects meta-regression found improved pain scores for individually designed programs (5.4 points [95% credible interval (CrI), 1.3 to 9.5 points]), supervised home exercise (6.1 points [CrI, –0.2 to 12.4 points]), group (4.8 points [CrI, 0.2 to 9.4 points]), and individually supervised programs (5.9 points [CrI, 2.1 to 9.8 points]) compared with home exercises only. High-dose exercise programs fared better than low-dose exercise programs (1.8 points [CrI, –2.1 to 5.5 points]). Interventions that included additional conservative care were better (5.1 points [CrI, 1.8 to 8.4 points]). A model including these most effective intervention characteristics would be expected to demonstrate important improvement in pain (18.1 points [CrI, 11.1 to 25.0 points] compared with no treatment and 13.0 points [CrI, 6.0 to 19.9 points] compared with other conservative treatment) and small improvement in function (5.5 points [CrI, 0.5 to 10.5 points] compared with no treatment and 2.7 points [CrI, –1.7 to 7.1 points] compared with other conservative treatment). Stretching and strengthening demonstrated the largest improvement over comparisons.” (J. A. Hayden, Inst. for Work & Health, Toronto; jhayden@iwh.on.ca)

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

PNN Pharmacotherapy Line
May 4, 2005 Vol. 12, No. 86
Providing news and information about medications and their proper use

>>>Pertussis Vaccine for Adolescents Approved
A combination vaccine that provides protection against pertussis is now available for America’s teens, thanks to yesterday’s approval of Boostrix (GlaxoSmithKline) by FDA. The product also induces immunity against tetanus and diphtheria, conditions that were covered by previously available products.

Because pertussis in adolescents is generally less severe than in younger patients, teenagers have not been vaccinated against the
Bordetella pathogen. However, over the past 20 years, rates of pertussis have been increasing among very young infants—who have not received all of their shots and in whom the disease is serious—and in adolescents and adults. Experts believe that adolescents may be passing the organism to younger siblings, a problem that will be addressed by use of Boostrix in teenage patients.

Boostrix is a Tetanus Toxoid (T), Reduced Diphtheria Toxoid (d), and Acellular Pertussis Vaccine (ap), Adsorbed. It contains reduced quantities of the same components as Infanrix, indicated for infants and young children. Boostrix is licensed for use as a single booster dose to adolescents 10–18 years of age.

In clinical trials, Boostrix produced more pain reactions at the site of injection than did Td vaccines. The frequency of redness and swelling after Boostrix was similar to what is expected following the administration of a Td vaccine. Other adverse effects included headaches, fever, and fatigue for a short period of time after the injection.

>>>JAMA Highlights
Source:
May 4 issue of JAMA (www.jama.com; 2005; 293).

ADEs on RADAR: The Research on Adverse Drug events And Reports (RADAR) project—a clinically based, hypothesis-driven approach to postmarketing surveillance—shows promise for identifying some of the many adverse drug events that are recognized after a drug reaches the U.S. market, according to an article that describes the first 6 years of the project’s operations (pp. 2131-40). “RADAR investigators identified 16 types of serious ADRs among 1699 patients, of whom 169 (10%) died as a result of the reaction,” the authors note. “Initial cases were identified by 7 RADAR investigators, 4 collaborating physicians, 2 attorneys, and by reviewing 3 published reports. Additional sources included queries of occupational health programs and medical directors of interventional cardiology laboratories (3 types of ADRs), published manuscripts and clinical trials (11 types of ADRs), review of medical records at a RADAR site (2 types of ADRs), unpublished clinical trial reports (3 types of ADRs), and reports from attorneys, family members, or patients (4 types of ADRs). Incidence estimates, ranging from 0.4% to 33%, were derived from 5 clinical trial reports, 2 physician queries, and 2 observational databases. Laboratory support for hypotheses included identification of 3 neutralizing antibodies and 3 histopathological findings. ADR reports were disseminated as 8 revised package inserts, 7 ‘dear doctor’ letters, and 9 peer-reviewed articles.” (C. L. Bennett, cbenne@northwestern.edu)

Tirofiban-Supported Drug-Eluting Stent Therapy: Use of tirofiban to support sirolimus-eluting stenting of infarcted arteries during primary intervention in patients with myocardial infarction improved outcomes while limiting costs (pp. 2109-17). “Cumulatively, 14 of 74 patients (19%; 95% confidence interval [CI], 10%–28%) in the tirofiban plus sirolimus-eluting stent group and 37 of 74 patients (50%; 95% CI, 44%–56%) in the abciximab plus bare-metal stent group reached the primary end point (hazard ratio, 0.33; 95% CI, 0.18–0.60; P<.001 [P<.001 by Fischer exact test]),” the authors wrote. “The cumulative incidence of death, reinfarction, stroke, or [target-vessel revascularization] was significantly lower in the tirofiban plus sirolimus-eluting stent group (18%) vs the abciximab plus bare-metal stent group (32%) (hazard ratio, 0.53; 95% CI, 0.28–0.92; P = .04), predominantly reflecting a reduction in the need for TVR. Binary restenosis was present in 6 of 67 (9%; 95% CI, 2%–16%) and 24– 66 (36%; 95% CI, 26%–46%) patients in the tirofiban plus sirolimus-eluting stent and abciximab plus bare-metal stent groups, respectively (P = .002).” (M. Valgimigli, U. Ferrara, Ferrara, Italy; vlgmrc@unife.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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 5, 2005 Vol. 12, No. 87
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
May 5 issue of the New England Journal of Medicine (content.nejm.org; 2005; 352).

Pharmacologic Cardioversion of AF: Amiodarone and sotalol proved equally efficacious for converting atrial fibrillation to sinus rhythm in a placebo-controlled trial of 665 patients, but amiodarone was more effective in maintaining the new rhythm (pp. 1861-72). Study participants, all of whom had persistent AF and were receiving anticoagulants, were monitored for recurrence of AF beginning 28 days after conversion using weekly transtelephonic monitoring. During 1 to 4.5 years of follow-up, the investigators found, “Spontaneous conversion occurred in 27.1 percent of the amiodarone group, 24.2 percent of the sotalol group, and 0.8 percent of the placebo group, and direct-current cardioversion failed in 27.7 percent, 26.5 percent, and 32.1 percent, respectively. The median times to a recurrence of atrial fibrillation were 487 days in the amiodarone group, 74 days in the sotalol group, and 6 days in the placebo group according to intention to treat and 809, 209, and 13 days, respectively, according to treatment received. Amiodarone was superior to sotalol (P < 0.001) and to placebo (P < 0.001), and sotalol was superior to placebo (P < 0.001). In patients with ischemic heart disease, the median time to a recurrence of atrial fibrillation was 569 days with amiodarone therapy and 428 days with sotalol therapy (P = 0.53). Restoration and maintenance of sinus rhythm significantly improved the quality of life and exercise capacity. There were no significant differences in major adverse events among the three groups.”

Based on these data, the authors conclude, “Amiodarone and sotalol are equally efficacious in converting atrial fibrillation to sinus rhythm. Amiodarone is superior for maintaining sinus rhythm, but both drugs have similar efficacy in patients with ischemic heart disease. Sustained sinus rhythm is associated with an improved quality of life and improved exercise performance.” (B. N. Singh, bsingh@ucla.edu)

Detecting Acute HIV Infection During Screenings: Nucleic acid amplification is a useful addition to standard HIV testing techniques, allowing the detection of “highly contagious, acutely infected persons,” report researchers who analyzed data from North Carolina screenings (pp. 1873-83). “Between November 1, 2002, and October 31, 2003, 109,250 persons at risk for HIV infection who had consented to HIV testing presented at state-funded sites. There were 606 HIV-positive results. Established infection, as identified by standard enzyme immunoassay or Western blot analysis, appeared in 583 participants; of these, 107 were identified, with the use of sensitive–less-sensitive enzyme immunoassay tests, as recent infections. A total of 23 acutely infected persons were identified only with the use of the nucleic acid amplification algorithm. With all detectable infections taken into account, the sensitivity of standard antibody testing was 0.962 (95 percent confidence interval, 0.944 to 0.976). There were two false positive results on nucleic acid amplification tests. The specificity and positive predictive value of the algorithm that included nucleic acid amplification testing were greater than 0.999 (95 percent confidence interval, 0.999 to >0.999) and 0.997 (95 percent confidence interval, 0.988 to >0.999), respectively. Of the 23 acute HIV infections, 16 were detected at sexually transmitted disease clinics. Emergency measures for HIV prevention protected 48 sex partners and one fetus from high-risk exposure to HIV.” (C. D. Pilcher, cpilcher@med.unc.edu)

Treating Low Back Pain: A regimen of pharmacologic treatment, rehabilitation, and exercise should be used to treat patients with persistent low back pain, according to a case vignette and discussion (pp. 1891-8). Referring to the patient presented in the case, the author writes, “I would prescribe an agent such as amitriptyline, starting at 25 to 50 mg at bedtime, and increasing the dosage as needed. If the patient has a strong preference for certain additional short-term treatments, such as spinal manipulation or massage, it is reasonable to accommodate him, especially since evidence supports better outcomes for patients who feel confident about the treatment prescribed.” (E. J. Carragee, carragee@stanford.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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 6, 2005 Vol. 12, No. 88
Providing news and information about medications and their proper use

>>>Pharmacotherapy Update
Source:
May issue of Pharmacotherapy (www.pharmacotherapy.org; 2005; 25).

Antithrombotic Effects of Antidiabetic Drugs: Metformin in combination with a sulfonylurea or thiazolidinedione improves the hypercoagulability associated with type 2 diabetes and the metabolic syndrome, conclude authors of a 95-patient study (pp. 637-45). Metformin was administered in doses of 1,500 mg/day to all patients, and participants were randomized to receive glimepiride 2 mg/day or rosiglitazone 4 mg/day during the 12-month study. “Compared with baseline values, significant decreases in BMI, fasting plasma glucose, postprandial plasma glucose, and hemoglobin A1c were observed at 12 months in both the glimepiride and rosiglitazone groups (p < 0.05 and p < 0.01, respectively),” report the researchers. “Decreases in fasting plasma insulin and postprandial plasma insulin were observed at 12 months (p < 0.05 and p < 0.01, respectively) compared with baseline values in the rosiglitazone group. Furthermore, improvement in the Homeostasis Model Assessment index was observed only at 9 and 12 months (p < 0.05 and p < 0.01, respectively) compared with baseline in the rosiglitazone group. Significant improvement in plasminogen activator inhibitor (PAI)-1 was present in the rosiglitazone group after 9 months (p < 0.05), and significant PAI-1 improvement was observed in the glimepiride and rosiglitazone groups after 12 months (p < 0.05 and p < 0.01, respectively).“ (G. Derosa, U. Pavia, Pavia, Italy; giuderosa@tin.it)

Cardiac Effects of Ephedra-Free Weight-Loss Product: In 20 healthy volunteers, Metabolife Ephedra Free did not affect QTc intervals or other electrocardiographic parameters when given at one half the recommended serving (pp. 654-9). In this placebo-controlled crossover study, investigators found no ECG changes over a 5-hour period following supplement administration. (C. M. White, Hartford Hosp., Hartford, Conn.; cmwhite@harthosp.org)

Persistence Rates with SSRIs: In a Pfizer-sponsored study, persistence rates were significantly higher and switching rates lower with sertraline and citalopram than with paroxetine (pp. 660-7). Retrospective cohort analysis of a managed care database containing records of 14,933 patients with depression, posttraumatic stress disorder, or social anxiety disorder showed: “Compared with patients receiving sertraline and citalopram, those receiving paroxetine had lower rates of persistence (23.79% vs 25.96% for sertraline [p = 0.0093] and 26.56% for citalopram [p = 0.0022]) and higher rates of switching (3.55% vs 3.32% for sertraline [p = 0.5076] and 2.78% for citalopram [p = 0.0359]) and discontinuation (72.66% vs 70.72% for sertraline [p = 0.0258] and 70.66% for citalopram [p = 0.0334]). Survival curves showed that persistence rates with sertraline and citalopram were significantly greater than with paroxetine (p < 0.05, log-rank and Wilcoxon tests). Age was an independent predictor of persistence; male sex and copayment were not. The comparisons across SSRIs were robust in the sensitivity analysis that varied the time to refill allowed.” (C. D. Mullins, dmullins@rx.umaryland.edu)

Pharmacist-Managed Anticoagulation: Frequency of adverse events and risk of hospitalization were decreased when a pharmacist-managed anticoagulation service provided care in a 300-bed community hospital (pp. 685-9). Describing the outcomes of 420 patients referred for anticoagulation management before and after discontinuation of a pharmacist-managed service, the authors note, “The total numbers of adverse events requiring hospitalization were three for the pharmacist-managed group and 14 for the usual care group (p = 0.0153). The number of patients experiencing an adverse event requiring hospitalization was also lower for the pharmacist-managed group than for the usual care group (3 vs 10, p = 0.0962). The median length of hospital stay associated with each adverse event was not significantly different between the two groups; however, the total number of hospital days accrued was higher in the usual care group.” (S. Ravnan, U. Pacific, Stockton, Calif.)

PNN Pharmacotherapy Line is published via e-mail each business day except 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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 9, 2005 Vol. 12, No. 89
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
May 7 issue of BMJ (www.bmj.org; 2005; 330).

Polypills for Ischemic Heart Disease: Dosage forms that combine statins, aspirin, and beta-blockers could improve survival among high-risk cardiovascular patients, conclude authors who studied outcomes among patients with a first diagnosis of ischemic disease in 1996 through 2003 who were treated with various medication combinations (pp. 1059-63). “13,029 patients had a first diagnosis of ischaemic heart disease (incidence rate 338 per 100 000 person years),” the authors note. “2266 cases were matched to 9064 controls. Drug combinations associated with the greatest reduction in all cause mortality were statins, aspirin, and beta blockers (83% reduction, 95% confidence interval 77% to 88%); statins, aspirin, beta blockers, and angiotensin converting enzyme inhibitors (75% reduction, 65% to 82%); and statins, aspirin, and angiotensin converting enzyme inhibitors (71% reduction, 59% to 79%). Treatments associated with the smallest reduction in all cause mortality were beta blockers alone (19% reduction, 37% reduction to 4% increase), angiotensin converting enzyme inhibitors alone (20% reduction, 1% to 35%), and combined statins and angiotensin converting enzyme inhibitors (31% reduction, 57% reduction to 12% increase).” (J Hippisley-Cox, School of Community Health Sciences, University Park, Nottingham, U.K.; julia.hippisley-cox@nottingham.ac.uk)

Commenting on feasibility of developing a “polypill” combining several medications, editorialists write (pp. 1035-6), “The underlying tenet of the polypill—that combination therapy is better than monotherapy—may well be correct, particularly with regard to secondary prevention of cardiovascular disease. Hippisley-Cox and Coupland's paper goes some way in providing data concerning the effects of combined treatment in secondary prevention of coronary heart disease. In terms of primary prevention, development and testing of combination pills aimed at reducing more than one risk factor seems entirely logical, particularly in the context of assessment of global cardiovascular risk. Funding bodies and the [National Health Service] need to support the necessary trials and cost effectiveness studies to further examine the polypill strategy in comparison with non-pharmacological alternatives.” (T. Fahey, U. Dundee, Dundee, U.K.)

>>>Lancet Report
Source:
May 7 issue of Lancet (www.thelancet.com; 2005; 365).

Managing Smoking Cessation: The pulmonary benefits of stopping smoking are oftentimes offset by the detrimental effects of resulting weight gain, according to an analysis of 6,654 participants at 27 centers (pp. 1629-35). Investigators gathered data on forced expiratory volume in 1 second, smoking patterns, and weight gain. They report, “Compared with those who had never smoked, decline in FEV1 was lower in male sustained quitters (mean difference 5.4 mL per year, 95% CI 1.7 to 9.1) and those who quit between surveys (2.5 mL, –1.9 to 7.0), and greater in smokers (–4.8 mL, –7.9 to –1.6). In women, estimates were 1.3 mL per year (–1.5 to 4.1), 2.8 mL (–0.8 to 6.3) and –5.1 mL (–7.5 to –2.8), respectively. These sex differences were not significant. FEV1 changed by –11.5 mL (–13.3 to –9.6) per kg weight gained in men, and by –3.7 mL per kg (–5.0 to –2.5) in women, which diminished the benefit of quitting by 38% in men, and by 17% in women.” (S. Chinn, King’s College, London; sue.chinn@kcl.ac.uk)

>>>PNN JournalWatch
* Psoriasis, in New England Journal of Medicine, 2005; 352: 1899–912. Reprints: content.nejm.org; M. P. Schön, Julius Maximilians U., Würzburg, Germany; michael.schoen@virchow.uni-wuerzburg.de

* The Medicare Prescription Drug, Improvement, and Modernization Act of 2003, in
Journal of the American Geriatrics Society, 2005; 52: 1013 ff. Reprints: www.blackwell-synergy.com; S. Emmer, Emmer Consulting, Bethesda, Md.; emmerconsulting@verizon.net

* Use of Highly Active Antiretroviral Therapy in Patients with Renal Insufficiency, in
Pharmacotherapy, 2005; 25: 698–708. Reprints: www.pharmacotherapy.org; J. M. Duggan, Medical College of Ohio, Toledo; jduggan@mco.edu.

* Cinacalcet: A New Treatment for Secondary Hyperparathyroidism in Patients Receiving Hemodialysis, in
Pharmacotherapy, 2005; 25: 709–16. Reprints: www.pharmacotherapy.org; B. M. Shepler, bshepler@pharmacy.purdue.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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 10, 2005 Vol. 12, No. 90
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
May 9 issue of Archives of Internal Medicine (www.archinternmed.com; 2005; 165).

NSAIDs & MIs: The cardiovascular safety of all nonaspirin NSAIDS should be investigated, conclude authors of a study showing a significantly increased risk of myocardial infarction with rofecoxib and near-significant elevations in the MI risk with naproxen and celecoxib (pp. 978-84). In a population-based case–control study, investigators analyzed hospital discharge records from three counties in Denmark and from the Danish Civil Registration System. Comparing 10,280 cases of first-time hospitalization for MI with 102,797 matched controls without MI, the authors found, “Current users of rofecoxib had an elevated risk estimate for hospitalization for MI compared with nonusers of any category of nonaspirin NSAIDs (adjusted relative risk [ARR], 1.80; 95% confidence interval [CI], 1.47–2.21). Increased risk estimates were also found among current users of celecoxib (ARR, 1.25; 95% CI, 0.97–1.62), other cyclooxygenase-2 selective inhibitors (ARR, 1.45; 95% CI, 1.09–1.93), naproxen (ARR, 1.50; 95% CI, 0.99–2.29), and other conventional nonaspirin NSAIDs (ARR, 1.68; 95% CI, 1.52–1.85). The highest ARRs were found among new users of all examined drug categories.” (S. P. Johnsen, Aarhus U. Hosp., Aarhus, Denmark; spj@dce.au.dk)

Unnecessary Use of COX-2 Inhibitors: During the last half of 2003, most American adults taking COX-2 inhibitors had no history of gastrointestinal bleeding that would make therapy with these drugs necessary, according to an analysis of data from the Slone Survey (pp. 1066-7). “A total of 219 (19%) of the 1,143 subjects reported a history of at least 1 of the gastrointestinal factors and were considered to have an elevated risk of gastrointestinal complications,” the researchers explain. “The prevalence of COX-2 inhibitor use, adjusted for household size and standardized to the age distribution of the survey population, was 9% in the high-risk subjects and 5.7% in the remainder. Of the 80 users, 57 (71%) were in the low-risk category. The pattern was similar for each individual COX-2 drug.” (D. W. Kaufman, Slone Epidemiology Center, Boston U., Boston; dkaufman@slone.bu.edu)

Brief Alcohol Intervention: A brief alcohol intervention reduces alcohol consumption 6 and 12 months later, conclude authors who conducted a systematic review and meta-analysis of 19 trials of 5,629 individuals (pp. 986-95). Selected studies were those conducted in outpatients who were seeking care for conditions other than alcohol dependence at primary health care centers or providers. Brief alcohol interventions included those that were individually delivered in a face-to-face session and were defined in the reports as “brief” or “motivational” in nature. “Seventeen trials reported a measure of alcohol consumption, of which 8 reported a significant effect of intervention,” the authors note. “The adjusted intention-to-treat analysis showed a mean pooled difference of –38 g of ethanol (approximately 4 drinks) per week (95% confidence interval, –51 to –24g/wk) in favor of the brief alcohol intervention group. Evidence of other outcome measures was inconclusive.” (B. Burnand, U. Hosp., Lausanne, Switzerland; Bernard.Burnand@chuv.ch)

>>>PNN NewsWatch
* The Tag-It Cystic Fibrosis Kit, approved yesterday by FDA, is the first DNA-based test available for detection of cystic fibrosis. The Tag-It test, manufactured by the manufactured by Tm Bioscience Corporation of Toronto, identifies a group of variations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. FDA approved Tag-It based on a manufacturer study of hundreds of DNA samples showing that the test identifies the CFTR gene variations with a high degree of certainty. However, since Tag-It detects a limited number of the more than 1,300 genetic variations identified in the CFTR gene, the test should not be used alone to diagnose cystic fibrosis. Physicians should interpret test results in the context of the patient’s clinical condition, ethnicity, and family history. Also, patients may need genetic counseling to help them understand their test results.

PNN Pharmacotherapy Line is published via e-mail each business day except 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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 11, 2005 Vol. 12, No. 91
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
May 11 issue of JAMA (www.jama.com; 2005; 293).

Pediatric HIV Infections: Two articles and an editorial explore various aspects of therapy for HIV infections in pediatric patients.

The lag time was short between identification of novel antiretroviral treatments and their adoption in the U.S., report authors who also note use of “some unorthodox therapies” (pp. 2213-20). Assessing initial regimens over the 1987–2003 time frame in 766 perinatally HIV-infected children and comparing those with recommendations for treatment, the authors found, “Single and dual [nucleoside reverse transcriptase inhibitor] regimens were used most frequently through 1997. In 1998, 2 years after protease inhibitors were approved for adult HIV infection and at the time pediatric guidelines were issued, regimens of highly active antiretroviral therapy including a protease inhibitor became most frequently used. From 1998–2003, 22% of children initiated ART with a regimen not recommended by pediatric guidelines. In multivariate regression, the risk of switching decreased with age at ART initiation (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.94–0.99) and increased with year of initiation (HR, 1.28; 95% CI, 1.23–1.33). The risk of switching was higher in children who started with 1 NRTI (HR, 8.05; 95% CI, 5.80–11.18), 2 NRTIs (HR, 4.08; 95% CI, 3.08–5.40), or an unconventional regimen (HR, 6.23; 95% CI, 3.36–11.54) vs children who started with a protease inhibitor–containing regimen; and in children who initiated ART at CD4 T lymphocyte percentages less than 15 vs 15 or greater (HR, 2.90; 95% CI, 1.03–8.13).” (S. Brogly, sbrogly@sdac.harvard.edu)

Very early treatment of HIV—even when it does not involve triple ART—can decrease early HIV progression and improve survival at 3 years of age, according to a retrospective study of HIV-infected children born between 1988 and 2001 (pp. 2221-31). “Of 205 children, 134 (65%) received ART and/or
Pneumocystis jiroveci pneumonia prophylaxis,” the researchers report. “By age 3 years, 81 (40%) progressed to a category C diagnosis, 41 (51%) of whom died. Untreated children were significantly more likely to progress to a category C diagnosis (62% [44/71] untreated vs 28% [37/134] treated children, P < .001); none of 23 infants who received triple ART progressed to category C. However, even without triple ART, very early mono/dual ART (by age 2 months vs 3–4 months) was associated with delayed and decreased progression to category C (P = .02). Of 33 children born between January 1, 1996, and December 31, 2001, only 7 (21%) progressed to category C (P = .02 compared with 1988–1995), 6 of 7 of whom received no therapy. More recent year of birth and more advanced therapy were associated with improved survival.” (Y. A. Maldonado, bonniem@stanford.edu)

An editorialist seeks to balance the upside and downside of highly active ART (pp. 2272-4): “While it is possible to celebrate the tremendous change in the outcomes of HIV-infected children treated with HAART, it is even more important to continue to prioritize research for the survivors who are now living with a chronic disease. The notion that the problem of HIV in children has been resolved is false—indeed, 15,000 to 20,000 perinatally-infected children and adolescents still need answers to problems such as salvage therapy, long-term complications from the disease or from ART, neurodevelopmental complications, and the ongoing need for new and simplified treatments. It would be a mistake to reduce funding for clinical research on HIV-infected children living in the United States, because such research might not only help these children but also contribute to the care of HIV-infected children worldwide who are starting to benefit from ART and who, in the near future, undoubtedly will develop the same problems that US children are now experiencing.” (R. Yogey, Children’s Memorial Hosp., Chicago; ryogev@childrensmemorial.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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 12, 2005 Vol. 12, No. 92
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
May 12 issue of the New England Journal of Medicine (content.nejm.org; 2005; 352).

COPD Pathophysiology: Progressive reductions in total histone deacetylase activity in lung tissue is significantly associated with the presence and severity of chronic obstructive pulmonary disease, according to a comparison of samples from normal patients and those with COPD, pneumonia, or cystic fibrosis (pp. 1967-76). “Specimens of lung tissue obtained from patients with increasing clinical stages of COPD had graded reductions in HDAC activity and increases in interleukin-8 messenger RNA (mRNA) and histone-4 acetylation at the interleukin-8 promoter,” the authors write. “The mRNA expression of HDAC2, HDAC5, and HDAC8 and expression of the HDAC2 protein were also lower in patients with increasing severity of disease. HDAC activity was decreased in patients with COPD, as compared with normal subjects, in both the macrophages and biopsy specimens, with no changes in HAT activity, whereas HAT activity was increased in biopsy specimens obtained from patients with asthma. Neither HAT activity nor HDAC activity was changed in lung tissue from patients with cystic fibrosis or pneumonia.” (P. J. Barnes, Imperial College, London; p.j.barnes@imperial.ac.uk)

These data could portend a resurrection of theophylline for treatment of COPD, writes an editorialist (pp. 2016-9): “COPD is now epidemic worldwide, and we have few effective therapies to offer patients as they slowly suffocate. But the HDAC theory may be more than molecular medicine for its own sake. A potential practical implication of the theory derives from the observation that low-dose theophylline markedly induces HDAC transcription. If true, then the combination of corticosteroids and theophylline should restore delivery of HDAC to the nucleus and disarm inflammation in COPD. I look forward to a future study showing that the combination of these two well-known drugs inhibits disease progression in patients with COPD.” (S. D. Shapiro, Harvard Med. Sch., Boston)

>>>Neurology Highlights
Source:
May 10 issue of Neurology (www.neurology.org; 2005; 64).

AD Treatment Decisions: Patients with even mild symptoms of Alzheimer’s disease frequently lack the awareness of their condition that would enable them to participate in decisions to begin treatments, conclude authors who conducted interviews with 48 patients and 102 family caregivers (pp. 1514-9). Recruiting participants from a clinic in an AD center, study researchers made these observations about their in-home interviews: “There was considerable variation in patients’ performance on the measures of decision-making abilities. Three expert raters found 19 of 48 (40%) of the subjects competent. Competent patients were more likely to show awareness of their symptoms, prognosis, and diagnosis. A sensitivity analysis suggests that a MMSE score is helpful in discriminating capacity from incapacity only when below 19 or above 23.” The group concludes, “Persons with mild to moderate Alzheimer disease (AD) have notable impairments in their ability to make an AD treatment decision, especially persons with moderate AD and persons who lack awareness of symptoms, prognosis, or diagnosis.” (J. H. T. Karlawish, jasonkar@mail.med.upenn.edu)

Lipid-Lowering Treatments & Dementia: Lowering serum lipids is an effective means of reducing one’s risk of non-Alzheimer’s dementia, according to results of an observational study of 9,294 subjects in three French cities (pp.1531-8 ).The authors note: “Overall 32.4% of participants had hyperlipidemia, and 15.6% were prescribed statins and 13.7% fibrates. After adjusting for age, gender, education level, and study center, the odds ratio (OR) for dementia was observed to be lower among LLA users (OR = 0.61, 95% CI = 0.41 to 0.91) compared with subjects taking no LLAs. There was no differential effect between statin and fibrate users. The odds for dementia were increased in subjects with hyperlipidemia (OR = 1.43, 95% CI = 1.03 to 1.99).” (C. Dufouil, Hopital La Salpêtrière, Paris; carole.dufouil@chups.jussieu.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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 13, 2005 Vol. 12, No. 93
Providing news and information about medications and their proper use

>>>Pediatrics Highlights
Source:
May issue of Pediatrics (www.pediatrics.org; 2005; 115).

Cost-Effectiveness of Conjugate Meningococcal Vaccination: Societal costs for routine use of the recently approved meningococcal conjugate A/C/Y/W-135 vaccine will be relatively high given the present cost of the product and the prevalence of meningococcal cases in the U.S., according to a cost-effectiveness study (pp. 1220-32). Comparing hypothetical routine vaccination of adolescents (1 dose at 11 years), toddlers (1 dose at 1 year), and infants (3 doses at 2, 4, and 6 months) with no vaccination, the group found, “Routine MCV-4 vaccination of US adolescents (11 years of age) would prevent 270 meningococcal cases and 36 deaths in the vaccinated cohort over 22 years, a decrease of 46% in the expected burden of disease. Before program costs are counted, adolescent vaccination would reduce direct disease costs by $18 million and decrease productivity losses by $50 million. At a cost per vaccination (average public-private price per dose plus administration fees) of $82.50, adolescent vaccination would cost society $633,000 per meningococcal case prevented and $121,000 per life-year saved. Key variables influencing results were disease incidence, case-fatality ratio, and cost per vaccination. The cost-effectiveness of toddler vaccination is essentially equivalent to adolescent vaccination, whereas infant vaccination would be much less cost-effective.” (C. W. Shepard, CDC, Atlanta)

Flexible Insulin Therapy: A flexible multiple daily insulin regimen using premeal lispro plus bedtime glargine improved glycemic control in 35 preschool-age children with type 1 diabetes and decreased episodes of severe hypoglycemia (pp. 1320-4). Data from a 2-year period showed, “Although there was no significant change in BMI with FMDI therapy (17.1 ± 1.8 kg/m2 vs 17.0 ± 1.7 kg/m2), 43% of patients (6 female subjects and 9 male subjects) were overweight (BMI of >85th percentile for age) both before and after treatment. The total daily insulin requirement (0.67 ± 0.13 U/kg per day vs 0.78 ± 0.14 U/kg per day) and bolus/basal insulin ratio (1.1 ± 0.4 vs 1.9 ± 0.6) were significantly increased and overall glycemic control was improved after transition to FMDI therapy (HbA1c levels: 8.8 ± 0.9% vs 8.3 ± 0.8%). However, HbA1c levels improved only among normal-weight subjects (9.0 ± 1.0% vs 8.3 ± 1.0%) and not among overweight subjects (8.7 ± 0.7% vs 8.4 ± 0.6%) after FMDI therapy. The overall rate of severe hypoglycemia was significantly decreased with the FMDI regimen (25.5 events per 100 patient-years vs 10.6 events per 100 patient-years) but again only for normal-weight children (29.7 events per 100 patient-years vs 7.4 events per 100 patient-years).” (R. Alemzadeh, Med. Coll. of Wisconsin, Milwaukee)

Morphine in Neonates: Because of the possibility of hypotension, morphine must be used cautiously in preterm neonates born at 23- to 26-weeks’ gestation and in premies with preexisting hypotension, according to an analysis of data from the NEOPAIN trial(pp. 1351-9). “Hypotension was associated with 23 to 26 weeks of gestation, morphine infusions, severity of illness, additional morphine doses, and prior hypotension,” the authors report of the 898 ventilated neonates included in the study. “Severe [intraventricular hemorrhage] was associated with shorter gestation, higher Clinical Risk Index for Babies scores, no prenatal steroids, pulmonary hemorrhage, hypotension before the loading dose, and morphine doses before intubation and at 25 to 72 hours. Neonatal deaths were associated with 23 to 26 weeks of gestation, higher Clinical Risk Index for Babies scores, pulmonary hemorrhage, patent ductus arteriosus, thrombocytopenia, and hypotension before the loading dose. Morphine infusions were not a significant factor in logistic models for severe IVH, any IVH, or death.” (R. W. Hall, Maryland Med. Res. Inst., Baltimore)

Fatty Acid Supplements for DCD: Fatty acid supplementation is a useful addition to educational and behavioral programs in children with developmental coordination disorder, note authors of a 117-patients trial (pp. 1360-6). Three months’ supplementation with omega-3 and omega-6 fatty acids improved reading, spelling, and behavior, compared with placebo. (A. J. Richardson, U. Oxford, Oxford)

PNN Pharmacotherapy Line is published via e-mail each business day except 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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 16, 2005 Vol. 12, No. 94
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
May 14 issue of Lancet (www.thelancet.com; 2005; 365).

Breast Cancer Treatments & 15-Year Survival: In an article that combines results from six meta-analyses, authors conclude that adjuvant drug treatments introduced in the 1980s have substantially reduced 15-year mortality rates among women with breast cancer (pp. 1687-717). Noting that the agents had previously been recognized as having more impact on 5-year recurrence rates than on 5-year mortality rates, the writers report, “For middle-aged women with [estrogen-receptor]–positive disease (the commonest type of breast cancer), the breast cancer mortality rate throughout the next 15 years would be approximately halved by 6 months of anthracycline-based chemotherapy (with a combination such as [fluorouracil, doxorubicin, cyclophosphamide] or [fluorouracil, epirubicin, cyclophosphamide]) followed by 5 years of adjuvant tamoxifen. For, if mortality reductions of 38% (age <50 years) and 20% (age 50–69 years) from such chemotherapy were followed by a further reduction of 31% from tamoxifen in the risks that remain, the final mortality reductions would be 57% and 45%, respectively (and, the trial results could well have been somewhat stronger if there had been full compliance with the allocated treatments). Overall survival would be comparably improved, since these treatments have relatively small effects on mortality from the aggregate of all other causes.” (Early Breast Cancer Trialists' Collaborative Group Secretariat, Radcliffe Infirmary, Oxford, U.K.; bc.overview@ctsu.ox.ac.uk)

>>>BMJ Highlights
Source:
May 14 issue of BMJ (www.bmj.org; 2005; 330).

MMR Vaccine & Crohn’s Disease: No increase in the occurrence of Crohn’s disease followed the introduction of a mumps–measles–rubella vaccination program in the U.K., according to an ecological analysis of national data on hospital admissions (pp. 1120-1). During the 12 years after MMR vaccine replaced a measles-only product, these age-specific trends in Crohn’s disease were observed: “There were 4,463 admissions for Crohn's disease, 923 of which occurred in populations with a vaccination rate of ≥84% (those born in 1988–9 or later). Although the age specific rates increased over the study period, no obvious changes occurred that coincided with the introduction of MMR vaccine.... The estimated rate ratio for the MMR vaccination programme (rates in populations with a vaccination rate of ≥84% compared with those with a rate of ≤7%) was 0.95 (95% confidence interval 0.84 to 1.08).” (V. Seagroatt, U. Oxford, Oxford, U.K.; valerie.seagroatt@dphpc.ox.ac.uk)

>>>PNN JournalWatch
* Antioxidant Supplementation for the Prevention of Kwashiorkor in Malawian Children: Randomised, Double Blind, Placebo Controlled Trial, in BMJ, 2005; 330: 1109 ff. Reprints: www.bmj.org; M. Manary, Baylor Coll. of Med., Houston; manary@kids.wustl.edu

* Patients' and Health Professionals' Views on Primary Care for People with Serious Mental Illness: Focus Group Study, in
BMJ, 2005; 330: 1122 ff. Reprints: www.bmj.org; H. E. Lester, U. Birmingham, Birmingham, U.K.; H.E.Lester@bham.ac.uk

* Meta-analysis of the Association of Beta-2-Adrenergic Receptor Polymorphisms with Asthma Phenotypes, in
Journal of Asthma and Clinical Immunology, 2005; 115: 963–72. Reprints: www2.us.elsevierhealth.com; J. P. A. Ioannidis, U. Ioannina, Ioannina, Greece; jioannid@cc.uoi.gr

* The Asthma and Obesity Epidemics: The Role Played by the Built Environment—A Public Health Perspective, in
Journal of Asthma and Clinical Immunology, 2005; 115: 1024–8. Reprints: www2.us.elsevierhealth.com; J. Plumb, james.plumb@jefferson.edu

* Diets and Cardiovascular Disease: An Evidence-Based Assessment, in
Journal of the American College of Cardiology, 2005; 45: 1379–87 Reprints: www.cardiosource.com; L. Sperling, The Emory Clinic, Atlanta.

* HIV Sexual Risk Behavior Over 36 Months of Follow-Up in the World's First HIV Vaccine Efficacy Trial, in
Journal of Acquired Immune Deficiency Syndromes, 2005; 39: 90–101. Reprints: www.jaids.com; B. N. Bartholow.

* Immunizations in the United States: Success, Structure, and Stress, in
Health Affairs, 2005; 24: 599–610. Reprints: www.healthaffairs.org; W. A. Orenstein.

* Why Are Pharmaceutical Companies Gradually Abandoning Vaccines?, in
Health Affairs, 2005; 24: 622–30. Reprints: www.healthaffairs.org; P. A. Offit.

PNN Pharmacotherapy Line is published via e-mail each business day except 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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 17, 2005 Vol. 12, No. 95
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
May 17 issue of the Annals of Internal Medicine (www.annals.org; 2005; 142).

Rifaximin for Travelers’ Diarrhea: For preventing travelers’ diarrhea to countries such as Mexico where Escherichia coli is the major pathogen, rifaximin is an effective preventive agent that produces minimal changes in fecal flora, conclude authors of a 210-participant, placebo-controlled trial (pp. 805-12). Using doses of rifaximin of 200 mg administered two or three times daily, the authors found, “Travelers’ diarrhea developed in 14.74% of participants taking rifaximin and 53.70% of those taking placebo (rate ratio, 0.27 [95% CI, 0.17 to 0.43]). Rifaximin provided 72% and 77% protection against travelers’ diarrhea and antibiotic-treated travelers’ diarrhea, respectively (P < 0.001 for both), and all rifaximin doses were superior to placebo. In the groups that did not report travelers’ diarrhea, rifaximin significantly reduced the occurrence of mild diarrhea (P = 0.02) and moderate and severe intestinal problems (P = 0.009 for pain or cramps; P = 0.02 for excessive gas). Rates of adverse events were comparable in the rifaximin and placebo groups. Minimal changes in coliform flora were found during rifaximin therapy.” (H. L. DuPont, St. Luke’s Episcopal Hosp., Houston; hdupont@sleh.com)

Arguing that the availability of effective treatments that reduce the symptoms of travelers’ diarrhea in just a few hours, an editorialist maintains that universal antibiotic prophylaxis is not justified (pp. 861-2): “DuPont and colleagues have shown that rifaximin is effective for preventing travelers’ diarrhea. Their convincing results do not strengthen the case for universal prophylaxis of travelers’ diarrhea. Rather, they have added an excellent alternative that will be valuable for selected patients. Rapid and judicious treatment of diarrhea, not antibiotic prophylaxis, is the best recommendation for most travelers.” (S. L. Gorbach, Tufts U., Boston)

Hepatitis B Treatment Options: In a cost-utility analysis stratified by hepatitis B e antigen status, a salvage strategy that reserves adefovir for lamivudine-associated viral resistance was highly cost-effective in most health care settings (pp. 821-31). Five strategies were analyzed (do nothing, interferon only, lamivudine only, adefovir only, lamivudine with crossover to adefovir upon resistance), with these results: “The ‘do nothing’ strategy was least effective yet least expensive. Compared with the ‘do nothing’ strategy, using interferon cost an incremental $6,337 to gain 1 additional [quality-adjusted life-year]. Compared with interferon, the adefovir salvage strategy cost an incremental $8,446 per QALY gained. Both the lamivudine and adefovir monotherapy strategies were more expensive yet less effective than the alternative strategies and were therefore dominated.” (B. M. R. Spiegel, BSpiegel@mednet.ucla.edu)

Editorialists make these observations about current and future hep B strategies (pp. 863-4): “In HBeAg-negative patients, adefovir salvage therapy, at $16,593 per QALY gained, easily falls within the range generally accepted as cost-effective. In contrast, adefovir monotherapy costs about $91,000 per QALY gained, which is relatively expensive compared with other interventions that most people accept as providing good value. The conclusion that adefovir salvage is a dominant (HBeAg-positive patients) or cost-effective (HBeAg-negative patients) strategy may change if newer drugs, or combinations of current drugs, are more effective, cheaper, or both. Thus, if new drug therapies become available for HBV (or if emergence of the YMDD mutation proves to have a greater downside), Kanwal and colleagues’ analysis should be revisited. Fortunately, bringing a decision model up to date can be as easy as inserting a new value in a spreadsheet.” (D. K. Owens, owens@stanford.edu)

Preventive Hormone Therapy in Postmenopausal Women: Recommendations of the U.S. Preventive Services Task Force are updated for hormone therapy in postmenopausal women, with specific advice concerning estrogens and progestins in a variety of clinical situations (pp. 855-60; www.preventiveservices.ahrq.gov; 800-358-9295).

PNN Pharmacotherapy Line is published via e-mail each business day except 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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 18, 2005 Vol. 12, No. 96
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
May 18 issue of JAMA (www.jama.com; 2005; 293).

Call for Action on Patient Safety: Five years since the publication of “To Err is Human,” leaders in the patient safety effort call for setting defined goals that can be achieved by 2010 (pp. 2384-90): “Five years ago, the Institute of Medicine (IOM) called for a national effort to make health care safe. Although progress since then has been slow, the IOM report truly ‘changed the conversation’ to a focus on changing systems, stimulated a broad array of stakeholders to engage in patient safety, and motivated hospitals to adopt new safe practices. The pace of change is likely to accelerate, particularly in implementation of electronic health records, diffusion of safe practices, team training, and full disclosure to patients following injury. If directed toward hospitals that actually achieve high levels of safety, pay for performance could provide additional incentives. But improvement of the magnitude envisioned by the IOM requires a national commitment to strict, ambitious, quantitative, and well-tracked national goals. The Agency for Healthcare Research and Quality should bring together all stakeholders, including payers, to agree on a set of explicit and ambitious goals for patient safety to be reached by 2010.” (L. L. Leape, leape@hsph.harvard.edu)

Sepsis with Chemotherapy: Doxorubicin–docetaxel is associated with a high risk of life-threatening complications that should preclude use of the combination as an alternative to doxorubicin–cyclophosphamide in the adjuvant chemotherapy of breast cancer, according to a 627-patient study from France (pp. 2367-71). Doses were doxorubicin 50 mg/sq m plus docetaxel 75 mg/sq m or doxorubicin 60 mg/sq m plus cyclophosphamide 600 mg/sq m given in four courses after surgery. The authors report that the study, Reposant sur des Arguments Pronostiques et Prédictifs (RAPP)-01, was terminated after a median follow-up of 24 months, too short to assess the primary endpoint of 5-year survival: “The trial was terminated prematurely when 2 deaths related to drug toxicity and 1 case of perforative peritonitis occurred among patients with febrile neutropenia, all in the doxorubicin–docetaxel group. The incidence of febrile neutropenia was significantly higher with the doxorubicin–docetaxel regimen (40.8%) than with the doxorubicin–cyclophosphamide regimen (7.1%) (P < .001).” (E. G. C. Brain, René Huguenin Cancer Ctr., Saint-Cloud, France; e.brain@stcloud-huguenin.org)

Neonatal Withdrawal After SRI Exposure In Utero: Discussing results reported in the Feb. 5 Lancet (see PNN, Feb. 7), authors of a review article shed further light on a neonatal withdrawal syndrome that can occur in newborns of mothers who used serotonin reuptake inhibitors during the last trimester of pregnancy (pp. 2372-83): “Compared with early gestational SRI exposure or no exposure, late SRI exposure carries an overall risk ratio of 3.0 (95% CI, 2.0–4.4) for a neonatal behavioral syndrome. The most SRI-related neonatal case reports involved fluoxetine and paroxetine exposures. Neonates primarily display central nervous system, motor, respiratory, and gastrointestinal signs that are usually mild and disappear by 2 weeks of age. Medical management has consisted primarily of supportive care in special care nurseries. A severe syndrome that consists of seizures, dehydration, excessive weight loss, hyperpyrexia, or intubation is rare in term infants (1/313 quantifiable cases). There have been no reported neonatal deaths attributable to neonatal SRI exposure.” (E. L. Moses-Kolko, U. Pittsburgh, Pittsburgh; mosesel@upmc.edu)

Early Exposure to Gluten-Containing Foods: Introducing gluten into the infant diet too early is associated with development of celiac disease autoimmunity, concludes a prospective observational study of 1,560 children (pp. 2343-51). During a mean follow-up of 4.8 years, investigators identified 51 children with CDA. The risk of developing CDA was 5-fold higher among children who were exposed to gluten-containing foods (wheat, barley, or rye) during the first 3 months of life, compared with exposure at 4–6 months. (Jill M. Norris, U. Colorado, Denver; jill.norris@uchsc.edu)

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

PNN Pharmacotherapy Line
May 19, 2005 Vol. 12, No. 97
Providing news and information about medications and their proper use

>>>ASCO Highlights
With 25,000 cancer specialists in attendance and more than 3,800 abstracts presented, the 41st annual meeting of the American Society of Clinical Oncology convened on May 13–17 in Orlando. Here are some of the highlights of the year’s foremost oncology conference. Most abstracts are posted on the ASCO Web site (www.asco.org), along with news releases and audio/slides from selected sessions.

Aromatase Inhibitors in Breast Cancer: Comparisons of the aromatase inhibitors in adjuvant care of postmenopausal women with hormone-receptor–positive breast cancer, and two studies indicated that exemestane has a clinical advantage over tamoxifen (abstracts 515 and 516). In addition to somewhat better outcomes (progression-free survival and response), exemestane is better tolerated, especially in terms of its lack of effects on lipids, cardiovascular events, and the uterus, researchers reported.

Endometrial Cancer Chemoprevention: In abstract 5001, investigators reported that the SERM raloxifene reduced the risk of endometrial cancer by 50%, compared with nonusers. Tamoxifen increased the risk of endometrial cancer by a significant 2.35-fold, although the increased risk fell to a nonsignificant 50% when data were adjusted for confounders such as body mass index and past history of breast cancer. In a Reuters Health report, presenter Angela DeMichele of U. Penn. commented, “If raloxifene proves effective at preventing both breast cancer and endometrial cancer, that information could weigh heavily on a woman's decision about which drug to choose.”

Sorafenib for Advanced Renal Cell Carcinoma: An oral dual-action Raf kinase and VEGFR inhibitor, sorafenib, significantly prolonged progression-free survival among 769 patients with previously treated advanced renal cell carcinoma, according to results of a late-breaking abstract (abstract LBA4510). Escudier et al. found a 12-week progression-free survival of 79% for the active drug and 50% for placebo. The drug’s safety profile was good, with grade 3/4 events reported by 30% of patients on sorafenib and 22% of those taking placebo.

Lenalidomide for Myelodysplastic Syndrome: A thalidomide derivative, lenalidomide, provided rapid responses among 148 patients with myelodysplastic syndrome (abstract 5). In a Phase II trial of patients at low to intermediate risk, median time to response was 4.4 weeks with lenalidomide, based on increase in hemoglobin. Time to transfusion independence was 24 weeks for 97 of the patients, and researchers termed the response “durable” based on transfusion independence lasting for a median of 47 weeks.

Panitumumab for Metastatic Colorectal Cancer: Researchers presented preliminary data on panitumumab, an investigational monoclonal antibody epidermal growth factor in patients with advanced colon cancer. The drug, under development by Amgen and Abgenix, reduced tumor size in 9% of patients with chemotherapy-refractory colon cancers. Pharmacokinetic, dosing, and safety studies of the drug were also presented (abstracts 259, 3059, and 3089).

Perioperative Chemotherapy for GI Cancers: Perioperative chemotherapy in patients with adenocarcinoma of the stomach, esophagogastric junction, or lower esophagus prolonged survival, according to data from the MAGIC (MRC Adjuvant Gastric Infusional Chemotherapy) trial. A total of 503 patients randomly received either surgery alone or three cycles of chemotherapy with epirubicin, cisplatin, and 5-fluorouracil over 9 weeks, followed by a break of 3–6 weeks, surgery, and then three more cycles of chemotherapy. Five-year survival was 36% among the chemotherapy patients, compared with 23% of those treated with surgery alone, a significant improvement. Progression-free survival was also significantly increased with chemotherapy. These results build on those presented as ASCO in 2003, and future research will focus on whether these drugs are the best ones for this indication and whether preoperative radiation could further enhance care (abstract 401).

PNN Pharmacotherapy Line is published via e-mail each business day except 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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 20, 2005 Vol. 12, No. 98
Providing news and information about medications and their proper use

>>>Geriatrics Highlights
Source:
June issue of the Journal of the American Geriatrics Society (www.blackwell-synergy.com; 2005; 52).

Drug Therapy Among Ontario Elderly: Drug therapy is better among nursing home residents in Ontario than among that province’s community-dwelling elderly, a difference that may be the result of clinical pharmacist interventions in long-term care facilities (pp. 861 ff). That conclusion is reached in a retrospective cohort analysis of Ontario administrative databases for 1.276 million adults aged 66 or older, including 1.217 million people living in the community and 59,000 nursing home residents. The researchers write: “Nursing home residents were older (mean age ± standard deviation = 84.2 ± 7.6 vs 75.0 ± 6.5, P<.001), included more women (73.3% vs 57.7%, P < .001), had higher comorbidity scores (measured by the number of distinct drug therapies dispensed in the prior year (10.7 ± 6.8 vs 7.2 ± 5.7, P < .001) and Charlson comorbidity scores (1.4 ± 1.6 vs 0.9 ± 1.5, P < .001)) than community-dwelling individuals.

“Community-dwelling older adults were significantly more likely to be dispensed at least one drug therapy in the always avoid or rarely appropriate category than nursing home residents (3.3% vs 2.3%, P < .001). Using a logistic regression model that controlled for age, sex, and comorbidity (number of distinct drug therapies dispensed in the prior year), nursing home residents were close to half as likely to be dispensed one of these potentially inappropriate drug therapies as community-dwelling older adults (odds ratio = 0.52, 95% confidence interval = 0.49–0.55, P < .001).” (P. A. Rochon, paula.rochon@utoronto.ca)

Pain Among NH Residents: Among residents of nursing homes, persistent pain is common and suboptimally managed, report authors who studied 21,830 individuals in nursing homes in 10 states (pp. 867 ff). Using Minimum Data Set assessments on pain and analgesics for residents aged 65 and older, the investigators found, “Persistent pain as determined using the MDS was identified in 49% of residents with an average age of 83; 83% were female. Persistent pain was prevalent in patients with a history of fractures (62.9%) or surgery (63.6%) in the past 6 months. One-quarter received no analgesics. The most common analgesics were acetaminophen (37.2%), propoxyphene (18.2%), hydrocodone (6.8%), and tramadol (5.4%). Only 46.9% of all analgesics were given as standing doses. Acetaminophen was usually prescribed as needed (65.6%), at doses less than 1,300 mg per day. Nonsteroidal antiinflammatory drugs (NSAIDs) were prescribed as a standing dose more than 70% of the time, and one-third of NSAIDs were prescribed at high doses.”

Based on these results, the group concludes, “In nursing home residents, persistent pain is highly prevalent, there is suboptimal compliance with geriatric prescribing recommendations, and acute pain may be an important contributing source of persistent pain. More effective provider education and research is needed to determine whether treatment of acute pain could prevent persistent pain.” (A. B. Won, won@mail.hrca.harvard.edu)

ACE Inhibitors & Lower Extremity Muscle Mass: Compared with other antihypertensive agents, ACE inhibitors produce increased lower extremity muscle mass, a finding that merits exploration in patients with wasting syndromes, according to authors of a 2,431-patient study (pp. 961 ff). In the Health, Aging and Body Composition (Health ABC) study, investigators looked at patients in their 70s who had no heart failure and were taking ACE inhibitors, beta-blockers, thiazides, calcium-channel blockers, or no antihypertensive agents: “LEMM significantly differed across the study groups, being larger in users of ACE inhibitors than in users of other drugs (unadjusted and adjusted models). LEMM was comparable in users of ACE inhibitors and no drug users. A trend toward larger LEMM was also observed in sex- and ethnicity-stratified analyses and in the subgroup of noncoronary hypertensive participants.” (M. Di Bari, U. Florence, Florence, Italy; dibari@unifi.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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 23, 2005 Vol. 12, No. 99
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
May 21 issue of Lancet (www.thelancet.com; 2005; 365).

Simvastatin Cost-Effectiveness: Statin therapy—particularly with lower-priced generic medications—is more cost-effective than previously recognized, according to a new analysis, and the level of vascular risk at which treatment is recommended should be revisited (pp. 1779-85). The MRC/BHF Heart Protection Study (HPS) included 20,536 adults aged 40–80 years, and hospitalization and statin costs were analyzed based on 2001 U.K. prices. The group reports, “Allocation to simvastatin was associated with a highly significant 22% (95% CI 16–27; p < 0.0001) proportional reduction in hospitalisation costs for all vascular events, with similar proportional reductions in every subcategory of participant studied. During an average of 5 years, estimated absolute reductions in vascular event costs per person allocated 40 mg simvastatin daily ranged from UK£847 (SE 137) in the highest risk quintile studied to £264 (48) in the lowest. Mean excess cost of statin therapy among participants allocated simvastatin was £1497 (8), with similar absolute increases in every subcategory. Costs of preventing a major vascular event with 40 mg simvastatin daily ranged from £4500 (95% CI 2300–7400) among participants with a 42% 5-year major vascular event rate to £31,100 (22,900–42,500) among those with a 12% rate (corresponding to 5-year major coronary event rates of 22% and 4%, respectively).” (Heart Protection Study, Radcliffe Infirmary, Oxford; hps@ctsu.ox.ac.uk)

The feasibility of incorporating economic analyses into clinical trials is the subject of an accompanying commentary (pp. 1749-50). The authors describe four challenges: “(1) It is essential to capture patients’ total use of health-care resources—both within and outside the clinical trial—because there is a complex interdependent relation between hospitalisation, outpatient care, and medication use.... (2) To facilitate comparisons across interventions for a particular disease, and interventions for different diseases, we should use standardised units to measure the consequences of health interventions.... (3) It is essential to collect information on patients’ quality of life, because health interventions often affect quality of life in various ways.... (4) A long-term perspective should be taken if a health intervention has an impact beyond the period for which data from clinical trials are available.” (K. Imai, CDC, Atlanta)

>>>PNN NewsWatch
* The product labeling for nesiritide (Natrecor, Scios) has been revised to reflect data published in the Apr. 20 JAMA and Mar. 29 Circulation (see PNN, Apr. 20). Safety information includes warnings about the possibility of hypotension and impact of the drug on renal function in susceptible individuals. The revised labeling reflects the emerging view that the agent should be a second-line drug used only when nitrates and diuretics have failed to adequately improve symptoms.

* FDA last week provided an annual update of its progress in fighting the
counterfeit-drug problem. In 2004, FDA's office of Criminal Investigations initiated 58 counterfeit drug investigations involving hundreds of thousands of fake dosage units. This increase over the 30 cases investigated in 2003 resulted partially from heightened vigilance and awareness by all parties in the drug-distribution system as a result of the FDA’s issuance of its original report in 2004, the agency said in a news release.

>>>PNN JournalWatch
* Systematic Review to Determine Whether Participation in a Trial Influences Outcome, in BMJ, 2005; 330: 1175 ff. Reprints: www.bmj.org; G. E. Vist, Norwegian Health Services Research Centre, Oslo; gev@nhsrc.no

* More Common Skin Infections in Children, in
BMJ, 2005; 330: 1194–8. Reprints: www.bmj.org; M. J. Sladden, U. Hosp., Leicester, U.K.; m.sladden@doctors.org.uk

* Multiple Birth Resulting from Ovarian Stimulation for Subfertility Treatment, in
Lancet, 2005; 365: 1807–16. Reprints: www.thelancet.com; B. C. J. M. Fauser, U. Med. Ctr., Utrecht, the Netherlands.

* Meta-Analysis: Accuracy of Rapid Tests for Malaria in Travelers Returning from Endemic Areas, in
Annals of Internal Medicine, 2005; 142: 836–46. Reprints: www.annals.org; P. Jüni, U. Berne, Bern, Switzerland; juni@ispm.unibe.ch

PNN Pharmacotherapy Line is published via e-mail each business day except 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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 24, 2005 Vol. 12, No. 100
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
May 23 issue of Archives of Internal Medicine (www.archinternmed.com; 2005; 165).

ADEs with CPOE: Rates of adverse drug events continue to be high after implementation of computerized physician order entry systems that do not include decision-support features, according to an assessment of experiences at a Veterans Administration hospital (pp. 1111-6). During a 20-week study period, pharmacists classified inpatient ADEs during prospective daily reviews of electronic medical records, finding that, “Among 937 hospital admissions, 483 clinically significant inpatient ADEs were identified, accounting for 52 ADEs per 100 admissions and an incidence density of 70 ADEs per 1000 patient-days. One quarter of the hospitalizations had at least 1 ADE. Of all ADEs, 9% resulted in serious harm, 22% in additional monitoring and interventions, 32% in interventions alone, and 11% in monitoring alone; 27% should have resulted in additional interventions or monitoring. Medication errors contributed to 27% of these ADEs. Errors associated with ADEs occurred in the following stages: 61% ordering, 25% monitoring, 13% administration, 1% dispensing, and 0% transcription. The medical record reflected recognition of 76% of the ADEs.”

Commenting on their findings, these authors write, “The high rate of ADEs and the seriousness of the ADEs in this study provide empirical support for improvements in computerized interventions. The CPOE systems must address dosing, prophylaxis, and monitoring errors through such approaches as standard order sets or automated suggestions for prophylaxis and monitoring strategies.... Bar code medication administration data on dosage and effectiveness of as-needed medications should feed into computerized algorithms for medication titration, such as insulin for diabetes or narcotics for pain control. Drug order checking could be revised to de-emphasize rare drug-drug interactions and emphasize common, additive drug-drug interactions. Finally, ADE documentation could be improved through computerized documentation systems that facilitate recording and displaying causality, seriousness, or dosage information, which would improve the usefulness of ADE reports to regulatory agencies and alerts at the time of drug ordering....” (J. R. Nebeker, Jonathan.Nebeker@hsc.utah.edu)

Persistence with Hypertension, Lipids Meds: Among patients started on medications for both hypertension and dyslipidemia, only one third are taking the products 6 months later (pp. 1147-52). That finding comes from a retrospective cohort study of patients who initiated therapy with the two types of medications within a 90-day period. At 3, 6, and 12 months, 44.7%, 35.9%, and 35.8% of patients had filled prescriptions that would cover 80% of days for both types of medications. (R. H. Chapman, ValueMedics Research, Falls Church, Va.; rick.chapman@valuemedics.com)

Bezafibrate for MI Prevention: A fibric acid derivative, bezafibrate, lowered the incidence of myocardial infarction among 1,470 patients with metabolic syndrome (pp. 1154-60). During 6.2 years of follow-up for events and 8.1 years for mortality, the investigators found, “Bezafibrate was associated with a reduced risk of any MI and nonfatal MI with hazard ratios (HRs) of 0.71 (95% confidence interval [CI], 0.54–0.95) and 0.67 (95% CI, 0.49–0.91), respectively. The cardiac mortality risk tended to be lower in patients taking bezafibrate (HR, 0.74; 95% CI, 0.54–1.03). In 575 patients with augmented features of MS (4–5 risk factors), the remarkable strengthening of cardiac mortality reduction when taking bezafibrate (HR, 0.44; 95% CI, 0.25–0.80) should be noted.” (A. Tenenbaum, Chaim Sheba Med. Ctr., Tel-Hashomer, Israel; altenen@post.tau.ac.il)

Psyllium, Simvastatin for Lipids: Supplemental psyllium husk can lower LDL cholesterol in patients taking simvastatin 10 mg daily just as much as raising the statin dose to 20 mg, note authors of a 12-week, 68-patient study (pp. 1161-6). Improvements in apolipoprotein B and total cholesterol were also noted with psyllium, but triglycerides and HDL cholesterol were largely unaffected by combination therapy. (A. E. Moreyra, U. Medicine & Dentistry of New Jersey, New Brunswick; abel.moreyra@rwjuh.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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 25, 2005 Vol. 12, No. 101
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
May 25 issue of JAMA (www.jama.com; 2005; 293).

Antidepressants & Suicides: Suicidal thoughts, plans, gestures, and attempts did not decrease during the 1990s, a period of dramatically higher use of antidepressants, conclude authors who analyzed data from national surveys conducted in 1990–92 and 2001–03 (pp. 2487-95). Based on self-reports of suicide-related behaviors and treatment in the year before interviews of 9,708 patients aged 18–54 years, the researchers report, “No significant changes occurred between 1990–1992 and 2001–2003 in suicidal ideation (2.8% vs 3.3%; P = .43), plans (0.7% vs 1.0%; P = .15), gestures (0.3% vs 0.2%; P = .24), or attempts (0.4%-0.6%; P = .45), whereas conditional prevalence of plans among ideators increased significantly (from 19.6% to 28.6%; P = .04), and conditional prevalence of gestures among planners decreased significantly (from 21.4% to 6.4%; P = .003). Treatment increased dramatically among ideators who made a gesture (40.3% vs 92.8%) and among ideators who made an attempt (49.6% vs 79.0%).”

Commenting on their study, the authors conclude, “Substantial barriers to uptake of effective interventions continue to exist, including competing clinical demands and distorted incentives for treating mental disorders and symptoms. Failure to disseminate evidence-based treatments widely may, in fact, help explain why suicidality did not decline in response to the treatment increases during the 1990s. This means that expansion of disease management programs, treatment quality-assurance programs, and ‘report cards’ to improve the quality of care for suicidal patients may all be needed to reduce the burden of suicidality.” (R. C. Kessler, kessler@hcp.med.harvard.edu)

Hair Dyes & Cancer: Risk of cancer was not markedly elevated among people who used personal hair dyes in a meta-analysis of 79 studies (pp. 2516-25). Assessing the risks of various types of cancer, the authors found these relative risks for ever-users of hair dyes: 1.06 (95% CI, 0.95–1.18) for breast cancer (14 studies), 1.01 (95% CI, 0.89–1.14) for bladder cancer (10 studies), and 1.15 (95% CI, 1.05–1.27) for hematopoietic cancers (40 studies). (B. Takkouche, U. Santiago de Compostela, Spain; mrbahi@usc.es)

>>>Circulation Highlights
Source:
Early-release articles from Circulation (circ.ahajournals.org).

Safety of Rosuvastatin: Adverse event reports during the first year of marketing of rosuvastatin were significantly more common than with atorvastatin, simvastatin, or pravastatin both during that time period and during the first years of marketing of these other agents. Assessing the frequency of AERs to FDA and combining that with IMS Health data on the numbers of prescriptions written, the investigators report, “With either timeframe comparison, rosuvastatin was significantly more likely to be associated with the composite end point of rhabdomyolysis, proteinuria, nephropathy, or renal failure AERs. Reported cases of rhabdomyolysis, proteinuria, or renal failure tended to occur early after the initiation of therapy and at relatively modest doses of rosuvastatin. The increased rate of rosuvastatin-associated AERs relative to other widely used statins was also observed in secondary analyses when other categories of AERs were examined, including adverse events with serious outcomes, liver toxicity, and muscle toxicity without rhabdomyolysis.” (R. H. Karas, rkaras@tufts-nemc.org)

Analysis of broader data sets leads one to a different conclusion, counters an editorialist: “It would first be prudent for anyone who takes a statin to review the FDA’s [analysis of all available data] before drawing conclusions.... It also would be appropriate to consult with one’s physician before making any decision about changing medication. Informing one’s physician of the FDA position on rosuvastatin would seem wise; the physician may not be aware of it. One must keep in mind that statins generally are safe and that they substantially reduce risk for coronary events in higher-risk patients. Nonetheless, statins, like all drugs, can have side effects, and care must be taken in their use in persons with predisposing conditions. Moreover, it seems unwise to use statins outside current cholesterol-management guidelines.” (S. M. Grundy, scott.grundy@utsouthwestern.edu)

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

PNN Pharmacotherapy Line
May 26, 2005 Vol. 12, No. 102
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
May 26 issue of the New England Journal of Medicine (content.nejm.org; 2005; 352).

Monitoring Asthma Treatments with Exhaled NO: Maintenance doses of inhaled corticosteroids can be reduced significantly through use of exhaled nitric oxide to guide therapy, according to a study of 97 patients with asthma (pp. 2163-73). Comparing therapy guided by the fraction of exhaled nitric oxide with treatment based on an algorithm, the investigators make these observations: “The final mean daily doses of fluticasone, the inhaled corticosteroid that was used, were 370 µg per day for the FENO group (95 percent confidence interval, 263 to 477) and 641 µg per day for the control group (95 percent confidence interval, 526 to 756; P = 0.003), a difference of 270 µg per day (95 percent confidence interval, 112 to 430). The rates of exacerbation were 0.49 episode per patient per year in the FENO group (95 percent confidence interval, 0.20 to 0.78) and 0.90 in the control group (95 percent confidence interval, 0.31 to 1.49), representing a nonsignificant reduction of 45.6 percent (95 percent confidence interval for mean difference, –78.6 percent to 54.5 percent) in the FENO group. There were no significant differences in other markers of asthma control, use of oral prednisone, pulmonary function, or levels of airway inflammation (sputum eosinophils).” (D. R. Taylor, Dunedin Sch. of Med., Dunedin, New Zealand; robin.taylor@stonebow.otago.ac.nz)

Statins & Colorectal Cancer: Use of statins was associated with a 47% decrease in the relative risk of colorectal cancer in the Molecular Epidemiology of Colorectal Cancer study, conducted in northern Israel in 1998–2004 (pp. 2184-92). “In analyses including 1953 patients with colorectal cancer and 2015 controls, the use of statins for at least five years (vs. the nonuse of statins) was associated with a significantly reduced relative risk of colorectal cancer (odds ratio, 0.50; 95 percent confidence interval, 0.40 to 0.63),” write the researchers. “This association remained significant after adjustment for the use or nonuse of aspirin or other nonsteroidal antiinflammatory drugs; the presence or absence of physical activity, hypercholesterolemia, and a family history of colorectal cancer; ethnic group; and level of vegetable consumption (odds ratio, 0.53; 95 percent confidence interval, 0.38 to 0.74). The use of fibric-acid derivatives was not associated with a significantly reduced risk of colorectal cancer (odds ratio, 1.08; 95 percent confidence interval, 0.59 to 2.01). Self-reported statin use was confirmed for 276 of the 286 participants (96.5 percent) who reported using statins and whose records were available. (S. B. Gruber, sgruber@umich.edu)

Links among aging-related diseases may provide targets for treatment, note editorialists (pp. 2238-9): “Disease clusters whose effects are modulated by drugs such as statins or aspirin (alone and perhaps synergistically) raise the possibility that disparate conditions share certain molecular themes. If so, this presents important opportunities—and perhaps the obligation—to probe these shared mechanisms and thereby gain insights into disease development and the means to achieve prevention in the broadest sense. A successful effort will transcend the limitations of the ‘one drug, one disease’ model and nudge the science toward more comprehensive and clinically relevant assessments of risk. It is tempting to think that systemically targeting multiple diseases common to aging is not only theoretically feasible but within our reach.” (E. Hawk, NCI, Bethesda, Md.)

Sargramostim for Crohn’s Disease: In 124 patients with moderate to severe Crohn’s disease, sargramostim failed to decrease disease activity significantly but showed some promise (pp. 2193-201). Improvements of 100 points in the Crohn’s Disease Activity Index score were observed in significantly more treated patients on day 57 (48%, compared with 26% of those taking placebo) and number of patients reaching remission, defined by a CDAI score of 150 points or less on day 57 (40% versus 19%). “The rates of either type of clinical response and of remission were significantly higher in the sargramostim group than in the placebo group on day 29 of treatment and 30 days after treatment,” the authors add. “The sargramostim group also had significant improvements in the quality of life.” (J. R. Korzenik, jkorzenik@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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 27, 2005 Vol. 12, No. 103
Providing news and information about medications and their proper use

>>>JAPhA Highlights
Source:
May/June issue of the Journal of the American Pharmacists Association (www.japha.org; 2005; 45).

McClellan on Medicare Part D: Pharmacists are the “key to success” for the coming Medicare Part D prescription drug benefit, Mark B. McClellan, MD, PhD, said in an address to the APhA2005 conference in Orlando (pp. 328-35). The CMS administrator’s speech, reprinted in this issue, outlines what CMS is doing to support pharmacists under the new drug benefit; create more time for pharmacists to spend with patients; and provide pharmacists with the relevant and useful information needed to help beneficiaries get the most out of the new drug coverage.

Costs of Community, Mail Service Pharmacy: While overall costs of prescription medications are lower when they are obtained from mail-service pharmacies, the costs to health plans is actually higher, according to an analysis of a plan with a three-tier benefits structure (pp. 336-43). Beneficiaries in this plan could obtain a 90-day supply of medication by paying 2 months’ copayments. Researchers made these calculations for the approximately 100,000 people in the plan during a 1-year period, “Total costs for the 44,847 prescriptions dispensed through mail service were $6,401,624. Had these prescriptions been dispensed at community pharmacies, costs would have been $6,902,252. Ingredient costs were $6,401,624 through mail versus $6,633,170 at community pharmacies. Total costs to the health plan were $4,726,637 through mail versus $4,417,733 at community pharmacies. Member costs were $1,674,987 through mail versus $2,484,519 at community pharmacies.” (N. V. Carroll, nvcarroll@vcu.edu)

Pharmacist Telemonitoring of Antidepressant Use: “Antidepressant telemonitoring by community pharmacists can significantly and positively affect patient feedback and collaboration with pharmacists,” conclude authors who studied 63 patients who were presenting new antidepressant prescriptions at eight Wisconsin pharmacies (pp. 344-53). Comparing three monthly telephone calls made using pharmacist-guided education and monitoring with usual care in the unblinded study, the investigators found, “Of the 60 patients who completed the study, 28 received PGEM and 32 received usual pharmacist’s care. Results showed that PGEM had a significant and positive effect on patient feedback, knowledge, medication beliefs, and perceptions of progress. There were no significant group differences in patient adherence or symptoms at 3 months; however, PGEM patients who completed the protocol missed fewer doses than did the usual care group at 6 months.” (N. M. Rickles, Northeastern U., Boston; nrickrxprof@aol.com)

Innovative Community Pharmacy Practices: Innovative community pharmacists have become “indispensable” in their areas, write authors who analyzed elements of successful pioneer practices (pp. 376-89). Four pharmacies—in Maquoketa, Iowa, and Bemidji, Anoka, and Minneapolis, Minn.—were studied. “Providing patient care services within dispensing practices is difficult because these two businesses require different sets of business practices and skills,” write the researchers. “By separating the physical environments and the patient care process of these two businesses, pharmacists maximize their chances of success in delivering services and receiving reimbursement for services from third-party payers. Interviews with four innovative community pharmacists from Minnesota and Iowa who have developed successful patient care businesses illuminate a checklist of the essential components of pharmaceutical care practices.” (B. J. Isetts, isett001@umn.edu)

>>>PNN NewsWatch
* AstraZeneca yesterday announced FDA approval of the carbapenem meropenem (Merrem) for treatment of adults and children with complicated skin and skin structure infections. The agent was previously approved for single-agent therapy of intra-abdominal infections and bacterial meningitis.

*
PNN will not be published on Monday, May 30, Memorial Day.

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

PNN Pharmacotherapy Line
May 31, 2005 Vol. 12, No. 104
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
May 28 issue of Lancet (www.thelancet.com; 2005; 365).

Antiviral Prophylaxis in Transplantation: The risk of cytomegalovirus disease and associated mortality is reduced by prophylaxis with antiviral medications among patients who have received solid-organ transplants, according to a systematic review of available literature (early online release). Using a meta-analytic random effects model to combine data, the authors report, “Compared with placebo or no treatment, prophylaxis with aciclovir, ganciclovir, or valaciclovir significantly reduced the risks of cytomegalovirus disease (19 trials, 1981 patients; relative risk 0.42 [95% CI 0.34–0.52]), cytomegalovirus infection (17 trials, 1786 patients; 0.61 [0.48–0.77]), and all-cause mortality (17 trials, 1838 patients; 0.63 [0.43–0.92]), mainly owing to lower mortality from cytomegalovirus disease (seven trials, 1300 patients; 0.26 [0.08–0.78]). Prophylaxis also lowered the risks of disease caused by herpes simplex or zoster virus, bacterial infections, and protozoal infections, but not fungal infection, acute rejection, or graft loss. Meta-regression showed no significant difference in the risk of cytomegalovirus disease or all-cause mortality by organ transplanted or cytomegalovirus serostatus; no conclusions were possible for cytomegalovirus-negative recipients of negative organs. In trials of direct comparisons, ganciclovir was more effective than aciclovir in preventing cytomegalovirus disease. Valganciclovir and intravenous ganciclovir were as effective as oral ganciclovir.” (E. Hodson, Children’s Hosp., Westmead, Australia)

Free Nicotine-Replacement Therapy Effort: Distribution of free nicotine-replacement therapy products to diverse populations in New York City facilitated high quit rates among some subgroups, report authors of a 6-week study (pp. 1849-54). Nicotine patches (2 weeks each of 21, 14, and 7 mg/day) were mailed to 34,090 eligible smokers who called a toll-free quitline, and cessation rates were assessed at 6 months among a random sample of 1,305 NRT recipients. The investigators write: “An estimated 5% of all adults in New York City who smoked ten cigarettes or more daily received NRT; most (64%) recipients were non-white, foreign-born, or resided in a low-income neighbourhood. Of individuals contacted at 6 months, more NRT recipients than comparison group members successfully quit smoking (33% vs 6%, p < 0.0001), and this difference remained significant after adjustment for demographic factors and amount smoked (odds ratio 8.8, 95% CI 4.4–17.8). Highest quit rates were associated with those who were foreign born (87 [39%]), older than 65 years (40 [47%]), and smoked less than 20 cigarettes per day (116 [35%]). Those who received a counselling call were more likely to stop smoking than those who did not (246 [38%] vs 189 [27%], p = 0.001). With the conservative assumption that every 6-month follow-up survey non-respondent continued to smoke, the stop rate among NRT recipients was 20%. At least 6038 successful quits were attributable to NRT receipt, and cost was US$464 per quit.” (T. R. Frieden, New York City Dept. of Health and Mental Hygiene, New York City)

>>>PNN JournalWatch
* Cardiovascular Risk Factors After Antenatal Exposure to Betamethasone: 30-Year Follow-up of a Randomised Controlled Trial, in Lancet, 2005; 365: 1856–62. Reprints: www.thelancet.com; J. Harding, U. Auckland, Auckland, New Zealand.

* Randomised Controlled Trial to Compare Surgical Stabilisation of the Lumbar Spine with an Intensive Rehabilitation Programme for Patients with Chronic Low Back Pain: The MRC Spine Stabilisation Trial, in
BMJ, 2005; 330: 1233 ff. Reprints: www.bmj.org; J. Fairbank, Nuffield Orthopaedic Ctr., Oxford, U.K.; jeremy.fairbank@ndos.ox.ac.uk

* Theophylline for Prevention of Contrast-Induced Nephropathy: A Systematic Review and Meta-analysis, in
Archives of Internal Medicine, 2005; 165: 1087–93. Reprints: www.archinternmed.com; W. A.. Ghali, wghali@ucalgary.ca

* Systematic Overview of Warfarin and Its Drug and Food Interactions, in
Archives of Internal Medicine, 2005; 165: 1095–106. Reprints: www.archinternmed.com; A. M. Holbrook, holbrook@mcmaster.ca

* Self-Monitoring of Blood Glucose in Patients with Type 2 Diabetes Who Are Not Using Insulin: A Systematic Review, in
Diabetes Care, 2005; 28: 1510–7. Reprints: care.diabetesjournals.org; L. M. C. Welschen, VU U. Med. Ctr., Amsterdam, the Netherlands; l.welschen@vumc.nl or www.emgo.nl

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

PNN Pharmacotherapy Line
June 1, 2005 Vol. 12, No. 105
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
June 1 issue of JAMA (www.jama.com; 2005; 293).

First-Line Treatment of AF: Pulmonary vein isolation provided benefits greater than those of antiarrhythmic drugs, making it a feasible first-line approach in patients with symptomatic atrial fibrillation, note authors of a 67-patient study (pp. 2634-40). The multicenter trial included participants whose symptoms had been present for at least 3 months but who had received no treatment with antiarrhythmic agents. They randomly received either PVI using radiofrequency ablation or antiarrhythmic drug treatment. At 1-year follow-up, the investigators found, “22 (63%) of 35 patients who received antiarrhythmic drugs had at least 1 recurrence of symptomatic AF compared with 4 (13%) of 32 patients who received PVI (P < .001). Hospitalization during 1-year follow-up occurred in 19 (54%) of 35 patients in the antiarrhythmic drug group compared with 3 (9%) of 32 in the PVI group (P < .001). In the antiarrhythmic drug group, the mean (SD) number of AF episodes decreased from 12 (7) to 6 (4), after initiating therapy (P = .01). At 6-month follow-up, the improvement in quality of life of patients in the PVI group was significantly better than the improvement in the antiarrhythmic drug group in 5 subclasses of the Short-Form 36 health survey. There were no thromboembolic events in either group. Asymptomatic mild or moderate pulmonary vein stenosis was documented in 2 (6%) of 32 patients in the PVI group.” (A. Natale, Cleveland Clinic Found., Cleveland; natalea@ccf.org)

Antichlamydial Therapy for CAD: No overall benefit was evident in a meta-analysis of data on 19,217 patients with coronary artery disease who were treated in 11 trials of antichlamydial antibiotics (pp. 2641-7). Comparing active therapies with placebo using a random-effects model, the authors report, “Antibiotic therapy had no impact on all-cause mortality among treated vs untreated patients (4.7% vs 4.6%; odds ratio [OR], 1.02; 95% confidence interval [CI], 0.89–1.16; P = .83), on the rates of MI (5.0% vs 5.4%; OR, 0.92; 95% CI, 0.81–1.04; P = .19), or on the combined end point of MI and unstable angina (9.2% vs 9.6%; OR, 0.91; 95% CI, 0.76–1.07; P = .25).” (D. L. Brown, david.brown@stonybrook.edu)

Physicians & Investment Industry: Broadening ethical concerns, authors write that nearly 10% of U.S. physicians are “currently engaged in a formal consultancy with the investment industry,” including individual stockbrokers and analysts, investment bankers, venture capital firms, and investment firms such as hedge funds (pp. 2654-7). “To assess complex and emerging technologies, it appears natural that entrepreneurs and physicians with particular expertise would come together. While it is clear that there has been an exponential increase in connections between physicians and the investment community in recent years, it may be appropriate to consider a reassessment. Despite the potential of a meaningful and intellectually stimulating dialogue between physicians and financiers, a substantial unintended jeopardy can be created. The relationships between physicians and the investment industry have clearly become pervasive, although not necessarily perverse. Additional study of this new convergence is clearly warranted, but considerable precautions need to be exercised by individual physicians and institutions who are engaged in such relationships.” (E. J. Topol, Cleveland Clinic Found., Cleveland; topole@ccf.org)

>>>PNN NewsWatch
* As FDA and Pfizer sort out the data on sudden blindness in men using sildenafil, state Medicaid agencies are working to figure out how to block sex offenders’ access to erectile dysfunction drugs. Responding to media reports last Friday, Pfizer issued a statement noting that reports of nonarteritic anterior ischemic optic neuropathy are rare despite use of Viagra by 23 million men worldwide. Further, men with erectile dysfunction often have diabetes and other conditions predisposing them to acute optic nerve disease, the company noted. On the Medicaid front, a New York State analysis showed that men convicted of rape and other sex crimes had later received sildenafil through the state’s Medicaid program, prompting a CMS alert that ED drugs do not have to be covered in such cases and activity in states to block access in such situations.

PNN Pharmacotherapy Line is published via e-mail each business day except 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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 2, 2005 Vol. 12, No. 106
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
June 2 issue of the New England Journal of Medicine (content.nejm.org; 2005; 352).

Zoster Vaccine: In older adults, a varicella–zoster virus vaccine significantly lowered the occurrence of herpes zoster and postherpetic neuralgia (pp. 2271-84). The live attenuated Oka/Merck zoster vaccine was tested in 38,546 adults aged 60 years or older, with these results: “More than 95 percent of the subjects continued in the study to its completion, with a median of 3.12 years of surveillance for herpes zoster. A total of 957 confirmed cases of herpes zoster (315 among vaccine recipients and 642 among placebo recipients) and 107 cases of postherpetic neuralgia (27 among vaccine recipients and 80 among placebo recipients) were included in the efficacy analysis. The use of the zoster vaccine reduced the burden of illness due to herpes zoster by 61.1 percent (P < 0.001), reduced the incidence of postherpetic neuralgia by 66.5 percent (P < 0.001), and reduced the incidence of herpes zoster by 51.3 percent (P < 0.001). Reactions at the injection site were more frequent among vaccine recipients but were generally mild.” (M. N. Oxman, mnoxman@ucsd.edu)

After noting the high prevalence of pain lasting more than 1 year in older patients with zoster, an editorialist writes (pp. 2344-6): “If the FDA were to require another large multi-institutional study before zoster vaccine is licensed, it will be another decade until the findings of Oxman et al. can be confirmed or repudiated. Since zoster and its attendant neurologic complication of postherpetic neuralgia are common and serious, it seems prudent to market the zoster vaccine, but only if a large number of those vaccinated are followed closely, particularly those over 85 years of age, among whom the cell-mediated immune response to [varicella–zoster virus] is likely to be less robust than among those 20 to 25 years younger. This follow-up would allow not only a further determination of possible risk to vaccine recipients but also an estimation of the vaccine's effectiveness in the population of the oldest old. The Census Bureau projects that by the year 2040, there will be 8 million to 13 million Americans 85 years of age or older. It is hoped that the use of a zoster vaccine will reduce or eradicate zoster and its related complications, just as measles vaccine has wiped out not only measles but also measles-associated postinfectious encephalomyelitis and subacute sclerosing pan-encephalitis in regions where the vaccine is used.” (D. H. Gilden, U. Colorado Health Sci. Ctr., Denver)

Genetic Variants & Warfarin Dose: Haplotypes of the vitamin K epoxide reductase complex 1 can be used to stratify patients into low-, intermediate-, and high-dose warfarin groups and may explain differences in dose requirements among patients of different ancestries, conclude authors of a retrospective study (pp. 2285-93). “We identified a low-dose haplotype group (A) and a high-dose haplotype group (B),” the investigators explain. “The mean (± SE) maintenance dose of warfarin differed significantly among the three haplotype group combinations, at 2.7 ± 0.2 mg per day for A/A, 4.9 ± 0.2 mg per day for A/B, and 6.2 ± 0.3 mg per day for B/B (P < 0.001). VKORC1 haplotype groups A and B explained approximately 25 percent of the variance in dose. Asian Americans had a higher proportion of group A haplotypes and African Americans a higher proportion of group B haplotypes.” (M. J. Rieder, mrieder@u.washington.edu)

Docetaxel for Node-Positive Breast Cancer: Disease-free survival was higher with docetaxel plus doxorubicin and cyclophosphamide (TAC) than with fluorouracil plus doxorubicin and cyclophosphamide (FAC) as adjuvant chemotherapy in 1,491 women with operable node-positive breast cancer (pp. 2302-13). The researchers found, “At a median follow-up of 55 months, the estimated rates of disease-free survival at five years were 75 percent among the 745 patients randomly assigned to receive TAC and 68 percent among the 746 randomly assigned to receive FAC, representing a 28 percent reduction in the risk of relapse (P = 0.001) in the TAC group. The estimated rates of overall survival at five years were 87 percent and 81 percent, respectively. Treatment with TAC resulted in a 30 percent reduction in the risk of death (P = 0.008).” (M. Martin, Hosp. Universitario San Carlos, Madrid, Spain; mmartin@geicam.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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 3, 2005 Vol. 12, No. 107
Providing news and information about medications and their proper use

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

CSII in Young Children: Continuous subcutaneous insulin infusion was safe and well tolerated among 26 children aged 1–6 years and may improve parents’ quality of life, but overall the “benefits and realistic expectations of CSII should be thoroughly examined before starting this therapy in very young children” (pp. 1277-81). Comparing current therapy (two or three shots per day using NPH insulin and rapid-acting analog) with CSII, the investigators note, “Eleven subjects from each group completed the trial (age 46.3 ± 3.2 months [means ± SE]). At baseline, there were no differences between groups in HbA1c, [mean blood glucose], age, sex, diabetes duration, or parental QOL. Mean HbA1c, MBG, and parental QOL were similar between groups at 6 months. Mean HbA1c and MBG did not change from baseline to 6 months in either group. The frequency of severe hypoglycemia, ketoacidosis, or hospitalization was similar between groups at any time period. Subjects on CSII had more fasting and predinner mild/moderate hypoglycemia at 1 and 6 months. Diabetes-related QOL improved in CSII fathers from baseline to 6 months. Psychological distress increased in current therapy mothers from baseline to 6 months. All subjects continued CSII after study completion.” (L. A. Fox, Florida Pediatric Diabetes Ctr., Jacksonville; lfox@lwpes.org)

Insulin Glargine Titration: An algorithm used by patients to titrate their insulin glargine doses performed better than one used by physicians, conclude authors of a 4,961-patient, multicenter trial (pp. 1282-8). Based on 24 weeks of open-label treatment of patients with suboptimally controlled type 2 diabetes, the authors write this about algorithms 1 (investigator led) and 2 (patient performed), “At baseline, mean diabetes duration was 12.3 ± 7.2 years, and 72% of subjects were pretreated with insulin. At end point, there was no significant difference in the incidence of severe hypoglycemia between algorithms 1 and 2 (0.9 vs. 1.1%). There was a significant reduction in HbA1c from 8.9 ± 1.3 to 7.8 ± 1.2%, with a greater decrease (P < 0.001) with algorithm 2 (–1.22%) versus algorithm 1 (–1.08%). Fasting blood glucose decreased from 170 to 110 mg/dl, with a greater decrease (P < 0.001) with algorithm 2 (–62 mg/dl) versus algorithm 1 (–57 mg/dl). Mean basal insulin dose increased from 22.9 ± 15.5 to 43.0 ± 25.5 IU, with a significant difference (P < 0.003) between algorithm 2 (21.6 IU) and algorithm 1 (18.7 IU).” (M. Davies, U. Hosp., Leicester, U.K.; melanie.davies@uhl-tr.nhs.uk)

Weight-Loss Strategies: Use of multiple therapies simultaneously was more effective at producing weight loss and improved diabetes control in a 2-year study of 59 overweight and obese patients (pp. 1311-5). Patients were randomly assigned to either combination therapy (meal replacement products, repetitive intermittent low-calorie-diet weeks, and pharmacologic therapy with sibutramine) for 2 years (C) or standard therapy for 1 year followed by combination therapy for the second year (S/C). The authors report, “After 2 years, the C therapy group had weight loss of 4.6 ± 1.2 kg (P < 0.001) and a decrease in HbA1c of 0.5 ± 0.3% (P = 0.08) from baseline. At 2 years, the C therapy group had significant reductions in BMI, fat mass, lean body mass, and systolic blood pressure. The S/C therapy group showed changes in weight and HbA1c in year 2 of the study that were similar to those demonstrated by the C therapy group in year 1.” (J. B. Redmon, redmo001@umn.edu)

Oral Insulin Spray: Tested in 7 healthy volunteers in a dose-ranging study, oral insulin spray had a faster onset and shorter duration of action than did subcutaneous regular insulin (pp. 1353-7). In addition, a dose-response relationship was demonstrated in the absorption and metabolic effects of four doses of the oral spray. While the maximum serum insulin levels were comparable between subcutaneous and high-dose oral insulin, the time to reach those levels was significantly shorter with the oral product (mean, 25.9 versus 145.7 minutes). (I. Raz, Hadassah Hosp., Jerusalem, Israel; ntv502@netvision.net.il)

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

PNN Pharmacotherapy Line
June 6, 2005 Vol. 12, No. 108
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
June 4 issue of Lancet (www.thelancet.com; 2005; 365).

Corticosteroids for Head Injury: Intravenous corticosteroids should not be used routinely in treatment of patients with head injuries, conclude investigators in the MRC CRASH trial (pp. 1957-9). The 10,008 adults who participated in the study randomly received either placebo or a 48-hour infusion of methylprednisolone beginning within 8 hours of head injury. At 6 months, the researchers recorded these outcomes: “The risk of death was higher in the corticosteroid group than in the placebo group (1,248 [25.7%] vs 1,075 [22.3%] deaths; relative risk 1.15, 95% CI 1.07–1.24; p = 0.0001), as was the risk of death or severe disability (1,828 [38.1%] vs 1,728 [36.3%] dead or severely disabled; 1.05, 0.99–1.10; p = 0.079). There was no evidence that the effect of corticosteroids differed by injury severity or time since injury.” (CRASH Trials Co-ordinating Ctr., London; crash@lshtm.ac.uk)

Palliative Care in Sub-Saharan Africa: For patients in sub-Saharan Africa who are dying of HIV or cancer, palliative care must be include resource considerations, according to a review article (pp. 1971-7). “Home and community-based care has been largely successful, but community capacity and the resources and clinical supervision necessary to sustain quality care are lacking,” authors write. “Coverage and referrals must be primary concerns. Simple lay and professional protocols have been developed, but opioid availability remains a major constraint. Areas of good practice, and areas where further success may be achieved include: attention to community needs and capacity; explicit frameworks for service development and palliative-care integration throughout the disease course (including antiretroviral provision); further education and protocols; strengthening and dissemination of diverse referral and care systems; increasing advocacy; and funding and technical skills to build audit and quality assessment.” (R. Harding, King's College, London)

>>>BMJ Highlights
Source:
June 4 issue of BMJ (www.bmj.org; 2005; 330).

Heroin for Drug Addiction: By reducing criminal behavior, coprescribing of heroin with methadone was less costly than provision of methadone alone in a study conducted in six Dutch clinics (pp. 1297 ff). Over a 12-month period, the cost-utility analysis conducted from a societal perspective showed 0.058 more quality-adjusted life-years per patient per year with coprescription of heroin plus methadone and a mean saving of 12,793 euros per patient per year. (M. G. W. Dijkgraaf, U. Amsterdam, Amsterdam; m.g.dijkgraaf@amc.uva.nl)

>>>PNN NewsWatch
* A Florida appeals court has broadened pharmacists’ liability by ruling that members of the profession have a duty to warn patients about the risks of medications. In Powers v. Thobani et al., two pharmacies are alleged to have filled prescriptions for narcotic analgesics, muscle relaxants, and benzodiazepines over a 6-month period during which the patient was being treated by a neurologist for neck and back pain. The patient died at age 46, and an autopsy concluded that the cause of death was “combined drug overdose” with oxycodone and diazepam. While a trial court had followed Florida precedents in dismissing the case against the pharmacies, the appeals court reversed this ruling, maintaining that the court was “unwilling to hold that under no set of alleged or discoverable facts could Powers sustain negligence claims against the pharmacies’ motions to dismiss under Florida law.” The defendants plan an appeal to the state supreme court (www.4dca.org/opfrm.html).

>>>PNN JournalWatch
* Attention-Deficit/Hyperactivity Disorder Among Adolescents: A Review of the Diagnosis, Treatment, and Clinical Implications, in Pediatrics, 2005; 115: 1734–46. Reprints: www.pediatrics.org; M. L. Wolraich, U. Oklahoma Health Sci. Ctr., Oklahoma City.

* Treatment of Attention-Deficit/Hyperactivity Disorder: Overview of the Evidence [technical report], in
Pediatrics, 2005; 115: e749–e757. Reprints: www.pediatrics.org; American Academy of Pediatrics.

* Informed Consent in Medication-Free Schizophrenia Research, in
American Journal of Psychiatry, 2005; 162: 1209–11. Reprints: ajp.psychiatryonline.org; D. J. Moser.

PNN Pharmacotherapy Line is published via e-mail each business day except 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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 7, 2005 Vol. 12, No. 109
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release articles and June 7 issue of the Annals of Internal Medicine (www.annals.org; 2005; 142).

Management of Menopause-Related Symptoms: Vasomotor symptoms, vaginal dryness and painful intercourse, sleep disturbances, and mood symptoms are some of the menopausal problems whose treatment is explored in an NIH statement (early-release article). After exploring therapies ranging hormones and antidepressants to complementary and alternative products, the panel concludes, “Menopause is ‘medicalized’ in contemporary U.S. society. There is great need to develop and disseminate information that emphasizes menopause as a normal, healthy phase of women's lives and promotes its demedicalization. Medical care and future clinical trials are best focused on women with the most severe and prolonged symptoms. Barriers to professional care for these women should be removed.” (NIH State-of-the-Science Panel, www.consensus.nih.gov; 888-644-2667)

Savings from Generic Drugs: Increased use of generic alternatives could reduce the nation’s prescription drug bill by $8.8 billion, report authors who analyzed data from the Medical Expenditure Panel Survey Household Component, 1997–2000 (pp. 891-7). “Fifty-six percent of all outpatient drugs were multisource products, accounting for 41% of total outpatient drug expenditures,” the researchers report. “Of these multisource drugs, 61% were dispensed as a generic. If a generic had been substituted for all corresponding brand-name outpatient drugs in 2000, the median annual savings in drug expenditures per person would have been $45.89 (interquartile range, $10.35 to $158.06) for adults younger than 65 years of age and $78.05 (interquartile range, $19.94 to $241.72) for adults at least 65 years of age. In these age groups, the national savings would have been $5.9 billion (95% CI, $5.5 billion to $6.2 billion) and $2.9 billion (CI, $2.6 billion to $3.1 billion), respectively, representing approximately 11% of drug expenditures.” (J. S. Haas, jhaas@partners.org)

OTC Statins: The role of pharmacists is one aspect explored in an analysis of whether statins could be available without a prescription (pp. 910-3): “The involvement of pharmacists and physicians in prescribing and dispensing statins should, in principle, reduce misuse. However, even the traditional prescription-based model of statin use has not resulted in optimal care. Many high-risk patients do not receive statins, and adherence to long-term therapy is poor. This may reflect the lack of a reliable system of primary care providers in the United States, especially for patients with inadequate insurance coverage. Interaction between pharmacists and patients was required in Britain's simvastatin policy, but it is not clear whether the more attenuated pharmacist–patient interaction that prevails in the United States would work as well.” (N. K. Choudhry, Brigham and Women’s Hosp., Boston)

>>>PNN NewsWatch
* Pfizer yesterday announced FDA approval of sildenafil for treatment of early-stage pulmonary arterial hypertension. For this indication, sildenafil will be marketed in white, round, 20-mg tablets under the brandname Revatio. In a news release, Pfizer notes that sildenafil is the first oral treatment for PAH to be approved for patients with an early stage of the disease, allowing physicians to treat patients earlier in this progressive disorder. The most common adverse effects observed in a 12-week clinical trial of 277 patients were headache, dyspepsia, flushing, epistaxis, and insomnia.

*
Pharmaceutical manufacturers are the targets of investigations in 150 cases of alleged pricing fraud, the Wall Street Journal reports in a page 1 story this morning. State and federal prosecutors are looking into “allegations that drug companies cheat state and federal health-care programs by inflating prices, offering undisclosed rebates to distributors or marketing drugs for unapproved uses,” the newspaper reports. The article points to several high-profile cases that have already been settled, including $430 million from Pfizer for Neurontin pricing practices; $355 million, AstraZeneca for Zoladex; $345 million, Schering-Plough for Claritin; $257 million, Bayer for Cipro and Adalat; and $88 million, GlaxoSmithKline for Paxil and Flonase.

PNN Pharmacotherapy Line is published via e-mail each business day except 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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 8, 2005 Vol. 12, No. 110
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
June 8 issue of JAMA, a special issue on tuberculosis (www.jama.com; 2005; 293).

Multidrug-Resistant TB in California: Multidrug-resistant Mycobacterium tuberculosis is a persistent problem at a low but troubling rate in California, according to an analysis of data from 1994 through 2003 (pp. 2732-9). “Of 38,291 reported TB cases, 28,712 (75%) were tested for resistance to at least isoniazid and rifampin; of these, 407 MDR-TB cases (1.4%) were reported from 38 of 61 California health jurisdictions (62%); the proportion of MDR-TB cases did not significantly change over the study period (P = .87),” write the researchers. “Cases of MDR-TB were twice as likely to have cavitary lesions compared with non–MDR-TB cases (P < .001) and were 7 times more likely to have reported previous treatment for TB (P < .001). Of MDR-TB cases with outcomes, 231 (67%) completed therapy, and those with MDR-TB were significantly less likely to complete therapy than those without MDR-TB (P < .001). Multivariate analysis identified previous TB diagnosis, positive acid-fast bacilli sputum smear results, Asian/Pacific Islander ethnicity, time in the United States less than 5 years at the time of diagnosis, and outcomes of ‘died’ and ‘moved’ as factors associated with MDR-TB.” (R. M. Granich, CDC, Atlanta; granichrm@state.gov)

Adding national and global perspectives on MDR-TB in an accompanying commentary, an author notes (pp. 2788-90), “With uncharacteristic optimism, the Centers for Disease Control and Prevention still has a Division of Tuberculosis Elimination. Using current tools, resistant TB is unlikely to be eradicated. However, history has shown that resistance can be reduced through more appropriate treatment programs and the spread of resistant strains can be reduced through public health measures. Some of the articles in this issue of
JAMA clearly show that multidrug resistance in the United States is inextricably linked to resistance in the rest of the world. Therefore, to control resistance in the United States, areas where resistance is epidemic must receive assistance and exquisite care must be taken not to create new problems on continents like Africa. In the future, with new drugs, tests, and vaccines, the elimination of multidrug resistance may be achievable but difficult.” (M. D. Nettleman, Michigan State U., East Lansing; mary.nettleman@ht.msu.edu)

Isoniazid Preventive Therapy in Men with HIV: In a South African clinic, use of primary isoniazid preventive therapy in men with HIV infections lowered the incidence of tuberculosis by 38% overall and by 46% among those with no TB history before the study (pp. 2719-25). Participants self-administered isoniazid 300 mg/day for 6 months, and they were followed for a median of 22.1 months, with these results: “A total of 1016 of 1655 men included in the analysis attended the clinic at least once. Six hundred seventy-nine (97%) of 702 men eligible to start primary isoniazid preventive therapy did so. The tuberculosis incidence rate before vs after clinic enrollment was 11.9 vs 9.0 per 100 person–years, respectively (incidence rate ratio [IRR] after adjustment for calendar period, 0.68; 95% confidence interval [CI], 0.48–0.96). In a multivariable analysis adjusting for calendar period, age, and silicosis grade, the tuberculosis IRR for clinic enrollment was 0.62 (95% CI, 0.43–0.89). In a further analysis excluding individuals with a history of tuberculosis (and, hence, ineligible for isoniazid preventive therapy), the adjusted IRR for clinic enrollment was 0.54 (95% CI, 0.35–0.83).” (A. D. Grant, London Sch. of Hygiene and Tropical Med., London; alison.grant@lshtm.ac.uk)

>>>PNN NewsWatch
* Geriatric pharmacists can help “sort the tangle of pills many seniors take,” according to a June 6 profile of U. Southern Calif. pharmacy professor Bradley Williams in California’s East Valley Tribune (www.eastvalleytribune.com/index.php?sty=42563).

* A
Wal-Mart pharmacy system of bar-code scanners and Palm Pilots “really frees [pharmacists] up to interact with customers and just listen,” pharmacist Yolanda Jones shares in a June 3 article in the Benton County (Ark.) Daily Record (nwanews.com/story.php?paper=bcdr§ion=News&storyid=21219).

PNN Pharmacotherapy Line is published via e-mail each business day except 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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 9, 2005 Vol. 12, No. 111
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
June 9 issue of the New England Journal of Medicine (content.nejm.org; 2005; 352).

Vitamin E, Donepezil for Cognitive Impairment: Among patients with mild cognitive impairment, progression to Alzheimer’s disease was significantly lower during the first of 3 years of therapy with donepezil, compared with placebo, but significant effects were more pronounced early in therapy, and vitamin E supplements showed no protective effects (pp. 2379-88; reported as an early-release article in PNN, Apr. 14; ). Researchers tested vitamin E 2000 IU daily and donepezil 10 mg daily, finding the following: “A total of 769 subjects were enrolled, and possible or probable Alzheimer’s disease developed in 212. The overall rate of progression from mild cognitive impairment to Alzheimer’s disease was 16 percent per year. As compared with the placebo group, there were no significant differences in the probability of progression to Alzheimer’s disease in the vitamin E group (hazard ratio, 1.02; 95 percent confidence interval, 0.74 to 1.41; P = 0.91) or the donepezil group (hazard ratio, 0.80; 95 percent confidence interval, 0.57 to 1.13; P = 0.42) during the three years of treatment. Prespecified analyses of the treatment effects at 6-month intervals showed that as compared with the placebo group, the donepezil group had a reduced likelihood of progression to Alzheimer’s disease during the first 12 months of the study (P = 0.04), a finding supported by the secondary outcome measures. Among carriers of one or more apolipoprotein E4 alleles, the benefit of donepezil was evident throughout the three-year follow-up. There were no significant differences in the rate of progression to Alzheimer’s disease between the vitamin E and placebo groups at any point, either among all patients or among apolipoprotein E4 carriers.” (R. C. Petersen, peter8@mayo.edu)

Listing lessons from the above study, an editorialist writes (pp. 2439-41): “First, symptoms of memory loss in older persons should be taken seriously, since they may represent the beginning of Alzheimer’s disease, and—once more effective early interventions are available—it will be critical to ask patients about these symptoms and learn to recognize them as early as possible. Second, at least one standard Alzheimer’s disease therapy, donepezil, may offer some benefit, but any such benefit is quite limited and apparently transient. Last and most important, this study puts to rest the hope that early intervention with vitamin E can delay the onset of Alzheimer’s disease, joining a group of recent trials of vitamin E with disappointing results.” (D. Blacker, Harvard Med. Sch., Boston)

Intensive Statin Therapy for Calcific Aortic Stenosis: In the Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression (SALTIRE), investigators learned that atorvastatin 80 mg daily does not halt the progression of calcific aortic stenosis or induce its regression (pp. 2389-97). “Seventy-seven patients were assigned to atorvastatin and 78 to placebo, with a median follow-up of 25 months (range, 7 to 36),” the authors note. “Serum low-density lipoprotein cholesterol concentrations remained at 130 ± 30 mg per deciliter in the placebo group and fell to 63 ± 23 mg per deciliter in the atorvastatin group (P < 0.001). Increases in aortic-jet velocity were 0.199 ± 0.210 m per second per year in the atorvastatin group and 0.203 ± 0.208 m per second per year in the placebo group (P=0.95; adjusted mean difference, 0.002; 95 percent confidence interval, –0.066 to 0.070 m per second per year). Progression in valvular calcification was 22.3 ± 21.0 percent per year in the atorvastatin group, and 21.7 ± 19.8 percent per year in the placebo group (P = 0.93; ratio of post-treatment aortic-valve calcium score, 0.998; 95 percent confidence interval, 0.947 to 1.050).” (D. E. Newby, Royal Infirmary, Edinburgh, U.K., d.e.newby@ed.ac.uk)

An editorialist notes that most studies of statins for this indication are small and relatively short induration (pp. 2441-3). He adds, “The prescription of statins is not justified for a stenotic aortic valve unless there are also other indications for therapy. This is an important study that underscores the necessity of conducting large randomized trials assessing the effects of statins on both hemodynamic progression and the outcome of aortic stenosis.” (R. Rosenhek, Med. U. Vienna, Vienna)

PNN Pharmacotherapy Line is published via e-mail each business day except 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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 10, 2005 Vol. 12, No. 112
Providing news and information about medications and their proper use

>>>Pharmacotherapy Update
Source:
June issue of Pharmacotherapy (www.pharmacotherapy.org; 2005; 25).

Measuring Adherence with Community Pharmacy Refill Records: For patients with HIV or AIDS, the community pharmacy refill record provides “a convenient, accessible, and useful tool for assessing adherence and predicting viral load outcomes,” concludes a retrospective review of 94 patients (pp. 790-6). Matching records of a university-based HIV clinic with refill records of a local community pharmacy, the authors found, “The continuous, multiple-interval measure of medication gaps (CMG), a measure of drug nonadherence, was calculated for each antiretroviral agent. Viral load information was retrieved from the clinic records of patients who had a community pharmacy refill record documenting the previous 2 years. As refill nonadherence increased, viral load response increased, following an approximately sigmoid relationship. When the CMG score was less than 0.10, the viral load response did not change appreciably. The steepest rise in viral load response occurred with a CMG score ranging from 0.10–0.19. For values of 0.20 or greater, the viral load response was less sensitive to adherence performance. The probability (i.e., sensitivity) of having at least a 10% nonadherence record given a viral load greater than 1000 copies/ml was 80%.” (A. L. Leeds, UCSF)

Pharmacist Detection of PAD: At a university-based geriatrics clinic, pharmacists successfully used a questionnaire and handheld Doppler instrument to screen 41 patients for peripheral arterial disease (pp. 797-802). Patients were older than 55 years and referred by primary care physicians. “The pharmacists administered the San Diego Claudication Questionnaire and performed Doppler examinations to calculate ankle-to-brachial indexes (ABIs),” the investigators report. “Patients with symptoms of claudication or with an ABI of 0.9 or less were considered to have possible peripheral arterial disease. Each diagnosis was confirmed by a physician. These patients were either referred for further evaluation, provided with immediate treatment, or told to continue their current drug regimen, if appropriate.... Eight (19.5%) of the 41 patients were diagnosed with peripheral arterial disease. Antiplatelet therapy was started in five patients, and one patient was referred to a vascular specialist.” (K. Zerumsky, U. Pittsburgh)

>>>PNN NewsWatch
* One of several pharmacy-related reports in this morning’s papers, an article in the Wall Street Journal details the efforts of pharmacy organizations to set up controls that will keep dextromethorphan products on retail shelves. With pharmaceutical manufacturers and trade groups conceding battles over laws at the state level that require restricted distribution of pseudoephedrine products, the National Association of Chain Drug Stores and the Consumer Healthcare Products Association are working to keep the same thing from happening to DXM products. Some 9% of teens in a recent national survey reported using these cough medications to get high, the Journal article notes.

* A page 1 story in the
New York Times details the interplay between FDA and Johnson & Johnson in the years leading up to the market withdrawal of cisapride. “Propulsid's history has striking parallels with the painkillers now at the center of controversy,” the article notes. “Dozens of studies sponsored by Johnson & Johnson that might have warned doctors away were never published, just as the pharmaceutical manufacturer Pfizer failed to publish an early study of Celebrex that indicated a heart risk. And Johnson & Johnson was able to delay and soften some proposed label changes, just as Merck later did with Vioxx.”

*
Rofecoxib, diclofenac, and ibuprofen increase patients’ risk of myocardial infarction, according to a nested case-control study in tomorrow’s BMJ (www.bmj.org) that is being highlighted in the lay media. Monday’s PNN will contain a full report on the study as part of its usual coverage of the British medical weeklies.

PNN Pharmacotherapy Line is published via e-mail each business day except 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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 13, 2005 Vol. 12, No. 113
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
June 11 issue of BMJ (www.bmj.org; 2005; 330).

Safety of NSAIDs: Two articles examine the interplay between various selective and nonselective NSAIDs and heart disease.

In an observational case–control study, current use of rofecoxib, diclofenac, and ibuprofen were all associated with elevated risks of myocardial infarction (pp. 1366 ff). “A significantly increased risk of myocardial infarction was associated with current use of rofecoxib (adjusted odds ratio 1.32, 95% confidence interval 1.09 to 1.61) compared with no use within the previous three years; with current use of diclofenac (1.55, 1.39 to 1.72); and with current use of ibuprofen (1.24, 1.11 to 1.39),” the investigators write of 9,218 patients with first-ever myocardial infarction and 86,349 matched controls. “Increased risks were associated with the other selective NSAIDs, with naproxen, and with non-selective NSAIDs; these risks were significant at < 0.05 rather than < 0.01 for current use but significant at < 0.01 in the tests for trend. No significant interactions occurred between any of the NSAIDs and either aspirin or coronary heart disease.” (J. Hippisley-Cox, U. Park, Nottingham, U.K.; Julia.hippisley-cox@nottingham.ac.uk)

In elderly patients with heart failure, celecoxib appeared to be safer than rofecoxib or nonselective NSAIDs, adding a new twist to the debate over safety of these agents (pp. 1370 ff.). Among 2,256 patients older than 65 who were prescribed a COX-2 inhibitor or a nonselective NSAID following hospitalization for heart failure in 2000–2002, the researchers found, “The risk of death and recurrent congestive heart failure combined was higher in patients prescribed NSAIDs or rofecoxib than in those prescribed celecoxib (hazard ratio 1.26, 95% confidence interval 1.00 to 1.57 and 1.27, 1.09 to 1.49, respectively). The findings were similar when the outcomes were assessed separately. In pairwise analysis, the risks of death and recurrent congestive heart failure, combined and separate, were similar between patients prescribed NSAIDs and rofecoxib.” (L. Pilote, McGill U., Montreal; louise.pilote@mcgill.ca)

>>>PNN NewsWatch
* Pregabalin (Lyrica, Pfizer) has been approved by FDA for a third indication, adjunctive treatment of partial-onset seizures in adults. The agent, whose market launch had been delayed pending this decision, was initially approved for management of neuropathic pain associated with diabetic peripheral neuropathy and postherpetic neuralgia (see PNN, Jan. 3).

* A second pertussis booster vaccine indicated for older patients,
Adacel, was licensed by FDA on Friday. It contains Tetanus Toxoid (T), Reduced Diphtheria Toxoid (d), and Acellular Pertussis Vaccine (ap), Adsorbed, and is indicated for use in adolescents and adults ages 11–64 years, a broader target age group than that garnered by the recently approved Boostrix (Glaxo-SmithKline; see PNN, May 4). Over the past 20 years, rates of pertussis have been increasing among very young infants—who have not received all of their shots and in whom the disease is serious—and in adolescents and adults. Experts believe that older family members may be passing the organism to younger siblings, a problem that will be addressed by use of these booster vaccines.

>>>PNN JournalWatch
* Treatment of Head Louse Infestation with 4% Dimeticone Lotion: Randomised Controlled Equivalence Trial, in BMJ, 2005 (early release). Reprints: www.bmj.org; doi:10.1136/bmj.38497.506481.8F; I. F. Burgess; ian@insectresearch.com

* Immediate Versus Deferred Antiepileptic Drug Treatment for Early Epilepsy and Single Seizures: A Randomised Controlled Trial, in
Lancet, 2005; 365: 2007–13. Reprints: www.thelancet.com; D. Chadwick, U. Liverpool, Liverpool; d.w.chadwick@liv.ac.uk

* Aspirin Under Fire: Aspirin Use in the Primary Prevention of Coronary Heart Disease, in
Pharmacotherapy, 2005; 25: 847–61. Reprints: www.pharmacotherapy.org; B. D. Lucas, Jr., Charleston Area Med. Ctr., Charleston, W.V.; dan.lucas@camc.org.

* Epoetin alfa for the Treatment of Combination Therapy–Induced Hemolytic Anemia in Patients Infected with Hepatitis C Virus, in
Pharmacotherapy, 2005; 25: 862–75. Reprints: www.pharmacotherapy.org; A. M. Rivkin, Long Island U., Brooklyn, N.Y.; anastasia.rivkin@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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 14, 2005 Vol. 12, No. 114
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
June 13 Archives of Internal Medicine (www.archinternmed.com; 2005; 165).

PPIs for Diagnosing GERD in Patients with Noncardiac Chest Pain: Primary care physicians can use a short course of proton pump inhibitor therapy (up to 4 weeks) to determine whether patients with noncardiac chest pain have gastroesophageal reflux disease, according to a meta-analysis that included six randomized controlled studies (pp. 1222-8). “The overall sensitivity and specificity of a PPI test were 80% (95% confidence interval [CI], 71%–87%) and 74% (95% CI, 64%–83%), respectively, compared with 19% (95% CI, 12%–29%) and 77% (95% CI, 62%–87%), respectively, in the placebo group. The PPI test showed a significant higher discriminative power, with a summary diagnostic odds ratio of 19.35 (95% CI, 8.54–43.84) compared with 0.61 (95% CI, 0.20–1.86) in the placebo group. The impact of the prevalence of GERD and treatment duration on the accuracy of the test could not be determined because of the lack of an adequate number of studies.” (B. C. Y. Wong, U. Hong Kong, Hong Kong; bcywong@hku.hk)

Calcium/Vitamin D & PMS: High intake of calcium and vitamin D may reduce the risk of premenstrual syndrome, conclude authors who conducted a case–control study nested within the prospective Nurses’ Health Study II (pp. 1246-52). Among 1,057 women with PMS and 1,968 women without symptoms or diagnosis of PMS, food-frequency questionnaires completed in 1991, 1995, and 1999 show the following, “After adjustment for age, parity, smoking status, and other risk factors, women in the highest quintile of total vitamin D intake (median, 706 IU/d) had a relative risk of 0.59 (95% confidence interval, 0.40–0.86) compared with those in the lowest quintile (median, 112 IU/d) (P = .01 for trend). The intake of calcium from food sources was also inversely related to PMS; compared with women with a low intake (median, 529 mg/d), participants with the highest intake (median, 1283 mg/d) had a relative risk of 0.70 (95% confidence interval, 0.50–0.97) (P = .02 for trend). The intake of skim or low-fat milk was also associated with a lower risk (P < .001).” (E. R. Bertone-Johnson, ebertone@schoolph.umass.edu)

Obese Women & Adequacy of Breast Cancer Chemotherapy: Overweight and obese women with breast cancer are receiving intentionally reduced doses of adjuvant chemotherapy, authors report, and use of full weight-based doses have the potential to improve outcomes (pp. 1267-73). A retrospective cohort study of 9,672 women with breast cancer who were treated with doxorubicin hydrochloride and cyclophosphamide between 1990 and 2001 assessed the quality of chemotherapy, showing that, “First-cycle dose reductions (defined as a dose proportion of <0.9 compared with standard published doses) were administered to 9% of the healthy weight, 11% of the overweight, 20% of the obese, and 37% of the severely obese women (P < .001). First-cycle reduction was independently associated with being overweight (P = .03), obese (P < .001), severely obese (P < .001), older than 60 years (P < .001), and having a serious comorbid condition (P = .03). Practices varied greatly in the use of dose reductions in overweight and obese patients. Severe obesity was independently associated with a lower likelihood of admission for febrile neutropenia, even among those subjects given full weight-based doses (odds ratio, 0.61; 95% confidence interval, 0.38–0.97).” (J. J. Griggs, U. Rochester, Rochester, N.Y.; Jennifer_Griggs@urmc.rochester.edu)

Quality of Antipsychotic Drug Prescribing in Nursing Homes: The use of antipsychotic agents among nursing home residents has rebounded, according to an analysis of data from 2000 and 2001, and the agents are often being used outside guidelines without any improvement in behavioral symptoms (pp. 1280-5). Analyzing a sample 2.5 million Medicare beneficiaries in NHs, the investigators report that 23.% of those on antipsychotic agents “had no appropriate indication, 17.2% had daily doses exceeding recommended levels, and 17.6% had both inappropriate indications and high dosing.” (B. A. Briesacher, Becky.Briesacher@umassmed.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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 15, 2005 Vol. 12, No. 115
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
June 15 issue of JAMA (www.jama.com; 2005; 293).

Orlistat Use in Adolescents: In a trial that supports the FDA-approved indication for use of orlistat for weight reduction in adolescents, 539 obese adolescents had significantly greater reductions in body mass index when treated with the lipase inhibitor than with placebo (pp. 2873-83). Used in combination with diet, exercise, and behavioral modification, orlistat 120 mg three times daily for 1 year produced these results: “There was a decrease in BMI in both treatment groups up to week 12, thereafter stabilizing with orlistat but increasing beyond baseline with placebo. At the end of the study, BMI had decreased by 0.55 with orlistat but increased by 0.31 with placebo (P = .001). Compared with 15.7% of the placebo group, 26.5% of participants taking orlistat had a 5% or higher decrease in BMI (P = .005); 4.5% and 13.3%, respectively, had a 10% or higher decrease in BMI (P = .002). At study end, weight had increased 0.53 kg with orlistat and 3.14 kg with placebo (P < .001). Dual-energy x-ray absorptiometry showed that this difference was explained by changes in fat mass. Waist circumference decreased in the orlistat group but increased in the placebo group (–1.33 cm vs +0.12 cm; P<.05). Generally mild to moderate gastrointestinal tract adverse events occurred in 9% to 50% of the orlistat group and in 1% to 13% of the placebo group.” (J-P Chanoine, British Columbia Children’s Hosp., Vancouver; jchanoine@cw.bc.ca)

An editorialist cautions against use of orlistat without the additional interventions used in this trial (pp. 2932-4): “Much more data are needed on the long-term benefits and risks of orlistat therapy (and other pharmacologic therapies) administered in a variety of treatment settings. Much more information also is needed about how best to deliver treatment (including in schools), the type of diet that is palatable to adolescents yet results in weight loss, and the types of sustainable exercise programs that adolescents find enjoyable. Until these data are available, use of orlistat should be limited to settings that offer comprehensive assessment and management of obese adolescents. There is no justification for using it as a stand-alone treatment.” (A. Joffe, Johns Hopkins U., Baltimore; ajoffe@jhu.edu)

Fish Oil Supplements & VT: Fish oil supplementation failed to help 200 patients with recent episodes of sustained ventricular arrhythmia and an implantable cardioverter defibrillator, and the agents may have been proarrhythmic in some patients, according to a trial that tested omega-3 polyunsaturated fatty acids (pp. 2884-91; M. H. Raitt, merritt.raitt@med.va.gov)

>>>PNN NewsWatch
* “The use of nesiritide should be strictly limited to patients presenting to the hospital with acutely decompensated congestive heart failure who have dyspnea at rest,” concludes a panel of cardiovascular and heart failure experts convened by Scios, the manufacturer of Natrecor. This use is narrower than the FDA-approved indication contained in product labeling, which includes patients who have symptoms with minimal activity. While advising that the FUSION 2 trial continue, the panel recommended that nesiritide not be used to replace diuretics and not be used for intermittent outpatient infusion, for scheduled repetitive use, to improve renal function, or to enhance diuresis. The panel’s full report is accessible at www.natrecor.com.

* Bristol-Myers Squibb, in a move that goes beyond voluntary restrictions expected to be announced next month, has announced that it plans a self-imposed moratorium on
direct-to-consumer advertising during the first year of marketing of new chemical entities. In an article in this morning’s New York Times, a BMS spokesperson is quoted as saying, “We want to make sure that before we start mass media—television, radio and print branded advertising—that physicians have a level of comfort about the treatment and which patients are appropriate for it.” The company’s new “communications code" is posted on its Web site at www.bms.com/static/pdf/DTC_6_13_05.pdf.

PNN Pharmacotherapy Line is published via e-mail each business day except 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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 16, 2005 Vol. 12, No. 116
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
June 16 issue of the New England Journal of Medicine (content.nejm.org; 2005; 352).

Treatment of Gestational Diabetes: Serious perinatal morbidity is reduced by treatment of gestational diabetes mellitus, and women’s health-related quality of life may be improved, according to a study of 1,000 women who were between 24 and 34 weeks’ gestation at study admission (pp. 2477-86). Intervention patients received dietary advice, blood glucose monitoring, and insulin therapy as needed, and cases of serious perinatal complications (death, shoulder dystocia, bone fracture, and nerve palsy) were significantly fewer in this group than in the routine-care arm (1% versus 4%). The authors add, “However, more infants of women in the intervention group were admitted to the neonatal nursery (71 percent vs. 61 percent; adjusted relative risk, 1.13; 95 percent confidence interval, 1.03 to 1.23; P = 0.01). Women in the intervention group had a higher rate of induction of labor than the women in the routine-care group (39 percent vs. 29 percent; adjusted relative risk, 1.36; 95 percent confidence interval, 1.15 to 1.62; P < 0.001), although the rates of cesarean delivery were similar (31 percent and 32 percent, respectively; adjusted relative risk, 0.97; 95 percent confidence interval, 0.81 to 1.16; P = 0.73). At three months post partum, data on the women's mood and quality of life, available for 573 women, revealed lower rates of depression and higher scores, consistent with improved health status, in the intervention group.” (C. A. Crowther, U. Adelaide; Adelaide, Australia)

Treatment of Relapsed Multiple Myeloma: For treating patients with multiple myeloma who have had a relapse after one to three previous therapies, bortezomib proved superior to high-dose dexamethasone in a study with 699 participants (pp. 2487-98). “Patients treated with bortezomib had higher response rates, a longer time to progression (the primary end point), and a longer survival than patients treated with dexamethasone,” write the investigators. “The combined complete and partial response rates were 38 percent for bortezomib and 18 percent for dexamethasone (P < 0.001), and the complete response rates were 6 percent and less than 1 percent, respectively (P < 0.001). Median times to progression in the bortezomib and dexamethasone groups were 6.22 months (189 days) and 3.49 months (106 days), respectively (hazard ratio, 0.55; P < 0.001). The one-year survival rate was 80 percent among patients taking bortezomib and 66 percent among patients taking dexamethasone (P = 0.003), and the hazard ratio for overall survival with bortezomib was 0.57 (P = 0.001). Grade 3 or 4 adverse events were reported in 75 percent of patients treated with bortezomib and in 60 percent of those treated with dexamethasone.” (P. G. Richardson, Dana–Farber Cancer Inst., Boston; paul_richardson@dfci.harvard.edu)

MLN02 for Ulcerative Colitis: A humanized antibody to alpha-4, beta-7 integrin was more effective than placebo for induction of clinical and endoscopic remission of active ulcerative colitis, report authors of a 181-pateint study (pp. 2499-507). The 6-week trial allowed use of mesalamine for eligible patients but no other treatments for colitis. The investigators report, “Clinical remission rates at week 6 were 33 percent, 32 percent, and 14 percent for the group receiving 0.5 mg of MLN02 per kilogram, the group receiving 2.0 mg per kilogram, and the placebo group, respectively (P = 0.03). The corresponding proportions of patients who improved by at least 3 points on the ulcerative colitis clinical score were 66 percent, 53 percent, and 33 percent (P = 0.002). Twenty-eight percent of patients receiving 0.5 mg per kilogram and 12 percent of those receiving 2.0 mg per kilogram had endoscopically evident remission, as compared with 8 percent of those receiving placebo (P = 0.007).” (B. G. Feagan, Robarts Research Inst., London, Ont., Canada; bfeagan@robarts.ca)

Survival After Rabies Infection: A 15-year-old girl with clinical rabies survived after treatment with coma induction, ketamine, midazolam, ribavirin, and amantadine (pp. 2508-14). In addition to the text description of the case, a video of the patient is available on the journal’s Web site. (R. E. Willoughby, Med. Coll. of Wisconsin, Milwaukee; rewillou@mail.mcw.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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 17, 2005 Vol. 12, No. 117
Providing news and information about medications and their proper use

>>>First-in-Class Tigecycline Approved for MRSA
Tigecycline (Tygacil, Wyeth), the first of the glycylcyclines, has been approved by FDA for intravenous treatment of complicated intra-abdominal infections (cIAI) and complicated skin and skin structure infections (cSSSI) in adults caused by a broad range of organisms, including methicillin-resistant Staphylococcus aureus. Tigecycline binds to the 30S subunit of bacterial ribosomes, thereby inhibiting protein translation and blocking entry of transfer RNA.

Tigecycline can be used as an empiric monotherapy to treat a variety of cIAI and cSSSI, both hospital- and community-acquired, including complicated appendicitis, infected burns, intra-abdominal abscesses, deep soft tissue infections, and infected ulcers, Wyeth noted in a news release. In clinical trials, empiric monotherapy with tigecycline provided comparable clinical cures rates in cSSSI to vancomycin and aztreonam. Empiric monotherapy with tigecycline also provided clinical cure rates comparable with those of imipenem/cilastatin. The overall discontinuation rate for tigecycline (5.0%) was comparable with those of vancomycin and aztreonam (5.3%) and imipenem/cilastatin (4.4%).

Tigecycline is contraindicated in patients with known hypersensitivity to the drug. It should be administered with caution in patients with known hypersensitivity to tetracyclines, as it may have adverse effects similar to these agents. In clinical trials, the most common treatment-emergent adverse events in patients treated with tigecycline were nausea (29.5%) and vomiting (19.7%).

The recommended dosage regimen is 100 mg initially followed by 50 mg infused over 30–60 minutes every 12 hours. Tigecycline does not require dosage adjustment in patients with impaired renal function, but maintenance doses should be halved in patients with severe hepatic impairment (Child Pugh category C).

>>>PNN NewsWatch
* MedImmune announced yesterday that its next-generation influenza vaccine proved immunogenic in a Phase III study. Among 980 healthy individuals aged 5 to 49 years, a refrigerator-stable formulation of live, attenuated intranasal influenza vaccine (cold adapted influenza vaccine, trivalent [CAIV-T]) produced immunogenic responses equivalent to those of the current frozen formulation, FluMist. Children between the ages of 5 and 8 years of age (n = 414) received two vaccine doses, while participants 9 years of age and older (n = 566) received one dose of the vaccines.

* Chiron Corp. has lowered its estimates of the amount of
influenza vaccine it will be able to supply this year. Rather than the 25–30 million doses the company predicted in April, Chiron now says its supply will be in the 18–26 million range. CDC officials responded that this should not cause problems with supply, assuming Sanofi Pasteur and GlaxoSmithKline produce the amount of vaccine they have estimated. Sterility problems at a Chiron plant in England produced last season’s shortfall in vaccine supply. British health authorities have since restored the plant’s license, but an FDA inspection coming up next month will determine whether product from the plant can be used in the U.S.

* FDA officials have determined that patients taking
risperidone have a higher incidence of benign pituitary tumors, according to this morning’s Wall Street Journal. These findings are being presented at a U. Pittsburgh conference today, the newspaper noted.

* An FDA advisory panel yesterday unanimously supported approval of a two-drug combination product for treatment of heart failure, and seven of nine members voted in favor of labeling that supports use specifically in blacks. NitroMed’s BiDil contains
isosorbide dinitrate and hydralazine hydrochloride. If FDA concurs with the panel’s majority, the product would become the first indicated for a specific race of people.

* President Bush will today kick off a $300 million government public relations campaign aimed at getting Medicare beneficiaries to enroll in the
Part D prescription drug benefit. The enrollment period runs Nov. 15 through May 15.

PNN Pharmacotherapy Line is published via e-mail each business day except 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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 20, 2005 Vol. 12, No. 118
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
June 18 issue of Lancet (www.thelancet.com; 2005; 365).

CMV Prevention Following Transplants: Recipients of solid-organ transplants should receive antiviral prophylaxis that guards against cytomegalovirus infection, according to results of a meta-analysis (pp. 2105-15). The authors note: “Compared with placebo or no treatment, prophylaxis with aciclovir, ganciclovir, or valaciclovir significantly reduced the risks of cytomegalovirus disease (19 trials, 1981 patients; relative risk 0.42 [95% CI 0.34–0.52]), cytomegalovirus infection (17 trials, 1786 patients; 0.61 [0.48–0.77]), and all-cause mortality (17 trials, 1838 patients; 0.63 [0.43–0.92]), mainly owing to lower mortality from cytomegalovirus disease (seven trials, 1300 patients; 0.26 [0.08–0.78]). Prophylaxis also lowered the risks of disease caused by herpes simplex or zoster virus, bacterial infections, and protozoal infections, but not fungal infection, acute rejection, or graft loss. Meta-regression showed no significant difference in the risk of cytomegalovirus disease or all-cause mortality by organ transplanted or cytomegalovirus serostatus; no conclusions were possible for cytomegalovirus-negative recipients of negative organs. In trials of direct comparisons, ganciclovir was more effective than aciclovir in preventing cytomegalovirus disease. Valganciclovir and intravenous ganciclovir were as effective as oral ganciclovir.” (E. Hodson, Children's Hosp., Westmead, Australia)

>>>PNN NewsWatch
* FDA on Friday took the expected action of restricting the indications of and access to gefitinib (Iressa, AstraZeneca). Approved under an accelerated application in May 2003 for treatment nonsmall-cell lung cancer, gefitinib has since failed to live up to its billing, with only about 10% of patients showing improvements in a surrogate marker of tumor response. In addition, erlotinib (Tarceva, Genentech) has since been approved, and it has established effectiveness for improved overall survival, a direct outcome, rather than just a surrogate marker. Under a new Iressa label posted to the FDA Web site (www.fda.gov/cder/foi/label/2005/021399s008lbl.pdf) and a related talk paper, the agent should be used only for patients locally advanced or metastatic conditions who are currently receiving and benefiting from gefitinib, those who have previously received and benefited from the drug, and previously enrolled patients or new patients in certain clinical trials previously approved by an institutional review board. In addition, according to a report in this morning’s Wall Street Journal, AstraZeneca will after Sept. 15 limit distribution of the drug to a single mail-service pharmacy.

* FDA’s new
Drug Safety Oversight Board met for the first time on Friday, discussing organizational issues and logistics. The board, made up primarily of FDA staff members and other government employees, was created after the Vioxx market withdrawal last fall.

>>>PNN JournalWatch
* Recognition and Management of Complications of New Recreational Drug Use, in Lancet, 2005; 365: 2137–45. Reprints: www.thelancet.com; G. A. Ricaurte, Johns Hopkins Med. Inst., Baltimore; Ricaurte@jhmi.edu

* Aspirin for Everyone Older than 50?: For and Against, in
BMJ, 2005; 330: 1400–1 and 1442–3. Reprints: www.bmj.org; P. Elwood; C. Baigent.

* Smoking and Timing of Cessation: Impact on Pulmonary Complications After Thoracotomy, in
Chest, 2005; 127: 1977–83. Reprints: www.chestjournal.org; D. A. White, Memorial Sloan-Kettering Hosp., New York; whited@mskcc.org

* Warfarin Maintenance Dosing Patterns in Clinical Practice: Implications for Safer Anticoagulation in the Elderly Population, in
Chest, 2005; 127: 2049–56. Reprints: www.chestjournal.org; D. A. Garcia, davgarcia@salud.unm.edu

* Executive Function and Cognitive Subprocesses in First-Episode, Drug-Naive Schizophrenia: An Analysis of N-Back Performance, in
American Journal of Psychiatry, 2005; 162: 1206–8. Reprints: ajp.psychiatryonline.org; S. Krieger.

* Informed Consent in Medication-Free Schizophrenia Research, in
American Journal of Psychiatry, 2005; 162: 1209–11. Reprints: ajp.psychiatryonline.org; D. J. Moser.

* Cost-Effective Screening for the Metabolic Syndrome in Patients Treated With Second-Generation Antipsychotic Medications, in
American Journal of Psychiatry, 2005; 162: 1209–11. Reprints: ajp.psychiatryonline.org; D. Straker.

PNN Pharmacotherapy Line is published via e-mail each business day except 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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 21, 2005 Vol. 12, No. 119
Providing news and information about medications and their proper use

>>>Internal Medicine Update
Source:
June 21 issue of the Annals of Internal Medicine (www.annals.org; 2005; 142).

Use of HRT in Patients with SLE: While mild or moderate flares sometimes occur when short courses of hormone-replacement therapy are used in patients with systemic lupus erythematosus, the agents provide more benefits than risks in managing symptoms of menopause (pp. 953-62). That conclusion is reached in a study of 351 women with a mean age of 50, 18.5% of whom had stable-active SLE and 81.5% had inactive conditions. During 12 months of treatment with conjugated estrogens 0.625 mg plus medroxyprogesterone 5 mg on 12 days per month, the investigators found these results in active and placebo patients: “Severe flare was rare in both treatment groups: The 12-month severe flare rate was 0.081 for the HRT group and 0.049 for the placebo group, yielding an estimated difference of 0.033 (P = 0.23). The upper limit of the 1-sided 95% CI for the treatment difference was 0.078, within the prespecified margin of 9% for noninferiority. Mild to moderate flares were significantly increased in the HRT group: 1.14 flares/person-year for HRT and 0.86 flare/person-year for placebo (relative risk, 1.34; P = 0.01). The probability of any type of flare by 12 months was 0.64 for the HRT group and 0.51 for the placebo group (P = 0.01). In the HRT group, there were 1 death, 1 stroke, 2 cases of deep venous thrombosis, and 1 case of thrombosis in an arteriovenous graft; in the placebo group, 1 patient developed deep venous thrombosis.” (J. P. Buyon, New York U., New York; jill.buyon@nyumc.org)

An editorialist cautions about the need to use hormone therapy in patients with characteristics similar to those of participants in this study (pp. 1014-5): “External validity is also important, since clinicians need to know whether the study results would apply to a specific patient. The authors excluded patients with very active SLE and patients with high-titer anticardiolipin antibodies or lupus anticoagulants (because of their increased risk for coagulopathy or vascular occlusions). The report provides limited demographic information on the study patients and no information about their socioeconomic status. The age range was wide (27 to 80 years), and the severe adverse events might have occurred mostly in older patients.” (E. V. Hess, U. Cincinnati, Cincinnati)

Antibiotic Prophylaxis in Neutropenic Patients: Fluoroquinolones appear to be the best options for reducing mortality among neutropenic patients who are receiving cytotoxic chemotherapy, according to a meta-analysis of 95 trials (pp. 979-95). “Antibiotic prophylaxis significantly decreased the risk for death when compared with placebo or no treatment (relative risk, 0.67 [95% CI, 0.55 to 0.81]),” write the authors. “All prophylactic antibiotics were associated with an increased risk for adverse events (relative risk, 1.69 [CI, 1.14 to 2.50]). Fluoroquinolone prophylaxis reduced the risk for all-cause mortality (relative risk, 0.52 [CI, 0.35 to 0.77]), as well as infection-related mortality, fever, clinically documented infections, and microbiologically documented infections. Fluoroquinolone prophylaxis increased the risk for harboring bacilli resistant to the specific drug after treatment and adverse events, but these results were not statistically significant (relative risks, 1.69 [CI, 0.73 to 3.92]) and 1.30 [CI, 0.61 to 2.76], respectively).” (L. Leibovici, Rabin Med. Ctr., Petah-Tiqva, Israel; leibovic@post.tau.ac.il)

>>>PNN NewsWatch
* NIH is offering to help bridge the “translational gap” between bench research in academic laboratories and clinical trials of experimental drugs, according to a page 1 article in this morning’s Wall Street Journal. The first target of the program is schizophrenia, which the article says “hasn't had a truly new drug-treatment approach in 50 years.”

* More than one third of U.S. community pharmacies are ready for
e-prescribing through SureScripts, which bills itself as “the nation’s largest network provider of true electronic prescribing services.” Some 36% of pharmacies are participating in the SureScripts Membership Program, including 65% of chain pharmacies, SureScripts reports in a news release.

PNN Pharmacotherapy Line is published via e-mail each business day except 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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 22, 2005 Vol. 12, No. 120
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
June 22/29 issue of JAMA (www.jama.com; 2005; 293).

Adding Pertussis to Adolescent/Adult Td Vaccine: Results of a clinical trial supporting effectiveness and safety of a recently approved tetanus–diphtheria–pertussis vaccine (Tdap) for adolescents and adults are published (pp. 3003-11). A single intramuscular dose of the acellular pertussis vaccine product, Adacel from Sanofi Pasteur (see PNN, June 13), was tested in healthy adolescents and adults aged 11–64 years by comparing serum antibody titers with those produced by Td vaccine or by an analogous pediatric diphtheria–tetanus–acellular pertussis vaccine (DTaP) tested in a previous trial, with these results: “A total of 4480 participants were enrolled. For both Tdap and Td, more than 94% and nearly 100% of vaccinees had protective antibody concentrations of at least 0.1 IU/mL for diphtheria and tetanus, respectively. Geometric mean antibody titers to pertussis toxoid, filamentous hemagglutinin, pertactin, and fimbriae types 2 and 3 exceeded (by 2.1 to 5.4 times) levels in infants following immunization at 2, 4, and 6 months with DTaP. The incidence of solicited local and systemic reactions and adverse events was generally similar between the Tdap and Td groups.” (M. E. Pichichero, michael_pichichero@urmc.rochester.edu)

Antibiotic Prescribing for Lower RTIs: Patients in a U.K. study were amenable to no or delayed prescribing of antibiotics for uncomplicated acute respiratory infections, and antibiotic use made little difference in symptoms (pp. 3029-35). Evaluating antibiotic prescriptions and provision of an informational leaflet to one half of participants in no, delayed, or immediate antibiotic groups, the researchers found, “A total of 562 patients (70%) returned complete diaries and 78 (10%) provided information about both symptom duration and severity. Cough rated at least ‘a slight problem,’ lasted a mean of 11.7 days (25% of patients had a cough lasting ≥17 days). An information leaflet had no effect on the main outcomes. Compared with no offer of antibiotics, other strategies did not alter cough duration (delayed, 0.75 days; 95% confidence intervals [CI], –0.37 to 1.88; immediate, 0.11 days; 95% CI, –1.01 to 1.24) or other primary outcomes. Compared with the immediate antibiotic group, slightly fewer patients in the delayed and control groups used antibiotics (96%, 20%, and 16%, respectively; P < .001), fewer patients were ‘very satisfied’ (86%, 77%, and 72%, respectively; P = .005), and fewer patients believed in the effectiveness of antibiotics (75%, 40%, and 47%, respectively; P < .001). There were lower reattendances within a month with antibiotics (mean attendances for no antibiotics, 0.19; delayed, 0.12; and immediate, 0.11; P = .04) and higher attendance with a leaflet (mean attendances for no leaflet, 0.11; and leaflet, 0.17; P = .02).” (P. Little, U. Southampton, Southampton, England; p.little@soton.ac.uk)

An author of a related editorial supports judicious use of antibiotics for these infections (pp. 3062-4): “In the current market-based health care system, it is tempting to confuse patient satisfaction with better outcomes, and to confuse more care with better quality care. Physicians have a duty to listen carefully to patients’ symptoms, to examine them carefully, and to take the time to explain their illness to them. However, physicians have no duty to fulfill patients’ expectations for inappropriate care, such as prescribing antibiotics when they are not indicated, and must be mindful of the duty to the larger community that suffers financially and medically when antibiotics are overused.” (M. H. Ebell, Michigan State U., East Lansing; ebell@msu.edu)

Opioids for Neuropathic Pain: “Short-term studies provide only equivocal evidence regarding the efficacy of opioids in reducing the intensity of neuropathic pain,” conclude authors of a systematic review/meta-analysis of 22 studies (pp. 3043-52). “Intermediate-term studies demonstrate significant efficacy of opioids over placebo for neuropathic pain, which is likely to be clinically important. Reported adverse events of opioids are common but not life-threatening. Further [randomized controlled trials] are needed to establish their long-term efficacy, safety (including addiction potential), and effects on quality of life.” (E. Eisenberg, Rambam Med. Ctr., Haifa, Israel; e_eisenberg@rambam.health.gov.il

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

PNN Pharmacotherapy Line
June 23, 2005 Vol. 12, No. 121
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
June 23 issue of the New England Journal of Medicine (content.nejm.org; 2005; 352).

Adjuvant Chemotherapy for Lung Cancer: Supporting a new standard of care in treatment of non–small-cell lung carcinoma, a research study shows prolonged disease-free survival and overall survival when vinorelbine plus cisplatin are used in patients with completely resected tumors (pp. 2589-97). Compared with observation only in patients with completely resected stage IB or II disease, adjuvant chemotherapy produced these results: “A total of 482 patients underwent randomization to vinorelbine plus cisplatin (242 patients) or observation (240); 45 percent of the patients had pathological stage IB disease and 55 percent had stage II, and all had an Eastern Cooperative Oncology Group performance status score of 0 or 1. In both groups, the median age was 61 years, 65 percent were men, and 53 percent had adenocarcinomas. Chemotherapy caused neutropenia in 88 percent of patients (including grade 3 febrile neutropenia in 7 percent) and death from toxic effects in two patients (0.8 percent). Nonhematologic toxic effects of chemotherapy were fatigue (81 percent of patients), nausea (80 percent), anorexia (55 percent), vomiting (48 percent), neuropathy (48 percent), and constipation (47 percent), but severe (grade 3 or greater) toxic effects were uncommon (<10 percent). Overall survival was significantly prolonged in the chemotherapy group as compared with the observation group (94 vs. 73 months; hazard ratio for death, 0.69; P = 0.04), as was relapse-free survival (not reached vs. 46.7 months; hazard ratio for recurrence, 0.60; P < 0.001). Five-year survival rates were 69 percent and 54 percent, respectively (P = 0.03).” (T. Winton, U. Alberta Hosp., Edmonton; twinton@cha.ab.ca)

The “smoke” has now cleared on this subject, writes an editorialist (pp. 2640-2): “The controversy surrounding adjuvant chemotherapy for resectable non–small-cell lung cancer is over. Adjuvant platinum-based chemotherapy should be recommended after complete resection of non–small-cell lung cancer in patients with a good performance status. Additional research will enable us to select those patients most likely to benefit from adjuvant therapy, to customize the therapy on the basis of the biology of the tumor, to lessen toxicity and increase compliance, to identify more effective regimens, and to further improve survival.” (K. M. W. Pisters, U. Texas M.D. Anderson Cancer Ctr., Houston)

Antibody Therapy of Type 1 Diabetes: Residual beta-cell function was preserved for at least 18 months when patients with recent-onset type 1 diabetes were treated with an aglycosylated human IgG1 antibody directed against CD3 (pp. 2598-608). Among those with beta-cell function above the 50th percentile of the 80 study participants, mean insulin dose at 18 months was 0.22 IU/kg/day, compared with 0.61 IU/kg/day among study participants who received placebo. Adverse effects of the antibody included a moderate “flu-like” syndrome and transient Epstein–Barr virus mononucleosis symptoms. (B. Keymeulen, Brussels Free U., Brussels; bart.keymeulen@az.vub.ac.be)

>>>PNN NewsWatch
* Levels of pharmaceuticals in waterways are reaching unacceptable levels, some believe, according to an article in today’s Washington Post. Thought to result primarily from people flushing unused products, medications were “among the most common chemicals found ... in 139 waterways,” the article notes. Steroids were detected in 89% of streams, nonprescription drugs in 81%, hormones in 37%, and other prescription drugs in 32%.

*
Surgical instruments at Duke University hospitals were inadvertently washed in hydraulic fluid rather than soap, reports this morning’s Wall Street Journal. An Associated Press article notes that the mistake happened after elevator workers drained hydraulic fluid into empty soap containers without changing the labels, leading to 2 months in late 2004 during which surgical patients were exposed to instruments described at the time by workers as feeling “slick.”

PNN Pharmacotherapy Line is published via e-mail each business day except 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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 24, 2005 Vol. 12, No. 122
Providing news and information about medications and their proper use

>>>Tipranavir Approved for Advanced HIV Infection
FDA yesterday approved tipranavir (Aptivus, Boehringer Ingelheim) for combination treatment of advanced HIV-1 disease in adults who are highly treatment-experienced or have viral strains resistant to multiple protease inhibitors. The agency acted under its accelerated-approval regulations to sanction the drug based on 24-week data, and the sponsor will continue studies so that FDA can later consider traditional approval of this nonpeptidic protease inhibitor.

Like lopinavir, tipranavir must be used with ritonavir to achieve sufficiently high serum concentrations. The approved dose of tipranavir is 500 mg taken with ritonavir 200 mg (Aptivus/r) twice daily. Aptivus will be marketed in 250-mg capsules, and these should be available to pharmacies within 2 weeks.
In clinical trials, a significantly greater proportion of patients receiving regimens that contained boosted tipranavir had undetectable HIV levels than in a boosted comparator group (lopinavir, indinavir, saquinavir, or amprenavir). At 24 weeks, 34% of patients in the tipranavir/r group and 16% of patients in the boosted comparator group achieved a viral load of less than 400 copies/mL, and 23% versus 9% achieved less than 50 copies/mL.

Tipranavir has been associated with clinical hepatitis and hepatic decompensation, and liver-function tests should be performed at baseline and frequently throughout treatment. Those with increased risk of hepatotoxicity and/or infected with hepatitis B or C should be monitored especially closely, and the drug should be stopped if laboratory or clinical indications of problems occur. Tipranavir/ritonavir is contraindicated in patients with moderate or severe hepatic insufficiency.

Drug interactions are an additional concern with tipranavir, which is an inhibitor of cytochrome P450 1A2, 2C9, 2C19, and 2D6 isoenzymes and a 3A substrate (ritonavir boosts tipranavir levels through 3A inhibition). Medications from several drug classes are contraindicated with tipranavir/ritonavir, including some antiarrhythmics, antihistamines, ergot derivatives, gastrointestinal promotility agents, neuroleptics, and sedatives/hypnotics. Dose adjustment or monitoring is required with medications from these classes: reverse transcriptase inhibitors, protease inhibitors, antifungals, antimycobacterials, calcium-channel blockers, antidepressants, HMG-CoA reductase inhibitors, hypoglycemics, immunosuppressants, narcotic analgesics, estrogens, PDE5 inhibitors, anticoagulants, antibiotics, and drugs to treat alcohol dependence.

>>>PNN NewsWatch
* FDA has approved BiDil, a combination of hydralazine and isosorbide dinitrate that will be marketed by NitroMed for treatment of heart failure in self-identified black patients. Neither drug component was previously approved for heart failure. The approval of BiDil was based in part on the results of the African-American Heart Failure Trial (A-HeFT). The study—of 1,050 self-identified black patients with severe heart failure who had already been treated with the best available therapy—was conducted because two previous trials in the general population of severe heart failure patients found no benefit, but suggested a benefit of BiDil in black patients. Patients on BiDil experienced a 43% reduction in death and a 39% decrease in hospitalization for heart failure compared with placebo, and a decrease of their symptoms of heart failure.

* Canadian authorities are set to announce restrictions
on Internet pharmacies operating from that country, reports this morning’s Wall Street Journal. Possible measures that have been discussed include prohibiting Canadian physicians from cosigning prescriptions for patients they have not examined, prohibiting prescriptions for citizens of other countries who are not physically present in Canada, barring a price reduction if medications are exported, and banning bulk exports, the newspaper reports.

*
Counterfeit Norvasc tablets were seized last week at a Toronto-area pharmacy, King West Pharmacy in Hamilton. The Ontario College of Pharmacists warns patients of this pharmacy to seek advice from other pharmacists about their medications.

PNN Pharmacotherapy Line is published via e-mail each business day except 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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 27, 2005 Vol. 12, No. 123
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
Online articles from Lancet (www.thelancet.com; 2005; 365).

Treating Infective Conjunctivitis: Antibiotic treatment of acute infective conjunctivitis in children is generally unnecessary, according to a study of chloramphenicol eye drops that concludes that most kids get better by themselves (doi 10.1016/S0140-6736(05)66709-8). Among 326 children aged 6 months to 12 years who were diagnosed by general practitioners as having conjunctivitis, the investigators found these outcomes when the participants were treated with chloramphenicol or placebo eye drops: “Clinical cure by day 7 occurred in 128 (83%) of 155 children with placebo compared with 140 (86%) of 162 with chloramphenicol (risk difference 3.8%, 95% CI –4.1% to 11.8%). Seven (4%) children with chloramphenicol and five (3%) with placebo had further conjunctivitis episodes within 6 weeks (1.2%, –2.9% to 5.3%). Adverse events were rare and evenly distributed between each group.” (P. Rose, U. Oxford, Oxford, U.K.; peter.rose@dphpc.ox.ac.uk)

Reducing Childhood Mortality: Feasibility of scaling up health delivery and lack of funds are the major obstacles to achieving the Millennium Development Goal of saving the lives of 6 million children annually (doi 10.1016/S0140-6736(05)66777-3). Focusing on the costs of drugs, materials, and program costs of 18 contacts between a child or mother and a health care provider until the child reaches 5 years of age, the investigators made these calculations, “US$5.1 billion in new resources is needed annually to save 6 million child lives in the 42 countries responsible for 90% of child deaths in 2000. This cost represents $1.23 per head in these countries, or an average cost per child life saved of $887. Sensitivity analyses for salary levels for community delivery agents, drug costs, and coverage rates for 2000 were used to develop uncertainty estimates around the US$5.1 billion annual price tag that range from about $3.1 billion to $8.0 billion.” (R. Black, Johns Hopkins U., Baltimore; rblack@jhsph.edu)

>>>BMJ Highlights
Source:
Online article from BMJ (www.bmj.org; 2005; 330).

UTIs & Antibiotics: Deciding when to treat dipstick-negative dysuria remains problematic, according to findings of a study of 59 women aged 16 to 50 years (doi 10.1136/bmj.38496.452581.8F). The women presented with a history of dysuria, but their midstream-urine dipstick tests were negative for both nitrites and leukocytes. Treated with placebo or trimethoprim 300 mg daily, the patients had these clinical and microbiologic results: “The median time for resolution of dysuria was three days for trimethoprim compared with five days for placebo (P = 0.002). At day 3, five (24%) of patients in the treatment group had ongoing dysuria compared with 20 (74%) in the placebo group (P = 0.005). This difference persisted until day 7: two patients (10%) in the treatment group v 11 (41%) in the placebo group; P = 0.02). The number needed to treat was 4. The median duration of constitutional symptoms (feverishness, shivers) was reduced by four days.” The investigators concluded, “These results support the practice of empirical antibiotic use guided by symptoms. Balancing the competing interests of symptom relief and the minimisation of antibiotic use remains a dilemma-—further research is needed to determine clinical predictors of response to antibiotics.” (D. Richards, Christchurch Sch. of Med., Christchurch, New Zealand; derelie.richards@chmeds.ac.nz)

>>>PNN JournalWatch
* Adjuvant Regional Chemotherapy and Systemic Chemotherapy Versus Systemic Chemotherapy Alone in Patients with Stage II–III Colorectal Cancer: A Multicentre Randomised Controlled Phase III Trial, in Lancet Oncology, 2005; DOI:10.1016/S1470-2045(05)70222-9. Reprints: www.thelancet.com; B. Nordlinger, Hosp. Boulogne-Billancourt, France.

* Paternal Depression in the Postnatal Period and Child Development: A Prospective Population Study, in
Lancet, 2005; 365: 2201–5. Reprints: www.thelancet.com; P. Ramchandani, U. Oxford, Oxford, U.K.

* Tailoring Arthritis Therapy in the Wake of the NSAID Crisis, in
New England Journal of Medicine, 2005; 352: 2578–80. Reprints: content.nejm.org; N. J. Olsen, U. Texas Southwestern Med. Ctr., Dallas.

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

PNN Pharmacotherapy Line
June 28, 2005 Vol. 12, No. 124
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
June 27 issue of Archives of Internal Medicine (www.archinternmed.com; 2005; 165).

Short-Acting Insulins: Compared with regular insulin, the short-acting insulin analogues provide only a modest improvement in glycosylated hemoglobin for patients with type 1 diabetes and no benefit in patients with type 2 conditions or gestational diabetes, according to a systematic review and meta-analysis of 42 trials involving 7,933 patients (pp. 1337-44). “The weighted mean difference between hemoglobin A1c values obtained using SAI analogues and regular insulin was –0.12% (95% confidence interval [CI], –0.17% to –0.07%) for adult patients with type 1 diabetes mellitus and –0.02% (95% CI, –0.10% to 0.07%) for patients with type 2 diabetes mellitus,” write the authors. “The standardized mean difference for overall hypoglycemia (episodes per patient per month) was –0.05 (95% CI, –0.22 to 0.11) and –0.04 (95% CI, –0.12 to 0.04) comparing SAI analogues with regular insulin in adult patients with type 1 and type 2 diabetes mellitus, respectively. No differences between treatments were observed in children with type 1 diabetes, pregnant women with type 1 diabetes mellitus, and women with gestational diabetes. Concerning quality of life, improvement was observed only in open-label studies in patients with type 1 diabetes mellitus. No differences were seen in a double-blinded study of patients with type 1 or in the studies of patients with type 2 diabetes mellitus.” (J. Plank, Med. U. Hosp., Graz, Austria; johannes.plank@klinikum-graz.at)

Voluntary ADR Reporting: FDA’s voluntary system of adverse drug reaction reports logged 2.3 million cases between 1969 and 2002, and these led to withdrawal of some 75 drugs or drug products and additions to labeling of many other products, agency authors report in an analysis of the Adverse Event Reporting System (pp. 1363-9). Reports also resulted in special requirements for prescriptions or restricted distribution systems for another 11 drugs. The authors conclude, “Despite the limitations of underreporting, differential reporting, and uneven quality, submitted reports often allow the identification of serious adverse events that are added to the product labeling information. In rare instances, additional regulations, up to and including market removal, have been required. We encourage physicians, pharmacists, other health care professionals, and patients to continue to report serious suspected and known adverse drug reactions to manufacturers and the Food and Drug Administration.” (D. K. Wysowski, FDA, Rockville, Md.)

Resistance Following Inadequate Initial Antimicrobial Therapy: For patients with nonurinary infections of beta-lactamase-producing Enterobacteriaceae, inadequate initial antimicrobial therapy is a significant predictor of mortality, according to a retrospective cohort study conducted in a 625-bed tertiary medical center and a 344-bed urban community hospital (pp. 1375-80). “Of 187 subjects, 32 (17.1%) died while in the hospital,” the researchers report. “Clinical site of infection was a significant effect modifier in the association between IIAT and mortality. The presence of IIAT was an independent risk factor for mortality, but only for nonurinary [extended-spectrum beta-lactamase–producing Escherichia coli and Klebsiella species] infections (adjusted odds ratio [95% confidence interval], 10.04 [1.90–52.96]). Independent risk factors for IIAT were (1) infection with a multidrug-resistant ESBL-EK (ie, resistant to sulfamethoxazole-trimethoprim, aminoglycosides, and quinolones) (14.58 [1.91–111.36]) and (2) health care–acquired ESBL-EK infection (4.32 [1.49–12.54]).” (E. Lautenbach, elautenb@mail.med.upenn.edu)

Carbapenem-Resistant Klebsiella pneumoniae: In New York City hospitals, isolates of carbapenem-resistant Klebsiella pneumoniae are emerging, but these are sometimes missed because automated laboratory susceptibility testing systems do not accurately identify them (pp. 1430-5). These highly resistant organisms represent “a new threat to our antibiotic armamentarium,” the authors maintain, because they “are resistant to virtually all commonly used antibiotics.” (J. Quale, State U. New York–Downstate, Brooklyn; jquale@downstate.edu)

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

PNN Pharmacotherapy Line
June 29, 2005 Vol. 12, No. 125
Providing news and information about medications and their proper use

>>>Infectious Disease Report
Source:
July 15 issue of Clinical Infectious Diseases (www.journals.uchicago.edu/CID; 2005; 41).

Streptococcal Resistance: Resistance patterns are flipping among Streptococcus pneumoniae isolates in the U.S., with resistance to fluoroquinolones on the rise but older agents showing fewer problems, according to an analysis of 1,817 isolates from patients with community-acquired respiratory tract infections in the winter of 2002–03 (pp. 139-48). Compared with data from four previous surveys going back as far as 1994–95, the new survey shows, “Overall rates of resistance (defined as the rate of intermediate resistance plus the rate of resistance) were as follows: penicillin, 34.2%; ceftriaxone, 6.9%; erythromycin, 29.5%; clindamycin, 9.4%; tetracycline, 16.2%; and trimethoprim-sulfamethoxazole (TMP-SMX), 31.9%. No resistance was observed with vancomycin, linezolid, or telithromycin; 22.2% of isolates were multidrug resistant; 2.3% of isolates had ciprofloxacin MICs of ≥4.0 mcg/mL. It was estimated that 21.9% of the isolates in this national collection had mutations in the [quinolone-resistance determining regions] of parC and/or gyrA, with parC only mutations occurring most often (in 21% of all isolates). Trend analysis since 1994–1995 indicated that rates of resistance to beta-lactams, macrolides, tetracyclines, TMP-SMX, and multiple drugs have either plateaued or have begun to decrease. Conversely, fluoroquinolone resistance among S. pneumoniae is becoming more prevalent.” (G. V. Doern, U. Iowa, Iowa City)

Adjuvant Immunotherapy for TB: Infliximab may be a useful adjunct to tuberculosis therapy because of its ability to disrupt granulomas in the body that harbor the causative mycobacteria, notes an author of a review article (pp. 201-8). “Four studies of therapeutic interferon indicated its inability to effectively augment the mycobactericidal capacity of lung macrophages,” the author writes. “One randomized, placebo-controlled trial of therapeutic interleukin-2 found that it delayed the microbiologic response to treatment, whereas 2 controlled trials of anti–tumor necrosis factor (TNF) therapies (high-dose prednisolone and etanercept [a soluble TNF receptor]) found that these interventions significantly accelerated the response to treatment. Four retrospective studies were identified in which the response to TB therapy was accelerated and/or the relapse risk was reduced in persons with human immunodeficiency virus coinfection; one study reported that immune reconstitution syndrome due to use of antiretroviral therapy was associated with increased risk of relapse. Several studies indicated that granulomas may be efficiently targeted and disrupted by the anti-TNF antibody infliximab, apparently because of its ability to bind to cell-surface TNF and to induce apoptosis in TNF-expressing cells.” (R. S. Wallis, PPD, Washington, D.C.)

>>>PNN NewsWatch
* Reports of psychiatric events such as visual hallucinations, suicidal ideation, psychotic behavior, aggression, and violent behavior have surfaced with Concerta and other methylphenidate products, FDA yesterday noted in a report to its Pediatric Advisory Committee, which meets tomorrow. The agency also indicated that it is analyzing data on atomoxetine and amphetamines for similar problems. The advisory committee was asked to comment on these adverse effects as well as the potential for agents in this class to produce cardiovascular problems such as hypertension, syncope, chest pain, prolonged QTc intervals, arrhythmias, and tachycardia. Marketing of Adderall XR was suspended earlier this year in Canada because of concerns about sudden death in patients taking that product.

* Use of
sildenafil is not associated with nonarteritic anterior ischemic optic neuropathy (NAION), Pfizer said yesterday based on an analysis of 38 reports of sudden-onset blindness in men who were using the drug. Despite the lack of causality, information about this problem will be added to Viagra labeling, the company indicated, adding that it believes that FDA will require similar warnings in the product information of the other marketed phosphodiesterase 5 inhibitors.

PNN Pharmacotherapy Line is published via e-mail each business day except 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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 30, 2005 Vol. 12, No. 126
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
June 30 issue of the New England Journal of Medicine (content.nejm.org; 2005; 352).

Hepatitis B Treatments: Two articles and a related editorial explore the “maze of treatments” for hepatitis B virus infections. The research studies report these findings about patients of positive and negative hepatitis B e antigen status:

* Continuous therapy is needed, according to a study of adefovir dipivoxil therapy in 185 patients with HBeAg-negative chronic hepatitis B. (pp. 2673-81). Patients on the drug who responded during 48 weeks of treatment relapsed after cessation, but those who continued on the medication for 144 weeks continued to benefit from treatment, with “infrequent emergence of viral resistance.” (S. J. Hadziyannis, Henry Dunant Hosp., Athens, Greece; hadziyannis@ath.forthnet.gr)

* Among 814 patients with HBeAg-positive chronic hepatitis B, peginterferon alfa-2a proved superior in efficacy to lamivudine based on HBeAg seroconversion, viral suppression, and HBsAg seroconversion (pp. 2682-95). HBeAg seroconversion rates were 32% with peginterferon monotherapy, 19% with lamivudine monotherapy, and 27% with both drugs. HBsAg seroconversion was observed in 16 patients on regimens with peginterferon, compared with 0 in the lamivudine group. While serious adverse events were more common with the peginterferon regimens (4% with monotherapy and 6% with combination therapy, versus 2% with lamivudine alone), two patients on lamivudine monotherapy had irreversible liver failure after the cessation of treatment, resulting in one death and one liver transplant. (G. K. K. Lau, Queen Mary Hosp., U. Hong Kong, Hong Kong SAR, China; gkklau@netvigator.com)

An editorialist made these points about the five approved treatments available in the U.S. (the three drugs investigated in the above studies plus interferon alfa-2b and entecavir) and the prognoses for the world’s 350 million carriers of HBV (pp. 2743-6): “For patients with HBeAg-positive chronic hepatitis B who do not yet have cirrhosis, the goal is to achieve HBeAg seroconversion. Because pretreatment aminotransferase levels are a strong predictor of HBeAg seroconversion..., current guidelines do not recommend treatment of patients with normal aminotransferase levels unless liver biopsy shows substantial inflammation or fibrosis. For patients with HBeAg-negative chronic hepatitis B who do not yet have cirrhosis, a one-year course of treatment is associated with a 15 to 35 percent chance of sustained response after interferon therapy but a less than 10 percent chance after treatment with lamivudine or adefovir.” (A. Suk-Fong Lok, U. Michigan Med. Ctr., Ann Arbor)

Capecitabine for Stage III Colon Cancer: For adjuvant treatment of resected stage III colon cancer, oral capecitabine is an effective alternative to fluorouracil plus leucovorin, according to a study of 1,987 patients (pp. 2696-704). Over a 24-week period, the investigators found, “Disease-free survival in the capecitabine group was at least equivalent to that in the fluorouracil-plus-leucovorin group (in the intention-to-treat analysis, P < 0.001 for the comparison of the upper limit of the hazard ratio with the noninferiority margin of 1.20). Capecitabine improved relapse-free survival (hazard ratio, 0.86; 95 percent confidence interval, 0.74 to 0.99; P = 0.04) and was associated with significantly fewer adverse events than fluorouracil plus leucovorin (P < 0.001).” (C. Twelves, U. Bradford, Bradford, U.K.; c.twelves@bradford.ac.uk)

Daclizumab After Cardiac Transplantation: Daclizumab, a humanized monoclonal antibody against the interleukin-2 receptor, was effective for preventing rejection among 434 patients undergoing their first cardiac transplantation, but six patients died when the agent was used concomitantly with cytolytic (induction) therapies with antilymphocyte antibodies (pp. 2705-13). Relative risk of rejection was reduced by 25% with daclizumab, and median time to rejection and other elements of a primary endpoint was significantly longer with the drug than with standard therapy alone (61 versus 21 days). (R. E. Hershberger, Oregon Health and Science U., Portland; hershber@ohsu.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 lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.