Dec 2007

PNN Quarterly File—Fourth Quarter 2007

PNN Pharmacotherapy Line
Oct. 1, 2007 * Vol. 14, No. 190
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Early-release articles from and Sept. 29 issue of Lancet (www.thelancet.com; 2007; 370).
HF But Not Deaths Increased with Glitazones: Congestive heart failure, while more common in patients taking thiazolidinediones as a result of fluid retention, may not carry the same mortality risk as CHF resulting from left ventricular dysfunction, according to authors who conducted a meta-analysis of seven randomized double-blind trials (pp. 1129-36). Focusing on the main outcome measures of CHF development and risk of cardiovascular death, the group reports: “360 of 20,191 patients who had either prediabetes or type 2 diabetes had congestive heart failure events (214 with TZDs and 146 with comparators). Results showed no heterogeneity of effects across studies (I2 = 22.8%; p for interaction = 0.26), which indicated a class effect for TZDs. Compared with controls, patients given TZDs had increased risk for development of congestive heart failure across a wide background of cardiac risk (relative risk [RR] 1.72, 95% CI 1.21–2.42, p = 0.002). By contrast, the risk of cardiovascular death was not increased with either of the two TZDs (0.93, 0.67–1.29, p = 0.68).” (R. W. Nesto, Lahey Clinic Med. Ctr., Burlington, Mass.; Richard.W.Nesto@lahey.org)
In an editorial,
Lancet editors emphasize the need to focus on outcomes important to patients (p. 1101): “It must be remembered that meta-analysis is a technique with important limitations. And the studies on which the thiazolidinedione meta-analyses are based have thus far all involved surrogate markers; the studies were not designed to assess cardiovascular outcomes, but rather improved glycaemic control. This outcome ... is not a patient-centred one. The current clinical emphasis on glucose control (as measured by HbA1c) skirts the outcomes that matter most to patients—microvascular and macrovascular complications, quality of life, and survival.”
Uncertainty of Influenza Vaccine Data: Concluding that “we must never again allow layers of poor research to mask substantial uncertainty about the effects of a public-health intervention and present a falsely optimistic view of policy,” authors (doi: 10.1016/S0140-6736(07)61389-0) provide this analysis of a review article being published in Lancet Infectious Diseases: “Influenza vaccines cannot prevent approximately 50% of deaths from all causes, as claimed, simply because in the USA the highest estimated excess burden of mortality related to influenza is 10% per year. The authors also prove that statistical methods for adjustment for residual bias used in the observational studies of influenza vaccines did not work, largely because of the difficulty of adjusting for frailty with data available in electronic records (ie, coded according to the International Classification of Diseases). Randomisation might be the only way around this systematic problem. The study further suggests that large retrospective data-linked cohort studies should no longer be done (because they are misleading), and suggest a series of five indicators for the identification of influenza-vaccine studies with a high likelihood of bias (one of them is the degree of vaccine–antigen match). Simonsen and colleagues ask again: how is it possible that no one noted the peculiar nature of the data? We would like to know too, but we have shown that selection bias is only one of the many problems in reports about influenza vaccines.” (T. Jefferson, Cochrane Vaccines Field, Alessandria, Italy; Jefferson.tom@gmail.com)

>>>PNN JournalWatch
* Managing Anovulatory Infertility and Polycystic Ovary Syndrome, in BMJ, 2007; 335: 663–6. Reprints: A. H. Balen, Leeds Genl. Infirmary, Leeds, U.K.; adam.balen@leedsth.nhs.uk
* Routine Psychological Screening in Youth with Type 1 Diabetes and Their Parents: A Notion Whose Time Has Come?, in
Diabetes Care, 2007; 30: 2716–24. Reprints: F. J. Cameron, Royal Children’s Hosp., Parkville, Melbourne, Victoria, Australia; fergus.cameron@rch.org.au
* Immunoglobulin E Blockade in the Treatment of Asthma, in
Pharmacotherapy, 2007; 27: 1412–24. Reprints: R. Kuhn, rjkuhn1@email.uky.edu
* Anticonvulsant Hypersensitivity Syndrome: Implications for Pharmaceutical Care, in
Pharmacotherapy, 2007; 27: 1425–39. Reprints: K. H. Bohan, Wilkes U., Wilkes-Barre, Pa.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Oct. 2, 2007 * Vol. 14, No. 191
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release articles from and the Oct. 2 issue of the Annals of Internal Medicine (www.annals.org/current.shtml; 2007; 147).
Treatment of Chronic Hepatitis B: Compared with adefovir, telbivudine produced greater and more consistent suppression of hepatitis B virus at both 24 and 52 weeks in 135 treatment-naive adult patients with chronic hepatitis B (early release). Patients received either telbivudine (group A), adefovir (group B), or 24 weeks of adefovir and then telbivudine for the remaining 28 weeks (group C), with these results: “At week 24, mean HBV DNA reduction was greater in group A than in pooled groups B and C (–6.30 vs. –4.97 log10 copies/mL; difference, –1.33 log10 copies/mL [95% CI, –1.99 to –0.66 log10 copies/mL]; P < 0.001), and more patients in group A were polymerase chain reaction–negative (39% vs. 12%; odds ratio, 4.46 [CI, 1.86 to 10.72]; P = 0.001). At week 52, mean residual HBV DNA was lower in patients treated continuously with (group A) or switched (group C) to telbivudine than in those who received continuous adefovir (group B) (3.01 log10 copies/mL [group A] and 3.02 log10 copies/mL [group C] vs. 4.00 log10 copies/mL [group B]; difference, –0.99 log10 copies/mL [CI, –1.67 to –0.32 log10 copies/mL] and –0.98 log10 copies/mL [CI, –1.64 to –0.32 log10 copies/mL]; P = 0.004). Adverse events were similar across groups; the most common were upper respiratory symptoms, headache, back pain, and diarrhea.” (H. L. Y. Chan, Chinese U., Hong Kong; hlychan@cuhk.edu.hk)
Treatment of Low Back Pain: One of three articles on clinical management of acute and chronic low back pain recommends specific agents for pharmacologic treatment (pp. 505-14). “We found good evidence that NSAIDs, acetaminophen, skeletal muscle relaxants (for acute low back pain), and tricyclic antidepressants (for chronic low back pain) are effective for pain relief,”the authors write. “The magnitude of benefit was moderate (effect size of 0.5 to 0.8, improvement of 10 to 20 points on a 100-point visual analogue pain scale, or relative risk of 1.25 to 2.00 for the proportion of patients experiencing clinically significant pain relief), except in the case of tricyclic antidepressants (for which the benefit was small to moderate). We also found fair evidence that opioids, tramadol, benzodiazepines, and gabapentin (for radiculopathy) are effective for pain relief. We found good evidence that systemic corticosteroids are ineffective. Adverse events, such as sedation, varied by medication, although reliable data on serious and long-term harms are sparse. Most trials were short term (4 weeks). Few data address efficacy of dual-medication therapy compared with monotherapy, or beneficial effects on functional outcomes.” (R. Chou, Oregon Evidence-based Practice Ctr., Portland; chour@ohsu.edu)
In a joint clinical practice guideline issued by the American College of Physicians and the American Pain Society, a variety of nonpharmacologic and alternative-medicine approaches are recommended for patients whose self-care efforts fail (pp. 478-91): “For patients who do not improve with self-care options, clinicians should consider the addition of nonpharmacologic therapy with proven benefits—for acute low back pain, spinal manipulation; for chronic or subacute low back pain, intensive interdisciplinary rehabilitation, exercise therapy, acupuncture, massage therapy, spinal manipulation, yoga, cognitive-behavioral therapy, or progressive relaxation (weak recommendation, moderate-quality evidence).” (A. Qaseem,
aqaseem@acponline.org)

>>>PNN NewsWatch
* Responding to concerns about atrial fibrillation in patients taking bisphosphonates raised in the May 3 issue of the New England Journal of Medicine, FDA yesterday said that it “does not believe that healthcare providers or patients should change either their prescribing practices or their use of bisphosphonates at this time.” Because AF occurs commonly in the bisphosphonate-target population of older patients, FDA explained that establishing a causal link is difficult. The agency is collecting additional data on this adverse event among patients taking these drugs, a process that could take 12 months to complete.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Oct. 3, 2007 * Vol. 14, No. 192
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Oct. 3 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2007; 298).
Treating Chronic Hypertension During Pregnancy: In a Clinician’s Corner case report and related editorial, “management of chronic hypertension before, during, and after a pregnancy is discussed with an emphasis on the goals of treatment and safety of medications during pregnancy and with breastfeeding” (pp. 1548-58). The case presents a 30-year-old woman with a history of chronic hypertension and possible preeclampsia during her first pregnancy, and the author provides this analysis of future trends: “Hypertension in pregnancy continues to have a remarkable lack of data available. Too few data exist about any antihypertensive agents to make definitive and meaningful statements about their safety or risk in pregnancy. Similarly, large, well-designed trials examining the risks and benefits of treating mild hypertension in pregnancy are still needed. Progress in understanding preeclampsia also remains frustratingly slow. There is hope that serologic markers, such as soluble fms-like tyrosine kinase 1, placental growth factor, and endoglin, may be used to identify patients who are destined to develop preeclampsia 8 to 12 weeks before they actually do. Detection before overt manifestation of disease would greatly help to effectively triage resources and also allow more expeditious evaluation of preventive strategies. Finally, researchers in preeclampsia may need to further explore the theoretical construct that preeclampsia is a heterogeneous disease and that there may not be just 1 ‘type’ of preeclampsia any more than there is 1 type of cancer or 1 type of acute respiratory distress syndrome. Preeclampsia may be the final common pathway for a variety of pathophysiologic processes. If preeclampsia is simply what happens when inadequate placentas stress susceptible mothers, perhaps prevention and understanding of the disease should focus more on particular subtypes of the syndrome rather than studying patients with the disease as if they were a homogenous population.” (R. O. Powrie, raymond_powrie@brown.edu)
Medical and legal concerns are stifling research in pregnant women, an editorialist adds (pp. 1566-8): “Despite the burden of illness and costs imposed by hypertension in pregnancy, evidence to date regarding benefits and risks of antihypertensive drugs and management plans to prolong gestation in preeclampsia remain scant and provide relatively little direction to clinicians. These problems have resulted, at least in part, from lack of support and, perhaps, reluctance by the government and pharmaceutical companies to conduct research in pregnant women because of regulatory and medicolegal concerns. As a result, many important clinical issues faced by physicians who care for pregnant women with hypertension remain unresolved. Therefore, prospective studies are urgently needed to evaluate potential biomarkers to identify women at high risk of preeclampsia and to identify women with hypertensive disease who will develop adverse maternal and perinatal outcomes. Large multicenter trials are needed to test antihypertensive drugs and novel interventions that are designed to prolong pregnancy and reduce adverse maternal-perinatal outcomes in women with various hypertensive disorders. While such trials will be logistically challenging and will require careful oversight, they are an essential step for improving outcomes of both mother and child and reducing the burden of hypertensive disease in pregnancy.” (B. M. Sibai, U. Cincinnati, Cincinnati;
baha.sibai@uc.edu)

>>>PNN NewsWatch
* Six influenza vaccines are on the U.S. market for this season, thanks to FDA’s recent licensing of Afluria (CSL Limited, Parkville, Australia). The product, licensed for use in adults, contains inactivated influenza type A and B viruses and is grown in chicken eggs. Administered as a single injection in the upper arm and available in both a single-dose, preservative-free, prefilled syringe and a multidose vial with thimerosal, the vaccine produces typical local reactions and headache, fatigue, and muscle aches in some recipients. CDC estimates that a record 132 million doses of influenza vaccine will be available for the 2007–08 season.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Oct. 4, 2007 * Vol. 14, No. 193
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Oct. 4 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2007; 357)
Influenza Vaccine in Community-Dwelling Elderly: Risks of both hospitalization and death were significantly reduced among community-dwelling patients who were vaccinated against influenza in a 10-year study conducted during the 1990s in health-maintenance organizations (pp. 1373-81). Data came from one HMO for 1990–91 through 1999–2000 and two other HMOs for 1996–97 through 1999–2000. Vaccinated patients had more existing high-risk medical conditions, the authors report. Despite this, patients showed these benefits from vaccination during 713,872 person–seasons: “Vaccination was associated with a 27% reduction in the risk of hospitalization for pneumonia or influenza (adjusted odds ratio, 0.73; 95% confidence interval [CI], 0.68 to 0.77) and a 48% reduction in the risk of death (adjusted odds ratio, 0.52; 95% CI, 0.50 to 0.55). Estimates were generally stable across age and risk subgroups. In the sensitivity analyses, we modeled the effect of a hypothetical unmeasured confounder that would have caused overestimation of vaccine effectiveness in the main analysis; vaccination was still associated with statistically significant—though lower—reductions in the risks of both hospitalization and death.” (K. L. Nichol, nicho014@umn.edu)
Other avenues for reducing influenza morbidity and mortality involve better vaccination of children and health care workers, an editorialist notes (pp. 1439-41): “Influenza cannot develop in elderly persons if they are not exposed to influenza virus from others. Elderly persons have frequent contact with health care workers and others in the health care system. Those people often report to work even when they are not feeling well and can easily serve as vehicles of doom for their unsuspecting patients. This is why the extraordinarily low rates of vaccination of health care workers in the United States are so appalling. The implementation of programs that bring the vaccine directly to the workplace, as well as of policies that require mandatory vaccination (with informed declination), can markedly increase vaccination rates and should be considered by all health care institutions.
“The most intriguing possibility is that high vaccination rates among the general population, particularly among children, might interrupt transmission and provide secondary protection to those who cannot be protected directly by vaccination. A similar phenomenon has been observed for pneumococcal disease. It has been suggested that vaccination of children results in reduced rates of influenza in the elderly. Although these studies are not definitive, they may be pointing toward a more effective strategy. Ultimately, the key to optimal control of the devastating effects of influenza in elderly persons may be found in our ability to effectively vaccinate the youngest members of the population.” (J. D. Treanor, U. Rochester , Rochester, N.Y.)
Donepezil for Agitation in Alzheimer's Disease: In a 12-week trial of 272 patients with Alzheimer’s disease, donepezil was no more effective than placebo for treating agitation (pp. 1382-92). Based on changes in the score on the Cohen–Mansfield Agitation Inventory, the investigators found: “There was no significant difference between the effects of donepezil and those of placebo on the basis of the change in CMAI scores from baseline to 12 weeks (estimated mean difference in change [the value for donepezil minus that for placebo], –0.06; 95% confidence interval [CI], –4.35 to 4.22). Twenty-two of 108 patients (20.4%) in the placebo group and 22 of 113 (19.5%) in the donepezil group had a reduction of 30% or greater in the CMAI score (the value for donepezil minus that for placebo, –0.9 percentage point; 95% CI, –11.4 to 9.6). There were also no significant differences between the placebo and donepezil groups in scores for the Neuropsychiatric Inventory, the Neuropsychiatric Inventory Caregiver Distress Scale, or the Clinician's Global Impression of Change.” (R. J. Howard, King's College, London; robert.howard@iop.kcl.ac.uk)

>>>PNN NewsWatch
* A Nov. 14 public meeting will obtain comments on a behind-the-counter (pharmacist-only) class of drugs in the U.S., FDA announced yesterday.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Oct. 5, 2007 * Vol. 14, No. 194
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Oct. issue of Pharmacotherapy (www.pharmacotherapy.org; 2007; 27).
Enoxaparin Dosage in Severe Renal Failure: Based on peak and trough antifactor Xa levels measured in 19 patients with stage 4 or 5 chronic kidney disease, dosage of enoxaparin 1 mg/kg subcutaneously every 24 hours was safe for full anticoagulation (pp. 1347-52). “Of the 19 study patients, 14 (74%) had peak antifactor Xa levels within the recommended range for full anticoagulation of 0.5–1.0 U/ml after their first enoxaparin dose; no concentration exceeded 1.0 U/ml,” write the researchers. “The mean peak antifactor Xa level was not significantly different after the first enoxaparin dose compared with the second and third doses. The mean ± SD trough antifactor Xa level, thought to be an indicator of drug accumulation, was 0.12 ± 0.12 U/ml; its clinical significance and target range are still unknown. No major bleeding events were noted.” (S. Zevin, Shaare Zedek Med. Ctr., Jerusalem, Israel)
Comprehensive Cardiac Care: Patients with coronary artery disease enrolled in a comprehensive cardiac care program were 89% less likely to die than a cohort of similar patients receiving usual care, according to a retrospective longitudinal study conducted at a health-maintenance organization (pp. 1370-8). Concluding that the earlier the patient was enrolled after a coronary event, the better the outcomes, the investigators noted: “Patients with any exposure to the CCC were less likely to die compared with the no CCC cohort (p < 0.001). After adjusting for baseline covariates, the early [within 90 days], delayed [after 90 days], and intermittent [not continuously enrolled] CCC cohorts had reduced hazard rate ratios for all-cause mortality of 0.11 (95% confidence interval [CI] 0.08–0.14), 0.35 (95% CI 0.29–0.44), and 0.54 (95% CI 0.41–0.70), respectively, compared with the no CCC cohort (all p < 0.001).” (J. A. Merenich, Kaiser Permanente Colorado, Denver)
Antiretroviral Drug Interactions: Clinicians need to recognize and manage the “highly prevalent” clinically significant drug interactions (CSDIs) in HIV-infected patients receiving antiretroviral therapy, concludes a retrospective medical record review (pp. 1379-86): “Of the 153 patients, at least one CSDI was found in 41.2% of their regimens: 34.6% with at least one drug interaction that required a dosage adjustment, 2.0% with at least one contraindicated drug combination, and 4.6% with at least one of each of these CSDIs. In the logistic regression model, risk factors independently associated with CSDIs were age older than 42 years (odds ratio [OR] 2.9, 95% CI 1.2–7.1), more than three comorbid conditions (OR 3.0, 95% CI 1.4–6.6), treatment with more than three antiretroviral agents (OR 2.4, 95% CI 1.0–5.8), and treatment with a protease inhibitor (OR 11.5, 95% CI 4.2–31.2). When directly compared, CSDIs were more prevalent among protease inhibitor–based than nonnucleoside reverse transcriptase inhibitor–based regimens (p < 0.001).” (C. D. Miller, Albany College of Pharm., Albany, N.Y.)

>>>PNN NewsWatch
* Cephalon is introducing a once-daily formulation of cyclobenzaprine hydrochloride, Amrix, indicated for short-term treatment (two to three weeks) of muscle spasm associated with musculoskeletal conditions. The extended-release product should be taken at about the same time, either day or night.
*
FDA is tightening potency specifications for levothyroxine sodium to ensure potency over the labeled shelf life. Specifically, the agency is mandating that levothyroxine sodium drug products meet a 95%–105% potency specification until their expiration date. Currently, these products are allowed a potency range of 90%–110%.
*
FDA also announced yesterday plans to hire and train new reviewers of generic drug applications in an effort to increase the number and variety of generic drug products available in the U.S. The agency also awarded a two-year, $1.5 million contract to the Center for Professional Development to assist with the transformation of FDA's Center for Drug Evaluation and Research, with a particular focus on steps to improve workplace leadership, empower staff, and establish more effective business practices.
*
PNN will not be published on Mon., Oct. 8, Columbus Day.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Oct. 9, 2007 * Vol. 14, No. 195
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Early-release article from Lancet (www.thelancet.com; 2007; 167).
Early TIA Treatments: The risk of early recurrent stroke was reduced by 80% when patients were started quickly on treatments following transient ischemic attacks or minor strokes, researchers report (doi: 10.1016/S0140-6736(07)61448-2). Comparing a prospective before (phase 1) period with a later period of more urgent assessment and immediate treatment in clinic (phase 2), the authors found: “Of the 1,278 patients ... who presented with TIA or stroke (634 in phase 1 and 644 in phase 2), 607 were referred or presented direct to hospital, 620 were referred for outpatient assessment, and 51 were not referred to secondary care. 95% (n = 591) of all outpatient referrals were to the study clinic. Baseline characteristics and delays in seeking medical attention were similar in both periods, but median delay to assessment in the study clinic fell from 3 ([interquartile range] 2–5) days in phase 1 to less than 1 (0–3) day in phase 2 (p < 0.0001), and median delay to first prescription of treatment fell from 20 (8–53) days to 1 (0–3) day (p < 0.0001). The 90-day risk of recurrent stroke in the patients referred to the study clinic was 10.3% (32/310 patients) in phase 1 and 2.1% (6/281 patients) in phase 2 (adjusted hazard ratio 0.20, 95% CI 0.08–0.49; p = 0.0001); there was no significant change in risk in patients treated elsewhere. The reduction in risk was independent of age and sex, and early treatment did not increase the risk of intracerebral haemorrhage or other bleeding.” (P. M. Rothwell, Radcliffe Infirmary, Oxford, U.K.; peter.rothwell@clneuro.ox.ac.uk)

>>>Internal Medicine Report
Source:
Oct. 8 issue of the Archives of Internal Medicine (http://archinte.ama-assn.org/current.dtl; 2007; 167).
Combination ACE/ARBs in Left Ventricular Dysfunction: Adverse drug events are significantly increased when patients with left ventricular dysfunction receive concomitant therapy with ACE inhibitors and angiotensin II receptor blockers, according to data from randomized controlled trials (pp. 1930-6). In a quantitative review, investigators report: “Four studies (N = 17,337; mean follow-up, 25 months [range, 11–41 months]) were selected. Combination ARB plus ACE inhibitor vs control treatment that included ACE inhibitors was associated with significant increases in medication discontinuations because of adverse effects in patients with chronic heart failure (RR, 1.38 [95% CI, 1.22–1.55]) or in patients with acute myocardial infarction with symptomatic left ventricular dysfunction (RR, 1.17 [95% CI, 1.03–1.34]), and for both conditions there were significant increases in worsening renal function (RR, 2.17 [95% CI, 1.59–2.97] and RR, 1.61 [95% CI, 1.31–1.98], respectively), hyperkalemia (RR, 4.87 [95% CI, 2.39–9.94] and RR, 1.33 [95% CI, 0.90–1.98], respectively; the latter was not significant), and symptomatic hypotension (RR, 1.50 [95% CI, 1.09–2.07], and RR, 1.48 [95% CI, 1.33–3.18], respectively).” (C. O. Phillips, Cleveland Clinic Lerner Coll. of Medicine, Cleveland; Chr_phi@yahoo.com)

>>>PNN JournalWatch
■ Tobacco Smoking, Harm Reduction, and Nicotine Product Regulation, in Lancet, 2007; doi: 10.1016/S0140-6736(07)61482-2. Reprints: J. Britton, U. Nottingham, Nottingham, U.K.; j.britton@virgin.net
* Dietary Antioxidants and Primary Prevention of Age Related Macular Degeneration: Systematic Review and Meta-analysis, in
BMJ, 2007; doi: 10.1136/bmj.39350.500428.47 . Reprints: T. Y. Wong, U. Melbourne, Victoria, Australia; twong@unimelb.edu.au
* Pharmacologic Management of Painful Bladder Syndrome/Interstitial Cystitis: A Systematic Review, in
Archives of Internal Medicine, 2007; 167: 1922–9. Reprints: J. Dimitrakov, Jordan.Dimitrakov@childrens.harvard.edu
* Effect of Pneumococcal Vaccination in Hospitalized Adults with Community-Acquired Pneumonia, in
Archives of Internal Medicine, 2007; 167: 1938–43. Reprints: S. R. Majumdar, me2.majumdar@ualberta.ca
* Cutaneous Reactions to Drugs in Children, in
Pediatrics, 2007; 120: e1082–96. Reprints: A. R. Segal, Mass. Coll. of Pharm., Boston.
* Pseudo-asthma: When Cough, Wheezing, and Dyspnea Are Not Asthma, in
Pediatrics, 2007; 120: 855–64. Reprints: M. Weinberger, U. Iowa, Iowa City.
* Olanzapine and Pediatric Bipolar Disorder: Evidence for Efficacy and Safety Concerns [editorial], in
American Journal of Psychiatry, 2007; 164: 1462–4. Reprints: J. M. McClellan.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Oct. 10, 2007 * Vol. 14, No. 196
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Oct. 10 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2007; 298).
Topiramate for Alcohol Dependence: The antiseizure drug topiramate proved to be a safe and effective treatment for alcohol dependence among 371 adult men and women in a multicenter U.S. trial (pp. 1641-51). Assessing self-reported percentages of heavy-drinking days among the patients and their adherence to topiramate in doses up to 300 mg/day, the investigators found: “Treating all dropouts as relapse to baseline, topiramate was more efficacious than placebo at reducing the percentage of heavy drinking days from baseline to week 14 (mean difference, 8.44%; 95% confidence interval, 3.07%–13.80%; P = .002). Prespecified mixed-model analysis also showed that topiramate compared with placebo decreased the percentage of heavy drinking days (mean difference, 16.19%; 95% confidence interval, 10.79%–21.60%; P < .001) and all other drinking outcomes (P < .001 for all comparisons). Adverse events that were more common with topiramate vs placebo, respectively, included paresthesia (50.8% vs 10.6%), taste perversion (23.0% vs 4.8%), anorexia (19.7% vs 6.9%), and difficulty with concentration (14.8% vs 3.2%).” (B. A. Johnson, bankolejohnson@virginia.edu)
A sea change in the way clinicians view alcohol dependence is a necessary first step in making progress, writes an editorialist (pp. 1691-2): “For patients with severe, relapsing or chronic disorders, specialty addiction treatment, especially the medical component, is needed. These patients often have serious coexisting physical and mental disorders that require disease management that integrates multiple approaches. Expanding the numbers of physicians specializing in addiction medicine and psychiatry is essential, as is research on effective disease management models. The first step in this process, however, will be for all physicians to begin to see alcohol dependence as a disorder they can and should treat, and treat effectively.” (M. L. Willenbring,
mlw@niaaa.nih.gov)
Personalized Medicine in the Era of Genomics: “Personalized medicine” and the “genomics revolution” may be overhyped as “a new medical paradigm,” two authors write in a Clinician’s Corner article (pp. 1682-4). Instead, they note, “A realistic appraisal suggests that genomics will make only modest contributions to personalized medicine as it is traditionally practiced,” concluding, “Personalized medicine has always been a component of good medical practice. Genetic tests may provide new tools, but they do not change the fundamental goal of clinicians to adapt available medical tests and technologies to the individual circumstance of their patients. As genetic tests become widely available, personalized medicine will include assisting patients to make wise use of genetic risk assessment, taking into account the cautions discussed in this article. When genetic testing is used, the personalized nature of the care will extend well beyond the patient’s base pair sequences.” (W. Burke, wbuk@u.washington.edu)

>>>PNN NewsWatch
* It’s official: Category I status has been granted for Current Procedural Terminology codes for medication therapy management services. The Pharmacist Services Technical Advisory Coalition submitted an application to the CPT Editorial Panel to change the MTM CPT code status from temporary Category III to the permanent Category I classification. The Category III codes (0115T, 0116T, 0117T) are replaced by these Category I codes that become effective on Jan. 1: 99605—MTM service(s) provided by a pharmacist, individual, face-to-face with patient, with assessment and intervention if provided, initial 15 minutes, new patient; 99606—initial 15 minutes, established patient; and 99607—each additional 15 minutes (list separately in addition to code for primary service). In preparing for the application, PSTAC funded a national survey of payers and providers to gather information pertaining to the widespread availability of MTM services. A total of 2.8 million face-to-face MTM service encounters were identified between 2004 and 2006 (see PNN, Jul. 13).

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Oct. 11, 2007 * Vol. 14, No. 197
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Oct. 11 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2007; 357).
Long-Term Coronary Prevention: Coronary events occurred significantly less often in the 10 years following completion of the 5-year West of Scotland Coronary Prevention Study among men who had been on statins during the study, compared with those originally on placebo (pp. 1477-86). Emphasizing the importance of early treatment in primary prevention among men with hypercholesterolemia, the researchers report these results based on time-to-event analyses using Cox proportional-hazards models: “Five years after the trial ended, 38.7% of the original statin group and 35.2% of the original placebo group were being treated with a statin. In the period approximately 10 years after completion of the trial, the risk of death from coronary heart disease or nonfatal myocardial infarction was 10.3% in the placebo group and 8.6% in the pravastatin group (P = 0.02); over the entire follow-up period, the rate was 15.5% in the placebo group and 11.8% in the pravastatin group (P <0.001). Similar percentage reductions were seen in the combined rate of death from coronary heart disease and hospitalization for coronary events for both periods. The rate of death from cardiovascular causes was reduced (P = 0.01), as was the rate of death from any cause (P = 0.03), over the entire follow-up period. There were no excess deaths from noncardiovascular causes or excess fatal or incident cancers.” (I. Ford, U. Glasgow, Glasgow, U.K.)
Exploring the “how low is too low” LDL cholesterol question, an editorialist notes (pp. 1543-5): “Interesting data come from studies of hunter-gatherers, Arctic Eskimos, and other civilizations not exposed to the diets and lifestyles of the ‘modern’ industrialized world. In these societies, cholesterol levels remain quite low (with LDL cholesterol in the range of 50 to 70 mg per deciliter [1.3 to 1.8 mmol per liter]), and clinical and postmortem studies show an absence of both the early indications of chronic disease seen in young people in Western societies and the atherosclerosis seen in older people. The ‘Westernization’ of such societies results in development of the same diseases that affect our own, a finding that suggests that genetic differences are not the primary reason for the disparity.... Comparisons with these societies offer the intriguing notion that very large reductions in coronary disease might attend pharmacologic achievement of the LDL cholesterol levels characteristic of those populations.” (M. J. Domanski, NIH, Bethesda, Md.)
Employer as Health Coach: Opening on-site medical clinics, gyms, pharmacies, and dental clinics is just one of the trends identified at large employers such as General Mills as part of an effort to improve the health and lifestyles of employees, reports a Perspective article (pp. 1465-9). Picking up on Asheville Project–like innovations pioneered in pharmacies, employers are taking aggressive steps to prevent and manage chronic diseases: “Besides seeking to improve risk profiles, some companies have gone to extraordinary lengths to increase access to preventive care and help employees manage chronic illnesses. Health benefits managers at Connecticut-based Pitney Bowes, which has 24,000 employees in the United States and 35,000 worldwide, studied workers’ medical claims and disability records and identified their highest-cost diseases: diabetes, heart disease, musculoskeletal disorders, asthma, and depression. They also found that two types of employees ultimately had the highest medical costs: those who normally filed no medical claims and those with chronic diseases who filled monthly prescriptions for maintenance medications fewer than 10 times per year. To encourage the first group to seek primary care, managers decided to charge employees nothing for most preventive services, no more than $20 for the most expensive ones, and $20 for visits to primary care providers. To encourage workers with chronic diseases to take medication, the company reduced copayments on all drugs for hypertension, asthma, and diabetes to 10%. Although the company’s spending on these drugs increased, its overall costs for the three diseases dropped, and it expanded the policy to cover several other conditions. Today, the firm says its health costs per employee are roughly 20% below those of comparable employers.” (S. Okie)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Oct. 12, 2007 * Vol. 14, No. 198
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
Oct. 16 issue of the Journal of the American College of Cardiology (http://content.onlinejacc.org/current.dtl; 2007; 50).
Platelet Reactivity in DM, CAD: Tailored antithrombotic therapy is needed in patients with type 2 diabetes mellitus and coronary artery disease when they are receiving long-term dual antiplatelet therapy, as this is associated with a higher risk of major adverse cardiovascular events (MACE) over the years, researchers conclude (pp. 1541-7). During up to 2 years of aspirin plus clopidogrel therapy, measures of high platelet reactivity (HPR; defined as the upper quartile of maximal platelet aggregation [Aggmax]) in 173 patients showed these results, compared with nondiabetic patients: “A total of 41 MACE occurred in 34 patients (19.7%) during the 2-year follow-up. The MACE occurred in 15.2%, 12.2%, 12.2%, and 37.7% of patients from the lowest to upper quartile, respectively (p = 0.005). The HPR was the strongest independent predictor of MACE (hazard ratio 3.35, 95% confidence interval [CI] 1.68 to 6.66, p = 0.001). Receiver-operating characteristic analysis indicated that a cutoff value of 62% Aggmax best predicted MACE (37.8% vs. 13.2%, odds ratio 3.96, 95% CI 1.8 to 8.7, p < 0.001). Patients with HPR had up-regulation of multiple platelet signaling pathways (p < 0.0001 for all assays), indicative of a global hyperreactive platelet status.” (D. J. Angiolillo, dominick.angiolillo@jax.ufl.edu)
Adenosine Blockade in HF: An investigational adenosine A1-receptor antagonist, KW-3902, enhanced the response to loop diuretics and may have had a renal protective effect in patients with acute decompensated heart failure or heart failure with diuretic resistance, according to results of a pair of randomized, controlled, proof-of-concept trials (pp. 1551-60). “In the ADHF protocol, 146 patients with volume overload and an estimated creatinine clearance (CrCl) of 20 to 80 ml/min were randomized to placebo or 1 of 4 doses of KW-3902 (rolofylline) infused over 2 h daily for up to 3 days,” the investigators write. “On day 1, KW-3902 monotherapy increased urine output during the first 6 h (445, 531, 631, and 570 ml in the 2.5-, 15-, 30-, and 60-mg groups, respectively) compared with placebo (374 ml; p = 0.02). On day 2, serum creatinine decreased in all KW-3902 groups and increased with placebo (p = 0.04). By day 4 or day of discharge if earlier, intravenous furosemide administration tended to be lower in the KW-3902 groups compared with placebo (p = 0.10). In the diuretic-resistant protocol, 35 patients with an average CrCl of 34 ml/min were randomized to a single infusion of placebo, 10, 30, or 60 mg of KW-3902. Compared with placebo, KW-3902 increased hourly urine volume and estimated CrCl with peak effects occurring at 2 to 3 h and at 24 h, respectively. Adverse events were not different between placebo and KW-3902.” (M. M. Givertz, mgivertz@partners.org)

>>>PNN NewsWatch
* With an FDA advisory panel hearing looming next week on the safety and effectiveness of OTC cough-and-cold products in children 6 years of age and younger, nonprescription drug manufacturers yesterday voluntarily recalled 14 products labeled and marketed for use in infants and children younger than 2 years old. A complete list of recalled products along with Web site addresses and toll-free numbers of manufacturers is available on www.pharmacist.com. Cough-and-cold products labeled for children aged 2 and older and single-ingredient analgesics and antipyretics labeled for infants are not affected by this product withdrawal. Some manufacturers have coupons on their Web sites to help compensate consumers for products already purchased and used, and a Consumer Healthcare Products Association Web site set up to communicate messages about the nonmandatory recall, www.OTCSafety.org, points out, “Parents can continue to trust and rely on over-the-counter cough and cold medicines for their children, as they have for generations, because these medicines are safe at recommended doses.” CHPA also announced that it would recommend to the FDA advisors that manufacturers relabel oral OTC products in this category with “do not use” in infants and children younger than 2 years of age, replacing the current advice of “asking your doctor.”

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Oct. 15, 2007 * Vol. 14, No. 199
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Oct. 13 issue of Lancet (www.thelancet.com; 2007; 370).
Abortion Trends: In a theme issue on women’s health timed to coincide with the Women Deliver conference in London on Oct. 18–20, researchers report that the number of abortions performed worldwide declined between 1995 and 2003 and that unsafe abortions during that period were concentrated almost entirely in developing countries (pp. 1338-45). “An estimated 42 million abortions were induced in 2003, compared with 46 million in 1995,” the authors note. “The induced abortion rate in 2003 was 29 per 1,000 women aged 15–44 years, down from 35 in 1995. Abortion rates were lowest in western Europe (12 per 1,000 women). Rates were 17 per 1,000 women in northern Europe, 18 per 1,000 women in southern Europe, and 21 per 1000 women in northern America (USA and Canada). In 2003, 48% of all abortions worldwide were unsafe, and more than 97% of all unsafe abortions were in developing countries. There were 31 abortions for every 100 livebirths worldwide in 2003, and this ratio was highest in eastern Europe (105 for every 100 livebirths).” The group concludes, “Ensuring that the need for contraception is met and that all abortions are safe will reduce maternal mortality substantially and protect maternal health.” (G. Sedgh, Guttmacher Inst., New York; gsedgh@guttmacher.org)

>>>BMJ Highlights
Source:
Early-release articles from and Oct. 13 issue of BMJ (www.bmj.org; 2007; 335).
Managing Left Ventricular Dysfunction: A Bayesian network meta-analysis shows that combined cardiac resynchronization (biventricular pacing) therapy and implantable cardioverter defibrillator therapy is superior to medical therapy for reducing mortality among patients with left ventricular dysfunction, but the analysis was unable to demonstrate that the combined therapy is better than cardiac resynchronization therapy alone (doi: 10.1136/bmj.39343.511389). The report notes these results: “12 studies including 1,636 events in 8,307 patients were identified. Combined cardiac resynchronisation and implantable cardioverter defibrillator therapy reduced the number of deaths by one third compared with medical therapy alone (odds ratio 0.57, 95% credible interval 0.40 to 0.80) but did not further improve survival when compared with implantable defibrillator therapy (0.82, 0.57 to 1.18) or resynchronisation (0.85, 0.60 to 1.22) therapy alone.” (S. K. H. Lam, Chi Lin Med. Ctr., Kowloon, Hong Kong; simon.lam@medsci.oxon.org)
Reducing Childhood Obesity: Promoting a healthy diet and discouraging the consumption of carbonated drinks had a measurable effect on the prevalence of overweight among children at 1 year, but the effect disappeared by the end of the 3-year monitoring period (pp. 335 ff). Based on the body mass indices of 644 children initially aged 7–11 years, the researchers report: “The BMI increased in the control group by 2.14 (SD 1.64) and the intervention group by 1.88 (SD 1.71), with mean difference of 0.26 (–0.07 to 0.58, P = 0.12). The waist circumference increased in both groups after three years with a mean difference of 0.09 (–0.06 to 0.26, P = 0.25).” (J. James, Royal Bournemouth Hosp., Bournemouth, U.K.; janet.james@rbch.nhs.uk)

>>>PNN JournalWatch
* Continuum of Care for Maternal, Newborn, and Child Health: From Slogan to Service Delivery, in Lancet, 2007; 370: 1358–69. Reprints: J. E. Lawn, Saving Newborn Lives, Save the Children-US, Cape Town, South Africa; joylawn@yahoo.co.uk
* Aspirin Prescription and Outcomes in Hemodialysis Patients: The Dialysis Outcomes and Practice Patterns Study (DOPPS), in
American Journal of Kidney Diseases, 2007; 50: 602–11. Reprints: J. Éthier, Centre Hospitalier de l’Université de Montréal, Montreal; ethierje@sympatico.ca
* Antivirals and the Control of Influenza Outbreaks, in
Clinical Infectious Diseases, doi: 10.1086/522661. Reprints: S. Hota.
* Reducing Antibiotic Overuse: A Call for a National Performance Measure for Not Treating Asymptomatic Bacteriuria, in
Clinical Infectious Diseases, doi: 10.1086/522183. Reprints: P. A. Gross, Hackensack U. Med. Ctr., Hackensack, N.J.
* The Genetics of Inflammatory Bowel Disease, in
Gastroenterology, 2007; 133. 1327–39 Reprints: J. H. Cho; judy.cho@yale.edu

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Oct. 16, 2007 * Vol. 14, No. 200
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Oct. 16 issue of the Annals of Internal Medicine (www.annals.org/current.shtml; 2007; 147).
Low-Dose Aspirin for VTE Prevention: Among nearly 40,000 initially healthy women aged 45 years or older, long-term, low-dose aspirin prophylaxis had little effect on the frequency of venous thromboembolism, according to a secondary analysis of data from the Women’s Health Study (pp. 525-33). During the 10-year trial, women took either aspirin 100 mg or placebo every other day, and these findings were observed based on 482 episodes of VTE: “The incidence of VTE (per 1,000 person–years) was 1.18 among women randomly assigned to active aspirin, compared with 1.25 among women randomly assigned to placebo (relative hazard, 0.95 [95% CI, 0.79 to 1.13]; rate difference, –0.06 [CI, –0.28 to 0.16]). For unprovoked VTE, the relative hazard was 0.90 (CI, 0.70 to 1.16) and the rate difference was –0.06 (CI, –0.21 to 0.10). Relative hazards associated with aspirin use in higher-risk subgroups were 0.83 (CI, 0.50 to 1.39) among women with either factor V Leiden or the prothrombin mutation and 1.36 (CI, 0.77 to 2.41) among those with a history of VTE.” (R. J. Glynn, rglynn@rics.bwh.harvard.edu)
Length of Treatment in H. pylori Eradication: Extending the duration of proton-pump inhibitor–based triple therapy beyond seven days is unlikely to be “a clinically useful strategy” for eradicating Helicobacter pylori, conclude authors of a meta-analysis (pp. 553-62). “Of 21 included studies, 11 compared 7-day therapy with 10-day therapy, and 13 compared 7-day therapy with 14-day therapy,” write the investigators. “Meta-analysis yielded relative risks (RRs) for eradication of 1.05 (95% CI, 1.01 to 1.10) for 7-day compared with 10-day amoxicillin-containing triple therapy (10 studies) and 1.07 (CI, 1.02 to 1.12) for 7-day compared with 14-day therapy (11 studies). Meta-analysis of the 3 studies that compared 7-day with 14-day metronidazole-containing therapy yielded an RR of 1.08 (CI, 0.96 to 1.22). The 7-day versus 10-day comparisons yielded RRs of 1.03 (CI, 0.97 to 1.10) for peptic ulcer disease and 1.10 (CI, 1.02 to 1.20) for nonulcer dyspepsia. For the 7-day versus 14-day comparisons, the RRs were 1.04 (CI, 0.99 to 1.09) and 1.03 (CI, 0.88 to 1.20), respectively. The RRs for frequency of adverse events were 0.98 (CI, 0.85 to 1.14) and 1.08 (CI, 0.84 to 1.40) for 7-day therapy compared with 10- and 14-day therapy, respectively. Diarrhea and taste disturbance were the most frequently reported adverse events (5%).” (F. Bazzoli, Università di Bologna, Bologna, Italy; franco.bazzoli@unibo.it)

>>>PNN NewsWatch
* A new carbapenem, doripenem for injection (Doribax, Ortho-McNeil) has been approved for single-agent treatment of complicated intra-abdominal infections caused by susceptible strains of several bacteria and complicated urinary tract infections, including pyelonephritis, caused by susceptible strains of Escherichia coli (including cases with concurrent bacteremia), Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, or Acinetobacter baumannii. The drug is contraindicated in patients with known serious hypersensitivity to doripenem or other carbapenems and in patients who have demonstrated anaphylactic reactions to beta-lactam antibiotics. Adverse reactions to doripenem occurring in more than 5% of patients are headache, nausea, diarrhea, rash and phlebitis. Because of a possible drug interaction, serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy. Clostridium difficile–associated diarrhea is also a concern, as it is with nearly all antibiotics. When doripenem has been used investigationally via inhalation, pneumonitis has occurred. The drug should not be administered by this route. In addition, safety and effectiveness in pediatric patients have not been established.
*
Topotecan (Hycamtin, GlaxoSmithKline) has been approved for treatment of patients with relapsed small cell lung cancer who had a complete or partial response to first-line chemotherapy and who are at least 45 days from the end of treatment. The agent becomes the only oral single-agent chemotherapy for this condition after first-line therapy.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Oct. 17, 2007 * Vol. 14, No. 201
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Oct. 17 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2007; 298).
MRSA in the U.S.: Older patients, blacks, and men have the highest rates of infection with methicillin-resistant Staphylococcus aureus, researchers report (pp. 1763-71). Using 2004–05 U.S. data from the Active Bacterial Core surveillance (ABCs)/Emerging Infections Program Network, the investigators found: “There were 8,987 observed cases of invasive MRSA reported during the surveillance period. Most MRSA infections were health care–associated: 5,250 (58.4%) were community-onset infections, 2,389 (26.6%) were hospital-onset infections; 1,234 (13.7%) were community-associated infections, and 114 (1.3%) could not be classified. In 2005, the standardized incidence rate of invasive MRSA was 31.8 per 100,000 (interval estimate, 24.4–35.2). Incidence rates were highest among persons 65 years and older (127.7 per 100,000; interval estimate, 92.6–156.9), blacks (66.5 per 100,000; interval estimate, 43.5–63.1), and males (37.5 per 100,000; interval estimate, 26.8–39.5). There were 1,598 in-hospital deaths among patients with MRSA infection during the surveillance period. In 2005, the standardized mortality rate was 6.3 per 100,000 (interval estimate, 3.3–7.5). Molecular testing identified strains historically associated with community-associated disease outbreaks recovered from cultures in both hospital-onset and community-onset health care–associated infections in all surveillance areas.” (R. M. Klevens, rmk2@cdc.gov)
Resistant Otopathogen: An otopathogenic strain of Streptococcus pneumoniae has emerged in the U.S. since the introduction of the pneumococcal 7-valent conjugate vaccine, and authors report that it is resistant to all antibiotics approved by FDA for treatment of acute otitis media in children (pp. 1772-8). In a prospective cohort study conducted in a Rochester, N.Y., pediatric practice, the authors report: “Among 1,816 children in whom AOM was diagnosed, tympanocentesis was performed in 212, yielding 59 cases of S pneumoniae infection. One strain of S pneumoniae belonging to serotype 19A was a new genotype and was resistant to all antibiotics approved by the FDA for use in children with AOM. This strain was identified in 9 cases (2 in 2003–2004, 2 in 2004–2005, and 5 in 2005–2006). Four children infected with this strain had been unsuccessfully treated with 2 or more antibiotics, including high-dose amoxicillin or amoxicillin–clavulanate and 3 injections of ceftriaxone; 3 had recurrent AOM; and for 2 others, the infection was their first in life. The first 4 cases required tympanostomy tube insertion after additional unsuccessful antibiotic therapies. Levofloxacin was used in the subsequent 5 cases, with resolution of infection without surgery.” (M. E. Pichichero, michael_pichichero@urmc.rochester.edu)

>>>PNN NewsWatch
* Raltegravir (Isentress, Merck) has been approved by FDA for treatment of HIV-1 infection in combination with other antiretroviral agents in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents. The first HIV integrase strand transfer inhibitor, raltegravir was studied in two double-blind, placebo-controlled studies in 699 HIV-1 infected adult patients with histories of extensive antiretroviral use. HIV in the blood was significantly reduced by raltegravir in combination therapy, compared with placebo and other drugs. Diarrhea, nausea, headache, and fever were the adverse effects most commonly reported with raltegravir. Elevations in creatine kinase levels have occurred in patients taking raltegravir, and myopathy and rhabdomyolysis may result. The drug should be used cautiously in patients at risk for these toxicities, including those taking other myotoxic drugs such as statins. Long-term effects of raltegravir are not known, and it is unstudied in children younger than 16 and pregnant women.
* Acute pancreatitis has been reported in 30 patients taking
exenatide (Byetta; Amylin/Lilly), prompting an alert from FDA. Health professionals should instruct patients taking the drug to seek prompt medical care if they experience unexplained persistent severe abdominal pain that may or may not be accompanied by vomiting, FDA advised. If pancreatitis is suspected, exenatide should be discontinued. If pancreatitis is confirmed, exenatide should not be restarted unless an alternative etiology is identified.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Oct. 18, 2007 * Vol. 14, No. 202
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Oct. 18 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2007; 357).
Prednisolone v. Acyclovir for Bell’s Palsy: While early treatment with prednisolone significantly improved chances of complete recovery from Bell’s palsy at 3 and 9 months, acyclovir provided no benefit, either alone or in combination with the steroid (pp. 1598-607). In a trial that began treatment within 72 hours of the onset of symptoms, patients randomly received 10 days of treatment with prednisolone, acyclovir, both agents, or placebo. Assessing recovery of facial function, as rated on the House–Brackmann scale, the investigators found: “Final outcomes were assessed for 496 of 551 patients who underwent randomization. At 3 months, the proportions of patients who had recovered facial function were 83.0% in the prednisolone group as compared with 63.6% among patients who did not receive prednisolone (P <0.001) and 71.2% in the acyclovir group as compared with 75.7% among patients who did not receive acyclovir (adjusted P = 0.50). After 9 months, these proportions were 94.4% for prednisolone and 81.6% for no prednisolone (P <0.001) and 85.4% for acyclovir and 90.8% for no acyclovir (adjusted P = 0.10). For patients treated with both drugs, the proportions were 79.7% at 3 months (P <0.001) and 92.7% at 9 months (P <0.001). There were no clinically significant differences between the treatment groups in secondary outcomes. There were no serious adverse events in any group.” (F. M. Sullivan, U. Dundee, Dundee, U.K.; f.m.sullivan@chs.dundee.ac.uk)
Editorialists maintain that despite the negative acyclovir results, the use of valacyclovir should not be ruled out (pp. 1653-5): “The study by Sullivan et al. clearly indicates that the addition of acyclovir provides no additional benefit to treatment with glucocorticoids alone. But what about valacyclovir? Valacyclovir is a prodrug that is nearly completely converted to acyclovir and l-valine and has substantially increased bioavailability, as compared with acyclovir. Both [this and a study by Hato et al.] show no benefit of antiviral therapy in patients with moderate palsy and thus provide no rationale for treating these patients with valacyclovir. The cost of a 5-day course of 500 mg of valacyclovir twice daily is approximately $70, and the number needed to treat for one additional full recovery in patients with complete facial palsy is approximately seven. Although the study by Hato et al. was methodologically flawed, the use of valacyclovir in combination with glucocorticoids could still be considered in patients with severe or complete facial palsy.” (D. H. Gilden, U. Colorado, Denver)
Payment for Results—Biologic Agents: In a Perspectives article that reviews experiences in the U.K. and the U.S. with payment for biologic agents based on clinical results, former FDA and CMS head Mark B. McClellan, MD, PhD, and a coauthor write (pp. 1575-7): “Payment by results also represents an innovative approach to addressing one of the central dilemmas in the allocation of drugs to patients — the fact that a treatment’s benefits vary greatly, often in predictable ways, from one patient to another. Survivors of myocardial infarction have larger short-term survival benefits from statins than do young women with hypercholesterolemia but with no other risk factors for heart disease. A much greater survival benefit of imatinib mesylate (Gleevec, Novartis) has been demonstrated among patients with gastrointestinal stromal tumors than among those with malignant glioma. Physicians may be aware of many other characteristics that determine whether a patient is likely to benefit more or less than the enrollees in a study. If the price of the compound is uniform, access is likely to be limited to patients in the population groups known to derive the greatest benefit (if the cost is paid by insurance) or willing to pay the most (if patients spend their own money). Patients in groups that are not expected to derive particularly large benefit are less likely to receive treatment, often because payers will create barriers to such use of the drug. In results-based payment, payers face much less financial risk from treating such groups.” (A. M. Garber, VA Health Care System, Palo Alto, 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 © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Oct. 18, 2007 * Special alert
Providing news and information about medications and their proper use

Pfizer announced this morning plans to discontinue sales of inhaled insulin (Exubera) over the next 3 months, citing poor acceptance by patients and physicians. In a news release announcing the company's third-quarter financial results, Jeff Kindler, Chairman and Chief Executive Officer, was quoted as saying, “Despite our best efforts, Exubera has failed to gain the acceptance of patients and physicians. We have therefore concluded that further investment in this product is unwarranted. We will work with physicians to transition Exubera patients to other treatment options in the next 3 months. We remain committed to investing significant resources in the development of new and innovative medicines to manage diabetes, including monitoring inhalation technologies and other innovative delivery systems for insulin and other medicines.”

PNN Pharmacotherapy Line
Oct. 19, 2007 * Vol. 14, No. 203
Providing news and information about medications and their proper use

>>>Psychiatry Highlights
Source:
Oct. issue of the American Journal of Psychiatry (http://ajp.psychiatryonline.org/current.dtl; 2007; 164).
Depression During Pregnancy: Depression requiring treatment with medications and/or mental health visits occurred in one in seven women who delivered live births between 1998 and 2001, researchers report (pp. 1515-20). Analyzing data from a health plan, the investigators determined: “Among 4,398 continuously enrolled women with eligible pregnancies ending in live births, 678 (15.4%) had depression identified during at least one pregnancy phase; 8.7%, 6.9%, and 10.4% had depression identified before, during, and/or after pregnancy, respectively. Among women with identified depression during the 39 weeks before pregnancy, 56.4% also had a depression diagnosis during pregnancy. Of women identified with depression during the 39 weeks following pregnancy, 54.2% had depression diagnoses either during or preceding pregnancy. Most women diagnosed with depression received antidepressant medications and/or had at least one mental health visit. Having at least one mental health visit did not vary before, during, or after pregnancy; however, antidepressant use was lower during pregnancy than before or after pregnancy.” (P. M. Dietz)
Genetics & Treatment-Emergent Suicidal Ideation: Markers with two genetic loci were associated with emergence of suicidal ideation during citalopram therapy, according to a study of 1,915 outpatients with major depressive disorder (pp. 1530-8). Data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial show: “Two markers were significantly associated with treatment-emergent suicidal ideation in this sample (marker rs4825476, p = 0.0000784, odds ratio = 1.94; permutation p = 0.01; marker rs2518224, p = 0.0000243, odds ratio = 8.23; permutation p = 0.003). These markers reside within the genes GRIA3 and GRIK2, respectively, both of which encode ionotropic glutamate receptors.” (G. Laje)

>>>PNN NewsWatch
* Make room in your pharmacy museum cabinet for Exubera, the inhaled insulin product Pfizer yesterday announced plans to discontinue. In ending sales of Exubera over the next 3 months, Pfizer is taking a $2.8 billion write-off on its books, including $661 million in inventory and $1.1 billion of intangible assets. The Wall Street Journal, terming this “one of the drug industry’s costliest failures,” notes this morning that the decision “rids the company of an albatross.” While Pfizer’s decision was based on poor sales—Exubera had only $12 million in sales this year—safety was a major concern in the minds of physicians who declined to prescribe the product. The size of the administration device made it inconvenient, and the Wall Street Journal article notes that its resemblance to a bong used for smoking marijuana made it embarrassing to use in public. Dosages were expressed in milligrams rather than units, and the Institute of Safe Medication Practices had written just this month in Pharmacy Today about dosing errors with the system.
* Recommendations on whether
nonprescription cough-and-cold medications should be marketed for children younger than 6 years will come in votes this afternoon by FDA’s advisory committees on pediatrics and nonprescription drugs. Meeting jointly yesterday in Silver Spring, Md., the two panels heard physicians call for an end to use of the agents in this age group, citing lack of benefits and clinical studies in young children. One physician who has petitioned FDA to ban use of these medications in young children told the panelists, “When a treatment is ineffective, its risks—if not zero—always will exceed its benefits,” Associated Press reports. The Consumer Healthcare Products Association, which last week took the preemptive measure of having its industry members pull from the market those products targeted at infants and children aged 2 years and under, has maintained that the products are safe when used correctly and that most adverse outcomes are the result of poisonings, unintentional overdoses, and other misuse. The association has called for improved labeling, more education of parents and caregivers, and further research.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Oct. 22, 2007 * Vol. 14, No. 204
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Oct. 20 issue of Lancet (www.thelancet.com; 2007; 370).
New Agent for CKD Anemia: Methoxy polyethylene glycol-epoetin beta, a long-acting erythropoiesis-stimulating agent, was as safe as conventional epoetin treatment and maintained hemoglobin levels over a 4-week dosing period in 1,115 adult patients with stable chronic renal anemia who were on dialysis (pp. 1415-21). Comparing doses of the new agent given every 2 and 4 weeks with conventional epoetin therapy, the researchers found: “The mean change from baseline haemoglobin for patients who had switched to intravenous methoxy polyethylene glycol-epoetin beta every 2 weeks (−0.71 g/L, 95% CI −2.20 to 0.77) or every 4 weeks (−0.25 g/L, −1.79 to 1.29) was non-inferior to the mean change for patients who continued treatment with epoetin (−0.75 g/L, −2.26 to 0.75) (p <0.0001 for both comparisons). Of the 666 patients who received at least one dose of study drug, the incidence of adverse events or serious adverse events did not differ between groups (p = 0.30 and p = 0.40, respectively).” (N. W. Levin, Renal Research Inst., New York; nlevin@rriny.com)
Nebulized Pitrakinra for Asthma: In two Phase 2a trials of 56 patients with atopic asthma, local treatment with the investigational interleukin-4 and IL-13 inhibitor pitrakinra substantially diminished asthma symptoms (pp. 1422-31). The first study used subcutaneous pitrakinra 25 mg or placebo once daily, while the second trial tested 60-mg doses of the drug administered by nebulization twice daily, with these results: “In study 1, there was a 17.1% maximum percentage decrease in FEV1 in the pitrakinra group; by contrast, the maximum decrease was 23.1% in the placebo group (difference 6%, 95% CI −4.37 to 16.32; p = 0.243). In study 2, there was a 4.4% average percentage decrease in FEV1 in the pitrakinra group; by contrast, the average percentage decrease was 15.9% in the placebo group (3.7 [95% CI 2.08–6.25] times lower in the pitrakinra group; p = 0.0001). There were fewer asthma-related adverse events (p = 0.069) and fewer adverse events requiring beta-agonist rescue (p = 0.031) after subcutaneous administration of pitrakinra than with placebo. There were too few asthma-related adverse events in study 2 to assess the effect of inhalation of pitrakinra on adverse events.” (M. Longphre, Aerovance Inc., Berkeley, Calif.; malinda.longphre@aerovance.com)

>>>BMJ Highlights
Source:
Early-release articles from BMJ (www.bmj.org; 2007; 335).
Protective Antibiotics After RTIs: The risk of serious complications of most respiratory tract infections is not reduced by protective antibiotic therapy, conclude authors of a retrospective cohort study (doi: 10.1136/bmj.39345.405243.BE). The exception is chest infection, especially in older people for whom the risk of pneumonia is highest, the authors report: “Serious complications were rare after upper respiratory tract infections, sore throat, and otitis media, and the number needed to treat was over 4,000. The risk of pneumonia after chest infection was high, particularly in elderly people, and was substantially reduced by antibiotic use, with a number needed to treat of 39 for those aged 65 or older and 96–119 in younger age groups.” (A. Hayward, U. College, London; a.hayward@pcps.ucl.ac.uk)

>>>PNN NewsWatch
* Recommendations to not use nonprescription cough and cold medicines in children younger than 6 years, made on Friday by FDA advisory committees, could leave pharmacists in limbo with the cough-and-cold season approaching. The panels were nearly unanimous that extrapolation of adult data to children younger than 12 years was unacceptable and that pediatric studies of these agents fail to establish safety and efficacy of the drug ingredients, APhA’s pharmacist.com reports. But the patchwork of federal statutes and regulations governing these products could delay action by FDA, even as parents and caregivers seek relief of symptoms in kids.

>>>PNN JournalWatch
* Treatment Failure in Community-Acquired Pneumonia, in Chest, 2007; 132: 1348–55. Reprints: R. Menendez, Hospital Universitario La Fe, Valencia, Spain; rmenend@separ.es

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Oct. 23, 2007 * Vol. 14, No. 205
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Oct. 22 issue of the Archives of Internal Medicine (http://archinte.ama-assn.org/current.dtl; 2007; 167).
Study Funding & Adverse Effects of Inhaled Steroids: Studies of inhaled corticosteroids funded by the pharmaceutical industry are less likely to identify adverse effects of the drugs, compared with trials without such funding, largely because of study designs that do not as frequently detect these events, authors report (pp. 2047-53). Comparing 275 studies with pharmaceutical manufacturer funding (PF) with 229 NoPF studies, the investigators write: “Overall, the finding of statistically significant differences for adverse effects was significantly less frequent in PF (34.5%) than in NoPF (65.1%) studies (prevalence ratio, 0.53; 95% confidence interval, 0.44–0.64). This association became nonsignificant (prevalence ratio, 0.94; 95% confidence interval, 0.77–1.15) after controlling for design features (such as dose or use of parallel groups) that tended to be associated with less frequent finding of adverse effects and were more common in PF studies. Among studies finding a statistically significant increase in adverse effects associated with the study drug, the authors of PF articles concluded that the drug was ‘safe’ more frequently than the authors of NoPF studies (prevalence ratio, 3.68; 95% confidence interval, 2.14–6.33).” (A. Mazon, Children's Hosp. La Fe, Valencia, Spain; amazon@comv.es)
Central Venous Catheter Care: For skin disinfection at catheter-insertion sites, chlorhexidine-based solutions should be considered as a replacement for povidone–iodine (including alcohol-based) formulations, conclude researchers who assessed care of consecutively scheduled central venous catheters (pp. 2066-72). Comparing 5% povidone–iodine in 70% ethanol or with a combination of 0.25% chlorhexidine gluconate, 0.025% benzalkonium chloride, and 4% benzylic alcohol, the authors found these results among 481 evaluable culture results: “Compared with povidone–iodine, the chlorhexidine-based solution was associated with a 50% decrease in the incidence of catheter colonization (11.6% vs 22.2% [P = .002]; incidence density, 9.7 vs 18.3 per 1000 catheter–days) and with a trend toward lower rates of catheter-related bloodstream infection (1.7% vs 4.2% [P = .09]; incidence density, 1.4 vs 3.4 per 1000 catheter–days). Independent risk factors for catheter colonization were catheter insertion into the jugular vein (adjusted relative risk, 2.01; 95% confidence interval, 1.24–3.24) and use of povidone–iodine (adjusted relative risk, 1.87; 95% confidence interval, 1.18–2.96).” (O. Mimoz, Centre Hospitalier et Universitaire de Poitiers, Poitiers, France; .mimoz@chu-poitiers.fr">o.mimoz@chu-poitiers.fr)

>>>PNN NewsWatch
* Ixabepilone (Ibxempra, Bristol-Myers Squibb) has been approved by FDA for use in patients with metastatic or locally advanced breast cancer who have not responded to certain other oncolytic agents. Reviewed on a priority basis, ixabepilone was approved for use in combination with capecitabine in patients who no longer benefit from treatment with an anthracycline plus a taxane and as a single agent in those who no longer benefit from an anthracycline, a taxane, and capecitabine. In 752 patients, ixabepilone plus capecitabine delayed cancer progression or death, compared to capecitabine alone. Clinically significant tumor shrinkage occurred in 12% of the patients treated with ixabepilone alone in a separate 126-patient trial. Serious adverse effects of the drug include peripheral neuropathy and bone marrow suppression. Other commonly observed toxicities are constipation, nausea, vomiting, muscle paint, joint pain, fatigue, and general weakness. Women taking ixabepilone should avoid taking drugs that are strong inhibitors of CYP 3A4, one of the enzymes that metabolizes ixabepilone. Ixabepilone should not be taken by women who have had severe allergic reactions to drugs that contain Cremophor or its derivatives, or by women who have baseline bone marrow suppression determined by low white blood cell or platelet count. The combination of ixabepilone and capecitabine should not be given to patients with moderate or severe liver impairment because of an increased risk of toxicity and death.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Oct. 24, 2007 * Vol. 14, No. 206
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Oct. 24 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2007; 298).
Treating Zambian Children with HIV: “Good outcomes” were achieved among patients younger than 16 years of age presenting with HIV at primary health facilities in Lusaka, Zambia, authors write (pp. 1888-99). But the high mortality rate observed during the first 90 days of highly active antiretroviral therapy point “to a need for earlier intervention,” the investigators conclude, adding these details: “After enrollment of 4,975 children into HIV care, 2,938 (59.1%) started ART. Of those initiating ART, the median age was 81 months (interquartile range, 36-125), 1,531 (52.1%) were female, and 2,087 (72.4%) with World Health Organization stage information were in stage III or IV. At the time of analysis, 158 children (5.4%) had withdrawn from care and 382 (13.0%) were at least 30 days late for follow-up. Of the remaining 2,398 children receiving ART, 198 (8.3%) died over 3,018 child–years of follow-up (mortality rate, 6.6 deaths per 100 child–years; 95% confidence interval [CI], 5.7–7.5); of these deaths, 112 (56.6%) occurred within 90 days of therapy initiation (early mortality rate, 17.4/100 child–years; post–90-day mortality rate, 2.9/100 child–years). Mortality was associated with CD4 cell depletion, lower weight-for-age, younger age, and anemia in multivariate analysis. The mean CD4 cell percentage at ART initiation among the 1,561 children who had at least 1 repeat measurement was 12.9% (95% CI, 12.5%–13.3%) and increased to 23.7% (95% CI, 23.1%–24.3%) at 6 months, 27.0% (95% CI, 26.3%–27.6%) at 12 months, 28.0% (95% CI, 27.2%–28.8%) at 18 months, and 28.4% (95% CI, 27.4%–29.4%) at 24 months.” (J. S. A. Stringer, Ctr. for Infectious Disease Research in Zambia, Lusaka, Zambia; stringer@cidrz.org)
Commenting on this and other articles in this special issue, part of a collaboration of 200 journals publishing simultaneously on poverty and human development, editorialists note (pp. 1940-2): “Use of antiretroviral regimens in low-income countries brings new questions and complexities with regard to monitoring, selection, adherence, and other issues.14 As multiple organizations mobilize to respond to the HIV treatment emergency in sub-Saharan Africa and other regions, evaluative studies are urgently needed to identify what types of infrastructure yield the most effective treatment, limit antiviral resistance, and ultimately are sustainable and cost-effective. There is a growing requirement to share and synthesize available evidence, and adapt and bring to scale effective local programs. Implementation science also is integral to the effective scaling up of HIV prevention and the testing of prevention algorithms to control HIV through combination interventions.” (R. B. Eiss,
eissr@mail.nih.gov)
Oral Drug Therapy for Tropical Diseases: With all the attention on HIV, tuberculosis, and malaria in many parts of the tropics, 13 other diseases are often forgotten, authors of a Clinician’s Corner article maintain (pp. 1911-24). They share these findings about seven of these conditions that can be treated with oral drug therapy, with attention to drugs that can treat more than one condition simultaneously: “Albendazole plus diethylcarbamazine significantly reduced prevalence of elephantiasis (16.7% to 5.3%), hookworm (10.3% to 1.9%), roundworm (34.5% to 2.3%), and whipworm (55.5% to 40.3%). Albendazole plus ivermectin significantly reduced prevalence of elephantiasis (12.6% to 4.6%), hookworm (7.8% to 0%), roundworm (33.5% to 6.1%), and whipworm (42.7% to 8.9%). Levamisole plus mebendazole significantly reduced prevalence of hookworm (94.0% to 71.8%), roundworm (62.0% to 1.4%), and whipworm (93.1% to 74.5%). Pyrantel-oxantel significantly reduced hookworm (93.4% to 85.2%), roundworm (22.8% to 1.4%), and whipworm (86.8% to 59.5%), while albendazole alone significantly reduced prevalence of hookworm (8.1% to 1.3%), roundworm (28.4% to 0.9%), and whipworm (51.9% to 31.9%). No RCT examined treatment of river blindness or trachoma as part of an intervention to target 2 or more neglected tropical diseases. Adverse events were generally inadequately reported.” (M. Reddy, madhurireddy@hrca.harvard.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Oct. 25, 2007 * Vol. 14, No. 207
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Oct. 25 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2007; 357).
Postexposure Hepatitis A Vaccine: In a study conducted in Kazakhstan, low rates of hepatitis A were observed among children and adults exposed to the virus who received either postexposure hepatitis A vaccine or immune globulin (pp. 1685-94). Concluding that the data show that the vaccine is “a reasonable alternative to immune globulin for postexposure prophylaxis in many situations,” the authors report these results for patients treated within 14 days of exposure to those with hepatitis A: “Of 4,524 contacts who underwent randomization, 1,414 (31%) were susceptible to hepatitis A virus and 1,090 were eligible for the per-protocol analysis. Among these contacts, 568 received hepatitis A vaccine and 522 received immune globulin. Most contacts were children (average age, 12 years), and most received prophylaxis during the second week after exposure (average interval after exposure, 10 days). The baseline characteristics of the contacts were similar in the two groups. Symptomatic infection with hepatitis A virus was confirmed in 25 contacts receiving vaccine (4.4%) and in 17 contacts receiving immune globulin (3.3%) (relative risk, 1.35; 95% confidence interval, 0.70 to 2.67).” (J. C. Victor, Program for Appropriate Technology in Health, Seattle; cvictor@path.org)
An editorialist calls the study “another success for hepatitis A vaccine” (pp. 1757-9): “The study suggests that hepatitis A vaccine is effective for the prevention of secondary infections. The results provide support for the recent change in U.S. policy to the preference for hepatitis A vaccine over immune globulin for postexposure prophylaxis in healthy persons 2 to 40 years of age, with the continued use of immune globulin in contacts outside this age range and in those who are immunocompromised or who have chronic liver disease.” (C. J. Baker, Baylor Coll. of Med., Houston)
Outcomes with Biphasic, Prandial, or Basal Insulin: Better glycemic control was observed at 1 year when patients with type 2 diabetes used biphasic or prandial insulin aspart rather than the basal insulin detemir, according to a study in which 708 patients with poor glycemic control received the interventions as add-on therapy to metformin and a sulfonylurea (pp. 1716-30). “At 1 year, mean glycated hemoglobin levels were similar in the biphasic group (7.3%) and the prandial group (7.2%) (P = 0.08) but higher in the basal group (7.6%, P <0.001 for both comparisons),” report the researchers. “The respective proportions of patients with a glycated hemoglobin level of 6.5% or less were 17.0%, 23.9%, and 8.1%; respective mean numbers of hypoglycemic events per patient per year were 5.7, 12.0, and 2.3; and respective mean weight gains were 4.7 kg, 5.7 kg, and 1.9 kg. Rates of adverse events were similar among the three groups.” (R. R. Holman, Churchill Hosp., Oxford, U.K.; rury.holman@dtu.ox.ac.uk)

>>>PNN NewsWatch
* Serious rash, including Stevens–Johnson Syndrome and hypersensitivity reactions, and psychiatric symptoms have occurred with modafinil (Provigil), FDA and Cephalon warned yesterday. During postmarketing surveillance of adults and children using the drug, rare cases of serious or life-threatening rash, including toxic epidermal necrolysis, and drug rash with eosinophilia and systemic symptoms, have been reported. Angioedema and multi-organ hypersensitivity reactions have also been reported. If a rash or other hypersensitivity reaction occurs, patients should be instructed to immediately discontinue the use of modafinil and contact the prescribing physician. Health professionals and consumers should also be aware that modafinil is not approved for use in pediatric patients for any indication. In addition, psychiatric adverse experiences (including anxiety, mania, hallucinations, and suicidal ideation) have been reported in patients treated with modafinil. Caution should be exercised when the drug is used in patients with history of psychosis, depression, or mania.
* For business reasons,
Ortho Biotech is discontinuing Sporanox injection (itraconazole) in the U.S. In a letter to health professionals, the company suggests use of oral Sporanox and alternative injectable antifungal agents for treatment and prophylaxis of mycotic infections.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Oct. 26, 2007 * Vol. 14, No. 208
Providing news and information about medications and their proper use

>>>Geriatrics Highlights
Source:
Oct. issue of the Journal of the American Geriatrics Society (www.blackwell-synergy.com/toc/jgs/55/10; 2007; 55).
Simultaneous Zoster, Flu Vaccines: Concomitant administration of zoster and influenza vaccines in adults aged 50 years or older was well tolerated and produced antibody responses similar to those of sequentially administered vaccines (pp. 1499-507). Based on primary immunogenicity end points of geometric mean titer (GMT) and geometric mean fold rise (GMFR) from baseline of varicella-zoster virus (VZV) antibody (Ab) at 4 weeks after vaccination with Zostavax and/or influenza vaccine, these results were recorded in 382 concomitantly and 380 sequentially vaccinated participants: “No serious [adverse experiences] related to Zostavax were observed during the study. VZV Ab GMTs 4 weeks [after vaccination] for the concomitant and sequential groups were 554 and 597 [glycoprotein enzyme-linked immunosorbent assay ] U/mL, respectively. The estimated VZV Ab GMT ratio was 0.9 (95% confidence interval (CI) = 0.8–1.0), indicating noninferior (P <.001 for the null hypothesis of GMT ratio <0.67) responses. Estimated VZV Ab GMFR from baseline in the concomitant group was 2.1 (95% CI = 2.0–2.3), indicating acceptable fold rise. Estimated GMT ratios (concomitant/sequential) for influenza strains A(H1N1), A(H3N2), and B were 0.9 (95% CI = 0.8–1.1), 1.1 (95% CI = 0.9–1.3), and 0.9 (95% CI = 0.8–1.1), respectively, and [seroconversion rates] were comparable across both groups, with more than 85% achieving titers of 1:40 or greater, meeting regulatory criteria.” (J. Silber, jeffrey_silber@merck.com)
Cholinesterase Inhibitor Use for Dementia: Questionable prescribing patterns of cholinesterase inhibitors for dementia are identified in a study of Ontario patients older than 65 (pp. 1517-23). The study population of 28,961 individuals, all of whom had received new prescriptions for ChEIs in 2000–02, had a mean age of 80 and was 63% women; included were 4,601 residents of nursing homes. The authors note: “Patients had on average more than 26 physician visits in the year before ChEI therapy, but only 28% had seen a dementia specialist. Concomitant use of potentially inappropriate medications (strongly anticholinergic medications and benzodiazepines) was noted in 37% of patients. The average length of treatment for all patients was 866 days. Many patients (43%) remained on the initial dose prescribed, 6% switched to another ChEI, and 19% died while on ChEI therapy.” (N. Herrmann, nathan.herrmann@sunnybrook.ca)
TB Skin Tests & BMI: Interpretation of tuberculin skin tests should take into account the body mass index of patients, concludes a study of 3,605 residents of Hong Kong facilities (pp. 1592-7): “After one-step and two-step testing, 46.3% and 69.6% of residents, respectively, had positive TST reactions (10 mm or more). Thirty-four residents developed active TB (323 per 100,000 person–years) during follow-up. The only significant risk factors associated with development of active TB were positive TST according to one-step testing (adjusted odds ratio (OR) = 2.91, 95% confidence interval (CI) = 1.26–6.74) and a BMI less than 18.5 (adjusted OR = 3.15, 95% CI = 1.45–6.86). Residents with a BMI less than 18.5 and a negative TST also had greater risk of active TB than residents with a BMI greater than 18.5 and negative TST (adjusted OR = 4.36, 95% CI = 1.04–18.3), whereas those with a positive TST had the highest risk (adjusted OR = 10.2, 95% CI = 2.63–39.4).” (M. Chan-Yeung, Queen Mary Hospital, Hong Kong; mmwchan@hkucc.hku.hk)

>>>PNN NewsWatch
* FDA is continuing its safety review of aprotinin injection (Trasylol, Bayer) and is anticipating “re-evaluation of the overall risks and benefits” of the drug based on preliminary findings from the Blood Conservation Using Antifibrinolytics: A Randomized Trial in a Cardiac Surgery Population (BART) study. In an early communication posted yesterday to the agency’s Web site , FDA indicated that the Drug Safety Monitoring Board had recommended stopping the BART study because preliminary findings show that, compared with epsilon-aminocaproic acid and tranexamic acid, aprotinin increases the 30-day mortality risk.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Oct. 29, 2007 * Vol. 14, No. 209
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Oct. 27 issue of Lancet (www.thelancet.com; 2007; 370).
ANP After MI: Administered as an adjunct to reperfusion therapy in 1,216 patients with acute myocardial infarction, atrial natriuretic peptide produced lower infarct size, fewer reperfusion injuries, and better outcomes than placebo or nicorandil (pp. 1483-93). Investigators in the J-WIND trial report: “Total creatine kinase was 66,459.9 IU/mL per h in patients given atrial natriuretic peptide, compared with 77,878.9 IU/mL per h in controls, with a ratio of 0.85 between these groups (95% CI 0.75–0.97, p = 0.016), which indicated a reduction of 14.7% in infarct size (95% CI 3.0–24.9%). The left ventricular ejection fraction at 6–12 months increased in the atrial natriuretic peptide group (ratio 1.05, 95% CI 1.01–1.10, p = 0.024). Total activity of creatine kinase did not differ between patients given nicorandil (70,520.5 IU/mL per h) and controls (70,852.7 IU/mL per h) (ratio 0.995, 95% CI 0.878–1.138, p = 0.94). Intravenous nicorandil did not affect the size of the left ventricular ejection fraction, although oral administration of nicorandil during follow-up increased the left ventricular ejection fraction between the chronic and acute phases. 29 patients in the atrial natriuretic peptide group had severe hypotension, compared with one in the corresponding placebo group.” (M. Kitakaze, National Cardiovascular Centre Suita, Osaka, Japan; kitakaze@hsp.ncvc.go.jp)
Controlling Extensively Drug-Resistant TB: Reduction of nosocomial transmission of extensively drug-resistant (XDR) tuberculosis is possible, even in resource-limited areas, but parallel efforts in the community will be needed, authors maintain (pp. 1500-7). Assessing data from a rural community in South Africa, the writers provide this assessment of a “synergistic combination” of strategies: “If no new interventions are introduced, about 1,300 cases of XDR tuberculosis are predicted to occur in the area of Tugela Ferry by the end of 2012, more than half of which are likely to be nosocomially transmitted. Mask use alone would avert fewer than 10% of cases in the overall epidemic, but could prevent a large proportion of cases of XDR tuberculosis in hospital staff. The combination of mask use with reduced hospitalisation time and a shift to outpatient therapy could prevent nearly a third of XDR tuberculosis cases. Supplementing this approach with improved ventilation, rapid drug resistance testing, HIV treatment, and tuberculosis isolation facilities could avert 48% of XDR tuberculosis cases (range 34–50%) by the end of 2012. However, involuntary detention could result in an unexpected rise in incidence due to restricted isolation capacity.” (S. Basu, sanjay.basu@yale.edu)

>>>BMJ Highlights
Source:
Oct. 27 issue of BMJ (www.bmj.org; 2007; 335).
Rapid Tranquilization in Psychiatric Emergencies: Rapid tranquilization was produced by intramuscular doses of either olanzapine or haloperidol/promethazine in a study from India, but the combination approach produced less need for additional medical interventions within 4 hours, researchers report (pp. 865 ff). The study of 300 patients with agitated or violent behavior caused by mental illness showed the following: “Both treatments resulted in similar proportions of people being tranquil or asleep at 15 minutes (olanzapine 131/150 (87%), haloperidol plus promethazine 136/150 (91%); relative risk 0.96, 95% confidence interval 0.34 to 1.47) and 240 minutes (olanzapine 144/150 (96%), haloperidol plus promethazine 145/150 (97%); relative risk 0.99, 0.95 to 1.03). However, more people given olanzapine than those given haloperidol plus promethazine required additional drugs over four hours (65/150 (43%) v 31/150 (21%); relative risk 2.07, 1.43 to 2.97). Adverse effects were uncommon with both treatments.” (P. Tharyan, Christian Med. Coll., Vellore, Tamil Nadu, India; prathap@cmcvellore.ac.in)

>>>PNN JournalWatch
* Type 1 Diabetes and Glucose Monitoring, in Diabetes Care, 2007; 30: 2965–71. Reprints: Z. T. Bloomgarden, Mount Sinai Sch. of Med., New York.
* Smoking Cessation: An Overview of Treatment Options with a Focus on Varenicline, in
Pharmacotherapy, 2007; 27: 1550–7. Reprints: N. M. Stack, Albany College of Pharmacy, Albany, N.Y.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Oct. 30, 2007 * Vol. 14, No. 210
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
Early-release article from and Nov. 6 issue of the Journal of the American College of Cardiology (http://content.onlinejacc.org/current.dtl; 2007; 50).
Universal MI Definition: The American College of Cardiology, along with the American Heart Association, European Society of Cardiology, and World Heart Federation, has established an Expert Consensus Document providing a universal definition of myocardial infarction (doi:10.1016/j.jacc.2007.09.011). In the past, a general consensus existed for the clinical syndrome designated as myocardial infarction, the groups note. In studies of disease prevalence, the World Health Organization defined myocardial infarction from symptoms, ECG abnormalities, and enzymes. However, the development of more sensitive and specific serological biomarkers and precise imaging techniques allows detection of ever smaller amounts of myocardial necrosis. Accordingly, current clinical practice, health care delivery systems, as well as epidemiology and clinical trials all require a more precise definition of myocardial infarction and a re-evaluation of previous definitions of this condition. The new definition supports a diagnosis of MI when any one of five criteria are met (K. Thygesen, Aarhus U. Hosp., Aarhus, Denmark; Kristian.Thygesen@as.aaa.dk):
* Detection of rise and/or fall of cardiac biomarkers (preferably troponin) with at least one value above the 99th percentile of the upper reference limit (URL) together with evidence of myocardial ischaemia with at least one of the following: symptoms of ischaemia; ECG changes indicative of new ischaemia (new ST-T changes or new left bundle branch block [LBBB]); development of pathological Q waves in the ECG; or imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.
* Sudden, unexpected cardiac death, involving cardiac arrest, often with symptoms suggestive of myocardial ischaemia, and accompanied by presumably new ST elevation, or new LBBB, and/or evidence of fresh thrombus by coronary angiography and/or at autopsy, but death occurring before blood samples could be obtained, or at a time before the appearance of cardiac biomarkers in the blood.
* For percutaneous coronary interventions (PCI) in patients with normal baseline troponin values, elevations of cardiac biomarkers above the 99th percentile URL are indicative of peri-procedural myocardial necrosis. By convention, increases of biomarkers greater than 3 times the 99th percentile URL have been designated as defining PCI-related myocardial infarction. A subtype related to a documented stent thrombosis is recognized.
* For coronary artery bypass grafting (CABG) in patients with normal baseline troponin values, elevations of cardiac biomarkers above the 99th percentile URL are indicative of periprocedural myocardial necrosis. By convention, increases of biomarkers greater than 5 times the 99th percentile URL plus either new pathological Q waves or new LBBB, or angiographically documented new graft or native coronary artery occlusion, or imaging evidence of new loss of viable myocardium have been designated as defining CABG-related myocardial infarction.
* Pathological findings of an acute myocardial infarction.
Nesiritide & Renal Function: Nesiritide had no impact on renal function in patients with acute decompensated heart failure and pre-existing renal dysfunction, researchers report (pp. 1835-40). Consecutive patients randomly received nesiritide 0.01 mcg/kg/min with or without a 2 mcg/kg bolus or placebo for 48 hours in addition to usual care, with these results: “Seventy-five patients were enrolled (39 nesiritide, 36 placebo). The groups had similar baseline age (74.9 vs. 75.5 years, respectively), blood pressure (123/64 vs. 125/64 mm Hg) and serum creatinine (1.82 vs. 1.86 mg/dl). There were no significant differences in the incidence of a 20% creatinine rise (23% vs. 25%) or in the change in serum creatinine (–0.05 vs. +0.05 mg/dl). There were no significant differences in the secondary end points of change in weight (–2.19 vs. –1.58 kg), intravenous furosemide (125 vs. 107 mg), discontinuation of the infusion due to hypotension (13% vs. 6%), or 30-day death/hospital readmission (33% vs. 25%).” (R. M. Witteles, witteles@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 © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Oct. 31, 2007 * Vol. 14, No. 211
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Nov. issue of Diabetes Care (http://care.diabetesjournals.org/current.shtml; 2007; 30).
Exenatide as Insulin Replacement: In 49 patients with type 2 diabetes using insulin plus oral antidiabetic agents, glycemic control was sustained when exenatide replaced insulin, according to a pilot study (pp. 2767-72). While the size of the study precludes firm conclusions, the authors note that patients with longer disease duration, those on higher insulin doses, and those with less endogenous beta-cell function fared more poorly than other patients during the substitution, as reflected in these results: “A total of 62% (18 of 29) of the exenatide-treated patients maintained glycemic control compared with 81% (13 of 16) of the insulin-treated patients. Of the 11 exenatide-treated patients who did not maintain control, 5 discontinued before week 16 because of loss of glucose control. The overall safety profile was generally consistent with previous exenatide trials. The mean overall hypoglycemia rates were 1.72 and 0.97 events/patient-year for the exenatide and insulin reference groups, respectively.” (S. N. Davis, steve.davis@vanderbilt.edu)
Pioglitazone & HF: Serious heart failure was more common among patients taking pioglitazone than placebo in the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive), investigators report, but “subsequent mortality or morbidity was not increased” (pp. 2794-9). Analyzing data on 5,238 patients for episodes of heart failure that required or prolonged hospitalization, was fatal or life-threatening, or caused disability, the researchers found: “More pioglitazone (5.7%) than placebo patients (4.1%) had a serious heart failure event during the study (P = 0.007). However, mortality due to heart failure was similar (25 of 2,605 [0.96%] for pioglitazone vs. 22 of 2,633 [0.84%] for placebo; P = 0.639). Among patients with a serious heart failure event, subsequent all-cause mortality was proportionately lower with pioglitazone (40 of 149 [26.8%] vs. 37 of 108 [34.3%] with placebo; P = 0.1338). Proportionately fewer pioglitazone patients with serious heart failure went on to have an event in the primary (47.7% with pioglitazone vs. 57.4% with placebo; P = 0.0593) or main secondary end point (34.9% with pioglitazone vs. 47.2% with placebo; P = 0.025).” (E. Erdmann, Universität zu Köln, Köln, Germany; erland.erdmann@uni-koeln.de)

>>>PNN NewsWatch
* Postmarketing reports of skin hypersensitivity reactions, including Stevens–Johnson syndrome, were quietly added to sitagliptin (Januvia, Merck) labeling earlier this month. Oct. 12 letters posted on the FDA Web site mention “hypersensitivity post-marketing adverse reaction data,” and a revised label on the Januvia Web site warns, “There have been postmarketing reports of serious allergic and hypersensitivity reactions in patients treated with Januvia such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens–Johnson syndrome. In such cases, promptly stop Januvia, assess for other potential causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes.” Dermatologic reactions to vildagliptin (Galvus, Novartis) in monkeys have kept that DPP-4 inhibitor off the U.S. market.
* Roche and
FDA have notified health providers that use of mycophenolate mofetil (CellCept) is associated with increased risk of first-trimester pregnancy loss and increased risk of congenital malformations, especially external ear and facial abnormalities including cleft lip and palate, and anomalies of the distal limbs, heart, esophagus, and kidney. As a result of the newly recognized risk, the pregnancy category for mycophenolate mofetil has been changed from Category C (risk of fetal harm cannot be ruled out) to Category D (positive evidence of fetal risk). Within 1 week of beginning mycophenolate mofetil therapy, women of childbearing potential should have a negative serum or urine pregnancy test. In addition, women of childbearing potential (including pubertal girls and perimenopausal woman) taking the drug must receive contraceptive counseling and use effective contraception. Health professionals and patients should be aware that mycophenolate mofetil reduces blood levels of the hormones in oral contraceptives and could theoretically reduce their effectiveness.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Nov. 1, 2007 * Vol. 14, No. 212
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Nov. 1 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2007; 357).
Adjuvant Chemotherapy for Gastric Cancer: An oral fluoropyrimidine, S-1, significantly improved overall survival rates when used as adjuvant treatment in East Asian patients with locally advanced gastric cancer who had undergone gastrectomy with extended (D2) lymph-node dissection (pp. 1810-20). Using 6-week cycles of 4 weeks of 80 mg/sq m and 2 weeks of no chemotherapy, the researchers made these comparisons with surgery only: “We randomly assigned 529 patients to the S-1 group and 530 patients to the surgery-only group between October 2001 and December 2004. The trial was stopped on the recommendation of the independent data and safety monitoring committee, because the first interim analysis, performed 1 year after enrollment was completed, showed that the S-1 group had a higher rate of overall survival than the surgery-only group (P = 0.002). Analysis of follow-up data showed that the 3-year overall survival rate was 80.1% in the S-1 group and 70.1% in the surgery-only group. The hazard ratio for death in the S-1 group, as compared with the surgery-only group, was 0.68 (95% confidence interval, 0.52 to 0.87; P = 0.003). Adverse events of grade 3 or grade 4 (defined according to the Common Toxicity Criteria of the National Cancer Institute) that were relatively common in the S-1 group were anorexia (6.0%), nausea (3.7%), and diarrhea (3.1%).” (S. Sakuramoto, Kitasato U., Sagamihara, Japan; sakura@med.kitasato-u.ac.jp)
Writing that “east meets west in the treatment of gastric cancer” in this research study, editorialists maintain that adjuvant chemotherapy should be a standard of care in resectable gastric cancer (pp. 1863-5): “Independent of the patient population or the practice location, surgery alone is no longer the standard treatment for patients with resectable gastric cancer. Regardless of the type of surgery or the timing of the adjuvant treatment, the use of combined treatments improves the prognosis for patients with the disease. Trials that are exploring ways of improving combined treatment strategies for resectable gastric cancer include the United Kingdom National Cancer Research Institute ST03 trial of perioperative epirubicin, cisplatin, and capecitabine—with or without the anti–vascular endothelial growth factor antibody bevacizumab—and the U.S. Cancer and Leukemia Group B protocol 80101 trial, which is testing a postoperative adjuvant strategy of epirubicin, cisplatin, and fluorouracil chemotherapy before and after chemoradiation.” (D. Cunningham, Royal Marsden Hosp., London)

>>>PNN NewsWatch
* FDA this week approved nilotinib (Tasigna, Novartis) capsules for treatment of Philadelphia chromosome–positive chronic myeloid leukemia (CML) in adult patients whose disease has progressed on or who cannot tolerate other therapies that included imatinib (Gleevec, Novartis), the first-line treatment for this condition. FDA’s approval of nilotinib includes a black-box warning concerning prolongation of the QT interval and associated cases of sudden death. Hypokalemia and hypomagnesemia must be corrected before use of this drug, and concomitant therapy with strong CYP 3A4 inhibitors should be avoided, as should grapefruit products. Food should be avoided 2 hours before and 1 hour after a dose of nilotinib. The effectiveness of nilotinib was demonstrated based on normalization of blood counts and bone marrow examinations observed in an ongoing clinical trial. Further follow-up of patients is needed to determine how long these responses will last. The most common drug-related adverse reactions (more than 10% of patients) were rash, pruritus, nausea, fatigue, headache, constipation, diarrhea, and vomiting. Other possible serious adverse effects include thrombocytopenia, neutropenia, pneumonia, febrile neutropenia, leukopenia, intracranial hemorrhage, elevated lipase, and pyrexia. The drug should not be used in women while pregnant or breastfeeding.
*
IMS Health will report today a slowing of the growth of prescription drug sales in the U.S., the Wall Street Journal reports this morning. The closely watched annual forecast predicts U.S. sales of brand-name and generic prescription drug products will grow in 2008 by 4% to 5%, to $305 billion.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Nov. 2, 2007 * Vol. 14, No. 213
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Nov. 6 issue of the Annals of Internal Medicine (www.annals.org/current.shtml; 2007; 147).
COPD Guidelines: A new clinical practice guideline for diagnosis and management of stable chronic obstructive pulmonary disease has been issued by the American College of Physicians (pp. 633-8; A. Qaseem, aqaseem@acponline.org). Based on a systematic review published in this issue (pp. 639-53; T. J. Wilt, tim.wilt@med.va.gov), the guideline makes these treatment-related recommendations:
* For symptomatic patients with COPD and FEV
1 less than 60% predicted, clinicians should prescribe one of these maintenance medications: long-acting inhaled beta-agonists, long-acting inhaled anticholinergics, or inhaled corticosteroids (grade: strong recommendation, high-quality evidence).
* Combination inhaled therapies can be considered for symptomatic patients with COPD and FEV
1 less than 60% predicted (grade: weak recommendation, moderate-quality evidence).
* Oxygen therapy should be prescribed for patients with COPD and resting hypoxemia as defined as a partial oxygen pressure of 55 mm Hg or less (grade: strong recommendation, moderate-quality evidence).
* Pulmonary rehabilitation should be considered for symptomatic individuals with COPD who have an FEV
1 less than 50% predicted (grade: weak recommendation, moderate-quality evidence).
Risperidone for Treatment-Refractory Depression: In a group of patients with major depressive disorder who did not respond optimally to antidepressant therapy, risperidone augmentation significantly reduced depressive symptoms, increased remission and response, and improved other patient- and clinician-rated measures (pp. 593-602). Researchers report these results from the 6-week trial: “Of the intention-to-treat population (268 patients), 81% (111 of 137) who received risperidone and 87.8% (115 of 131) who received placebo completed 6 weeks of double-blind treatment. Mean (± SE) [Hamilton Rating Scale for Depression]-17 scores improved more in the risperidone augmentation group than in the placebo group (13.4 ± 0.54 vs. 16.2 ± 0.53; difference, –2.8 ± 0.72 [95% CI, –4.2 to –1.4]; P <0.001). More risperidone recipients than placebo recipients experienced remission of depression (24.5% [26 of 106] vs. 10.7% [12 of 112]; P = 0.004) and had a response (46.2% [49 of 106] vs. 29.5% [33 of 112]; P = 0.004). Headache (8.8% of risperidone recipients vs. 14.5% of placebo recipients), somnolence (5.1% vs. 1.5%), and dry mouth (5.1% vs. 0.8%) were the most frequently reported adverse events.” (R. A. Mahmoud, Ethicon, Inc., Somerville, N.J.; rmahmou@ethus.jnj.com)

>>>PNN NewsWatch
* In an FDA survey, 88% of 2,069 drug packages intercepted as they entered the U.S. contained prescription medications that are available in this country, and 53% of the products had generic equivalents often sold at prices lower than those in Canada or Western Europe. “Consumers continue to buy risky drugs online,” FDA said in a news release. “In general, a Web site can appear legitimate, but in fact be a front for an illegal operation. FDA urges consumers to beware of unregulated Internet drug sellers, because many of their products might not contain the correct ingredients and could contain toxic substances. Several drugs found in this survey require special monitoring by physicians or other health care professionals for potential adverse events and to ensure their effectiveness. These include antibiotics, antidepressants, the blood thinner warfarin, and levothyroxine.”
* U.S. Marshals on Wednesday seized more than $300,000 worth of product—including the antifungal product NC Solution and other drugs for human or animal use, dietary supplements, and ingredients to make those products—because some lacked FDA approval and all were maintained under grossly unsanitary conditions by
General Therapeutics Corp., of St. Louis, Mo., FDA reports. Agency inspectors recently found that the company was manufacturing drugs and dietary supplements under unsanitary conditions, including insects and rodent filth on and around manufacturing equipment, despite a 1999 warning by FDA of serious violations. Following that inspection, a company official told FDA in January 2000 that it would stop manufacturing drugs.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Nov. 5, 2007 * Vol. 14, No. 214
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Nov. 3 issue of Lancet (www.thelancet.com; 2007; 370).
Malaria Vaccine: Among 214 infants in a Phase I/IIb trial, those receiving the malaria vaccine RTS,S/AS02D responded well, tolerating the vaccine and having immunogenic responses (pp. 1543-51). “There were 17 children (15.9%; 95% CI 9.5–24.2) with serious adverse events in each group. In the follow-up which ended on March 6, 2007, there were 31 serious adverse events in the RTS,S/AS02D group and 30 serious adverse events in the Engerix-B group, none of which were reported as related to vaccination. There were four deaths during this same follow-up period; all of them after the active detection of infection period had finished at study month 6 (two in RTSS/AS02D group and two in the Engerix-B group). RTS,S/AS02D induced high titres of anti-circumsporozoite antibodies. 68 first or only [Plasmodium] falciparum infections were documented: 22 in the RTS,S/AS02D group and 46 in the control group. The adjusted vaccine efficacy was 65.9% (95% CI 42.6–79.8%, p <0.0001).” (P. L. Alonso, Universitat de Barcelona, Barcelona; palonso@clinic.ub.es)

>>>BMJ Highlights
Source:
Early-release article from BMJ (www.bmj.org; 2007; 335).
Physicians’ Estimates of Asthma/COPD Prognosis: For 832 patients aged 45 years or older with asthma and/or chronic obstructive pulmonary disease, physicians underestimated survival rates at 6 months after hospitalization, a finding that could affect the intensity of care provided to such patients (doi: 10.1136/bmj.39371.524271.55). This finding comes from a U.K. study conducted in 92 intensive-care units and 3 respiratory-care centers. Results showed: “517 patients (62%) survived to 180 days. Clinicians’ prognoses were pessimistic, with a mean predicted survival of 49% at 180 days. For the fifth of patients with the poorest prognosis according to the clinician, the predicted survival rate was 10% and the actual rate was 40%. Information from a database covering 74% of intensive care units in the UK suggested no material difference between units that participated and those that did not. Patients recruited were similar to those not recruited in the same units.” The researchers conclude: “Historically, access to intensive care in the UK has been problematic and it has not always been possible to admit every patient who might benefit. A culture of pessimism might protect clinicians from the cognitive dissonance involved in being unable to intubate patients they knew to have a reasonable prognosis.” (M. Wildman, Northern Genl. Hosp., Sheffield, U.K.; martin.wildman@sth.nhs.uk)

>>>PNN NewsWatch
* Bayer has agreed to a market suspension of aprotinin injection (Trasylol), FDA announced this morning. The agency said that it had requested the suspension in the interest of patient safety based on the serious nature of the outcomes suggested in the preliminary data from a Canadian study released recently (see PNN, Oct. 26). FDA is working with Bayer to phase aprotinin out of the marketplace in a way that does not cause shortages of the few other drugs used to control bleeding during cardiac surgery. Until the data from the terminated study can be reviewed, FDA said that it cannot determine and identify a population of patients undergoing cardiac surgery for which the benefits of aprotinin outweigh the risks. Understanding that individual physicians may identify specific cases where benefit outweighs risk, FDA indicated that it is committed to exploring ways for those clinicians to have continued but limited access to aprotinin.

>>>PNN JournalWatch
* The Evidence for Using Conjugate Vaccines to Protect HIV-Infected Children Against Pneumococcal Disease, in Lancet Infectious Diseases, 2007; doi: 10.1016/S1473-3099(07)70242-6. Reprints: S. J. Bliss, Johns Hopkins Sch. of Public Health, Baltimore; sandrajbliss@yahoo.com
* Efficacy of Minocycline in Patients with Amyotrophic Lateral Sclerosis: A Phase III Randomised Trial, in
Lancet Neurology, 2007; doi: 10.1016/S1474-4422(07)70270-3. Reprints: P. H. Gordon, phg8@columbia.edu
* Inhaled Nitric Oxide for Preterm Infants: A Systematic Review, in
Pediatrics, 2007; 120: 1088–99. Reprints: K. J. Barrington, McGill U., Montreal.
* Chronic Restlessness with Antipsychotics, in
American Journal of Psychiatry, 2007; 164: 1648–54. Reprints: I. M. Bratti.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Nov. 6, 2007 * Vol. 14, No. 215
Providing news and information about medications and their proper use

>>>Pharmacotherapy Highlights
Source:
Nov. issue of Pharmacotherapy; www.pharmacotherapy.org; 2007; 27).
Alcohol Use & Acetaminophen Hepatotoxicity: Elevated gamma-glutamyl transferase (GGT) concentrations may be a clinical marker of depleted glutathione in alcoholic subjects who are using acetaminophen in therapeutic or excessive doses, according to a study of 188 people who answered “yes” to one or more elements of the CAGE (Cut down–Annoyed–Guilty–Eye-opener) questionnaire (pp. 1473-82). Comparing various parameters with those in 10 healthy volunteers, researchers found these patterns: “A significantly higher proportion of daily drinkers were regular daily users (29.2% [45/154] vs 11.8% [4/34], p = 0.0497) as well as abusers (35.7% [55/154] vs 14.7% [5/34], p = 0.0237) of acetaminophen compared with nondaily drinkers. Alcoholic subjects with elevated GGT ... levels had significantly lower median plasma glutathione concentrations (2.33 µmol/L, 95% confidence interval [CI] 1.74–2.69 µmol/L) compared with those of alcoholic subjects with normal GGT concentrations (5.97 µmol/L, 95% CI 4.39–7.03 µmol/L, p <0.0001) and healthy volunteers (6.59 µmol/L, 95% CI 4.79–9.65 µmol/L, p = 0.0002). A significant inverse correlation was also noted between the GGT concentration and the plasma total glutathione concentration (r = –0.62, p <0.0001). None of the 188 subjects met all preset criteria for hepatotoxicity.” (C. F. Seifert, charles.seifert@ttuhsc.edu)
Antibiotic Dosing for Pseudomonal Infections: Improved pharmacodynamics were evident with either prolonged or continuous infusions of piperacillin–tazobactam, compared with traditional 30-minute intermittent-infusion regimens, according to a Monte Carlo simulation model of 5,000 surgical patients and patients with neutropenia (pp. 1490-7). Focusing on minimum inhibitory concentrations of local Pseudomonas aeruginosa isolates, the investigators determined: “The probability of achieving 50% free time above the MIC against 470 P. aeruginosa isolates was calculated. The cumulative fractions of response for the intermittent-infusion regimens were 74.7% (3.375 g every 6 hrs), 79.9% (4.5 g every 6 hrs), and 85.6% (3.375 g every 4 hrs). For prolonged-infusion regimens, the cumulative fractions of response were 83.3% (3.375 g every 8 hrs, 4-hr infusion), 87.1% (4.5 g every 8 hrs, 4-hr infusion), and 89.6% (4.5 g every 6 hrs, 3-hr infusion). For continuous-infusion regimens, the cumulative fractions of response were 82.3% (10.125 g), 86.5% (13.5 g), 89.2% (18 g), 90.0% (20.25 g), and 90.6% (22.5 g).” (D. P. Nicolau, Hartford Hosp., Hartford, Ct.)
Adrenal Insufficiency in Critically Ill Patients: Diagnosis of adrenal insufficiency using the adrenocorticotropic hormone (ACTH) stimulation test and management of the condition with corticosteroids are reviewed (pp. 1512-28): “The low-dose ACTH stimulation test has been shown to be more sensitive and specific than the high-dose test; however, the high-dose test is preferred since the low-dose test has not been validated. Although diagnosing adrenal insufficiency continues to be difficult in the critically ill patient, administration of high-dose corticosteroids, defined as methylprednisolone 30 mg/kg/day or more (or its equivalent), over a short period of time provides no overall benefit and may even be harmful; however, administration of low-dose corticosteroids for a longer duration decreases both the amount of the time that vasopressors are required and mortality at 28 days. Hydrocortisone 200–300 mg/day, administered in divided doses or as a continuous infusion, is the preferred corticosteroid in patients with septic shock and should be started as early as possible. For patients in whom the ACTH stimulation test cannot be given immediately, clinicians are urged to consider using dexamethasone until such time that the test can be administered, since, unlike hydrocortisone, it does not interfere with the cortisol test.” (K. Asare, St. Thomas Hosp., Nashville, Tenn.; Kasare@stthomas.org)

>>>PNN NewsWatch
* Fifteen voting members of the Risk Communication Advisory Committee have been named, FDA announced yesterday. Representing pharmacy is Betsy L. Sleath, PhD, of the U. North Carolina Sch. of Pharmacy, who specializes in sociology, health literacy, and health communication.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Nov. 7, 2007 * Vol. 14, No. 216
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Nov. 7 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2007; 298).
Tezosentan for Heart Failure: The endothelin receptor antagonist tezosentan improved neither symptoms nor clinical outcomes of heart failure among patients in VERITAS, the Value of Endothelin Receptor Inhibition with Tezosentan in Acute Heart Failure Studies (pp. 2009-19). Looking at patients treated within 24 hours of admission for heart failure with tezosentan or placebo, the investigators found these results in VERITAS-1 and -2: “Of the 1,435 patients who received treatment as assigned, 855 (60%) were men; mean age was 70 years. Mean left ventricular ejection fraction (measured in 779 patients [54%]) was 29% (SD, 11%). Baseline dyspnea scores were similar in the 2 treatment groups. Tezosentan did not improve dyspnea more than placebo in either trial, with a mean treatment difference of –12 (95% confidence interval [CI], –105 to 81) mm • h (P = .80) in the first trial and –25 (95% CI, –119 to 69) mm • h (P = .60) in the second. The incidence of death or worsening heart failure at 7 days in the combined trials was 26% in each treatment group (odds ratio, 0.99; 95% confidence interval, 0.82–1.21; P = .95).” (J. J. V. McMurray, Western Infirmary, Glasgow, U.K.; j.mcmurray@bio.gla.ac.uk)
Mass & Mortality: Cause-specific mortality reveals a complicated relationship between body mass and causes of increased death rates (pp. 2028-37). Researchers analyzed data from the three National Health and Nutrition Examination Surveys, finding these differences: “Based on total follow-up, underweight was associated with significantly increased mortality from noncancer, non-[cardiovascular disease] causes (23,455 excess deaths; 95% confidence interval [CI], 11,848 to 35,061) but not associated with cancer or CVD mortality. Overweight was associated with significantly decreased mortality from noncancer, non-CVD causes (–69,299 excess deaths; 95% CI, –100,702 to –37,897) but not associated with cancer or CVD mortality. Obesity was associated with significantly increased CVD mortality (112,159 excess deaths; 95% CI, 87,842 to 136,476) but not associated with cancer mortality or with noncancer, non-CVD mortality. In further analyses, overweight and obesity combined were associated with increased mortality from diabetes and kidney disease (61,248 excess deaths; 95% CI, 49,685 to 72,811) and decreased mortality from other noncancer, non-CVD causes (–105,572 excess deaths; 95% CI, –161,816 to –49,328). Obesity was associated with increased mortality from cancers considered obesity-related (13,839 excess deaths; 95% CI, 1,920 to 25,758) but not associated with mortality from other cancers. Comparisons across surveys suggested a decrease in the association of obesity with CVD mortality over time.” (K. M. Flegal, kmf2@cdc.gov)
Commenting on this and a related study in this issue (pp. 2020-7; D. Alley,
alley@wharton.upenn.edu), editorialists ask whether disability is “obesity’s price of longevity” (pp. 2066-7): “Disability represents in part the collective effects of multiple obesity-related conditions, which bodes poorly for any simple clinical or public health solutions to modify the obesity-associated disability trends. This challenge is compounded by the lack of commonly practiced interventions directly aimed at reducing disability in at-risk populations. Structured exercise and weight loss programs may be among the most promising unifying interventions because they appear to help prevent type 2 diabetes, reduce arthritis symptoms, and improve physical functioning—ie, they can reduce each of the outcomes of obesity that have persisted over time. Thus, these findings make a compelling case to overcome the barriers of integrating effective lifestyle and exercise programs into health systems and communities. In the end, however, reducing the effect of obesity on morbidity by simply altering its course or accommodating its presence may never have an impact equal to a successful public health strategy to prevent obesity.” (E. W. Gregg, edg7@cdc.gov)

>>>PNN NewsWatch
* Dose-related elevations in liver enzymes have been found with Novartis’s vildagliptin (Galvus), further delaying the drug’s path to market in Europe and the U.S.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Nov. 8, 2007 * Vol. 14, No. 217
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Nov. 8 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2007; 357).
Caffeine for Apnea of Prematurity: Among 2,006 infants with birth weights of 500–1,250 grams, caffeine improved the survival rate significantly more than did placebo, and it did so without producing neurodevelopmental disabilities at 18–21 months (pp. 1893-902). Using a primary outcome of a composite of death, cerebral palsy, cognitive delay, deafness, or blindness at a corrected age of 18–21 months, the investigators found: “Of the 937 infants assigned to caffeine for whom adequate data on the primary outcome were available, 377 (40.2%) died or survived with a neurodevelopmental disability, as compared with 431 of the 932 infants (46.2%) assigned to placebo for whom adequate data on the primary outcome were available (odds ratio adjusted for center, 0.77; 95% confidence interval [CI], 0.64 to 0.93; P = 0.008). Treatment with caffeine as compared with placebo reduced the incidence of cerebral palsy (4.4% vs. 7.3%; adjusted odds ratio, 0.58; 95% CI, 0.39 to 0.87; P = 0.009) and of cognitive delay (33.8% vs. 38.3%; adjusted odds ratio, 0.81; 95% CI, 0.66 to 0.99; P = 0.04). The rates of death, deafness, and blindness and the mean percentiles for height, weight, and head circumference at follow-up did not differ significantly between the two groups.” (B. Schmidt, schmidt@mcmaster.ca)
This study “provides needed support for a treatment approach that had already become routine clinical practice,” writes an editorialist (pp. 1967-8): “Physicians guessed correctly (or at least were lucky) that the benefits of caffeine outweighed the risks, long before they had conducted the necessary trials to confirm this. For many proposed treatments, we are not so lucky, and our randomized, controlled trials debunk our preconceived notions, as in the cases of prenatal phenobarbital treatment (which failed to prevent intraventricular hemorrhage) and postnatal steroids (which failed to prevent bronchopulmonary dysplasia). For caffeine, in contrast, we can now conclude that the possible risks of therapy have been ‘carefully balanced against the treatment gains,’ and the gains of therapy outweigh the possible risks.” (D. K. Stevenson, Stanford U., Stanford, Calif.)
Treatment of Early Hodgkin’s Disease: Treatment for Hodgkin’s disease is explored in a study of 1,538 patients who participated in two trials conducted from 1993 to 1999 (pp. 1916-27). Based on those with untreated stage I or II supradiaphragmatic Hodgkin’s disease with favorable prognostic features (the H8-F trial) or unfavorable features (the H8-U trial), the investigators determined: “The median follow-up was 92 months. In the H8-F trial, the estimated 5-year event-free survival rate was significantly higher after three cycles of [mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) combined with doxorubicin, bleomycin, and vinblastine (ABV)] plus involved-field radiotherapy than after subtotal nodal radiotherapy alone (98% vs. 74%, P <0.001). The 10-year overall survival estimates were 97% and 92%, respectively (P = 0.001). In the H8-U trial, the estimated 5-year event-free survival rates were similar in the three treatment groups: 84% after six cycles of MOPP-ABV plus involved-field radiotherapy, 88% after four cycles of MOPP-ABV plus involved-field radiotherapy, and 87% after four cycles of MOPP-ABV plus subtotal nodal radiotherapy. The 10-year overall survival estimates were 88%, 85%, and 84%, respectively.” Based on these results, the authors conclude: “Chemotherapy plus involved-field radiotherapy should be the standard treatment for Hodgkin’s disease with favorable prognostic features. In patients with unfavorable features, four courses of chemotherapy plus involved-field radiotherapy should be the standard treatment.” (C. Fermé, Institut de Cancérologie Gustave Roussy, Villejuif, France; christophe.ferme@igr.fr)

>>>PNN NewsWatch
* Citing scientists who presented yesterday at an HIV Vaccine Trials Network conference, the Wall Street Journal reports this morning that Merck’s HIV vaccine—trials of which were stopped in Sept.—may have made recipients more susceptible to infection with the virus. Rather than inducing a protective immunity, the adenovirus vaccine may have “altered the immune system to facilitate infection,” the newspaper reports. This has implications for other HIV vaccines in currently in development.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Nov. 9, 2007 * Vol. 14, No. 218
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
Nov. 13 issue of the Journal of the American College of Cardiology http://content.onlinejacc.org/current.dtl; 2007; 50).
Genomics in Coronary Artery Disease: The genetic basis of coronary artery disease portends a role for genomics in future management of this leading cause of mortality in industrialized countries, an author writes (pp. 1933-40): “Recent advances in genotyping technology have allowed for easier identification and confirmation of susceptibility genes for complex traits across different cohorts via increased power of studies stemming from faster accrual of cases and control subjects and more precise genetic mapping. These technological advances have resulted in defining the genes contributing to a substantial or even majority of population-attributable risk for type 2 diabetes and age-related macular degeneration (AMD) cases. Similar progress in replicating novel susceptibility genes for CAD and specifically [myocardial infarction] is now rapidly occurring, with a recent gene marker on chromosome 9p21 representing a highly significant and common variant susceptibility factor. With improved resequencing technology and better phenotypic characterization of our CAD cases and control subjects, we should achieve successes in gene identification and confirmation similar to diabetes and AMD, thereby allowing us to better quantify CAD risk earlier in life and institute more effective therapy reducing the individual propensity to develop CAD.” (E. J. Topol, etopol@scripps.edu)
Triad of Serum Markers for MI Risk: High rates of cholesteryl ester transfer are associated with acute myocardial infarction at younger ages, and CET rates can be gauged using a triad of markers, a research study shows (pp. 1948-55). Those at higher risk had high CET protein mass, high non–HDL cholesterol, and low HDL2b levels, researchers report, based on these findings: “Among 347 patients with first MI, CETP concentration, triglycerides, and non–HDL-cholesterol increased across tertiles of the CET rate, whereas HDL-cholesterol, HDL, and LDL sizes decreased gradually. Among lipoprotein donors and acceptors, the best predictors of the CET rate were HDL2b and non–HDL-cholesterol, respectively. Mean age at first MI was 8.5 years lower in the patients from the highest CET tertile than in those in the lowest CET tertile. Diagonal stratification according to both non–HDL-cholesterol and HDL2b tertiles revealed that patients in the highest CET group were 18 years younger than patients in the lowest CET group. Parameters of the high CETP mass/high non–HDL-cholesterol/low HDL2b triad were independently associated with the CET rate.” (L. Lagrost, INSERM U866, Medical School, Dijon, France; laurent.lagrost@u-bourgogne.fr)

>>PNN NewsWatch
* FDA yesterday mandated revisions to the product labeling for erythropoiesis-stimulating agents to warn of a variety of risks recognized in recent months. For patients with cancer, the new boxed warnings emphasize that ESAs such as erythropoietin and darbepoetin alfa caused tumor growth and shortened survival in patients with advanced breast, head and neck, lymphoid, and non-small cell lung cancer when they received a dose that attempted to achieve a hemoglobin level of 12 g/dL or greater. The boxed warnings also emphasize that no clinical data are available to determine whether there is a similar risk of shortened survival or increased tumor growth for patients with cancer who receive an ESA dose that attempts to achieve a hemoglobin level of less than 12 g/dL. For patients with chronic kidney failure, the new boxed warning states that ESAs should be used to maintain a hemoglobin level of 10–12 g/dL. Maintaining higher hemoglobin levels in patients with chronic kidney failure increases the risk for death and for serious cardiovascular reactions such as stroke, heart attack or heart failure, the boxed warning states. The new labeling also provides specific instructions for dosage adjustments and hemoglobin monitoring for chronic kidney failure patients who do not respond to ESA treatment with an adequate increase in their hemoglobin levels. No data from controlled trials demonstrate that ESAs improve symptoms of anemia, quality of life, fatigue, or patient well-being for patients with cancer or for patients with HIV undergoing zidovudine therapy, the label states.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Nov. 12, 2007 * Vol. 14, No. 219
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Nov. 10 issue of Lancet (www.thelancet.com; 2007; 370).
OCs & Cervical Cancer: The relative risk of cervical cancer increases during use of combined oral contraceptives and declines after discontinuance, according to an analysis of data from 24 studies of 16,573 women with cervical cancer and 35,509 women without the condition (pp. 1609-21). Concluding that “10 years’ use of oral contraceptives from around age 20 to 30 years is estimated to increase the cumulative incidence of invasive cervical cancer by age 50 from 7.3 to 8.3 per 1,000 in less developed countries and from 3.8 to 4.5 per 1,000 in more developed countries,” the authors report: “Among current users of oral contraceptives the risk of invasive cervical cancer increased with increasing duration of use (relative risk for 5 or more years’ use versus never use, 1.90 [95% CI 1.69–2.13]). The risk declined after use ceased, and by 10 or more years had returned to that of never users. A similar pattern of risk was seen both for invasive and in-situ cancer, and in women who tested positive for high-risk human papillomavirus. Relative risk did not vary substantially between women with different characteristics.” (J. Green, U. Oxford, Oxford, U.K.; jane.green@ceu.ox.ac.uk)
Treatment of Low Back Pain: Addition of diclofenac and/or spinal manipulative therapy provided no added benefits to recommended first-line therapy (acetaminophen plus advice) for low back pain (pp. 1638-43). These results were recorded for 240 patients: “Neither diclofenac nor spinal manipulative therapy appreciably reduced the number of days until recovery compared with placebo drug or placebo manipulative therapy (diclofenac hazard ratio 1.09, 95% CI 0.84–1.42, p = 0.516; spinal manipulative therapy hazard ratio 1.01, 95% CI 0.77–1.31, p = 0.955). 237 patients (99%) either recovered or were censored 12 weeks after randomisation. 22 patients had possible adverse reactions including gastrointestinal disturbances, dizziness, and heart palpitations. Half of these patients were in the active diclofenac group, the other half were taking placebo. One patient taking active diclofenac had a suspected hypersensitivity reaction and ceased treatment.” (M. Hancock, U. Sydney, Lidcombe, Australia; M.Hancock@usyd.edu.au)

>>>BMJ Highlights
Source:
Nov. 10 issue of BMJ (www.bmj.org; 2007; 335).
Antibiotics for Respiratory Infections: The use of antibiotics for preventing serious complications of respiratory infections is generally not justified, other than for chest infections in patients at high risk for pneumonia, concludes a study of U.K. primary care practices (pp. 982 ff). Looking at 3.36 million episodes of respiratory infections, the investigators determined: “Serious complications were rare after upper respiratory tract infections, sore throat, and otitis media, and the number needed to treat was over 4,000. The risk of pneumonia after chest infection was high, particularly in elderly people, and was substantially reduced by antibiotic use, with a number needed to treat of 39 for those aged [65 or older] and 96–119 in younger age groups.” (A. Hayward, U. College, London; a.hayward@pcps.ucl.ac.uk)

>>>PNN NewsWatch
* Zyrtec-D can now be obtained by patients without a prescription, FDA announced on Friday. Combining cetirizine hydrochloride 5 mg and pseudoephedrine hydrochloride 120 mg), the McNeil Consumer Healthcare product is approved for use in adults and children 12 years of age and older for relief of symptoms of hay fever or other upper respiratory allergies, such as runny nose, sneezing, itchy, watery eyes, itching of the nose or throat, and nasal congestion. Zyrtec-D is also used for reducing swelling of nasal passages, relief of sinus congestion and pressure, and restoring freer breathing through the nose. Because Zyrtec-D contains pseudoephedrine, it is subject to that drug’s storage, purchasing, and recordkeeping requirements.

>>>PNN JournalWatch
* Allergic Rhinoconjunctivitis in Children, in BMJ, 2007; 335: 985–8. Reprints: H. de Groot, Erasmus Med. Ctr., Rotterdam, the Netherlands; h.degroot@erasmusmc.nl

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Nov. 13, 2007 * Vol. 14, No. 220
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Nov. 12 issue of the Archives of Internal Medicine (http://archinte.ama-assn.org/current.dtl; 2007; 167).
Beta-Carotene & Cognitive Decline: While short-term supplementation with beta-carotene provided no cognitive benefits among men in the Physicians’ Health Study II, continued supplementation over a longer period showed promise, yielding significantly better scores on a test of verbal memory (pp. 2184-90).Based on assessments of 5,956 participants older than 65 years who were interviewed at the termination of beta-carotene 50 mg on alternate days, the researchers found: “Among 1,904 newly recruited subjects (mean treatment duration, 1 year), cognition was similar across treatment assignments. Among 4,052 continuing participants from the PHS (mean treatment duration, 18 years), the mean global score was significantly higher in the beta carotene group than in the placebo group (mean difference in z scores, 0.047 standard units; P = .03). On verbal memory, men receiving long-term beta carotene supplementation also performed significantly better than the placebo group (mean difference in z scores, 0.063; P = .007).” (F. Grodstein, phfrg@channing.harvard.edu)
An editorialist concludes that, despite these positive data, the risk–benefit relationship for beta-carotene tilts toward excess risk (pp. 2167-8): “For the clinician, there is no convincing justification to recommend the use of antioxidant dietary supplements to maintain cognitive performance in cognitively normal adults or in those with mild cognitive impairment. Furthermore, there is new concern that high-dose antioxidant supplementation, including beta carotene, may have adverse health consequences including mortality.” (K. Yaffe, kristine.yaffe@ucsf.edu)
Decision Aid for Antibiotics: For 331 women with suspected cystitis, a three-item decision aid showed promise for significantly reducing unnecessary antibiotic prescriptions and urine culture testing (pp. 2201-6). Investigators worked with 225 Canadian family practice physicians to determine how many of the decision aid items were present for each patient, and then compared results with the gold standard of a positive urine culture: “Three of the original decision aid variables (dysuria, the presence of leukocytes [greater than a trace amount], and the presence of nitrites [any positive]) were associated with having a positive urine culture result (P .001), but 1 variable (symptoms for 1 day) was not (P = .96). A simplified decision aid incorporating the 3 significant variables (empirical antibiotics without culture if 2 variables present; otherwise obtain a culture and wait for results) had a sensitivity of 80.3% (167/208) and a specificity of 53.7% (66/123). Following decision aid recommendations would have reduced antibiotic prescriptions by 23.5%, unnecessary prescriptions by 40.2%, and urine cultures by 59.0% compared with physician care (P <.001 for all).” (W. J. McIsaac, Granovsky-Gluskin Family Med. Ctr., Toronto; wmcisaac@mtsinai.on.ca)
Nitrofurantoin for Cystitis: Five days of nitrofurantoin provides an effective fluoroquinolone-sparing strategy for management of acute uncomplicated cystitis in women, researchers conclude, based on a comparison with trimethoprim–sulfamethoxazole (pp. 2207-12). In a group of 338 young women who received open-label double-strength trimethoprim–sulfamethoxazole twice daily for 3 days or nitrofurantoin 100 mg twice daily for 5 days, these results were recorded: “Clinical cure was achieved in 79% of the trimethoprim–sulfamethoxazole group and in 84% of the nitrofurantoin group, for a difference of –5% (95% confidence interval, –13% to 4%). Clinical and microbiological cure rates at the first follow-up visit were also equivalent between the 2 groups. In the trimethoprim–sulfamethoxazole arm, 7 of 17 women (41%) with a trimethoprim–sulfamethoxazole–nonsusceptible isolate had a clinical cure compared with 84% of women with a trimethoprim-sulfamethoxazole–susceptible isolate (P <.001).” (K. Gupta, Kalpana.gupta@yale.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Nov. 14, 2007 * Vol. 14, No. 221
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Nov. 14 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2007; 298).
Morbidity, Mortality for Vaccine-Preventable Diseases: Cases of most of 13 vaccine-preventable diseases are at an all-time low, a CDC analysis shows, and hospitalizations and deaths have shown striking decreases since 1980 (pp. 2155-63). Using historical data to use as points of comparison with the most recent morbidity (2006) and mortality (2004) data, the authors report: “A greater than 92% decline in cases and a 99% or greater decline in deaths due to diseases prevented by vaccines recommended before 1980 were shown for diphtheria, mumps, pertussis, and tetanus. Endemic transmission of poliovirus and measles and rubella viruses has been eliminated in the United States; smallpox has been eradicated worldwide. Declines were 80% or greater for cases and deaths of most vaccine-preventable diseases targeted since 1980 including hepatitis A, acute hepatitis B, Hib, and varicella. Declines in cases and deaths of invasive S pneumoniae were 34% and 25%, respectively.” (S. W. Roush, sroush@cdc.gov)
Chagas Disease in the U.S.: An increasing number of patients with suspected or confirmed chronic Trypanosoma cruzi infection (Chagas disease) is expected in the U.S. as a result of migration from endemic areas and newly instituted blood-bank screening (pp. 2171-81). “The patient newly diagnosed with Chagas disease should undergo a medical history, physical examination, and resting 12-lead electrocardiogram (ECG) with a 30-second lead II rhythm strip,” authors note in a Clinician’s Corner article. “If this evaluation is normal, no further testing is indicated; history, physical examination, and ECG should be repeated annually. If findings suggest Chagas heart disease, a comprehensive cardiac evaluation, including 24-hour ambulatory ECG monitoring, echocardiography, and exercise testing, is recommended. If gastrointestinal tract symptoms are present, barium contrast studies should be performed. Antitrypanosomal treatment is recommended for all cases of acute and congenital Chagas disease, reactivated infection, and chronic T cruzi infection in individuals 18 years or younger. In adults aged 19 to 50 years without advanced heart disease, etiologic treatment may slow development and progression of cardiomyopathy and should generally be offered; treatment is considered optional for those older than 50 years. Individualized treatment decisions for adults should balance the potential benefit, prolonged course, and frequent adverse effects of the drugs. Strong consideration should be given to treatment of previously untreated patients with human immunodeficiency virus infection or those expecting to undergo organ transplantation.” (C. Bern, cbern@cdc.gov)
Congressional Reform of FDA: Reviewing the provisions of the recently passed FDA Amendments Act of 2007, editorialists are positive about the changes Congress has wrought in the nation’s drug-approval and -safety systems (pp. 2185-7): “Despite high-quality preapproval evaluations, some drugs with unrecognized toxicity will reach the market. The goal of a well-functioning postmarketing system is to identify risks and confirm health benefits of drugs in a timely fashion so that patients and physicians can make informed decisions. An optimal system will require cooperative interactions among the pharmaceutical industry, academic medicine, and the FDA; yet the credibility of the system demands that the agency orchestrate and oversee the system, foster improvements, and respond promptly and effectively to new safety signals. Congress has provided FDA with the resources and the tools to fulfill its mission to protect and promote the health of the public. The measure of the FDA leadership in coming years will be the degree to which the newly deployed postmarketing system becomes a model for other drug regulatory authorities.” (B. M. Psaty, psaty@u.washington.edu)

>>>PNN NewsWatch
* FDA hearings on a behind-the-counter class of medications in the U.S. are being held today in the nation’s capital.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Nov. 15, 2007 * Vol. 14, No. 222
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Nov. 15 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2007; 357).
Prasugrel for Acute Coronary Syndromes: A new thienopyridine, prasugrel, had significantly lower rates of ischemic events, compared with clopidogrel, but also produced increased risk of major bleeding, according to data from the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction (TRITON–TIMI) 38 (pp. 2001-15). Comparing prasugrel administered as a 60-mg loading dose and a 10-mg daily maintenance dose with clopidogrel as a 300-mg loading dose and a 75-mg daily maintenance dose for 6–15 months, the investigators found these results for a primary efficacy end point of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke: “The primary efficacy end point occurred in 12.1% of patients receiving clopidogrel and 9.9% of patients receiving prasugrel (hazard ratio for prasugrel vs. clopidogrel, 0.81; 95% confidence interval [CI], 0.73 to 0.90; P <0.001). We also found significant reductions in the prasugrel group in the rates of myocardial infarction (9.7% for clopidogrel vs. 7.4% for prasugrel; P <0.001), urgent target-vessel revascularization (3.7% vs. 2.5%; P <0.001), and stent thrombosis (2.4% vs. 1.1%; P <0.001). Major bleeding was observed in 2.4% of patients receiving prasugrel and in 1.8% of patients receiving clopidogrel (hazard ratio, 1.32; 95% CI, 1.03 to 1.68; P = 0.03). Also greater in the prasugrel group was the rate of life-threatening bleeding (1.4% vs. 0.9%; P = 0.01), including nonfatal bleeding (1.1% vs. 0.9%; hazard ratio, 1.25; P = 0.23) and fatal bleeding (0.4% vs. 0.1%; P = 0.002).” (E. M. Antman, eantman@rics.bwh.harvard.edu)
Glucocorticoid-Induced Osteoporosis: Teriparatide produced significantly better bone mineral density measurements than did alendronate among 428 men and women at high risk for fractures because of osteoporosis induced by 3 months or more of glucocorticoids (pp. 2028-39). Patients received teriparatide 20 mcg or alendronate 10 mg once daily for 18 months, with these results: “At the last measurement, the mean (± SE) bone mineral density at the lumbar spine had increased more in the teriparatide group than in the alendronate group (7.2±0.7% vs. 3.4±0.7%, P <0.001). A significant difference between the groups was reached by 6 months (P <0.001). At 12 months, bone mineral density at the total hip had increased more in the teriparatide group. Fewer new vertebral fractures occurred in the teriparatide group than in the alendronate group (0.6% vs. 6.1%, P = 0.004); the incidence of nonvertebral fractures was similar in the two groups (5.6% vs. 3.7%, P = 0.36). Significantly more patients in the teriparatide group had at least one elevated measure of serum calcium.” (K. G. Saag, ksaag@uab.edu)

>>>PNN NewsWatch
* Boxed warnings cautioning of myocardial infarctions are being added to the labeling of rosiglitazone (Avandia, GlaxoSmithKline), FDA announced yesterday. The agency said that it has concluded that there is not enough evidence to indicate that the risks of MI or death are different between rosiglitazone and some other oral treatments for type 2 diabetes, leading it to agree with advisory panels that the drug should remain on the market (see PNN, July 31). However, FDA has requested that GSK conduct a new long-term study to evaluate the potential cardiovascular risk of rosiglitazone, compared with an active control agent.
* Pharmacy groups supported a
behind-the-counter category of medications at FDA’s public hearing held yesterday in Washington, D.C. But AMA adamantly opposed the idea, APhA reports on pharmacist.com, maintaining that the agency does not have statutory authority for a third class of drugs. Others argued that such a category—not a class necessarily—already exists, in that FDA routinely places limits on how and where approved products can be distributed and dispensed. Michael Moné, speaking on behalf of APhA, concluded, “As consumers become more aware of product risks and benefits, pharmacists can play a valuable role in patient’s self-care decisions. Providing patients with safe and appropriate medications after consultation and clinical intervention by a pharmacist will increase patient access to medications, enhance patient education, and improve medication use.”

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Nov. 16, 2007 * Vol. 14, No. 223
Providing news and information about medications and their proper use

>>>Pediatrics Highlights
Source:
Nov. issue of Pediatrics (http://pediatrics.aappublications.org/current.shtml; 2007; 120).
Childhood Vaccinations & Asthma: The risk of asthma is neither raised nor lowered by administration of whole-cell pertussis and BCG vaccines to children and adolescents, concludes a meta-analysis of observational studies (pp. e1269-77). Reviewing literature published from 1966 to Mar. 2006, the researchers found: “Seven studies of pertussis vaccination (with a total of 186,663 patients) and 5 studies of BCG vaccination (with a total of 41,479 patients) met our inclusion criteria. No statistically significant association was detected between either whole-cell pertussis or BCG vaccination and incidence rates of asthma during childhood and adolescence. This lack of a significant association proved to be robust on sensitivity analyses for BCG but not for pertussis vaccine.” (R. D. Balicer, Ben-Gurion U. of the Negev, Beer Sheva, Israel)
CPOE & Adverse Drug Events: Among hospitalized children, both actual and potential adverse drug events were reduced in frequency through implementation of a computerized physician order entry system supported by substantive decision support (pp. 1058-66). Comparing data from a previous study of general and intensive units (1,197 admissions) with experiences over a 6-month postimplementation phase (1,210 admissions), researchers report: “After computerized physician order entry implementation ... the number of preventable adverse drug events (46 vs 26) and potential adverse drug events (94 vs 35) was reduced. Reductions in overall errors, dispensing errors, and drug-choice errors were associated with computerized physician order entry. There were reductions in significant events, as well as those events rated as serious or life threatening, after the implementation of computerized physician order entry. Some types of adverse drug events continued to persist, specifically underdosing of analgesics. There were no differences in length of stay or patient disposition between preventable adverse drug events and potential adverse drug events in either study period.” (M. T. Holdsworth, U. New Mexico, Albuquerque)
Antireflux Meds for Regurgitation in Infants: In an analysis of 64 infants with persistent regurgitation and no neurodevelopmental abnormalities, most who received antireflux medications did not meet diagnostic criteria for gastroesophageal reflux disease (pp. 946-9). Esophageal pH monitoring in 44 of the infants showed that only 8 had abnormal acid reflux, yet 42 of the infants were being treated with antireflux medications, study authors report, and stopping the drugs did not worsen symptoms among those with normal pH studies. (V. Khoshoo, West Jefferson Med. Ctr., New Orleans)
Contraception & Adolescents: Updated information on contraception methods and guidelines for counseling adolescents is provided in a policy statement from the American Academy of Pediatrics (pp. 1135-48). “As advocates for the health and well-being of all young people, the American Academy of Pediatrics strongly supports the recommendation that adolescents postpone consensual sexual activity until they are fully ready for the emotional, physical, and financial consequences of sex,” the statement explains. “The academy recognizes, however, that some young people will choose not to postpone sexual activity, and as health care providers, the responsibility of pediatricians includes helping teens reduce risks and negative health consequences associated with adolescent sexual behaviors, including unintended pregnancies and sexually transmitted infections.” (AAP Committee on Adolescence)

>>>PNN NewsWatch
* FDA is working with Bristol-Myers Squibb to assess the safety of cefepime (Maxipime). A systematic review and meta-analysis published in May in Lancet Infectious Diseases (2007; 7: 338-48) had concluded that patients on the broad-spectrum cephalosporin had higher mortality rates than those on other beta-lactams.
*
FDA has received reports of cases of sudden decreases or loss of hearing, sometimes accompanied by tinnitus and dizziness, following the use of PDE5 inhibitors for erectile dysfunction and pulmonary arterial hypertension. Product labeling for sildenafil, vardenafil, and tadalafil has been or is being changed to warn of this adverse effect.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Nov. 19, 2007 * Vol. 14, No. 224
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Nov. 17 issue of Lancet (www.thelancet.com; 2007; 370).
Fenofibrate & Progression to Diabetic Retinopathy: The need for laser treatment for diabetic retinopathy was significantly reduced among patients on long-term lipid-lowering therapy with fenofibrate, report investigators with the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study (pp. 1687-97). Participants included 9,795 patients aged 50–75 years with type 2 diabetes. They were randomized to fenofibrate 200 mg/day or placebo, and 1,012 patients underwent retinal photography, with these results: “The requirement for first laser treatment for all retinopathy was significantly lower in the fenofibrate group than in the placebo group (164 [3.4%] patients on fenofibrate vs 238 [4.9%] on placebo; hazard ratio [HR] 0.69, 95% CI 0.56–0.84; p = 0.0002; absolute risk reduction 1.5% [0.7–2.3]). In the ophthalmology substudy, the primary endpoint of 2-step progression of retinopathy grade did not differ significantly between the two groups overall (46 [9.6%] patients on fenofibrate vs 57 [12.3%] on placebo; p = 0.19) or in the subset of patients without pre-existing retinopathy (43 [11.4%] vs 43 [11.7%]; p = 0.87). By contrast, in patients with pre-existing retinopathy, significantly fewer patients on fenofibrate had a 2-step progression than did those on placebo (three [3.1%] patients vs 14 [14.6%]; p = 0.004). An exploratory composite endpoint of 2-step progression of retinopathy grade, macular oedema, or laser treatments was significantly lower in the fenofibrate group than in the placebo group (HR 0.66, 95% CI 0.47–0.94; p = 0.022).” (A. C. Keech, U. Sydney, Camperdown, Australia; tony@ctc.usyd.edu.au)
Rimonabant & Adverse Psychiatric Events: Depressed mood, anxiety, and other psychiatric adverse events are more common among those using the weight-loss drug rimonabant than with placebo, concludes a meta-analysis of four randomized trials (pp. 1706-13). Noting that FDA has concluded that the risk of suicide is increased with use of the drug (still unapproved in the U.S.), the investigators add these details about 4,105 study participants who received either rimonabant 20 mg/day or placebo: “Patients given rimonabant had a 4.7 kg (95% CI 4.1–5.3 kg; p <0.0001) greater weight reduction after 1 year than did those given placebo. Rimonabant caused significantly more adverse events than did placebo (OR = 1.4; p = 0.0007; number needed to harm = 25 individuals [95% CI 17–58]), and 1.4 times more serious adverse events (OR = 1.4; p = 0.03; number needed to harm = 59 [27–830]). Patients given rimonabant were 2.5 times more likely to discontinue the treatment because of depressive mood disorders than were those given placebo (OR = 2.5; p = 0.01; number needed to harm = 49 [19–316]). Furthermore, anxiety caused more patients to discontinue treatment in rimonabant groups than in placebo groups (OR = 3.0; p = 0.03; number needed to harm = 166 [47–3716]).” (A. Astrup, U. Copenhagen, Frederiksberg, Denmark; ast@life.ku.dk)

>>>PNN JournalWatch
* Rationale for the Major Changes in the Pharmacotherapy Section of the National Asthma Education and Prevention Program Guidelines, in Journal of Allergy and Clinical Immunology, 2007; 120: 989–94. Reprints: H. W. Kelly, hwkelly@salud.unm.edu
* Role of Inflammation in Initiation and Perpetuation of Atrial Fibrillation: A Systematic Review of the Published Data, in
Journal of the American College of Cardiology, 2007; 50: 2021–8. Reprints: N. M. Lakkis, Baylor College of Med., Houston; nlakkis@bcm.tmc.edu
* Pioglitazone Improves Myocardial Blood Flow and Glucose Utilization in Nondiabetic Patients with Combined Hyperlipidemia, in
Journal of the American College of Cardiology, 2007; 120: 2051–8. Reprints: P. G. Camici, Hammersmith Hosp., London; paolo.camici@csc.mrc.ac.uk
* Diagnostics of Inflammatory Bowel Disease, in
Gastroenterology, 2007; 133: 1670–89. Reprints: S. Schreiber, Christian-Albrechts-University, Kiel, Germany; s.schreiber@mucosa.de
* Countering Anthrax: Vaccines and Immunoglobulins, in
Clinical Infectious Diseases, 2007. Reprints: J. D. Grabenstein, john_grabenstein@merck.com
* Pertussis, Still a Formidable Foe, in
Clinical Infectious Diseases, 2007; 45: 1487–91. Reprints: K. Forsyth, Flinders U., Adelaide, Australia.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Nov. 20, 2007 * Vol. 14, No. 225
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release articles from and Nov. 20 issue of the Annals of Internal Medicine (www.annals.org/current.shtml; 2007; 147).
DMARD Review: For adults with early rheumatoid arthritis, available agents used as monotherapy or in combination are poorly studied in head-to-head trials, making firm conclusions impossible about first- versus second-line treatment choices (early release). In a systematic review, researchers considered studies of disease-modifying antirheumatic drugs with at least 100 participants and having a minimum of 12 weeks’ follow-up, finding that: “Head-to-head trials (n = 23) showed no clinically important differences in efficacy among synthetic DMARDs (limited to methotrexate, leflunomide, and sulfasalazine) or among anti–tumor necrosis factor drugs (adalimumab, etanercept, and infliximab). Monotherapy with anti–tumor necrosis factor drugs resulted in better radiographic outcomes than did methotrexate but no important differences in clinical outcomes (for example, 20%, 50%, or 70% improvement according to American College of Rheumatology response criteria). Various combinations of biological DMARDs plus methotrexate improved clinical response rates and functional outcomes more than monotherapy with either methotrexate or biological DMARDs. In patients whose monotherapy failed, combination with synthetic DMARDs improved response rates. Numbers and types of short-term adverse events were similar for biological and synthetic DMARDs. The evidence was insufficient to draw conclusions about differences for rare but serious adverse events for biological DMARDs.” (K. E. Donahue, U. North Carolina, Chapel Hill)
Low Back Pain Among Home Care Workers: Use of lumbar supports by home care workers can reduce recurrence of low back pain, but a randomized controlled trial of 360 staff members at a Dutch organization showed that the intervention had no impact on overall absenteeism (pp. 685-92). “Over 12 months, participants in the lumbar support group reported an average of –52.7 days (CI, –59.6 to –45.1 days) fewer days with low back pain than participants who received only the short course,” the investigators report. “However, the total sick days in the lumbar support group did not decrease (–5 days [CI, –21.1 to 6.8 days]). Small but statistically significant differences in pain intensity and function favored lumbar support.” (P.D.D.M. Roelofs, Erasmus Med. Ctr., Rotterdam, the Netherlands; p.roelofs@erasmusmc.nl)
Tuberculosis with Infliximab: Clinicians need to “be vigilant in screening and monitoring for tuberculosis in patients receiving infliximab,” according to FDA researchers who analyzed patients with infliximab-associated tuberculosis reported to the Adverse Event Reporting System (pp. 699-702). The group writes: “The U.S. Food and Drug Administration received 130 domestic, spontaneous reports of tuberculosis in patients treated with infliximab between 1 November 2001 and 30 May 2006, including 59 (45%) with extrapulmonary disease. The most commonly reported risk factors included concomitant immunosuppressant use (n = 89), history of latent or active tuberculosis (n = 33), and being born into or having spent extensive time in an area where tuberculosis is endemic (n = 25). In the subset of 67 cases with documented initiation of infliximab therapy after the drug labeling change, 34 patients with a negative tuberculin skin test result before initiation of infliximab therapy developed tuberculosis after receiving infliximab.” (G. Akhavan-Toyserkani, FDA, Silver Spring, Md.)

>>>PNN NewsWatch
* Sorafenib (Nexavar; Bayer, Onyx) was approved yesterday by FDA for use in patients with inoperable hepatocellular carcinoma. The approval was based on a study of 602 patients in which those receiving sorafenib survived a median of 10.7 months, compared with 7.9 months among those on placebo. The trial was stopped early based on the positive results. Sorafenib was originally approved in 2005 for treatment of patients with advanced renal cell carcinoma.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Nov. 21, 2007 * Vol. 14, No. 226
Providing news and information about medications and their proper use

>>>Circulation Highlights
Source:
Early-release articles from and Nov. 20 issue of Circulation (http://circ.ahajournals.org/current.dtl; 2007; 116).
Health Benefits of Dark Chocolate: Just in time for the holidays, Swiss researchers report that flavanoid-rich dark chocolate induces coronary vasodilation, improves coronary vascular function, and decreases platelet adhesion (pp. 2376-82). Compared with cocoa-free “control” chocolate, 40 grams of dark chocolate containing 70% cocoa provided these potentially beneficial physiologic effects among 22 heart-transplant patients: “Two hours after ingestion of flavonoid-rich dark chocolate, coronary artery diameter was increased significantly (from 2.36 ± 0.51 to 2.51 ± 0.59 mm, P <0.01), whereas it remained unchanged after control chocolate. Endothelium-dependent coronary vasomotion improved significantly after dark chocolate (4.5 ± 11.4% versus –4.3 ± 11.7% in the placebo group, P = 0.01). Platelet adhesion decreased from 4.9 ± 1.1% to 3.8 ± 0.8% (P = 0.04) in the dark chocolate group but remained unchanged in the control group.” (R. Corti, U. Hosp., Zurich; roberto.corti@usz.ch)
Effects of Aptamer Antagonist: ARC1779, a therapeutic aptamer antagonist of the A1 domain of von Willebrand factor, provided a clinical useful duration of effect in the agent’s first in-human tests (doi: 10.1161/CIRCULATIONAHA.107.724864). Checking for ARC1779’s dose- and concentration-dependent inhibition of vWF activity and platelet function in 47 healthy volunteers who received doses of 0.05–1 mg/kg, the researchers found: “The mean apparent elimination half-life was [approximately] 2 hours, and mean residence time was [approximately] 3 hours. The mean apparent volumes of distribution (at steady state and during terminal phase) were approximately one half the blood volume, suggesting that ARC1779 distribution is in the central compartment. The mean clearance ranged from [approximately] 10% to 21% of the glomerular filtration rate, suggesting that renal filtration may not be a major mechanism of clearance of ARC1779. Inhibition of vWF A1 binding activity was achieved with an EC90 value of 2.0 µg/mL (151 nmol/L) and of platelet function with an EC90 value of 2.6 µg/mL (196 nmol/L). ARC1779 was generally well tolerated, and no bleeding was observed. Adverse events tended to be minor and not dose related.” (J. C. Gilbert, jgilbert@archemix.com)

>>>PNN NewsWatch
* FDA announced yesterday that it has received reports of suicidal thoughts and aggressive and erratic behavior in patients taking varenicline (Chantix, Pfizer) during smoking-cessation attempts. FDA is reviewing case reports, including a highly publicized case of erratic behavior leading to a patient’s death. Preliminary assessment shows many of the cases reflect new-onset depressed mood, suicidal ideation, and changes in emotion and behavior within days to weeks of initiating varenicline treatment, FDA said. The role of varenicline in these cases is not clear since smoking cessation, with or without treatment, is associated with nicotine-withdrawal symptoms and has also been associated with the exacerbation of underlying psychiatric illness. However, not all patients described in these cases had pre-existing psychiatric illness and not all had discontinued smoking, FDA emphasized.
* Merck and Schering-Plough yesterday announced they were changing the primary endpoint in the long-awaited
ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) trial, the New York Times reports this morning. “Doctors say [this] decision is highly unusual and will do little to quell concerns about the trial, as well as broader questions about the effectiveness of the drugs,” the newspaper notes. “Cardiologists have been awaiting the results of the trial ... to learn how well Zetia and Vytorin work. If they are not as effective as other cholesterol medicines, patients taking them may be putting themselves at unnecessary risk of heart attacks.”
* During the holiday season,
PNN will not be published on Thurs. and Fri., Nov. 22–23, Thanksgiving; Mon. and Tues., Dec. 24–25, Christmas Eve and Day; and Mon. and Tues., Dec. 31–Jan. 1, New Year’s Eve and 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 © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Nov. 26, 2007 * Vol. 14, No. 227
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Nov. 24 issue of Lancet (www.thelancet.com; 2007; 370).
Rotavirus Vaccine Effectiveness: Among 3,994 participants from six European countries, two doses of the oral live attenuated human rotavirus vaccine Rotarix (RIX4414, GlaxoSmithKline) were significantly more effective than placebo for preventing any episodes and severe cases of rotavirus gastroenteritis, researchers report (pp. 1757-63). The vaccine, coadministered with the first two doses of childhood vaccines, showed these benefits in the clinical trial: “During the first efficacy follow-up period (mean duration 5.7 months [SD 1.2]), 24 of 2,572 infants allocated RIX4414 versus 94 of 1,302 given placebo had rotavirus gastroenteritis episodes of any severity, resulting in a vaccine efficacy of 87.1% (95% CI 79.6–92.1; p <0.0001). For the combined efficacy follow-up period, vaccine efficacy against severe rotavirus gastroenteritis was 90.4% (85.1–94.1; p <0.0001), for admission owing to rotavirus gastroenteritis 96.0% (83.8–99.5; p <0.0001), and for rotavirus-related medical attention 83.8% (76.8–88.9; p <0.0001), and significant protection against severe rotavirus gastroenteritis by circulating G1, G2, G3, G4, and G9 rotavirus types was shown.” (T. Vesikari, U. Tampere, Tampere, Finland; timo.vesikari@uta.fi)

>>>NEJM Highlights
Source:
Nov. 22 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2007; 357).
Morbidity, Mortality of Torcetrapib: Despite raising HDL and lowering LDL cholesterol, torcetrapib for unknown reasons increased patients’ risk of morbidity and mortality in the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial, investigators report (pp. 2109-22). These outcomes occurred in 15,067 patients at high cardiovascular risk who were randomized to placebo or this currently unapproved cholesteryl ester transfer protein (CETP) inhibitor: “At 12 months in patients who received torcetrapib, there was an increase of 72.1% in high-density lipoprotein cholesterol and a decrease of 24.9% in low-density lipoprotein cholesterol, as compared with baseline (P <0.001 for both comparisons), in addition to an increase of 5.4 mm Hg in systolic blood pressure, a decrease in serum potassium, and increases in serum sodium, bicarbonate, and aldosterone (P <0.001 for all comparisons). There was also an increased risk of cardiovascular events (hazard ratio, 1.25; 95% confidence interval [CI], 1.09 to 1.44; P = 0.001) and death from any cause (hazard ratio, 1.58; 95% CI, 1.14 to 2.19; P = 0.006). Post hoc analyses showed an increased risk of death in patients treated with torcetrapib whose reduction in potassium or increase in bicarbonate was greater than the median change.” (P. J. Barter, Heart Research Inst., Sydney; barterp@hri.org.au)
Assessing the viability of HDL cholesterol as a therapeutic target, an editorialist writes (pp. 2180-3): “The ILLUMINATE trial will undoubtedly stand as a watershed event in the field of HDL-targeted therapies. It may ultimately be seen as the study that brought about the rejection of the ‘HDL hypothesis.’ At a minimum, it will have been responsible for shifting the focus from HDL concentration to HDL function and raising the bar for approval of new HDL-targeted therapies. Despite the light that the ILLUMINATE study has shed onto part of the HDL journey, many poorly lit paths remain to be explored.” (D. J. Rader, U. Penn., Philadelphia)

>>>PNN JournalWatch
* The Safety of Statins in Clinical Practice, in Lancet, 2007; 370: 1781–90. Reprints: J. Armitage, U. Oxford, Oxford; jane.armitage@ctsu.ox.ac.uk
* Treatment of Peritoneal Dialysis–Associated Peritonitis: A Systematic Review of Randomized Controlled Trials, in
American Journal of Kidney Diseases, 2007; 50: 967–88. Reprints: K. J. Wiggins, St. Vincent’s Hosp., Fitzroy, Australia.
* Vasopressor Support in Septic Shock, in
Chest, 2007; 132: 1678–87. Reprints: S. M. Hollenberg, Cooper U. Hosp., Camden, N.J.; Hollenberg-Steven@cooperhealth.edu
* Sleep Complaints in Community-Living Older Persons: A Multifactorial Geriatric Syndrome, in
Journal of the American Geriatrics Society, 2007; 55: 1853–66. Reprints: C. A. Vaz Fragoso, Yale U., New Haven, Ct.; carlos.fragoso@ynhh.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 © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Nov. 27, 2007 * Vol. 14, No. 228
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Nov. 26 issue of the Archives of Internal Medicine (http://archinte.ama-assn.org/current.dtl; 2007; 167).
Patient Knowledge of Coronary Risk Profile: Educating patients about their coronary risk profiles results in small but measurable improvements in the effectiveness of lipid-lowering therapy, researchers report (pp. 2296-303). In a primary-care setting, patients randomly received either usual care or ongoing feedback about their coronary risk profiles during lifestyle and pharmacologic interventions targeting dyslipidemias, including information about the gap between their calculated cardiovascular age and chronologic age. Results showed the following: “Two hundred thirty primary care physicians enrolled 3,053 patients. After 12 months of follow-up, 2,687 patients (88.0%) remained in the study. After adjustment for baseline lipid values, significantly greater mean reductions in low-density lipoprotein cholesterol levels and the total cholesterol to high-density lipoprotein cholesterol ratio were observed in patients receiving risk profiles (51.2 mg/dL ... and 1.5, respectively) vs usual care (48.0 mg/dL and 1.3, respectively), but the differences were small (–3.3 mg/dL; 95% confidence interval [CI], –5.4 to –1.1 mg/dL; and –0.1; 95% CI, –0.2 to –0.1, respectively). Patients in the risk profile group were also more likely to reach lipid targets (odds ratio, 1.26; 95% CI, 1.07 to 1.48). A significant dose–response effect was also noted when the impact of the risk profile was stronger in those with worse profiles.” (S. A. Grover, steven.grover@mcgill.ca)
Commenting on use of the risk profiles and the “age gap” to get patients’ attention, editorialists write (pp. 2286-7): “Risk prediction has ... to make sense to patients. We think that Grover and colleagues may have found the right metric to translate predicted cardiovascular risk into something meaningful to patients and physicians: the age gap between real age and cardiovascular age. We must, however, acknowledge that risk prediction and risk-based management are more difficult than single–risk factor assessment and management, but this method is much more clinically appropriate. Cardiovascular risk management is a lifetime task, so the greater complexity of risk-based treatment decisions is surely justifiable.” (R. Jackson, U. Auckland, Auckland, New Zealand;
rt.jackson@auckland.ac.nz)
Quinolone Use & TB Onset: The risk of culture-negative tuberculosis is not increased when fluoroquinolones have been used before diagnosis, according to an analysis of 2000–2004 data from the TennCare Medicaid database (pp. 2317-22). The authors report these results: “Of 1,562 tuberculosis cases reported, 1,055 occurred in TennCare participants; of these 1,055 TennCare patients, 507 were enrolled in TennCare more than 300 days during the year before tuberculosis diagnosis. Of the 507 patients, 119 (23%) received a fluoroquinolone before tuberculosis diagnosis. The proportion of fluoroquinolone-exposed patients increased from 9% in 2000 to 41% in 2004 (2 test for trend P <.001). In multivariate logistic regression analysis, factors associated with fluoroquinolone exposure were older age (odds ratio [OR], 1.03 per year; 95% confidence interval [CI], 1.02–1.04) and year of diagnosis (OR, 1.64 per 1-year increase; 95% CI, 1.39–1.93); human immunodeficiency virus infection tended to be associated with increased exposure (OR, 1.94; 95% CI, 0.97–3.90). After controlling for age, sex, race, site of disease, human immunodeficiency virus, and year of diagnosis, prior fluoroquinolone exposure was not associated with culture-negative tuberculosis (OR, 0.81; 95% CI, 0.41–1.60).” (T. R. Sterling, timothy.sterling@vanderbilt.edu)

>>>PNN NewsWatch
* Posted in advance of today’s meeting of the pediatric advisory committee, an FDA staff analysis of antiasthmatic medications calls into question use of salmeterol and inhaled corticosteroids in children. The agency also is recommending updates to the product labeling of oseltamivir (Tamiflu, Roche) and zanamivir (Relenza, GSK) to warn of psychiatric events, including hallucinations in children taking the medications for influenza. The analysis cites cases reported to FDA similar to a cluster of patients identified previously in Japan.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Nov. 28, 2007 * Vol. 14, No. 229
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Nov. 28 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2007; 298).
Glucose–Insulin–Potassium Infusion in STEMI: Among more than 25,000 patients in two clinical trials of ST-segment elevation myocardial infarction, infusions of glucose–insulin–potassium provided no benefit and might have been harmful, researchers report (pp. 2399-405). Assessing the effects of a high-dose GIK solution consisting of 25% glucose, regular insulin 50 U/L, and potassium 80 meq/L infused at 1.5 mL/kg/hr for 24 hours, the investigators determined: “At 6 months, 148 (10.8%) GIK infusion patients and 143 (10.4%) control patients died in the OASIS-6 trial (hazard ratio [HR], 1.04; 95% CI, 0.83–1.31; P = .72); 153 (11.1%) GIK patients and 185 (13.5%) control patients had heart failure (HR, 0.83; 95% CI, 0.67–1.02; P = .08); and 240 (17.5%) GIK patients and 264 (19.2%) control patients had a composite of death or heart failure (HR, 0.91; 95% CI, 0.76–1.08; P = .27). In the prespecified analyses of the combined trial data, there were 712 deaths (6.2%) in the GIK group and 632 deaths (5.5%) in the control group at 3 days (HR, 1.13; 95% CI, 1.02–1.26; P = .03). This difference disappeared by 30 days, with 1,108 deaths (9.7%) in the GIK group and 1068 (9.3%) in the control group (HR, 1.04; 95% CI, 0.96–1.13; P = .33). GIK therapy increased levels of glucose, potassium, and net fluid gain postinfusion, all 3 of which predicted death after adjusting for multiple confounders. Adjusting for glucose, potassium, and net fluid gain eliminated the apparent increase in mortality at 3 days observed with GIK infusion, suggesting a direct association with these factors. Administration of GIK infusion within 4 hours of symptom onset yielded no benefit compared with later initiation.” (A. Goyal, agoyal4@sph.emory.edu)

>>>Infectious Diseases Report
Source:
Dec. 15 issue of Clinical Infectious Diseases (www.journals.uchicago.edu/CID/home.html; 2007; 45).
Antiviral Agents for Influenza: Among a highly vaccinated population of patients hospitalized for influenza in southern Ontario, treatment of the infection with antiviral drugs significantly reduced mortality (pp. 1568-75). During 2005–06, these outcomes were noted: “Data were available for 512 of 541 eligible patients. There were 185 children (<15 years of age), none of whom died and none of whom were treated with antiviral drugs. The median age of the 327 adults was 77 years (range, 15–98 years), 166 (51%) were male, 245 (75%) had a chronic underlying illness, and 216 (71%) had been vaccinated against influenza. Of the 327 adult patients, 184 (59%) presented to the emergency department within 48 h after symptom onset, 52 (16%) required intensive care unit admission, and 27 (8.3%) died within 15 days after symptom onset. Most patients (292 patients; 89%) received antibacterial therapy; 106 (32%) were prescribed antiviral drugs. Treatment with antiviral drugs active against influenza was associated with a significant reduction in mortality (odds ratio, 0.21; 95% confidence interval, 0.06–0.80; P = .03). There was no apparent impact of antiviral therapy on length of stay in survivors.” (A. McGeer, Mount Sinai Hosp., Toronto)
Pneumococcal Vaccination During Stem-Cell Transplant: While both performed poorly, pneumococcal conjugate vaccine (PCV7) proved better than pneumococcal polysaccharide vaccine (PPV23) when used for donor and recipient vaccination during adult allogenic hematopoietic stem cell transplant (pp. 1576-82). Vaccinations were administered to donors before transplantation and recipients at 6 months after transplantation, with these results: “Overall, immunogenicity was poor with both strategies. However, at 6 months, response to at least 1 serotype was seen in 0 (0%) of 19 and 8 (38.6%) of 21 evaluable recipients whose donors had received PPV23 and PCV7, respectively (P = .003). At 12 months, response was seen in 10 (55.6%) of 18 and 20 (90.9%) of 22 HSCT recipients who had received PPV23 and PCV7, respectively (P = .02). Multivariate logistic regression revealed that, at 12 months after transplantation, the type of vaccine given was the only significant factor affecting response, with an odds ratio of 8.85 (95% confidence interval, 1.62–47.6; P = .012) favoring PCV7.” (D. Kumar, U. Alberta, Edmonton)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Nov. 29, 2007 * Vol. 14, No. 230
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Nov. 29 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2007; 357).
Eltrombopag for Thrombocytopenia: Two research articles and an editorial explore the utility of eltrombopag, an investigational, orally active thrombopoietin-receptor agonist.
Among 74 patients with cirrhosis caused by hepatitis C, 4 weeks’ therapy with eltrombopag significantly increased platelet counts in patients with thrombocytopenia due to HCV-related cirrhosis, permitting initiation of peginterferon and ribavirin (pp. 2227-36). In this dose-ranging study, researchers observed: “At week 4, platelet counts were increased to 100,000 per cubic millimeter or more in a dose-dependent manner among patients for whom these data were available: in 0 of the 17 patients receiving placebo, in 9 of 12 (75%) receiving 30 mg of eltrombopag, in 15 of 19 (79%) receiving 50 mg of eltrombopag, and in 20 of 21 (95%) receiving 75 mg of eltrombopag (P <0.001). Antiviral therapy was initiated in 49 patients (in 4 of 18 patients receiving placebo, 10 of 14 receiving 30 mg of eltrombopag, 14 of 19 receiving 50 mg of eltrombopag, and 21 of 23 receiving 75 mg of eltrombopag) while the administration of eltrombopag or placebo was continued. Twelve weeks of antiviral therapy, with concurrent receipt of eltrombopag or placebo, were completed by 36%, 53%, and 65% of patients receiving 30 mg, 50 mg, and 75 mg of eltrombopag, respectively, and by 6% of patients in the placebo group. The most common adverse event during the initial 4 weeks was headache; thereafter, the adverse events were those expected with interferon-based therapy.” (J. G. McHutchison,
mchut001@mc.duke.edu)
Dose-dependent increases in platelet counts were also observed in 118 adult patients with chronic idiopathic thrombocytopenia purpura after they received 43 days of eltrombopag therapy (pp. 2237-47). Using a platelet count of 50,000 or more per cubic millimeter as the primary end point, the investigators found: “In the eltrombopag groups receiving 30, 50, and 75 mg per day, the primary end point was achieved in 28%, 70%, and 81% of patients, respectively. In the placebo group, the end point was achieved in 11% of patients. The median platelet counts on day 43 for the groups receiving 30, 50, and 75 mg of eltrombopag were 26,000, 128,000, and 183,000 per cubic millimeter, respectively; for the placebo group the count was 16,000 per cubic millimeter. By day 15, more than 80% of patients receiving 50 or 75 mg of eltrombopag daily had an increased platelet count. Bleeding also decreased during treatment in these two groups. The incidence and severity of adverse events were similar in the placebo and eltrombopag groups” (J. B. Bussel,
jbussel@med.cornell.edu)
“From agony to agonist” is the description given to the hope these reports bring to clinical research into immune thrombocytopenic purpura, an editorialist writes (pp. 2299-301): “The results reported for thrombopoietin-receptor agonists are too preliminary for any definitive statement about applications in clinical practice, but they surely encourage further work in this direction. Hematologists everywhere are thwarted by patients with ITP in whom every available treatment has failed to improve the platelet count. A new, safe way of treating the disease would be a considerable advance.” (R. S. Schwartz)
Rosuvastatin in Systolic Heart Failure: While statin use poses “theoretical risks” in patients with systolic heart failure, a trial of 5,011 patients taking rosuvastatin identified no safety problems (pp. 2248-61). However, benefits were minimal, with no significant change in a primary composite outcome (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) over a median of 32.8 months. Among secondary outcomes, hospitalizations for cardiovascular conditions were reduced significantly. (J. Kjekshus, U. Oslo, Oslo, Norway; john.kjekshus@medisin.uio.no)

>>>PNN NewsWatch
* New warnings are likely forthcoming concerning pediatric use of modafinil (not approved for use in children), salmeterol (asthma-related deaths), and the influenza drugs oseltamivir and zanamivir (abnormal behavior and hallucinations), if FDA follows the advice proffered this week by its Pediatric Advisory Committee.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Nov. 30, 2007 * Vol. 14, No. 231
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Dec. issue of Diabetes Care (http://care.diabetesjournals.org/current.shtml; 2007; 30).
Lessons from Avandia: A number of lessons for clinicians and diabetes researchers can be learned from this year’s controversy over rosiglitazone (Avandia, GlaxoSmithKline), an author writes (pp. 3141-4). These include (R. I. Misbin, robert.misbin@fda.hhs.gov):
* Reducing A1C may not be enough.
* Outcomes trials need to be considered.
* Combination therapy trials should be re-evaluated.
* A new paradigm for development of drugs for type 2 diabetes is needed, one with new trial designs, approval criteria, and better labeling.
Benefits of Clinical Trial Recruitment: Patients who are recruited into clinical trials experience improvements in their glycemic control, even if they receive no therapeutic interventions, researchers find based on data from three trials of patients with type 1 diabetes and three studies of those with type 2 conditions (pp. 2989-92). The trials included time periods between a single screening visit and randomization in which no pharmacotherapy changes were made, and the authors found these effects of the recruitment process: “A1C changed by –0.13% (range +0.09 to –0.26%) in those with type 1 diabetes at a median of 28 days and by –0.16% (–0.14 to –0.27%) for those with type 2 diabetes at a median of 14 days. The mean change in A1C in those with an interval of 28 days was –0.24% for those with type 1 diabetes and –0.23% for those with type 2 diabetes. The reduction was proportional to initial A1C, with large decreases in those with the poorest initial control but no overall change in those at or below the 10th percentile of A1C.” (E.A.M. Gale, Southmead Hosp., Bristol, U.K.; edwin.gale@bristol.ac.uk)
Diabetes, Metabolic Syndrome, & Stroke: A review article considers the relationships among diabetes, metabolic aberrations, and stroke, reaching this conclusion (pp. 3131-40): “The potential benefit of aggressive multiple risk-reduction measures in those with diabetes has been highlighted by the Steno-2 Study. Intensive standardized risk factor reduction, including 1) treatment of hyperglycemia, hypertension, dyslipidemia, and microalbuminuria; 2) secondary prevention of cardiovascular disease with aspirin; and 3) behavioral modification, resulted in significant reductions in cardiovascular disease, including stroke (HR 0.47 [95% CI 0.24–0.73]). This effect was larger than that seen in studies that targeted treatment to individual risk factors. Although the specific mechanisms that underlie the relationship between diabetes, the metabolic syndrome, and stroke require ongoing investigation to provide new methods for prevention and treatment, these data underscore the strides that can be made with the tools at hand.” (B. M. Kissela, U. Cincinnati, Cincinnati; brett.kissela@uc.edu)
Vildagliptin as Initial Monotherapy: Among 1,890 younger and 374 older treatment-naive patients with type 2 diabetes, vildagliptin monotherapy “was effective and well tolerated” among those aged 65 years or older (pp. 3017-22). Pooling data from eight safety and five efficacy trials, the investigators report: “Mean baseline A1C and fasting plasma glucose (FPG) were significantly lower in older (70 years: 8.3 ± 0.1% and 9.6 ± 0.1 mmol/l, respectively) than in younger (50 years: 8.7 ± 0.0% and 10.5 ± 0.1 mmol/l, respectively) patients. Despite this, the adjusted mean change from baseline (AM) in A1C was –1.2 ± 0.1% in older and –1.0 ± 0.0% in younger vildagliptin-treated patients (P = 0.092), and the AM in FPG was significantly larger in older (–1.5 ± 0.2 mmol/l) than in younger (–1.1 ± 0.1 mmol/l, P = 0.035) patients. Body weight was significantly lower at baseline in older (83.4 ± 1.0 kg) than in younger (92.0 ± 0.6 kg) patients. Weight decreased significantly in the older subgroup (AM –0.9 ± 0.3 kg, P = 0.007), whereas smaller, nonsignificant decreases occurred in younger patients (AM –0.2 ± 0.1 kg). Adverse event rates were slightly higher in older than in younger subgroups but were lower among older, vildagliptin-treated subjects (63.6%) than in the pooled active comparator group (68.1%). Vildagliptin treatment did not increase adverse events among older patients with mild renal impairment (62.0%). Hypoglycemia was rare (0.8%) in the elderly patients, and no severe events occurred.” (A. Schweizer, anja.schweizer@novartis.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 © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Dec. 3, 2007 * Vol. 14, No. 232
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Dec. 1 issue of Lancet (www.thelancet.com; 2007; 370).
Statins & Stroke: “Statins substantially reduce not only coronary event rates but also total stroke rates in patients with a wide range of ages and blood pressures,” concludes a meta-analysis of 61 prospective observational studies of nearly 900,000 adults (pp. 1829-39). However, for older patients (70–89 years) with systolic blood pressures greater than 145 mm Hg, total cholesterol was negatively related to hemorrhagic and total stroke mortality, a finding the authors wrote “invites further research.” Among patients in early middle age (40–59 years), total cholesterol was “weakly positively related” to ischemic and total stroke mortality, but the authors noted, “This finding could be largely or wholly accounted for by the association of cholesterol with blood pressure.” (PSC secretariat, U. Oxford, Oxford, U.K.; psc@ctsu.ox.ac.uk)
Unusual Diseases Related to Globalization: In an era of globalization and worldwide travel, clinicians must be on guard for diseases endemic in one area presenting in another region, investigators conclude, based on occurrence of chikungunya virus in two contiguous villages in northeastern Italy (pp. 1840-6). A large number of cases of febrile illness led to an outbreak investigation and implementation of an active surveillance system, uncovering interesting results: “Analysis of samples from human beings and from mosquitoes showed that the outbreak was caused by CHIKV. We identified 205 cases of infection with CHIKV between July 4 and Sept 27, 2007. The presumed index case was a man from India who developed symptoms while visiting relatives in one of the villages. Phylogenetic analysis showed a high similarity between the strains found in Italy and those identified during an earlier outbreak on islands in the Indian Ocean. The disease was fairly mild in nearly all cases, with only one reported death.” (A. Cassone, Istituto Superiore di Sanità, Roma, Italy; cassone@iss.it)

>>>BMJ Highlights
Source:
Early-release article from BMJ (www.bmj.org; 2007; 335).
Rapid Chlamydial Test: A new Chlamydia Rapid Test, one that uses self-collected vaginal swabs, proved to be an effective same-day diagnostic and screening tool in 1,349 women aged 16 to 54 years, researchers report (doi: 10.1136/bmj.39402.463854.AE). Based on samples collected at a young people’s sexual health center (site 1) and two genitourinary medicine clinics (sites 2 and 3) in the U.K., the researchers report: “Polymerase chain reaction positivity rates for Chlamydia trachomatis infection were 8.4% (56/663) at site 1, 9.4% (36/385) at site 2, and 6.0% (18/301) at site 3. Compared with polymerase chain reaction assay, the resolved sensitivity, specificity, positive predictive value, and negative predictive value of the Chlamydia Rapid Test were 83.5% (91/109), 98.9% (1,224/1,238), 86.7% (91/105), and 98.6% (1,224/1,242). Compared with strand displacement amplification assay, sensitivity and specificity of the Chlamydia Rapid Test were 81.6% (40/49) and 98.3% (578/588). Organism load of self collected vaginal swabs ranged from 5.97 x 102 to 1.09 x 109 Chlamydia plasmids per swab, which correlated well with the Chlamydia Rapid Test’s visual signal (r = 0.6435, P <0.0001). Most (95.9%) surveyed participants felt comfortable about collecting their own swabs.” (H. H. Lee, U. Cambridge, Cambridge, U.K.; hl207@cam.ac.uk)

>>>PNN JournalWatch
* Alcohol Hand Rubs: Hygiene and Hazard, in BMJ, 2007; 335: 1154–5. Reprints: J. R. H. Archer, Guy’s and St. Thomas’ Poisons Unit, London; jrh_archer@yahoo.com
* State of the Evidence on Acute Asthma Management in Children: A Critical Appraisal of Systematic Reviews, in
Pediatrics, 2007; 120: 1334–43. Reprints: N. Boluyt, Academic Med. Ctr., Amsterdam.
* To What Extent Do Educational Interventions Impact Medical Trainees’ Attitudes and Behaviors Regarding Industry-Trainee and Industry-Physician Relationships?, in
Pediatrics, 2007; 120: e1528–35. Reprints: A. E. Carroll, Indiana U., Indianapolis.
* Ranolazine: A New Option in the Management of Chronic Stable Angina, in
Pharmacotherapy, 2007; 27: 1659–76. Reprints: P. P. Dobesh, U. Nebraska, Omaha; pdobesh@unmc.edu
* Key Articles and Guidelines in the Management of Acute Coronary Syndromes and in Percutaneous Coronary Intervention: 2007 Update, in
Pharmacotherapy, 2007; 27: 1722–58. Reprints: P. P. Dobesh, U. Nebraska, Omaha; pdobesh@unmc.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 © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Dec. 4, 2007 * Vol. 14, No. 233
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release articles from and Dec. 4 issue of the Annals of Internal Medicine (http://www.annals.org/current.shtml; 2007; 147).
Drug Therapy of Chronic Hepatitis: Among 135 treatment-naive adults with chronic hepatitis B who were positive for the hepatitis B e antigen, telbivudine demonstrated greater and more consistent HBV DNA suppression than adefovir after 24 weeks of treatment, researchers report (pp. 745-54). Telbivudine also showed an advantage at 52 weeks among those on continuous therapy and patients switched from adefovir at 24 weeks, the article explains. (H. L. Y. Chan, Chinese U., Hong Kong; hlychan@cuhk.edu.hk)
After describing the evolution of therapy for chronic hepatitis B, editorialists pose several questions about the Chan et al. study, reaching this conclusion (pp. 806-8): “Although therapy has improved over the past decade and most patients with chronic hepatitis B respond to treatment, rates of sustained response and HBsAg loss remain poor. Therefore, we urgently need new drugs aimed at novel antiviral targets if we are to achieve HBsAg loss and successfully prevent and manage resistance. Until then, studies should focus on optimizing currently available drugs by finding the best regimen to treat chronic hepatitis B and the appropriate measures for changing or discontinuing therapy. Unfortunately, this study leaves us with more questions than answers.” (M. G. Ghany,
marcg@intra.niddk.nih.gov)
ADEs & ED visits: Among visits by older patients to emergency departments for adverse drug events, medications that should be avoided according to the Beers criteria are disproportionately involved, and warfarin, insulin, and digoxin are responsible for one-third of the problems (pp. 755-65). In an analysis of data from three surveys in 2004–05, these results were found: “Among U.S. patients 65 years of age or older, an estimated 177,504 emergency department visits (95% CI, 100,155 to 254,854 visits) for adverse drug events occurred both years. An estimated 3.6% (CI, 2.8% to 4.5%) of these visits were for adverse events medications considered to be always potentially inappropriate, according to the Beers criteria, and 33.3% (CI, 27.8% to 38.7%) of visits were for adverse events from 3 other medications (warfarin [17.3%], insulin [13.0%], and digoxin [3.2%]). Accounting for outpatient prescription frequency, the risk for emergency department visits for adverse events due to these 3 medications was 35 times (CI, 9.6 to 61) greater than that for medications considered to be always potentially inappropriate.” (D. S. Budnitz, dbudnitz@cdc.gov)
Health Care Reform: To achieve a “high-performance health care system with universal access,” the U.S. can learn much from systems in other countries, the American College of Physicians concludes in a three-part article slated for publication in the Jan. 1, 2008, issue of Annals (early release): “All Americans should have access to a primary care physician and should have a patient-centered medical home for their ongoing, continuous, comprehensive, and coordinated care. All Americans should have health insurance coverage that includes preventive and primary care services, as well as protection from catastrophic health care costs. Federal health policy should support the patient-centered primary care model. The United States lacks a national health care workforce policy. It should provide for sufficient support for the infrastructure required to educate and train an adequate supply of health professionals that would properly meet the nation’s health care needs, including primary and principal care physicians that are trained to manage care of the whole patient. Workforce planning should specify an appropriate mix of physicians between primary and specialty care and describe the policies required to achieve that goal. Public and private investments in research must continue to support advances in basic and clinical medical science as well as in health services research. Other ACP recommendations call for financial incentives to encourage quality improvement and reduction of avoidable medical errors, support for a health information technology infrastructure to assist patients and physicians in making informed decisions about the appropriate use of health care services, and use of technology to achieve a more efficient health care system.” (American College of Physicians, Philadelphia)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Dec. 5, 2007 * Vol. 14, No. 234
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Dec. 5 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2007; 298).
Treatment of Acute Maxillary Sinusitis: Tested alone and in combination in a study of 240 patients aged 16 years or older, neither an antibiotic nor topical intranasal steroid was effective for treating acute nonrecurrent maxillary sinusitis (pp. 2487-96). Patients received amoxicillin 500 mg three times daily for 7 days and/or budesonide 200 mcg in each nostril once daily for 10 days in the placebo-controlled factorial trial, with these results: “The proportions of patients with symptoms lasting 10 or more days were 29 of 100 (29%) for amoxicillin vs 36 of 107 (33.6%) for no amoxicillin (adjusted odds ratio, 0.99; 95% confidence interval, 0.57–1.73). The proportions of patients with symptoms lasting 10 or more days were 32 of 102 (31.4%) for topical budesonide vs 33 of 105 (31.4%) for no budesonide (adjusted odds ratio, 0.93; 95% confidence interval, 0.54–1.62). Secondary analysis suggested that nasal steroids were significantly more effective in patients with less severe symptoms at baseline.” (I. G. Williamson, U. Southampton, Southampton, England; igw@soton.ac.uk)
An editorialist weighs the full body of evidence in advising clinicians on whether to treat acute sinusitis (pp. 2543-4): “Although the study by Williamson et al has demonstrated that patients with a clinical diagnosis of sinusitis do not benefit from treatment with an antibiotic or a topical steroid, there may be subgroups that might benefit from either. This issue may be better studied in a large meta-analysis with individual patient data, such as the meta-analysis by Rovers et al, which included children with acute otitis media. This meta-analysis demonstrated that children younger than 2 years with bilateral otitis media or with otorrhea benefited from antibiotic treatment. Such studies may be informative for adults with acute sinusitis based on clinical diagnosis if subgroups of patients who may benefit could be identified. In the meantime, cautious use of antibiotics in the general practice setting for patients with sinusitis is warranted.” (M. Lindbaek, U. Oslo, Blindern, Norway;
morten.lindbak@medisin.uio.no)
Antithrombotic Strategies in Acute Coronary Syndromes: One-year results from the ACUITY (Acute Catheterization and Urgent Intervention Triage StrategY) trial confirm preliminary findings showing that bivalirudin monotherapy is equivalent to Gp IIb/IIIa inhibitors plus bivalirudin or heparin (pp. 2497-506). These results were noted in 13,819 patients with moderate- or high-risk acute coronary syndromes: “Composite ischemia [death, myocardial infarction, or unplanned revascularization for ischemia] at 1 year occurred in 15.4% of patients assigned to heparin plus GP IIb/IIIa inhibitors and 16.0% assigned to bivalirudin plus GP IIb/IIIa inhibitors (compared with heparin plus GP IIb/IIIa inhibitors, HR, 1.05; 95% CI, 0.95–1.16; P = .35), and 16.2% assigned to bivalirudin monotherapy (HR, 1.06; 95% CI, 0.95–1.17; P = .29). Mortality at 1 year occurred in an estimated 3.9% of patients assigned to heparin plus GP IIb/IIIa inhibitors, 3.9% assigned to bivalirudin plus GP IIb/IIIa inhibitors (HR, 0.99; 95% CI, 0.80–1.22; P = .92), and 3.8% assigned to bivalirudin monotherapy (HR, 0.96; 95% CI, 0.77–1.18; P = .67). Composite ischemia occurred in 16.3% of patients assigned to deferred use compared with 15.2% of patients assigned to upstream administration (HR, 1.08; 95% CI, 0.97–1.20; P = .15).” (G. W. Stone, gs2184@columbia.edu)
Persistence of Contradicted Claims: Despite being refuted years ago, claims for cardiovascular and cancer benefits of vitamin E, beta-carotene, and estrogen are discussed favorably in recently published articles (pp. 2517-26). Investigators report: “In 2006, 62.5% of articles referencing the highly cited article that had proposed beta-carotene and 61.7% of those referencing the highly cited article on estrogen effectiveness were still favorable; 100% and 96%, respectively, of the citations appeared in specialty journals; and citations were significantly less favorable (P = .001 and P = .009, respectively) when the major contradicting trials were also mentioned.” (J. P. A. Ioannidis, U. Ioannina, Ioannina, Greece; jioannid@cc.uoi.gr)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Dec. 6, 2007 * Vol. 14, No. 235
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Dec. 6 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2007; 357).
Tesamorelin in Patients with HIV: In a 26-week trial, daily subcutaneous injections of the growth hormone–releasing factor tesamorelin decreased visceral fat and improved lipid profiles among 412 patients with HIV (pp. 2359-70). Study participants, 86% of whom were men and all with an accumulation of abdominal fat, showed these benefits of 2-mg doses of the agent: “The measure of visceral adipose tissue decreased by 15.2% in the tesamorelin group and increased by 5.0% in the placebo group; the levels of triglycerides decreased by 50 mg per deciliter and increased by 9 mg per deciliter, respectively, and the ratio of total cholesterol to HDL cholesterol decreased by 0.31 and increased by 0.21, respectively (P <0.001 for all comparisons). Levels of total cholesterol and HDL cholesterol also improved significantly in the tesamorelin group. Levels of IGF-I increased by 81.0% in the tesamorelin group and decreased by 5.0% in the placebo group (P <0.001). Adverse events did not differ significantly between the two study groups, but more patients in the tesamorelin group withdrew from the study because of an adverse event. No significant differences were observed in glycemic measures.” (S. Grinspoon, sgrinspoon@partners.org)
Many questions about HIV lipodystrophy remain unanswered, an editorialist warns (pp. 2397-9): “Numerous questions remain about the long-term administration of tesamorelin or other growth hormone–releasing analogues. Would such a regimen lower cardiovascular morbidity and mortality; overstimulate the pituitary gland or central nervous system, with an increased risk of pituitary neoplasms or neurobehavioral dysfunction; augment the risk of cancer in susceptible patients; improve the quality of life; elicit different response profiles according to age, sex, race, and atopic or genetic predisposition; or be supplanted by orally active growth hormone secretagogues, which might exert a better risk–benefit profile and be less expensive? The findings of [the above study] suggest that without answers to these questions, the treatment of HIV lipodystrophy remains unresolved.” (M. R. Blackman, VA Med. Ctr., Washington, D.C.)
Pediatric Use of Nonprescription Cough, Cold Meds: Lead signers of the petition to FDA calling for market withdrawal of nonprescription cough and cold medications for use in children provide this post–open hearing assessment of the situation (pp. 2321-4): “After the meeting, the major manufacturers of these products announced that they disagreed with the committee and would continue to market these preparations for children between 2 and 5 years of age. Because the monograph is still in effect, the products and their ‘toddler’ formulations are still being widely advertised to parents in ways that suggest that they are known to be safe, effective, and recommended by most pediatricians. Despite their own proposal that the use of these products for sedation be stopped, companies are still marketing ‘nighttime’ preparations containing sedating antihistamines. Although the FDA does not need to follow the recommendations of its advisory committees, we believe that it should immediately ask companies to remove these products from store shelves and begin legal proceedings to require them to do so. Rep. Henry A. Waxman (D-CA) and Sen. Edward Kennedy (D-MA) have recently introduced legislation to expedite this process by strengthening the FDA’s oversight of the marketing and advertising of over-the-counter medications.” (J. M. Sharfstein, Commissioner of Health, Baltimore)

>>>PNN NewsWatch
* Certain patients taking desmopressin are at risk for developing severe hyponatremia that can result in seizures and death, FDA has cautioned. Children treated with desmopressin intranasal formulations for primary nocturnal enuresis are particularly susceptible to severe hyponatremia and seizures. As such, desmopressin intranasal formulations are no longer indicated for the treatment of primary nocturnal enuresis and should not be used in hyponatremic patients or patients with a history of hyponatremia. PNE treatment with desmopressin tablets should be interrupted during acute illnesses that may lead to fluid and/or electrolyte imbalance. All desmopressin formulations should be used cautiously in patients at risk for water intoxication with hyponatremia.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Dec. 7, 2007 * Vol. 14, No. 236
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Dec. issue of Pharmacotherapy (www.pharmacotherapy.org; 2007; 27).
Treatments for Rheumatoid Arthritis: Two review articles and an editorial examine emerging therapies for rheumatoid arthritis.
Abatacept provides a useful option for this disease, authors write, adding (pp. 1693-701). “Abatacept is the first drug in a new class of disease-modifying antirheumatic drugs (DMARDs) known as selective costimulation modulators. Costimulation modulators block the second signal and decrease T-cell activation. Abatacept has been approved by the United States Food and Drug Administration for reducing signs and symptoms, inducing major clinical response, slowing the progression of structural damage, and improving physical function in adults with moderate-to-severe active rheumatoid arthritis who have had an inadequate response to at least one other DMARD, such as methotrexate or tumor necrosis factor (TNF)-alpha inhibitors. Randomized controlled trials have shown that abatacept improves both clinical outcomes and health-related quality of life in patients who have had an inadequate response to other DMARDs. Abatacept has been shown to be well tolerated. In clinical trials, however, abatacept treatment was associated with a higher rate of infections compared with placebo. This finding was compounded when abatacept was used with TNF-alpha inhibitors; thus, this combination should be avoided. Abatacept appears to be a useful treatment option for patients with rheumatoid arthritis who have previously failed other DMARDs. However, additional clinical trials evaluating its long-term effect on patient safety and disease outcomes are needed.” (C. Marra, St. Paul’s Hosp., Vancouver, B.C., Canada;
carlo.marra@ubc.ca)
The author of the second review, in discussing rituximab, also notes a need for long-term data (pp. 1702-10): “Rituximab has been approved by the United States Food and Drug Administration in combination with methotrexate for the treatment of rheumatoid arthritis in patients who failed to achieve adequate benefit from tumor necrosis factor-alpha inhibitors. Rituximab is a biologic agent that depletes peripheral B cells—an action thought to reduce rheumatoid arthritis activity—and induces prolonged clinical improvement. Two 1,000-mg infusions administered 2 weeks apart can result in a response that lasts for months. Most patients will require retreatment, but the effect of repeated dosing on patient outcomes has not yet been determined. Combination therapy with methotrexate is recommended as this appears to achieve the best outcomes. Rituximab also has been shown to be safe, although the lack of long-term efficacy and safety data limit its use. More studies are needed, but this agent has been demonstrated to be safe and effective in patients who fail to achieve adequate clinical response to methotrexate and tumor necrosis factor-alpha inhibitors.” (Arthur A. Schuna,
aaschuna@wisc.edu)
Commenting on the reviews, an editorialist provides this perspective (pp. 1609-10). “Based on current data, abatacept and rituximab should not be used before TNF-alpha inhibitors. Moreover, when considering cost and lack of long-term safety data, the biologic DMARD anakinra (an interleukin-1 receptor antagonist that does not exacerbate heart failure) also should be considered for patients with an inadequate response to TNF-alpha inhibitors.” (J. J. Saseen, U. Colorado, Denver;
joseph.saseen@uchsc.edu)

>>>PNN NewsWatch
* FDA has slightly relaxed the regulatory requirements for isotretinoin, eliminating a 23-day lockout for girls and women of childbearing potential if they did not have prescriptions filled within 7 days of a pregnancy test. Other changes to the iPledge program include linkage of the 7-day prescription window for females of childbearing potential to the date of pregnancy testing rather than the date of the physician office visit, and extension of the prescription window from 7 days to 30 days for males and females not of childbearing potential who are taking the antiacne drug.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Dec. 10, 2007 * Vol. 14, No. 237
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Dec. 8 issue of Lancet (www.thelancet.com; 2007; 370).
Anacetrapib Effects on Lipids: Marketing of a cholesteryl ester transfer protein inhibitor could be on the horizon, if results of a new study of anacetrapib hold up (pp. 1907-14). Noted in the Merck-funded study were increases in HDL cholesterol, decreases in LDL cholesterol similar to those of statins, and no increases in blood pressure (which undermined torcetrapib in its clinical trials), with these specific results: “Anacetrapib produced dose-dependent lipid-altering effects with peak lipid-altering effects of 129% (mean 51.1 [SD 3.8]−114.9 [7.9] mg/dL) increase in HDL-C and a 38% (138.2 [11.4]−77.6 [7.9] mg/dL) decrease in LDL-C in patients with dyslipidaemia. In the 24-h ambulatory blood pressure study in healthy individuals, least squares difference between anacetrapib and placebo groups on day 10 were 0.60 (90% CI −1.54 to 2.74; p = 0.634) mm Hg for systolic blood pressure and 0.47 (90% CI −0.90 to 1.84; p = 0.561) mm Hg for diastolic blood pressure.” (R. Krishna, rajesh-krishna@merck.com)
Baclofen for Alcohol Abstinence: Among 148 patients with alcohol dependence and liver cirrhosis, baclofen proved effective for promoting alcohol abstinence, researchers report (pp. 1915-22). Testing oral doses of the drug against placebo for 12 weeks, the trial showed: “Of 42 patients allocated baclofen, 30 (71%) achieved and maintained abstinence compared with 12 (29%) of 42 assigned placebo (odds ratio 6.3 [95% CI 2.4–16.1]; p = 0.0001). The number of dropouts (termination of treatment) did not differ between the baclofen (6/42 [14%]) and placebo (13/42 [31%]) groups (p = 0.12). Cumulative abstinence duration was about twofold higher in patients allocated baclofen than in those assigned placebo (mean 62.8 [SE 5.4] vs 30.8 [5.5] days; p = 0.001). No hepatic side-effects were recorded.” (G. Addolorato, Catholic U., Rome; g.addolorato@rm.unicatt.it)
Development of Antiretroviral Drug Resistance: Among 7,916 patients who began antiretroviral therapy with three or more drugs, extensive virological failure to the three main classes of HIV drugs occurred slowly in routine clinical practice, an analysis shows (pp. 1923-8). “167 patients developed extensive triple-class failure during 27,441 person–years of follow-up,” reported the investigators. “The Kaplan–Meier estimate for the cumulative risk of extensive triple-class failure was 9.2% by 10 years (95% CI 5.0–13.4). There was evidence that this rate has decreased over time (adjusted hazard ratio 0.86 [0.77–0.96] per year more recent; p = 0.006). Of the 167 patients with extensive triple-class failure, 101 (60%) subsequently had at least one viral load less than 50 copies per mL. The risk of death by 5 years from the time of extensive triple-class failure was 10.6% (2.4–18.8, nine deaths).” (A. N. Phillips, Royal Free and U. College Med. Sch., London; a.phillips@pcps.ucl.ac.uk)

>>>BMJ Highlights
Source:
Dec. 8 issue of BMJ (www.bmj.org; 2007; 335).
Drug Management of Weight: Three agents are beneficial in patients with overweight and obesity, authors of a meta-analysis of 30 trials write, adding (pp. 1194-9): “Orlistat reduced the incidence of diabetes and improved concentrations of total cholesterol and low density lipoprotein cholesterol, blood pressure, and glycaemic control in patients with diabetes but increased rates of gastrointestinal side effects and slightly lowered concentrations of high density lipoprotein. Sibutramine lowered concentrations of high density lipoprotein cholesterol and triglycerides but raised blood pressure and pulse rate. Rimonabant improved concentrations of high density lipoprotein cholesterol and triglycerides, blood pressure, and glycaemic control in patients with diabetes but increased the risk of mood disorders.” (R. Padwal, rpadwal@ualberta.ca)

>>>PNN JournalWatch
* The Year in Heart Failure, in Journal of the American College of Cardiology, 2007; 50: 2344–51. Reprints: W. H. W. Tang.
* Screening for High Blood Pressure: U.S. Preventive Services Task Force Reaffirmation Recommendation Statement, in
Annals of Internal Medicine, 2007; 147: 783–6. Reprints: U.S. Preventive Services Task Force.
* The Revised Warning for Antidepressants and Suicidality: Unveiling the Black Box of Statistical Analyses, in
American Journal of Psychiatry, 2007; 164: 1786–9. Reprints: A. C. Leon.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Dec. 11, 2007 * Vol. 14, No. 238
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Dec. 10/24 issue of the Archives of Internal Medicine (http://archinte.ama-assn.org/current.dtl; 2007; 167).
Poor Control of Systolic Hypertension: Among the nearly three-fourths of patients with cardiovascular disease who have concomitant hypertension, control of elevated systolic blood pressure remains poor, investigators find in an analysis of data from the National Health and Nutrition Examination Survey 2003–04 (pp. 2431-6). “The overall prevalence rate of HTN was 31.4% (n = 1,671, N = 60.5 million), ranging from 23.1% in those without [cardiovascular comorbidities] to 51.8% to 81.8% in those with CVCs (P <.01). Despite HTN treatment rates for diabetes mellitus, stroke, heart failure, and coronary artery disease that are higher (83.4%–89.3%) than the rates of those without these conditions (66.5%) (P <.01), control rates for treatment remained poor (23.2%–49.3%) (P <.001 to P = .048). Isolated systolic HTN was the most common hypertensive subtype in those with CVCs ( 63.5%) with systolic blood pressure averaging at least 20 mm Hg from goal.” (N. D. Wong, U. Calif., Irvine; ndwong@uci.edu)
Asking why treatment guidelines diffuse into clinical practice so slowly, an editorialist writes (pp. 2394-5): “[This] study highlights a legitimate concern about inadequate blood pressure control in high-risk patients with hypertension. This concern is based on an analysis of federally funded survey data and blood pressure control guidelines developed by a committee supported entirely by the National Heart, Lung, and Blood Institute. The study does not mention specific antihypertensive agents. A robust clinical research enterprise, committed to improving health and more effectively preventing and treating disease, is dependent on this type of collaboration involving an academic medical center, federal funding agencies, and the pharmaceutical industry.” (T. A. Kotchen, Med. Coll. of Wisc., Milwaukee;
tkotchen@mcw.edu)
Safety of Medications for Opiate Maintenance Treatment: In a study of 154 patients being treated for opioid dependence, buprenorphine was associated with less QTc prolongation than levomethadyl or methadone, perhaps making it a safer alternative, researchers conclude (pp. 2469-75). After 17 weeks of maintenance therapy, the study showed: “Baseline QTc was similar in the 3 groups. The levomethadyl and methadone groups were significantly more likely to manifest a QTc greater than 470 or 490 milliseconds (28% for the levomethadyl group vs 23% for the methadone group vs 0% for the buprenorphine group; P <.001) or an increase from baseline in QTc greater than 60 milliseconds (21% of the levomethadyl group [odds ratio, 15.8; 95% confidence interval, 3.7–67.1] and 12% of the methadone group [odds ratio, 8.4; 95% confidence interval, 1.9–36.4]) compared with the buprenorphine group (2% of subjects; P <.001). In subjects whose dosage of levomethadyl or methadone remained fixed over at least 8 weeks, the QTc continued to increase progressively over time (P = .08 for the levomethadyl group, P = .01 for the methadone group).” (M. C. P. Haigney, Uniformed Services U. Health Sci., Bethesda, Md.; mhaigney@usuhs.edu)

>>>PNN NewsWatch
* The difference in the frequency of myocardial infarction and other heart-related problems seen in earlier analyses of two small long-term studies of omeprazole and esomeprazole does not indicate the presence of a true effect, FDA concluded yesterday. The agency added that long-term use of these drugs is not likely to be associated with an increased risk of heart problems. FDA recommends that health care providers continue to prescribe and patients continue to use these products as described in the labeling for the two drugs.
* Distribution of dispersible tablets of
methadone hydrochloride 40 mg has been voluntarily restricted to treatment centers for opiate addiction and hospitals, DEA and Mallinckrodt announced yesterday. “This restriction was triggered by recent increases in methadone-related adverse events, cardiotoxicity, and deaths,” APhA reported on its pharmacist.com Web site. “The number of providers prescribing methadone has also increased, leading to concerns about their lack of knowledge and experience working with this specific drug.”

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Dec. 12, 2007 * Vol. 14, No. 239
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Dec. 12 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2007; 298).
Geriatric Care Model: Among 951 adults aged 65 years or older with annual incomes 200% below the federal poverty level, an “integrated and home-based geriatric care management resulted in improved quality of care and reduced acute care utilization,” report investigators in a 2-year trial (pp. 2623-33). A nurse practitioner and social worker collaborated with primary care physicians and a geriatrics interdisciplinary team (which included a pharmacist) and used 12 care protocols for common geriatric conditions in caring for patients. Assessing outcomes based differences in Medical Outcomes 36-Item Short Form (SF-36) scores, instrumental and basic activities of daily living (ADLs), and emergency department (ED) visits, the researchers report: “Intention-to-treat analysis revealed significant improvements for intervention patients compared with usual care at 24 months in 4 of 8 SF-36 scales: general health (0.2 vs –2.3, P = .045), vitality (2.6 vs –2.6, P < .001), social functioning (3.0 vs –2.3, P = .008), and mental health (3.6 vs –0.3, P = .001); and in the Mental Component Summary (2.1 vs –0.3, P <.001). No group differences were found for ADLs or death. The cumulative 2-year ED visit rate per 1,000 was lower in the intervention group (1445 [n = 474] vs 1748 [n = 477], P = .03) but hospital admission rates per 1,000 were not significantly different between groups (700 [n = 474] vs 740 [n = 477], P = .66). In a predefined group at high risk of hospitalization (comprising 112 intervention and 114 usual-care patients), ED visit and hospital admission rates were lower for intervention patients in the second year (848 [n = 106] vs 1,314 [n = 105]; P = .03 and 396 [n = 106] vs 705 [n = 105]; P = .03, respectively).” (S. R. Counsell, Indiana U., Indianapolis; scounsel@iupui.edu)
Noting that most of the services provided in this intervention are not reimbursed under current fee-for-service payment systems, an editorialist writes (pp. 2673-4): “Diffusion of new health delivery innovations requires a relative advantage over current care and a business case.” (D. B. Reuben,
dreuben@mednet.ucla.edu)
Thiazolidinediones & Cardiovascular Outcomes: Compared with other antidiabetic agents in a population-based study of 159,026 patients aged 66 years or older, thiazolidinedione therapy, especially with rosiglitazone, increased risk of congestive heart failure, acute myocardial infarction, and mortality (pp. 2634-43). Mining databases from Ontario in a nested case–control study, the authors noted: “During a median follow-up of 3.8 years, 12,491 patients (7.9%) had a hospital visit for congestive heart failure, 12,578 (7.9%) had a visit for acute myocardial infarction, and 30,265 (19%) died. Current treatment with TZD monotherapy was associated with a significantly increased risk of congestive heart failure (78 cases; adjusted rate ratio [RR], 1.60; 95% confidence interval [CI], 1.21–2.10; P <.001), acute myocardial infarction (65 cases; RR, 1.40; 95% CI, 1.05–1.86; P = .02), and death (102 cases; RR, 1.29; 95% CI, 1.02–1.62; P = .03) compared with other oral hypoglycemic agent combination therapies (3,478 congestive heart failure cases, 3,695 acute myocardial infarction cases, and 5,529 deaths). The increased risk of congestive heart failure, acute myocardial infarction, and mortality associated with TZD use appeared limited to rosiglitazone.” (L. L. Lipscombe, Inst. for Clinical Evaluative Sciences, Toronto; lorraine.lipscombe@ices.on.ca)
Active Smoking & Type 2 Diabetes: Tobacco smoking increases the risk of type 2 diabetes, concludes a systematic review and meta-analysis (pp. 2654-64). Looking at 25 prospective cohort studies with 1.2 million participants reporting 45,844 incident cases of diabetes during a study follow-up period ranging from 5 to 30 years, the authors found: “Of the 25 studies, 24 reported adjusted RRs greater than 1 (range for all studies, 0.82–3.74). The pooled adjusted RR was 1.44 (95% confidence interval [CI], 1.31–1.58). Results were consistent and statistically significant in all subgroups. The risk of diabetes was greater for heavy smokers (20 cigarettes/day; RR, 1.61; 95% CI, 1.43–1.80) than for lighter smokers (RR,1.29; 95% CI, 1.13–1.48) and lower for former smokers (RR, 1.23; 95% CI, 1.14–1.33) compared with active smokers, consistent with a dose-response phenomenon.” (C. Willi, U. Lausanne, Lausanne, Switzerland; carole.willi@hospvd.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 © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Dec. 13, 2007 * Vol. 14, No. 240
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Dec. 13 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2007; 357).
Steroids in Bacterial Meningitis: Two studies and an editorial examine use of corticosteroids in patients with bacterial meningitis.
Among 435 Vietnamese adults and adolescents with suspected bacterial meningitis, dexamethasone therapy improved outcomes but only in those with confirmed cases (pp. 2431-40): “An intention-to-treat analysis of all the patients showed that dexamethasone was not associated with a significant reduction in the risk of death at 1 month (relative risk, 0.79; 95% confidence interval [CI], 0.45 to 1.39) or the risk of death or disability at 6 months (odds ratio, 0.74; 95% CI, 0.47 to 1.17). In patients with confirmed bacterial meningitis, however, there was a significant reduction in the risk of death at 1 month (relative risk, 0.43; 95% CI, 0.20 to 0.94) and in the risk of death or disability at 6 months (odds ratio, 0.56; 95% CI, 0.32 to 0.98). These effects were not found in patients with probable bacterial meningitis. Results of multivariate analysis indicated that dexamethasone treatment for patients with probable bacterial meningitis was significantly associated with an increased risk of death at 1 month, an observation that may be explained by cases of tuberculous meningitis in the treatment group.” (J. J. Farrar, Oxford U. Clin. Res. Unit, Hosp. for Tropical Diseases, Ho Chi Minh City, Vietnam;
jfarrar@oucru.org)
In sub-Saharan Africa, adjuvant dexamethasone did not reduce morbidity or mortality among 465 patients with bacterial meningitis, 90% of whom were HIV positive (pp. 2441-50). The study also found no significant difference in intravenous versus intramuscular administration of the antibiotic (ceftriaxone) used in the study. (M. Scarborough, John Radcliffe Hosp., Oxford, U.K.;
matthew.scarborough@ndcls.ox.ac.uk)
An editorialist notes that, in the developing world, vaccines are key (pp. 2507-9): “The use of corticosteroids or other adjunctive therapies will have only a marginal effect on survival. The goal should be to prevent most forms of these devastating infections, which are associated with a high morbidity, through the widespread use of the conjugate vaccines that are becoming increasingly available.” (B. M. Greenwood, London Sch. of Hygiene and Tropical Medicine, London)

>>>PNN NewsWatch
* Merck has initiated a voluntary recall of 11 lots of its Haemophilus influenzae type B vaccine, PEDVAXHIB [Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate)], and 2 lots of its combination Haemophilus influenzae type B/ hepatitis B vaccine, COMVAX [Haemophilus b Conjugate (Meningococcal Protein Conjugate)]. Affected doses were distributed starting in April 2007. Merck said that it is conducting this recall because it cannot assure sterility of these specific vaccine lots while also stating that sterility tests have not shown any contamination. Emphasize to patients that children who have received lots of this vaccine do not need revaccination, as no potency concerns have been found, and that despite the similarity of biologic names, these vaccines have nothing to do with influenza vaccine.
* Patients with Asian ancestry should have a genetic blood test before beginning
carbamazepine therapy to minimize their chances of rare but serious skin reactions to the drug, FDA announced yesterday. Novartis, Shire, and Validus—which manufacture the drug under the respective trade names Tegretol, Carbatrol, and Equetro—have agreed to add the need for the test to product labeling, which already warns of the possibility in any patients of toxic epidermal necrolysis and Stevens–Johnson syndrome, characterized by multiple skin lesions, blisters, fever, itching and other symptoms. The skin reaction warnings will be moved to the current boxed warning section of the labeling. The new recommendation that health care providers give patients with Asian ancestry a genetic test before starting treatment will also be added to the boxed warning section. To screen for presence of the genetic marker HLA-B* 1502, a patient’s blood can be drawn by a health care provider and the test administered at a laboratory. Patients testing positive for this gene should not be treated with carbamazepine unless the benefit clearly outweighs the increased risk of these serious skin reactions.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Dec. 14, 2007 * Vol. 14, No. 241
Providing news and information about medications and their proper use

>>>Psychiatry Highlights
Source:
Dec. issue of the American Journal of Psychiatry (http://ajp.psychiatryonline.org/current.dtl; 2007; 164).
Recurrence of Bipolar Disorder During Pregnancy: For women with bipolar disorder who plan to become pregnant, the risks of fetal exposure to mood stabilizers should be balanced against a high risk of recurrence and morbidity associated with stopping the drugs, concludes a study of 89 women who were euthymic at conception (pp. 1817-24). In the prospective observational clinical cohort study, recurrence risk and survival-analysis-based time were compared for women who continued mood stabilizer treatment or stopped therapy, with these results: “The overall risk of at least one recurrence in pregnancy was 71%. Among women who discontinued versus continued mood stabilizer treatment, recurrence risk was twofold greater, median time to first recurrence was more than fourfold shorter, and the proportion of weeks ill during pregnancy was five times greater. Median recurrence latency was 11 times shorter after abrupt/rapid versus gradual discontinuation of mood stabilizer. Most recurrences were depressive or mixed (74%), and 47% occurred during the first trimester. Predictors of recurrence included bipolar II disorder diagnosis, earlier onset, more recurrences/year, recent illness, use of antidepressants, and use of anticonvulsants versus lithium.” (A. C. Viguera)
Even with a 71% recurrence rate, this study “may actually underrepresent the risk in the broader population,” an editorialist adds, noting that patients in the study were mostly white, educated, married, and employed outside the home and therefore had greater access to resources and care than many patients (pp. 1771-3). “The finding that relapse rates were higher after rapid versus slow discontinuation of mood stabilizers is not surprising and is consistent with the literature in this area, including Viguera et al.’s previous retrospective study of relapse rates in pregnancy and the postpartum,” the editorialist continues. “However, this finding is profoundly relevant to clinical practice and invites us to consider a paradigm shift in the treatment of women with bipolar disorder of reproductive age. A large number of women suffer from bipolar disorders, as bipolar I disorder generally affects women and men with equal prevalence and bipolar II disorder disproportionately affects women. The onset of bipolar disorder is frequently in childhood and adolescence. When considering the chronic and recurrent course of bipolar disorder, optimal treatment for most women with this illness includes mood stabilizing medications for most, if not all, of their reproductive years.” (M. P. Freeman)

>>>PNN NewsWatch
* Cases of hepatic failure, some with a fatal outcome, have been reported during the postmarketing use of deferasirox (Exjade), Novartis and FDA warned yesterday. Labeling is being revised to include information about postmarketing reports of hepatic failure, some with a fatal outcome, in patients treated with deferasirox. Most of these events occurred in patients older than 55 years of age. Most reports of hepatic failure involved patients with significant comorbidities, including liver cirrhosis and multiorgan failure. These warnings are in addition to similar precautions issued in May about acute renal failure in patients on this drug.
*
Low-dose lovastatin should not be sold without a prescription in the U.S., FDA advisory panels voted yesterday by a decisive 10–2 margin. Merck’s proposal for the Rx-to-OTC switch would have restricted distribution of the product to pharmacies and retail outlets that have a pharmacy, but it stopped short of a true behind-the-counter product in which the professional intervention of a pharmacist was required. Panelists agreed that patients were able to interpret cautions and warnings well enough, but studies showed that patients did not adequately understand whether their medical conditions required use of an LDL-lowering drug. This is the third time an FDA panel has rejected nonprescription availability of low-dose lovastatin, and today’s Wall Street Journal surmises that the vote “leaves little hope Merck can win regulatory approval.”

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Dec. 17, 2007 * Vol. 14, No. 242
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Dec. 15 issue of Lancet (www.thelancet.com; 2007; 370).
Cardiotoxicity with Sunitinib: Patients being treated with sunitinib, especially those with a history of coronary artery disease or other cardiac risk factors, should be closely monitored for hypertension and reductions in left ventricular ejection fraction, concludes a study of 75 patients (mean age, 54.3 years) with gastrointestinal stromal tumors (pp. 2011-9). Advising clinicians that the tyrosine kinase inhibitor may be exerting a direct cardiomyocyte toxicity, the investigators report these results: “Eight of 75 (11%) patients given repeating cycles of sunitinib in the phase I/II trial had a cardiovascular event, with congestive heart failure recorded in six of 75 (8%). Ten of 36 (28%) patients treated at the approved sunitinib dose had absolute LVEF reductions in ejection fraction (EF) of at least 10%, and seven of 36 (19%) had LVEF reductions of 15 EF% or more. Sunitinib induced increases in mean systolic and diastolic blood pressure, and 35 of 75 (47%) individuals developed hypertension (>150/100 mm Hg). Congestive heart failure and left ventricular dysfunction generally responded to sunitinib being withheld and institution of medical management. Sunitinib caused mitochondrial injury and cardiomyocyte apoptosis in mice and in cultured rat cardiomyocytes.” (M. H. Chen, Children’s Hosp., Boston; minghui.chen@cardio.chboston.org)
Adjuvant Chemotherapy in Colorectal Cancer: Among 3,239 patients with apparently curative resections of node-negative colon or rectal cancer, addition of adjuvant chemotherapy provided small but significant improvements in survival (pp. 2020-9). Using fluorouracil and low versus high doses of folinic acid, the researchers found: “After a median follow-up of 5.5 (range 0–10.6) years, there were 311 deaths in the chemotherapy group and 370 in the observation group; the relative risk of death from any cause with chemotherapy versus observation alone was 0.82 (95% CI 0.70–0.95; p = 0.008). There were 293 recurrences in the chemotherapy group and 359 in the observation group; the relative risk of recurrence with chemotherapy versus observation alone was 0.78 (0.67–0.91; p = 0.001). ” (QUASAR Study Office, Medical School, Birmingham, U.K.; QUASAR@trials.bham.ac.uk)

>>>BMJ Highlights
Source:
Dec. 15 issue of BMJ (www.bmj.org; 2007; 335).
Antithrombin III in Sepsis: Antithrombin III cannot be recommended for patients with sepsis, septic shock, disseminated intravascular coagulation, and other critical illnesses, conclude authors of a systematic review and meta-analysis (pp. 1248-51). “20 trials randomly assigning 3,458 patients met inclusion criteria,” write the researchers. “Eight trials had low risk of bias. Compared with placebo or no intervention, antithrombin III did not reduce overall mortality (relative risk 0.96, 95% confidence interval 0.89 to 1.03). No subgroup analyses on risk of bias, populations of patients, or with and without adjuvant heparin yielded significant results. Antithrombin III increased the risk of bleeding events (1.52, 1.30 to 1.78). Heterogeneity was observed in only a few analyses.” (A. Afshari, U. Copenhagen, Copenhagen; arriba_a@yahoo.dk)

>>>PNN NewsWatch
* While calling for further research into dose–response relationship for phenylephrine, an FDA advisory panel on Friday voted 11–1 that the nonprescription decongestant is effective at currently recommended 10-mg doses. Siding with the Consumer Healthcare Products Association, the panelists were unconvinced by U. Florida pharmacy professors whose review showed that the 10-mg dose is based on a mixed bag of 1970s-era research, mostly conducted by the industry and never published, and that an oral 25-mg dose is likely needed to clear stuffy noses.

>>>PNN JournalWatch
* A Wearable Haemodialysis Device for Patients with End-Stage Renal Failure: A Pilot Study, in Lancet, 2007; 370: 2005–10. Reprints: A. Davenport, Royal Free and U. Coll. Med. Sch., London; andrew.davenport@royalfree.nhs.uk
* 2007 Focused Update of the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention, in
Journal of the American College of Cardiology, doi: doi:10.1016/j.jacc.2007.10.002; American College of Cardiology/American Heart Association Task Force on Practice Guidelines.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Dec. 18, 2007 * Vol. 14, No. 243
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release articles from and Dec. 18 issue of the Annals of Internal Medicine (http://www.annals.org/current.shtml; 2007; 147).
Treating Low BMD & Osteoporosis: Evidence supports use of several agents for preventing fractures in patients with low bone mineral density or osteoporosis, but the available literature is insufficient to compare the relative effects of drugs such as estrogen, the bisphosphonates, and selective estrogen receptor modulators (early release). Comparing medications’ benefits in fracture reduction with harms from adverse events, authors of a systematic review report: “Good evidence suggests that alendronate, etidronate, ibandronate, risedronate, zoledronic acid, estrogen, parathyroid hormone (1-34), and raloxifene prevent vertebral fractures more than placebo; the evidence for calcitonin was fair. Good evidence suggests that alendronate, risedronate, and estrogen prevent hip fractures more than placebo; the evidence for zoledronic acid was fair. The effects of vitamin D varied with dose, analogue, and study population for both vertebral and hip fractures. Raloxifene, estrogen, and estrogen–progestin increased the risk for thromboembolic events, and etidronate increased the risk for esophageal ulcerations and gastrointestinal perforations, ulcerations, and bleeding.” (M. Maglione, maglione@rand.org)
Rituximab in Castleman Disease: Rituximab was clinically useful in a small uncontrolled study of patients with a rare lymphoproliferative disorder, Castleman disease, and HIV infection (pp. 836-9): At three English teaching hospitals, investigators determined: “21 consecutive patients (18 men) with plasmablastic multicentric Castleman disease were recruited. The median follow-up was 12 months (range, 1 to 49 months). One patient died before completing therapy, 20 achieved remission of symptoms, and 14 (67%) achieved a radiologic response. The overall and disease-free survival rates at 2 years were 95% (95% CI, 86% to 100%) and 79% (CI, 49% to 100%), respectively. Plasma acute-phase proteins, immunoglobulins, and Kaposi sarcoma–associated herpesvirus viral load decreased after rituximab therapy. The main adverse effect was reactivation of Kaposi sarcoma.” (M. Bower, Chelsea and Westminster Hosp., London; m.bower@imperial.ac.uk)
Vitamin D in Chronic Kidney Disease: Inconsistent effects and unproven benefits creates uncertainty about the use of vitamin D in patients with chronic kidney disease, conclude authors who report a meta-analysis of 76 trials with 3,667 participants (pp. 840-53). “Vitamin D compounds did not reduce the risk for death, bone pain, vascular calcification, or parathyroidectomy,” write the authors. “Compared with placebo, established vitamin D sterols were associated with an increased risk for hypercalcemia (relative risk, 2.37 [95% CI, 1.16 to 4.85]) and hyperphosphatemia (relative risk, 1.77 [CI, 1.15 to 2.74]) but did not show a consistent reduction in parathyroid hormone (PTH) levels. Compared with placebo, more recently developed vitamin D analogues were associated with hypercalcemia (relative risk, 5.15 [CI, 1.06 to 24.97]) but not hyperphosphatemia, and levels of PTH were reduced (weighted mean difference, –10.77 pmol/L [CI, –20.51 to –1.03 pmol/L]). For suppression of PTH, intravenous administration was superior to oral vitamin D, but higher intravenous doses were used.” (S. C. Palmer, Christchurch School of Med. and Health Sci., Christchurch, New Zealand; strippoli@negrisud.it)
Noting there is “nothing new under the sun” when it comes to vitamin D in patients with chronic kidney disease, an editorialist advises (pp. 880-1): “Palmer and colleagues’ findings should serve as yet another warning to the nephrology community that we do not have good evidence to defend many of our common practices. Researchers and funding agencies should work together to close this knowledge gap for metabolic bone disease and other complications of kidney failure. In the meantime, it is hard to argue strongly for the use of vitamin D in patients receiving dialysis or those with less-severe forms of chronic kidney disease. Current practices are costly but provide no proven benefit despite their theoretical appeal, and they have the potential to harm. Pending new evidence from randomized trials, decision makers, physicians, and payers should consider modifying practice guidelines, prescribing patterns, and reimbursement policies to reflect the current state of evidence.” (M. Tonelli, U. Alberta, Edmonton)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Dec. 19, 2007 * Vol. 14, No. 244
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Dec. 19 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2007; 298).
Physician Participation in Lethal Injection: In an ethical analysis with implications for pharmacists and for a case now being considered by the U.S. Supreme Court, an AMA attorney and a physician member of the group argue that any participation by physicians in executions by lethal injection is unethical (pp. 2779-81). “During policy deliberations, all participants in regulating the medical profession—federal and state government, licensing authorities, professional societies, and individual physicians—should consider the specific role of physicians in society, which is preventing and healing illness and relieving suffering,” the writers argue. “The core requirement for that role is trust in the profession, which is advanced and preserved by ethical principles. Any form of participation in causing death by lethal injection is unethical because it violates the physician’s role, thereby undermining trust. Courts and legislatures should not ask physicians to violate ethical standards to solve problems raised by legal challenges. The penal system, not the medical profession, is responsible for finding a way to perform executions. Physicians who are asked to assist in capital punishment should remember that transgressions against ethical obligations may evoke sanctions against their licenses by state medical boards and elicit disciplinary actions against membership by their medical societies.” (L. Black, lee.black@ama-assn.org)
Health Care ‘Markets’: Policy initiatives cannot correct distortions inherent in the health care market, concludes the author of a commentary (pp. 2785-7): “This is an especially vexing problem in the United States, where the political system and social consensus is not as clear as in other developed countries where health care is considered a ‘merit good’ (ie, every person in society has the right to health care, regardless of ability to pay).” (A. S. Detsky, Mount Sinai Hosp., Toronto; allan.detsky@uhn.on.ca)

>>>PNN NewsWatch
* FDA has approved a new beta-blocker, nebivolol (Bystolic, Forest) for once-daily treatment of hypertension as either a single agent or in combination with other antihypertensive medications. Already marketed in more than 50 countries outside North America, nebivolol is a selective beta-1 antagonist. Like other agents in this class, nebivolol decreases heart rate and myocardial contractility, and suppresses renin activity. It acts by producing vasodilation and reducing total peripheral resistance The safety and efficacy of nebivolol in lowering blood pressure was assessed in three randomized, double-blind, multi-center, placebo-controlled clinical trials that ran for up to 3 months. A fourth placebo-controlled clinical trial demonstrated additional blood pressure-lowering effects when nebivolol was given with up to two other antihypertensive medications in patients with inadequate blood pressure control. In total, more than 2,000 people received the drug during the trials. Its efficacy during the trials was similar to those of other FDA-approved beta-blockers. The most common adverse effects reported by patients taking nebivolol in clinical trials were headache, fatigue, dizziness, and diarrhea.
*
FDA yesterday issued a final rule that requires manufacturers of nonprescription standalone vaginal contraceptive and spermicidal products (those used solely for contraception) containing nonoxynol 9 to include a warning that this ingredient does not provide protection against infection from HIV or other sexually transmitted diseases (STDs). In addition, FDA is requiring that the labels warn consumers that the N9 in standalone vaginal contraceptives and spermicides can irritate the vagina and rectum, which may increase the risk of contracting HIV from an infected partner. Specifically, the following warnings must be added to product labeling: For vaginal use only; not for rectal (anal) use; sexually transmitted diseases (STDs) alert: This product does not protect against HIV/AIDS or other STDs and may increase the risk of getting HIV from an infected partner; do not use if you or your sex partner has HIV/AIDS. If you do not know if you or your sex partner is infected, choose another form of birth control; when using this product you may get vaginal irritation (burning, itching, or a rash); and stop use and ask a doctor if you or your partner get burning, itching, a rash or other irritation of the vagina or penis.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Dec. 20, 2007 * Vol. 14, No. 245
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Dec. 20 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2007; 357).
Immunosuppression in Renal Transplantation: Compared with older immunosuppressive regimens in 1,645 renal-transplant recipients, renal function, allograft survival, and acute rejection rates were better with low doses of the calcineurin inhibitor tacrolimus, administered in combination with daclizumab, mycophenolate mofetil, and corticosteroids (pp. 2562-75). In the 12-month study, patients received either standard-dose cyclosporine, mycophenolate mofetil, and corticosteroids, or daclizumab induction, mycophenolate mofetil, and corticosteroids in combination with low-dose cyclosporine, low-dose tacrolimus, or low-dose sirolimus. Cockcroft–Gault estimates of glomerular filtration rates showed the following results: “The mean calculated GFR was higher in patients receiving low-dose tacrolimus (65.4 ml per minute) than in the other three groups (range, 56.7 to 59.4 ml per minute). The rate of biopsy-proven acute rejection was lower in patients receiving low-dose tacrolimus (12.3%) than in those receiving standard-dose cyclosporine (25.8%), low-dose cyclosporine (24.0%), or low-dose sirolimus (37.2%). Allograft survival differed significantly among the four groups (P = 0.02) and was highest in the low-dose tacrolimus group (94.2%), followed by the low-dose cyclosporine group (93.1%), the standard-dose cyclosporine group (89.3%), and the low-dose sirolimus group (89.3%). Serious adverse events were more common in the low-dose sirolimus group than in the other groups (53.2% vs. a range of 43.4 to 44.3%), although a similar proportion of patients in each group had at least one adverse event during treatment (86.3 to 90.5%).” (H. Ekberg, U. Hosp., Malmö, Sweden; henrik.ekberg@med.lu.se)
Balancing efficacy and toxicity of immunosuppressive regimens in patients following renal transplantation is a challenge, writes an editorialist (pp. 2625-7): “Taken together, the data presented by Ekberg et al. on the short-term efficacy of combination immunotherapy with tacrolimus, mycophenolate mofetil, and corticosteroids are compelling and reproducible. Even though the investigators used relatively low initial targets for tacrolimus trough levels and conventional midrange dosing strategies, their study does not address the question of whether limiting the initial dose of tacrolimus would result in long-term conserved efficacy and reduced toxic effects. The question of whether such an approach would improve long-term function of renal allografts and the overall health and quality of life of kidney-transplant recipients remains unanswered.” (A. B. Leichtman, U. Mich., Ann Arbor)
Telbivudine v. Lamivudine for Hepatitis B: Compared with lamivudine 100 mg once daily, telbivudine 600 mg once daily produced significantly higher rates of therapeutic and histologic responses in 1,370 patients with chronic hepatitis B (pp. 2576-88). Looking for reductions in serum HBV DNA levels along with loss of hepatitis B e antigen or normalization of alanine aminotransferase levels, the investigators found: “At week 52, a significantly higher proportion of HBeAg-positive patients receiving telbivudine than of those receiving lamivudine had a therapeutic response (75.3% vs. 67.0%, P = 0.005) or a histologic response (64.7% vs. 56.3%, P = 0.01); telbivudine also was not inferior to lamivudine for these end points in HBeAg-negative patients. In HBeAg-positive and HBeAg-negative patients, telbivudine was superior to lamivudine with respect to the mean reduction in the number of copies of HBV DNA from baseline, the proportion of patients with a reduction in HBV DNA to levels undetectable by polymerase-chain-reaction assay, and development of resistance to the drug. Elevated creatine kinase levels were more common in patients who received telbivudine, whereas elevated alanine aminotransferase and aspartate aminotransferase levels were more common in those who received lamivudine.” (C-L Lai, Queen Mary Hosp., Hong Kong; hrmelcl@hkucc.hku.hk)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Dec. 21, 2007 * Vol. 14, No. 246
Providing news and information about medications and their proper use

>>>JAPhA Highlights
Source:
Nov/Dec. issue of the Journal of the American Pharmacists Association (www.japha.org; 2007; 47).
Pharmacists & Emergency Contraception: Pharmacists’ and student pharmacists’ views and opinions about emergency contraception in the years before the product was changed to dual status are explored in two research articles.
A 2002 survey of 76 pharmacists at San Francisco–area Walgreens demonstrates a high capability and support for an enhanced professional role regarding EC (pp. 702-10): “Knowledge among the pharmacists was very high.... Most pharmacists (91%) reported that participation in a direct pharmacy-access program would make them feel more important in their pregnancy prevention role, and nearly all (99%) supported pharmacy-access legislation for EC. Knowledge and attitudes did not differ by highest degree earned, position, age, or sex.” (S.Y. El-Ibiary,
elibiarys@pharmacy.ucsf.edu)
A national survey of 752 student pharmacists conducted in 2006 found a rising level of EC knowledge as years of school increased (pp. 711-6). Those who knew more about EC were more favorable toward its use, with political beliefs and religious affiliations significantly influencing attitudes about EC. (E. Evans, eevans@ulm.edu)

>>>Gastroenterology Report
Source:
Dec. issue of Gastroenterology (www.gastrojournal.org/current; 2007; 133).
Mortality with Inflammatory Bowel Disease Medications: Infections, respiratory diseases, and secondary digestive diseases are principal causes of an increased mortality rate among patients with inflammatory bowel disease, a risk that varies according to which IBD medications the patient is using, a study reports (pp. 1779-86). This retrospective, population-based cohort analysis of 9,032 members of a health maintenance organization who were diagnosed with IBD during 1996–2002 shows the following: “Compared with health plan members without IBD, mortality was increased in patients with Crohn’s disease (CD) (1.4; 95% confidence interval, 1.2–1.6) but not ulcerative colitis (UC) (1.0; 95% CI, 0.9–1.2). CD was associated with increased mortality from infectious and parasitic diseases (4.1; 95% CI, 1.7–8.5), septicemia (6.8; 95% CI, 2.2–15.8), small intestinal cancer (48.1; 95% CI, 5.8–17.4), respiratory diseases (1.9; 95% CI, 1.3–2.7), digestive diseases other than IBD (2.4; 95% CI, 1.0–4.8), and liver diseases (2.6; 95% CI, 1.0–5.3). UC was associated with increased mortality from digestive diseases other than IBD (3.9; 95% CI, 2.4–6.0). The relationship with CD mortality was 0.7 for aminosalicylates (95% CI, 0.5–1.1), 1.3 (95% CI, 0.9–1.9) for immunomodulators, and 1.0 (95% CI, 0.7–1.4) for corticosteroids. Among patients with UC, these odds ratios were 0.8 (95% CI, 0.5–1.1) for aminosalicylates, 0.5 (95% CI, 0.3–0.9) for immunomodulators, and 0.8 (95% CI, 0.6–1.1) for corticosteroids.” (L. J. Herrinton, Kaiser Permanente, Oakland, Calif.; lisa.herrinton@kp.org)
Beta-Blockers for Variceal Hemorrhage: Assessing the “black and white” and the “shades of grey” when it comes to using nonselective beta-blockers among patients with esophageal varices and related hemorrhage, authors of a review article note (pp. 2029-36): “Although some of the hemodynamic nonresponders might indeed be ‘black’ and thus doomed to a worse prognosis, a substantial part of nonresponders are only ‘grey,’ ie, they do not share the appealing pure status of hemodynamic responders yet are protected from adverse outcomes (in particular variceal bleeding) by treatment with nonselective beta-blockers.... Propranolol (or other nonselective beta-blockers) may well turn out to be the hepatologist’s ‘aspirin’—cheap, few contraindications, relatively little intolerance, and of universal application in cirrhotic patients irrespective of the presence of varices or history of bleeding, as they affect outcomes other than bleeding. This therapeutic possibility needs urgent exploration, not only because of its potential clinical importance but also because it may define the need for [hepatovenous pressure gradient] measurement in the future.” (A. K. Burroughs, Royal Free Hosp., London; Andrew.Burroughs@royalfree.nhs.uk)

>>>PNN NewsWatch
* PNN will not be published on Mon. and Tues., Dec. 24–25, Christmas Eve and 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 © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Dec. 26, 2007 * Vol. 14, No. 247
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Dec. 22 issue of Lancet (www.thelancet.com; 2007; 370).
Pharmacogenetics in Asthma: Contrary to previous evidence, two studies show that patients with asthma can use long-acting beta-2 agonists without regard to beta-2-adrenergic receptor genotype (pp. 2118-25). Efficacy of these drugs in people homozygous for arginine at amino acid 16 of the beta-2-adrenergic receptor (ADRB2) had previously been questioned, but these results were noted in a double-blind study of inhaled corticosteroids plus beta-2-agonists in 2,250 patients with asthma (study 1) and an open-label trial of similar combination therapy in 405 patients with asthma (study 2): “In study 1, Gly16Arg genotype had no effect on the percentage of participants with severe exacerbations across all treatment groups (99 [12%] of 833 Gly/Gly, 110 [11%] of 1028 Gly/Arg, and 32 [9%] of 361 Arg/Arg participants). Secondary endpoints, including forced expiratory volume in 1 s, peak expiratory flow, use of as-needed medication, and number of nights with awakenings were similar between genotype groups. No relation was recorded between ADRB2 haplotype and primary and secondary endpoints. In study 2, the frequency of asthma exacerbations (15 [9%] of 168 Gly/Gly, 13 [8%] of 169 Gly/Arg, and 6 [9%] of 67 Arg/Arg participants) and other study endpoints were closely similar for all ADRB2 genotypes.” (E. R. Bleecker, Wake Forest U. Health Sci., Winston-Salem, N.C.; ebleeck@wfubmc.edu)

>>>JAMA Highlights
Source:
Dec. 26 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2007; 298).
Transient Neurological Attacks: Higher risks of major vascular diseases and dementia are associated with occurrence of nonfocal transient neurological attacks, according to a study of 6.062 community-dwelling Rotterdam Study participants aged 55 years or older at baseline in 1990–93 (pp. 2877-85). Followed through 2005, those participants with temporary symptoms (lasting less than 24 hours) that were not focal in nature (that is, not transient ischemic attacks) had similar risks of stroke as patients with TIAs and higher risks of myocardial infarction and dementia. (M. M. B. Breteler, Erasmus Med. Ctr., Rotterdam, the Netherlands; m.breteler@erasmusmc.nl)

>>>PNN NewsWatch
* FDA on Friday issued an alert regarding transdermal fentanyl patches, noting that the agency continues to receive reports of death and life-threatening adverse events related to fentanyl overdose that have occurred when the patch was used to treat pain in opioid-naive patients and when opioid-tolerant patients have applied more patches than prescribed, changed the patch too frequently, and exposed the patch to a heat source. The fentanyl patch is only indicated for use in patients with persistent, moderate to severe chronic pain who have been taking a regular, daily, around-the-clock narcotic pain medicine for longer than 1 week and are considered to be opioid-tolerant. FDA added that patients must avoid exposing the patch to excessive heat, as this promotes the release of fentanyl from the patch and increases the absorption of fentanyl through the skin, which can result in fatal overdose. Directions for prescribing and using the fentanyl patch must be followed exactly to prevent death or other serious adverse effects from fentanyl overdose.
* New requirements of reporting of
adverse drug experiences for nonprescription drugs, including those kept behind the pharmacy counter, went into effect on Dec. 23. FDA must be notified of such events by holders of the drug application and certain manufacturers, packers, and distributors of the products, FDA explained on its Web site.

>>>PNN JournalWatch
* Bevacizumab plus Interferon Alfa-2a for Treatment of Metastatic Renal Cell Carcinoma: A Randomised, Double-Blind Phase III Trial, in Lancet, 2007; 370: 2103–11. Reprints: B. Escudier, Institut Gustave Roussy, Villejuif, France; escudier@igr.fr
* Use of Epoetin and Darbepoetin in Patients with Cancer: 2007 American Society of Clinical Oncology/American Society of Hematology Clinical Practice Guideline Update, in
Journal of Clinical Oncology, 2007; 10.1200/JCO.2007.14.3396. Reprints: J. D. Rizzo.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Dec. 27, 2007 * Vol. 14, No. 248
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Dec. 27 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2007; 357).
Bevacizumab/Paclitaxel for Metastatic Breast Cancer: Compared with paclitaxel alone, paclitaxel plus bevacizumab prolonged progression-free survival but not overall survival in a Phase III trial of patients with metastatic breast cancer (pp. 2666-76). Testing open-label treatments, the investigators found: “From December 2001 through May 2004, a total of 722 patients were enrolled. Paclitaxel plus bevacizumab significantly prolonged progression-free survival as compared with paclitaxel alone (median, 11.8 vs. 5.9 months; hazard ratio for progression, 0.60; P <0.001) and increased the objective response rate (36.9% vs. 21.2%, P <0.001). The overall survival rate, however, was similar in the two groups (median, 26.7 vs. 25.2 months; hazard ratio, 0.88; P = 0.16). Grade 3 or 4 hypertension (14.8% vs. 0.0%, P <0.001), proteinuria (3.6% vs. 0.0%, P <0.001), headache (2.2% vs. 0.0%, P = 0.008), and cerebrovascular ischemia (1.9% vs. 0.0%, P = 0.02) were more frequent in patients receiving paclitaxel plus bevacizumab. Infection was more common in patients receiving paclitaxel plus bevacizumab (9.3% vs. 2.9%, P <0.001), but febrile neutropenia was uncommon (<1% overall).” (K. Miller, Indiana Cancer Pavilion, Indianapolis; kathmill@iupui.edu)
Antisense Treatment of Duchenne’s Muscular Dystrophy: A single, intramuscular dose of an antisense oligonucleotide, PRO051, induced dystrophin synthesis in four patients with Duchenne’s muscular dystrophy who had suitable mutations, investigators report (pp. 2677-86). Biopsies obtained 28 days after the 0.8-mg dose suggested that further studies “might be feasible,” the researchers concluded: “PRO051 injection was not associated with clinically apparent adverse events. Each patient showed specific skipping of exon 51 and sarcolemmal dystrophin in 64 to 97% of myofibers. The amount of dystrophin in total protein extracts ranged from 3 to 12% of that found in the control specimen and from 17 to 35% of that of the control specimen in the quantitative ratio of dystrophin to laminin alpha-2.” (J. C. van Deutekom, Prosensa B.V., Leiden, the Netherlands; j.vandeutekom@prosensa.nl)
Odds of an AIDS Vaccine: Describing research into a vaccine against HIV/AIDS as “one step forward, two steps back,” the author of a Perspective article writes (pp. 2653-5): “Although the STEP trial and others that failed to achieve their desired end points have brought new knowledge, each disappointment also reinforces the view that a licensed AIDS vaccine is at least a decade away—and that is if things go well, which has not happened yet. Meanwhile, individuals and public health officials can only try to prevent HIV transmission through education and behavior modification, condom use, needle-exchange programs, and other effective, albeit imperfect, means that are already available.” (R, Steinbrook, rsteinbrook@attglobal.net)

>>>PNN NewsWatch
* Cardinal Health is voluntarily recalling all Alaris Pump modules, model 8100 (formerly known as Medley Pump module), shipped before Sept. 27. Distributed to 46 states, the District of Columbia, Canada, Guam, Puerto Rico, and Saudi Arabia, the pump module may contain misassembled occluder springs (bent, broken, nested, or missing) that occurred during manufacturing. Misassembled springs could lead to overinfusion that could result in serious adverse health consequences or death. Overinfusion may be difficult to detect because the misassembled springs can work intermittently, and there is no warning or notification of an overinfusion.
* Bayer Diabetes Care has issued a voluntary market recall of
test strips used with the Contour TS Blood Glucose Meter. The test strips from specific lots could result in blood glucose readings with a positive bias of 5% to 17%. Health professionals, retailers, patients, and others who use Contour TS are advised to check the lot number of the test strips in their inventory and contact Bayer Diabetes Care for information regarding the return and replacement of strips.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Dec. 28, 2007 * Vol. 14, No. 249
Providing news and information about medications and their proper use

>>>PNN’s Top 10 of 2007
Perhaps stagnation best summarizes 2007, a year that featured more negatives than positives. MRSA became a household term, and even the licensing exam for pharmacists was suspended for a few months. Here’s how the rest of pharmacy/pharmacotherapy looked in PNN.
1: Nonprescription Drug Problems: Medications available without a prescription are frequently ignored, both in education and practice. But 2007 taught pharmacists the danger in doing that, with CDC reports of pediatric deaths from cough and cold meds beginning the year (see PNN, Jan. 24) and market withdrawals and FDA hearings closing it (Oct. 12, 19, 22). Phenylephrine lacks sufficient oral data to state a dose with certainty, yet marketing continues (Feb. 14, Dec. 17). While FDA approved OTC orlistat (Feb. 8) and cetirizine (Nov. 12), an FDA advisory panel soundly rejected the notion of lovastatin without a prescription, even if it were kept behind pharmacy counters (Dec. 14).
2: Diabetic Drugs Falter: Antidiabetic drugs were a second area of disappointment in 2007, particularly rosiglitazone (May 22, June 7, July 20, Aug. 7, Sept. 12 and 30, Dec. 12) and now-gone inhaled insulin (Mar. 2, Oct. 18, 19). Exenatide continued to excite diabetologists (Apr. 3, May 30, Oct. 31), but reports of pancreatitis with it (Oct. 17), skin problems with sitagliptin (Oct. 31, and liver toxicities with the still-unmarketed vildagliptin (Nov. 7) created uncertainties.
3: Adverse Prescription Drug Events: The number of warnings, black boxes, and withdrawals far exceeded the small number of new chemical/biologic entities approved this year. Erythropoiesis-stimulating agents stayed in the news (Feb. 21, Mar. 12, May 9, Sept. 12, Nov. 9), as did antidepressants (May 3, June 13, July 25) and aprotinin (Sept. 14, Oct. 26, Nov. 5). Gone are pergolide (Mar. 30), trimethobenzamide suppositories (Apr. 9) and itraconazole injection (Oct. 25). Tegaserod was suspended (Apr. 2) but later returned selectively (July 30).
4: Pharmacists’ New MTM Roles: Whether called clinical pharmacy, pharmaceutical care, or medication therapy management, the good that pharmacists can do filled the pharmacy literature (Mar. 21, Apr. 6, June 1, Dec. 21). Reports were also prominent in the medical literature (Feb. 22, Feb. 26, Mar. 27, May 15, May 18, May 26, May 28, Oct. 11) and lay media (Feb. 23).
5: Pharmacogenetics Goes Mainstream: FDA made strong recommendations for increased use of genetic testing before or during drug use (Aug. 17 and 20, Dec. 13), and a role for genomics in coronary artery disease was examined (Nov. 9). However, some questioned whether the movement is being “overhyped” (Oct. 10, Dec. 26).
6: FDA Reformed: Congress passed and President Bush signed a bill reforming FDA (Sept. 21, 28). The agency floated a trial balloon at Mar. meetings, calling for a discussion into a behind-the-counter category of medications in the U.S. (Mar. 22) and followed up with hearings near year end (Nov. 15).
7: Get Ready for Health Care Reform (Again): With presidential nominations being contested in both parties, candidates positioned for an anticipated reform of the U.S health care system during the next administration (Mar. 13, May 16 and 24, Aug. 23).
8: An Aging, Obese Population: Even injection drug users are getting older in the U.S. (Jan. 23, and medical researchers finally made sure that the aging baby boomers knew about the health risks of smoking marijuana (Feb. 13). The obesity epidemic continued in all age groups (Jan. 3, Dec. 10), with one report advising kids to watch their Coke consumption (Oct. 15).
9: Medicare Part D Goes On: The federal prescription drug benefit for Medicare beneficiaries enters its third year in relative calm (Aug. 22), despite reports of slow payments to pharmacies (Sept. 7) and poor coverage of brandname drug products (June 20).
10: Progress with Vaccines Despite controversy regarding use of cervical cancer vaccine (July 2) and serious difficulties with HIV vaccine (Nov. 8, Dec. 27), vaccines generally provided a bright spot for the year, with injectable and intranasal influenza vaccine being approved for use in young children (Feb. 15, Sept. 20), six flu vaccines on the U.S. market (Oct. 3), and progress with development of a malaria vaccine (Nov. 5).

>>>PNN NewsWatch
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