PNN Pharmacotherapy Line
Apr. 1, 2009 * Vol. 16, No. 61
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source: Apr. issue of Diabetes Care (2009; 32).
Statins & Testosterone Levels: Total testosterone levels are not accurate reflections of androgen status in men with type 2 diabetes who are taking statins, according to a study with 335 participants (pp. 541–6). Measurement of total testosterone, sex hormone–binding globulin (SHBG), and estradiol with an enzyme-linked immunosorbent assay showed that bioavailable or free testosterone levels must be measured, especially in those taking atorvastatin: “Statins were associated with lower total testosterone (11.9 vs. 13.4 nmol/l, P = 0.006) and a trend toward lower SHBG (29.4 vs. 35.3 nmol/l, P = 0.034) compared with no treatment. Bioavailable testosterone, free testosterone, estradiol, and hypogonadal symptoms were not affected. Subanalysis showed that atorvastatin was associated with reduced total testosterone (11.4 vs. 13.4 nmol/l, P = 0.006) and a trend toward reduced SHBG (27.6 vs. 35.3 nmol/l, P = 0.022) compared with no treatment, and there was an apparent dose-response effect with the lowest levels of total testosterone seen in men treated with 20 mg atorvastatin (9.6 nmol/l, P = 0.017). Simvastatin use was not associated with significant reductions in testosterone or SHBG levels.” (T. Hugh Jones, hugh.jones@nhs.net)
Bezafibrate in Diabetes: Patients taking the fibrate bezafibrate may have reduced or delayed risk of developing type 2 diabetes, researchers report, citing their analysis of the General Practice Research Database in the U.K. (pp. 547–51). The study calculated hazard ratios for incident type 2 diabetes using a Cox proportional hazards model, with these results: “Bezafibrate users had a lower hazard for incident diabetes than users of other fibrates (HR 0.66 [95% CI 0.53–0.81]). This effect became stronger with increasing duration of therapy. Post hoc analysis of the effect of bezafibrate on progression of preexisting diabetes also showed a lower hazard for progression to use of antidiabetic medication (0.54 [0.38–0.76]) or progression to use of insulin (0.78 [0.55–1.10]).” (J. Flory, jflory@mail.med.upenn.edu)
Insulin Therapy During Enteral Nutrition Therapy: In non–critically ill hospitalized patients with type 2 diabetes who were receiving enteral nutrition therapy (ENT), similar efficacy and safety were found with sliding-scale regular insulin (SSRI) supplemented with NPH insulin and the long-acting agent insulin glargine (pp. 594–6). Among 50 inpatients with diabetes, these results were recorded: “Glycemic control was similar in the SSRI and glargine groups (mean ± SD study glucose 8.9 ± 1.6 vs. 9.2 ± 1.6 mmol/l, respectively; P = 0.71). NPH insulin was added in 48% of the SSRI group subjects. There were no group differences in frequency of hypoglycemia (1.3 ± 4.1 vs. 1.1 ± 1.8%; P = 0.35), total adverse events, or length of stay.” (Mary T. Korytkowski, korytkowski@dom.pitt.edu)

>>>PNN NewsWatch
* Making good on letters sent in 2006, FDA yesterday warned nine companies to stop manufacturing 14 unapproved narcotic analgesics, including high-concentrate morphine sulfate oral solutions and immediate-release morphine sulfate, hydromorphone, and oxycodone tablets. This action does not include oxycodone capsules. Companies receiving warning letters are Boehringer Ingelheim Roxane, Cody Laboratories, Inc., Glenmark Pharmaceuticals Inc., Lannett Company, Inc., Lehigh Valley Technologies, Inc., Mallinckrodt Inc. Pharmaceuticals Group, Physicians Total Care Inc., Roxane Laboratories Inc., and Xanodyne Pharmaceuticals Inc. Manufacturers have 60 days to stop manufacturing these products. Distributors have 90 days to stop shipping existing products. Previously manufactured products may remain on pharmacy shelves for a short time.
* Video coverage of the American College of Cardiology 2009 Annual Scientific Sessions, which wrapped up yesterday in Orlando, is available at cardiosource.com. Topics include the “polypill” (a combination of five cardioprotective medications—a beta-blocker, ACE inhibitor, diuretic, simvastatin, aspirin), clopidogrel versus aspirin in patients unable to take warfarin, and use of simulated patients to improve care in hospitals. Theheart.org also has coverage, and a Twitter feed is available using the hashtag #ACC_09.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 2, 2009 * Vol. 16, No. 62
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source: Early-release articles from and Apr. 2 issue of the New England Journal of Medicine (2009; 360).
Early Initiation of Antiretroviral Therapy: Starting antiretroviral therapy early significantly improves survival, authors of a 17,517-patient study report (10.1056/NEJMoa0807252). All patients were asymptomatic and infected with HIV when they received care in the U.S. and Canada in 1996–2005. Stratification of CD4+ counts at the time antiretroviral therapy was initiated showed these relationships with morbidity in two parallel analyses: “In the first analysis, which involved 8,362 patients, 2,084 (25%) initiated therapy at a CD4+ count of 351 to 500 cells per cubic millimeter, and 6,278 (75%) deferred therapy. After adjustment for calendar year, cohort of patients, and demographic and clinical characteristics, among patients in the deferred-therapy group there was an increase in the risk of death of 69%, as compared with that in the early-therapy group (relative risk in the deferred-therapy group, 1.69; 95% confidence interval [CI], 1.26 to 2.26; P < 0.001). In the second analysis involving 9,155 patients, 2,220 (24%) initiated therapy at a CD4+ count of more than 500 cells per cubic millimeter and 6,935 (76%) deferred therapy. Among patients in the deferred-therapy group, there was an increase in the risk of death of 94% (relative risk, 1.94; 95% CI, 1.37 to 2.79; P < 0.001).” (M. M. Kitahata, kitahata@u.washington.edu)
Editorialists describe the shift in thinking about early HIV treatment (10.1056/NEJMe0902713): “Five years ago, if an asymptomatic patient with HIV infection and a CD4+ count of more than 500 cells per cubic millimeter wished to start antiretroviral therapy, most experienced clinicians could have made an excellent case why treatment should be deferred. Today, if a similar patient were eager to start, we should be ready and willing to prescribe therapy—with ongoing careful monitoring of toxic effects that could arise during decades of treatment.” (P. E. Sax)
Rosuvastatin in Hemodialysis: While rosuvastatin lowered LDL cholesterol levels in 2,776 patients undergoing hemodialysis, the drug had no significant effect on a composite primary end point of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (pp. 1395–407). The patients, aged 50–70 years, received rosuvastatin 10 mg daily or placebo, with these results: “After 3 months, the mean reduction in low-density lipoprotein (LDL) cholesterol levels was 43% in patients receiving rosuvastatin, from a mean baseline level of 100 mg per deciliter (2.6 mmol per liter). During a median follow-up period of 3.8 years, 396 patients in the rosuvastatin group and 408 patients in the placebo group reached the primary end point (9.2 and 9.5 events per 100 patient–years, respectively; hazard ratio for the combined end point in the rosuvastatin group vs. the placebo group, 0.96; 95% confidence interval [CI], 0.84 to 1.11; P = 0.59). Rosuvastatin had no effect on individual components of the primary end point. There was also no significant effect on all-cause mortality (13.5 vs. 14.0 events per 100 patient–years; hazard ratio, 0.96; 95% CI, 0.86 to 1.07; P = 0.51).” (B. C. Fellström, bengt.fellstrom@medsci.uu.se)
Initial Treatment for Metastatic Colorectal Cancer: The risk of progression of metastatic colorectal cancer was reduced by first-line cetuximab plus chemotherapy, compared with chemotherapy alone (pp. 1408–17). Cetuximab plus irinotecan, fluorouracil, and leucovorin (FOLFIRI) showed these effects in 1,198 patients with epidermal growth factor receptor–positive colorectal cancer with unresectable metastases: “The hazard ratio for progression-free survival in the cetuximab–FOLFIRI group as compared with the FOLFIRI group was 0.85 (95% confidence interval [CI], 0.72 to 0.99; P = 0.048). There was no significant difference in the overall survival between the two treatment groups (hazard ratio, 0.93; 95% CI, 0.81 to 1.07; P = 0.31). There was a significant interaction between treatment group and KRAS mutation status for tumor response (P = 0.03) but not for progression-free survival (P = 0.07) or overall survival (P = 0.44). The hazard ratio for progression-free survival among patients with wild-type–KRAS tumors was 0.68 (95% CI, 0.50 to 0.94), in favor of the cetuximab–FOLFIRI group. [Several] grade 3 or 4 adverse events were more frequent with cetuximab plus FOLFIRI than with FOLFIRI alone.” (E. Van Cutsem, eric.vancutsem@uz.kuleuven.ac.be)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 3, 2009 * Vol. 16, No. 63
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source: Apr. issue of Pharmacotherapy (2009; 29).
Intermittent Hypoxia & Drug-Resistant Cardiovascular Disease: Data from a rat model indicate that intermittent hypoxia during obstructive sleep apnea may induce changes in gene expression that can make patients resistant to drug therapy for hypertension, arrhythmias, and heart failure, especially when medications are substrates for P-glycoprotein transporters (pp. 365–72). Comparing 12 adult male Sprague–Dawley rats who were exposed to intermittent hypoxia for 2 weeks with 18 controls, the investigators found: “Band density of myocardial (but not hepatic) P-gp expression (standardized by beta-actin) was significantly higher in hypoxic rats than in control rats (p = 0.03). Quantitative polymerase chain reaction revealed that myocardial and hepatic Abcb1a and myocardial Abcb1b mRNA expression were significantly increased in hypoxic rats compared with controls (p < 0.05).” (J. M. Dopp, jmdopp@pharmacy.wisc.edu)
Trimethoprim–Sulfamethoxazole in HIV Infection: An ex vivo study shows that peripheral B-lymphocyte function can be altered by trimethoprim–sulfamethoxazole (TMP-SMX) exposure in HIV-infected patients who are taking zidovudine (pp. 373–82). Before and after a 28-day course of TMP-SMX 160/800 mg/day in 14 men with HIV infection who were taking zidovudine, peripheral blood mononuclear cells (PBMCs) were harvested and tested for three mitogens: pokeweed mitogen ([PWM] T-cell– dependent B-cell mitogen), Staphylococcus aureus Cowan ([SAC] T-cell– independent B-cell mitogen), and phytohemagglutinin A ([PHA] T-cell mitogen), with these results: “Reduced proliferative capacities of both PBMC and B cells stimulated with mitogens were observed at the 3-day culture time point in response to PWM, PHA, and SAC (p = 0.029, 0.028, and 0.026, respectively). Proliferative capacity at day 7 of culture was not significantly different for any condition examined. Cytokine production was not altered by combination drug exposure after 10 days of culture when cells were stimulated with either PWM or PHA. Although antibody responses to PWM and PHA were similar, total immunoglobulin G concentration was lower in cells stimulated with SAC in samples obtained after TMP-SMX regimen completion compared with those obtained before exposure (p = 0.005).” (D. J. Feola, djfeol2@email.uky.edu)
Guidelines for Prevention of Venous Thromboembolism: A practice insights article provides a review of key articles and guidelines on prevention of venous thromboembolism (pp. 410–58): “Venous thromboembolism (VTE) is an important medical problem that affects millions of patients each year. With appropriate prophylaxis, many of these thromboembolic events can be prevented. Although strong evidence supporting VTE prophylaxis spans several decades, several large American and global registries have documented very poor use of appropriate prophylaxis. Because of increasing regulatory requirements, hospitals nationwide are in the process of developing documentation of appropriate VTE prophylaxis programs for both surgical and medical patients. A wide range of clinicians must understand what constitutes appropriate VTE prophylaxis in various patient populations. With the existence of numerous pharmacologic agents, abundance of data from major clinical trials, and several nationally recognized clinical guidelines, compiling the needed reference material to make evidence-based decisions on appropriate VTE prophylaxis can be difficult for clinicians. Therefore, we provide a bibliography of key articles and guidelines related to the prevention of VTE in various patient groups. We hope this compilation will serve as a resource for pharmacists, physicians, nurses, residents, and students responsible for the care of patients who may be at risk for VTE.” (P. P. Dobesh, pdobesh@unmc.edu)

>>>PNN NewsWatch
* Caraco Pharmaceutical Laboratories and FDA notified health care professionals of a consumer-level recall of Caraco brand Digoxin, USP, 0.125 mg, and Digoxin, USP, 0.25 mg, distributed before March 31, 2009, which are not expired and are within the expiration date of Sept. 2011. The tablets are being recalled because they may differ in size and therefore potency. Consumers with the recalled product should return these products to their pharmacy or place of purchase.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 6, 2009 * Vol. 16, No. 64
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: Apr. 4 issue of Lancet (2009; 372).
LDL, CRP Reductions with Rosuvastatin: Patients achieve cardiovascular benefits from a lowering of both LDL cholesterol and C-reactive protein following initation of rosuvastatin, report investigators from the JUPITER (Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) trial (pp. 1175–82). In 15,548 initially healthy patients, rosuvastatin 20 mg daily and placebo had these effects on rates of nonfatal myocardial infarction, nonfatal stroke, admission for unstable angina, arterial revascularisation, or cardiovascular death during a median follow-up of 1.9 years: “Compared with placebo, participants allocated to rosuvastatin who achieved LDL cholesterol less than 1.8 mmol/L had a 55% reduction in vascular events (event rate 1.11 vs 0.51 per 100 person–years; hazard ratio [HR] 0.45, 95% CI 0.34—0.60, p < 0.0001), and those achieving hsCRP less than 2 mg/L a 62% reduction (event rate 0.42 per 100 person–years; HR 0.38, 95% CI 0.26—0.56, p < 0.0001). Although LDL cholesterol and hsCRP reductions were only weakly correlated in individual patients (r values <0.15), we recorded a 65% reduction in vascular events in participants allocated to rosuvastatin who achieved both LDL cholesterol less than 1.8 mmol/L and hsCRP less than 2 mg/L (event rate 0.38 per 100 person–years; adjusted HR 0.35, 95% CI 0.23—0.54), versus a 33% reduction in those who achieved one or neither target (event rate 0.74 per 100 person-years; HR 0.67, 95% CI 0.52—0.87) (p across treatment groups <0.0001). In participants who achieved LDL cholesterol less than 1.8 mmol/L and hsCRP less than 1 mg/L, we noted a 79% reduction (event rate 0.24 per 100 person–years; HR 0.21, 95% CI 0.09—0.52). Achieved hsCRP concentrations were predictive of event rates irrespective of the lipid endpoint used, including the apolipoprotein B to apolipoprotein AI ratio.” (P. M. Ridker, pridker@partners.org)
Moxifloxacin for Initial Treatment of Tuberculosis: Compared with ethambutol, moxifloxacin improved rates of culture conversion when used as initial therapy in a Phase II trial of 170 patients with tuberculosis (pp. 1183–9). After 8 weeks of therapy with moxifloxacin 400 mg or ethambutol 15—20 mg/kg 5 days per week, these results were noted: “74 patients assigned to the moxifloxacin group and 72 in the ethambutol group were included in the modified ITT population. 125 patients had 8-week data (moxifloxacin n = 64, ethambutol n = 61); the main reason for absence of data was culture contamination. At 8 weeks, culture conversion to negative had occurred in 59 (80%) of 74 patients in the moxifloxacin group compared with 45 (63%) of 72 in the ethambutol group (difference 17.2%, 95% CI 2.8—31.7; p = 0.03). There were 16 adverse events (eight in each group) in 12 patients. Only one event was judged related to study drug (grade 3 cutaneous reaction in the ethambutol group).” (R. E. Chaisson)

>>>PNN JournalWatch
* Effectiveness and Safety of Nicotine Replacement Therapy Assisted Reduction to Stop Smoking: Systematic Review and Meta-analysis, in BMJ, 2009; 338: b1024. (D. Moore, d.j.moore@bham.ac.uk)
* The Effect of Computerized Physician Order Entry on Medication Prescription Errors and Clinical Outcome in Pediatric and Intensive Care: A Systematic Review, in Pediatrics, 2009; 123: 1184–90. (F. van Rosse)
* Iron Homeostasis in the Neonate, in Pediatrics, 2009; 123: 1208–16. (K. J. Collard)
* Consensus Statement on the Use of Gonadotropin-Releasing Hormone Analogs in Children, in Pediatrics, 2009; 123: e752–62. (J-C Carel)
* Postpartum Psychosis: Detection of Risk and Management, in American Journal of Psychiatry, 2009; 166: 405–8. (M. G. Spinelli)
* Treatment-Resistant Depression and Mortality After Acute Coronary Syndrome, in American Journal of Psychiatry, 2009; 166: 410–7. (R. M. Carney)
* Alanine Aminotransferase, Gamma-Glutamyltransferase, and Incident Diabetes: The British Women’s Heart and Health Study and Meta-analysis, in Diabetes Care, 2009; 32: 741–50. (A. Fraser, abigail.fraser@bristol.ac.uk)
* Heart Failure in Hispanics, in Journal of the American College of Cardiology, 2009; 53: 1167–75. (R. P. Vivo, rpvivo_upsilon@yahoo.com)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 7, 2009 * Vol. 16, No. 65
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: Apr. 7 issue of and early-release article from the Annals of Internal Medicine (2009; 150).
Smoking Cessation: Two articles and an editorial explore aspects of smoking cessation.
To stop smoking, patients need repeated attempts, researchers report, noting that successive disease-management efforts are associated with progressively higher abstinence rates (pp. 437–46). Studied were 750 people who were smoking more than 10 cigarettes per day and who sought care at one of 50 rural primary care practices. Results showed: “Pharmacotherapy utilization was similar across treatment groups, with 473 of 741 (63.8%), 302 of 739 (40.9%), 175 of 732 (23.9%), and 179 of 726 (24.7%) participants requesting pharmacotherapy during the first, second, third, and fourth 6-month treatment cycles, respectively. Of participants who saw a physician during any given treatment cycle, 37.5% to 59.5% reported that they had discussed smoking cessation with their physician; this did not differ across the treatment groups. Abstinence rates increased throughout the study, and overall (0 to 24 months) analyses demonstrated higher abstinence among the high-intensity disease management group than the moderate-intensity disease management group (odds ratio [OR], 1.43 [95% CI, 1.00 to 2.03]) and among the combined disease management groups than the pharmacotherapy-alone group (OR, 1.47 [CI, 1.08 to 2.00]). Self-reported abstinence at 24 months was 68 of 244 (27.9%) and 56 of 238 (23.5%) participants in the high- and moderate-intensity disease management groups, respectively (OR, 1.33 [CI, 0.88 to 2.02]), and 56 of 244 (23.0%) participants in the pharmacotherapy-alone group (OR, 1.12 [CI, 0.78 to 1.61] for combined disease management vs. pharmacotherapy alone).” (E. F. Ellerbeck, eellerbe@kumc.edu)
In a 6-month trial, flexibly dosed triple-combination pharmacotherapy was more effective than standard-duration nicotine patch therapy among 127 adult outpatient smokers with medical illnesses (pp. 447–54). Random allocation of patients to triple therapy using nicotine patch, nicotine oral inhaler, and bupropion ad libitum or to standard care with nicotine patches alone showed these results: “Abstinence rates at 26 weeks were 35% (22 of 63 patients) for the combination group versus 19% (12 of 64 patients) for the patch–alone group (relapse benefit, 16% [95% CI, 1% to 31%]; P = 0.040). The adjusted odds ratio for abstinence in the combination group was 2.57 (CI, 1.05 to 6.32; P = 0.041). The median time to relapse was significantly longer in the combination group than in the patch-alone group (65 days vs. 23 days; P = 0.005). Some side effects occurred more frequently in the combination group (for example, insomnia [25% vs. 9%] and anxiety [22% vs. 3%]), but the proportion of participants who discontinued study medications because of adverse events was similar in both groups (6%).” (M. B. Steinberg, michael.steinberg@umdnj.edu)
An editorialist writes that these two articles “provide glimpses of what tobacco treatment in the health care setting might look like in the future” (pp. 496–7; N. A. Rigotti): “The details remain to be worked out, but it is a promising new strategy with the potential to link current office-based and community-based approaches to managing tobacco dependence.”
AIDS Relief in Africa: The President’s Emergency Plan for AIDS Relief (PEPFAR) has reduced HIV-related deaths in sub-Saharan Africa focus countries in the 4 years since its inception, but efforts have failed to affect the prevalence of AIDS in adults, a study shows (early release). Results for the 5-year, $15 billion program are reported as follows: “Between 2004 and 2007, the difference in the annual change in the number of HIV-related deaths was 10.5% lower in the focus countries than the control countries (P = 0.001). The difference in trends between the groups before 2003 was not significant. The annual growth in the number of people living with HIV was 3.7% slower in the focus countries than the control countries from 1997 to 2002 (P = 0.05), but during PEPFAR’s activities, the difference was no longer significant. The difference in the change in HIV prevalence did not significantly differ throughout the study period. These estimates were stable after sensitivity analysis.” (E. Bendavid, ebd@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 © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 8, 2009 * Vol. 16, No. 66
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source: Apr. 8 issue of JAMA (2009; 301).
CBT for Anxiety in Older Adults: In the primary care setting, worry severity, depressive symptoms, and general mental health were all improved significantly in 134 older adults with generalized anxiety disorder through use of cognitive–behavioral therapy, compared with enhanced usual care, researchers report (pp. 1460–7). CBT was provided for 3 months, and effectiveness was assessed for up to 1 year after completion of the intervention, with these results: “Cognitive behavior therapy compared with EUC significantly improved worry severity (45.6 [95% confidence interval {CI}, 43.4–47.8] vs 54.4 [95% CI, 51.4–57.3], respectively; P < .001), depressive symptoms (10.2 [95% CI, 8.5–11.9] vs 12.8 [95% CI, 10.5–15.1], P = .02), and general mental health (49.6 [95% CI, 47.4–51.8] vs 45.3 [95% CI, 42.6–47.9], P = .008). There was no difference in GAD severity in patients receiving CBT vs those receiving EUC (8.6 [95% CI, 7.7–9.5] vs 9.9 [95% CI, 8.7–11.1], P = .19). In intention-to-treat analyses, response rates defined according to worry severity were higher following CBT compared with EUC at 3 months (40.0% [28/70] vs 21.9% [14/64], P = .02).” (M. A. Stanley, mstanley@bcm.tmc.edu)
Chest Pain Without Obstructive Coronary Disease: In a Clinician’s Corner contribution, authors explore the causes of chest pain in patients without obstructive coronary artery disease (pp. 1468–74): “Patients with persistent chest pain and no obstructive coronary artery disease are often labeled as having noncardiac pain and not offered further cardiologic testing or treatment. Diagnostic uncertainty for persistent chest pain is associated with adverse quality of life, morbidity, and health care costs. Two underdiagnosed cardiac causes for persistent chest pain include microvascular coronary disease and abnormal cardiac nociception. Microvascular coronary disease is associated with an increased risk of adverse cardiovascular events such as myocardial infarction, congestive heart failure, and sudden cardiac death, and treatment directed at improving endothelial function can improve outcomes. Abnormal cardiac nociception is also a cause for persistent chest pain caused by heightened coronary pain perception. Coronary reactivity testing allows for direct measurement of blood flow characteristics in response to vasoactive agents for the diagnoses of microvascular coronary disease and can be a useful tool to differentiate causes of chest pain. Coronary reactivity testing is an invasive method for assessing coronary vascular function, with current evidence suggesting that its associated risk is relatively low compared with the adverse prognosis associated with microvascular coronary dysfunction. Accurate diagnosis in patients with persistent chest pain and normal coronary arteries can be challenging and deserves adequate investigation in light of the associated morbidity, mortality, and health care costs.” (C. N. Bairey Merz, merz@cshs.org)
Adolescents & Alcohol Advertising: Exposure of adolescents to alcohol advertising and promotion during televised sports is a problem, authors of a Commentary conclude, adding this advice for countries that continue to allow such advertising (pp. 1479–82): “Clearly, there is a mismatch between mounting research evidence and political will in countries like the United States, Canada, and Australia. It is time for governments to put commercial considerations aside and address a significant adolescent health issue by banning alcohol advertising and promotion through televised sports and exploring the potential usefulness of other regulatory measures.” (R. Hoye, r.hoye@latrobe.edu.au)

>>>PNN NewsWatch
* Meeting in San Antonio on Apr. 3–6, the APhA House of Delegates adopted a new policy regarding health information technology. Two other statements that came through APhA’s policy-development process were referred to the policy committee; these involved independent pharmacist practice and the pharmacist’s role in patient safety. Also at the meeting, Florida hospital pharmacist Ed Hamilton was installed as APhA president; outgoing Executive Vice President John A. Gans received the Remington Honor Medal and was recognized in a video tribute shown at a general session, and the new CEO taking over on July 1, Thomas E. Menighan, was formally introduced to the membership.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 9, 2009 * Vol. 16, No. 67
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source: Apr. 9 issue of the New England Journal of Medicine (2009; 360).
Esomeprazole for Poorly Controlled Asthma: A 412-participant study of patients with poorly controlled asthma shows that esomeprazole does not improve asthma control despite a high prevalence of asymptomatic gastroesophageal reflux in such patients (pp. 1487–99). Over 24 weeks, esomeprazole 40 mg twice daily produced these effects as recorded using daily asthma diaries, spirometry performed once every 4 weeks, and questionnaires that asked about asthma symptoms: “Episodes of poor asthma control occurred with similar frequency in the placebo and esomeprazole groups (2.3 and 2.5 events per person–year, respectively; P = 0.66). There was no treatment effect with respect to individual components of the episodes of poor asthma control or with respect to secondary outcomes, including pulmonary function, airway reactivity, asthma control, symptom scores, nocturnal awakening, or quality of life. The presence of gastroesophageal reflux, which was documented by pH monitoring in 40% of participants with minimal or no symptoms, did not identify a subgroup of patients that benefited from treatment with proton-pump inhibitors. There were fewer serious adverse events among patients receiving esomeprazole than among those receiving placebo (11 vs. 17).” (R. A. Wise, rwise@jhmi.edu)
Discussing the relationship between gastroesophageal reflux and asthma, editorialists write (pp. 1551–3): “What [these investigators] have shown is that neither esophageal pH monitoring nor the empirical treatment with proton-pump inhibitors identifies the patients in whom asthma is worse because of factors related to gastroesophageal reflux. We believe that a clinical trial should be undertaken in which the inclusion criteria include objective evidence of acidic and nonacidic esophageal reflux and patients are randomly assigned to treatment with medication or surgical repair of gastroesophageal reflux. Until such a trial is undertaken, empirical treatment with proton-pump inhibitors does not make sense.” (K. Asano)
Professional Conscientious Objection: Calling for a restoration of “selfless professionalism in medicine,” a physician–attorney assesses the recent controversy over U.S. Department of Health and Human Services rulings regarding the conflict between professionals’ personal beliefs and their duty to provide care to patients (pp. 1484–5): “Health care providers already enjoy broad rights—perhaps too broad—to follow their guiding moral or religious tenets when it comes to sterilization and abortion. An expansion of those rights is unwarranted. Instead, patients deserve a law that limits objections and puts their interests first. Physicians should support an ethic that allows for all legal options, even those they would not choose. Federal laws may make room for the rights of conscience, but health care providers—and all those whose jobs affect patient care—should cast off the cloak of conscience when patients’ needs demand it. Because the Bush administration’s rule moves us in the opposite direction, it should be rescinded.” (J. D. Cantor)

>>>PNN NewsWatch
* Citing an increased risk of progressive multifocal leukoencephalopathy (PML) associated with use of efalizumab (Raptiva), Genentech announced yesterday a phased voluntary withdrawal of the psoriasis drug from the U.S. market. Efalizumab is indicated for the treatment of chronic moderate-to-severe plaque psoriasis in adults 18 years or older who are candidates for systemic therapy or phototherapy. PML is a rare, progressive, demyelinating disease of the central nervous system that leads to death or severe disability. The company said that, effective immediately, physicians should not issue prescriptions for efalizumab for any new patients and should promptly contact patients currently receiving efalizumab to assess the most appropriate treatment alternatives. Raptiva will no longer be available after June 8, 2009. Because of the potential for severe psoriasis worsening with abrupt discontinuation of efalizumab, Genentech said that it is important that patients talk with their physician before stopping treatment. The company estimates that approximately 2,000 patients in the United States may currently be receiving efalizumab for chronic plaque psoriasis. Since FDA approval of this drug in 2003, approximately 46,000 patients worldwide have been treated with efalizumab.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 10, 2009 * Vol. 16, No. 68
Providing news and information about medications and their proper use

>>>Infectious Disease Report
Source: May 1 issue of Clinical Infectious Diseases (2009; 48).
Influenza Virus Resistance to Antiviral Agents: Making a plea for “rational use” of antiviral agents in patients with flulike symptoms, authors of a viewpoint article write (pp. 1254–6): “At the current time, nearly all influenza A/H3N2 viruses and a percentage of influenza A/H1N1 viruses are adamantane resistant, which leaves only neuraminidase inhibitors available for treatment of infection with these viruses. In December 2008, the Centers for Disease Control and Prevention released new data demonstrating that a high percentage of circulating influenza A/H1N1 viruses are now resistant to oseltamivir. In addition, oseltamivir-resistant influenza B and A/H5N1 viruses have been identified. Thus, use of monotherapy for influenza virus infection is irrational and may contribute to mutational pressure for further selection of antiviral-resistant strains. History has demonstrated that monotherapy for influenza virus infection leads to resistance, resulting in the use of a new monotherapy agent followed by resistance to that new agent and thus resulting in a background of viruses resistant to both drugs. We argue that combination antiviral therapy, new guidelines for indications for treatment, point-of-care diagnostic testing, and a universal influenza vaccination recommendation are critical to protecting the population against influenza virus and to preserving the benefits of antiviral agents.” (G. A. Poland, poland.gregory@mayo.edu)

>>>PNN NewsWatch
* Reversing an earlier decision (see PNN, Apr. 1), FDA is allowing seven pharmaceutical companies to continue marketing unapproved morphine sulfate oral solution 20 mg/mL products. “Currently, there are no approved morphine sulfate oral solution 20 mg/ml products being marketed in the U.S.,” the agency noted. “FDA has heard from the pain management community that the impending market removal of unapproved morphine sulfate oral solution 20 mg/ml products announced in the Warning Letters would impose unacceptable hardship on palliative care patients, their families and caregivers.” In letters to the companies, FDA wrote that it expects the companies to pursue approval of these products and that permission to continue to market unapproved products would extend only 180 days beyond the approval of oral solutions of morphine sulfate.
* Benzyl Alcohol Lotion 5% (Sciele) yesterday received full FDA approval as a prescription medication, indicated for treatment Pediculosis capitis infestation in patients 6 months of age and older. This is the first head lice product approved by FDA with benzyl alcohol as the active pharmaceutical ingredient. The safety and effectiveness of Benzyl Alcohol Lotion 5% was demonstrated in two studies of 628 people, 6 months of age and older, with active head lice infestation. The subjects received two 10-minute treatments of either Benzyl Alcohol Lotion or a topical placebo, 1 week apart. Fourteen days after the final treatment, more than 75% of those in the active-treatment group were lice free. Common adverse effects of the medication include irritations of the skin, scalp, and eyes, and numbness at the site of application. Patients and caregivers should be counseled to use benzyl alcohol 5% as labeled to maximize benefits and minimize risks. The product should be applied only to the scalp or the hair attached to the scalp. It is not approved for use in children younger than 6 months. Use in premature infants could lead to serious respiratory-, heart-, or brain-related adverse events such as seizure, coma, or death.
* Coartem tablets (Novartis), a combination of artemether and lumefantrine, have been approved by FDA for treatment of acute uncomplicated malaria infections in adults and children weighing at least 5 kg. Artemether is the first agent in the artemesinin class drug approved by FDA; the artemesinins are derived from the leaves of the Artemisia annua plant, which have been used to treat malaria. Coartem is not approved for the treatment of severe malaria or to prevent malaria. Coartem should be taken with food, particularly food that contains fat, because this allows the body to absorb the drug well. The most common adverse reactions to Coartem in clinical trials in adults were headache, anorexia, dizziness, asthenia, arthralgia, and myalgia. The most common adverse reactions reported in children have been pyrexia, cough, vomiting, loss of appetite, and headache.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 13, 2009 * Vol. 16, No. 69
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: Apr. 11 issue of Lancet (2009; 372).
Prevention and Treatment of Osteoporosis: Among 813 patients at 54 centers on four continents, a single dose of intravenous zoledronic acid was noninferior to and possibly more effective than oral doses of risedronate 5 mg daily (pp. 1253–63). Adding that patients preferred the intravenous dosage route, HORIZON (Health Outcomes and Reduced Incidence with Zoledronic acid ONce yearly) researchers report these 1-year results: “Zoledronic acid was non-inferior and superior to risedronate for increase of lumbar spine bone mineral density in both the treatment (least-squares mean 4.06% [SE 0.28] vs 2.71% [SE 0.28], mean difference 1.36% [95% CI 0.67—2.05], p = 0.0001) and prevention (2.60% [0.45] vs 0.64% [0.46], 1.96% [1.04—2.88], p < 0.0001) subgroups at 12 months. Adverse events were more frequent in patients given zoledronic acid than in those on risedronate, largely as a result of transient symptoms during the first 3 days after infusion. Serious adverse events were worsening rheumatoid arthritis for the treatment subgroup and pyrexia for the prevention subgroup.” (D. M. Reid, d.m.reid@abdn.ac.uk)
Editorialists provide this perspective on possible future developments with osteoporosis agents (pp. 1225–6); “Anabolic drugs such as teriparatide, which stimulate bone formation by acting on osteoblasts and osteocytes, could lead to a more compelling rationale for use than bisphosphonates. This drug is superior to alendronate in glucocorticoid-induced osteoporosis not only for changes in bone mineral density but also in terms of morphometric vertebral fractures. On the other hand, bisphosphonates can prevent osteoblast and osteocyte apoptosis in vivo and in vitro, raising the possibility that perhaps part of their antifracture efficacy in glucocorticoid-induced osteoporosis might result from preservation of the integrity of the osteocyte network and extension of the working life of bone-forming cells. Further studies are needed to address these issues, so that we have greater assurance about the effectiveness of available antiresorptive and anabolic drugs for prevention and treatment of glucocorticoid-induced osteoporosis.” (L. Gennari, gennari@unisi.it)
Avotermin for Skin Scarring: Accelerated and permanent improvements in skin scarring were noted among patients treated with human transforming-growth factor beta-3 (avotermin), compared with placebo, in three double-blind studies of wounds created in healthy patients (pp. 1264–74): “In two studies, avotermin 50 ng/100 µL per linear cm significantly improved median score on a 100 mm visual analogue scale (VAS) by 5 mm (range −2 to 14; p = 0.001) at month 6 and 8 mm (−29 to 18; p = 0.0230) at month 12. In the third, avotermin significantly improved total scar scores at all concentrations versus placebo (mean improvement: from 14.84 mm [95 % CI 5.5—24.2] at 5 ng/100 µL per linear cm to 64.25 mm [49.4—79.1] at 500 ng/100 µL per linear cm). Nine [60%] scars treated with avotermin 50 ng/100 µL per linear cm showed 25% or less abnormal orientation of collagen fibres in the reticular dermis versus five [33%] placebo scars. After only 6 weeks from wounding, avotermin 500 ng/100 µL per linear cm improved VAS score by 16.12 mm (95% CI 10.61—21.63). Adverse events at wound sites were similar for avotermin and controls. Erythema and oedema were more frequent with avotermin than with placebo, but were transient and deemed to be consistent with normal wound healing.” (M. W. J. Ferguson, mark.ferguson@renovo.com)

>>>PNN NewsWatch
* FDA announced on Friday that it had obtained a permanent injunction barring Neilgen Pharmaceuticals Inc. of Westminster, MD, its parent company, Advent Pharmaceuticals, Inc., of East Windsor, NJ, and two of their officers, Bharat Patel and Pragna Patel, from manufacturing and distributing any unapproved, adulterated, or misbranded drugs. Neilgen has also done business as Unigen Pharmaceuticals Inc.

>>>PNN JournalWatch
* Emergency and Early Management of Burns and Scalds, in BMJ, 2009; 338: b1037. (M. Shah, mamta.shah@cmmc.nhs.uk)
* Pain Management Principles in the Critically Ill, in Chest, 2009; 135: 1075–86. (B. L. Erstad, erstad@pharmacy.arizona.edu)
* Geriatric Literature Review: Revisited, in Journal of the American Geriatrics Society, 2009; 57: 585–7. (M. Rich, mrich@im.wustl.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 © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 14, 2009 * Vol. 16, No. 70
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: Apr. 13 issue of the Archives of Internal Medicine (2009; 169).
IBS & Celiac Disease: Patients who meet the diagnostic criteria for irritable bowel syndrome have a 4-fold higher prevalence of celiac disease, according to a systematic review and meta-analysis (pp. 651–8). Looking at studies that provided data on serologic indications of celiac disease as well as biopsy-proven cases, the researchers report: “Fourteen studies were identified comprising 4,204 individuals, of whom 2278 (54%) met diagnostic criteria for IBS. Pooled prevalence of positive IgA-class antigliadin antibodies, either positive endomysial antibodies or tissue transglutaminase, and biopsy-proved celiac disease were 4.0% (95% confidence interval, 1.7–7.2), 1.63% (0.7–3.0), and 4.1% (1.9–7.0), respectively. Pooled odds ratios (95% confidence intervals) for positive IgA-class antigliadin antibodies, either positive endomysial antibodies or tissue transglutaminase, and biopsy-proved celiac disease in cases meeting diagnostic criteria for IBS compared with controls without IBS were 3.40 (1.62–7.13), 2.94 (1.36–6.35), and 4.34 (1.78–10.6).” (A. C. Ford, alexf12399@yahoo.com)
CAM Research in Clinical Practice: Training of clinicians in interpretation of study results and better dissemination of studies of complementary and alternative medicine is needed, conclude investigators who surveyed 1,561 American acupuncturists, naturopaths, internists, and rheumatologists (pp. 670–7). Asking the clinicians about two high-profile studies of osteoarthritis of the knee—one involving acupuncture and the other treatment with glucosamine/chondroitin—the authors found: “Of the respondents, 59% were aware of at least 1 major CAM clinical trial; only 23% were aware of both trials. A minority of acupuncturists (20%), naturopaths (25%), internists (17%), and rheumatologists (33%) were ‘very confident’ in interpreting research results (P < .001). Fewer acupuncturists (17%) and naturopaths (24%) than internists (58%) and rheumatologists (74%) rated the results of randomized controlled trials as ‘very useful’ (P < .001). Twice as many internists (53%) and rheumatologists (64%) rated patient preferences as ‘least important’ compared with acupuncturists (27%) and naturopaths (31%) (P < .001). In multivariate analyses, for clinicians aware of at least 1 trial, male sex (odds ratio [OR], 1.30 [95% confidence interval {CI}, 1.05–1.62]), prior research experience (OR, 1.45 [95% CI, 1.13–1.86]), institutional or academic practice setting (ORs, 1.98 [95% CI, 1.01–3.91], and 1.23 [95% CI, 0.73–2.09], respectively), and rating randomized trials as ‘very useful’ (OR, 1.46 [95% CI, 1.12–1.91]) (P < .001) for clinical decision making were positively associated with CAM trial awareness. Acupuncturists, naturopaths, and internists (ORs, 0.15 [95% CI, 0.10–0.23], 0.15 [95% CI, 0.09–0.24], and 0.18 [95% CI, 0.12–0.28], respectively) were all similarly less aware of CAM trial results compared with rheumatologists.” (J. C. Tilburt, tilburt.jon@mayo.edu)
Playing off the title of a recent book, an editorialist writes of the “drunkard’s walk” (“humans are notoriously bad at, and often even averse to, the straightforward use of data and probability in making daily judgments&rdquo when it comes to incorporation of scientific evidence into medical practice (pp. 649–50): “Physicians need to know how to use a complete ‘evidence house’ and not just the ‘evidence hierarchy’ currently dominating [evidence-based medicine] in both conventional and complementary medicine. As with any skill, sufficient time and supervised application is needed before EBM can become a habit in daily practice. Thus, both CAM and conventional practitioners should each seek to fill their respective gaps in knowledge and skills to make practices both more patient relevant and scientifically rigorous.” (W. B. Jonas, wjonas@siib.org)
PDA-Based Decision Support: A multifactorial intervention aimed at improving cholesterol management produced modest benefits, researchers report (pp. 678–86). Prescribers in intervention practices received personal digital assistants programmed with ATP III guidelines, and screening rates and prescribing patterns were reviewed for 2001–03 and 2004–06. Overtreatment declined in the intervention while rising in control practices, and the net change in appropriate cholesterol management was significantly better with the intervention. (A. G. Bertoni, abertoni@wfubmc.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 © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 15, 2009 * Vol. 16, No. 71
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source: Apr. 15 issue of JAMA, a theme issue on diabetes (2009; 301).
Hypoglycemia in AMI: Spontaneous hypoglycemia, but not lowered blood glucose after insulin administration, was associated with increased mortality among a group of 7,820 patients who were hospitalized with acute myocardial infarction and hyperglycemia (pp. 1556–64). At 40 U.S. hospitals in 2000–05, these trends in all-cause in-hospital mortality and subsequent hypoglycemia were observed: “Among patients treated or not treated with insulin, those with hypoglycemia were older and had more comorbidity. Hypoglycemia was associated with increased mortality in patients not treated with insulin (18.4% [25/136] mortality in patients with hypoglycemia vs 9.2% [425/4,639] in those without hypoglycemia; P<.001), but not in those treated with insulin (10.4% [36/346] mortality in patients with hypoglycemia vs 10.2% [276/2,699] in those without hypoglycemia; P = .92). After multivariable adjustment, there was a significant interaction between hypoglycemia and insulin therapy (P value for interaction = .01). Hypoglycemia was a predictor of higher mortality in patients who were not treated with insulin (odds ratio, 2.32 [95% confidence interval, 1.31–4.12] vs patients without hypoglycemia), but not in patients treated with insulin (odds ratio, 0.92 [95% confidence interval, 0.58–1.45] vs patients without hypoglycemia).” (M. Kosiborod, mkosiborod@cc-pc.com)
Severe Hypoglycemia & Dementia: In a longitudinal cohort study of 16,667 patients with a mean age of 65 years and type 2 diabetes, histories of severe hypoglycemic episodes were associated with greater risks for dementia, researchers report (pp. 1565–72). Data were analyzed for members of a northern California health system, with cohort members chosen based on absence of dementia, mild cognitive impairment, or general memory complaints as of Jan. 1, 2003. Follow-up in early 2007 showed the following: “At least 1 episode of hypoglycemia was diagnosed in 1,465 patients (8.8%) and dementia was diagnosed in 1,822 patients (11%) during follow-up; 250 patients had both dementia and at least 1 episode of hypoglycemia (16.95%). Compared with patients with no hypoglycemia, patients with single or multiple episodes had a graded increase in risk with fully adjusted hazard ratios (HRs): for 1 episode (HR, 1.26; 95% confidence interval [CI], 1.10–1.49); 2 episodes (HR, 1.80; 95% CI, 1.37–2.36); and 3 or more episodes (HR, 1.94; 95% CI, 1.42–2.64). The attributable risk of dementia between individuals with and without a history of hypoglycemia was 2.39% per year (95% CI, 1.72%–3.01%). Results were not attenuated when medical utilization rates, length of health plan membership, or time since initial diabetes diagnosis were added to the model. When examining emergency department admissions for hypoglycemia for association with risk of dementia (535 episodes), results were similar (compared with patients with 0 episodes) with fully adjusted HRs: for 1 episode (HR, 1.42; 95% CI, 1.12–1.78) and for 2 or more episodes (HR, 2.36; 95% CI, 1.57–3.55).” (R. A. Whitmer, raw@dor.kaiser.org)
Stem Cell Transplantation for Type 1 Diabetes: Increased C-peptide levels and insulin independence occurred in the majority of patients recently diagnosed with type 1 diabetes mellitus after autologous nonmyeloablative hematopoietic stem cell transplantation (HSCT), according to authors who cared for 23 patients in a Phase I/II trial (pp. 1573–9). “During a 7- to 58-month follow-up (mean, 29.8 months; median, 30 months), 20 patients without previous ketoacidosis and not receiving corticosteroids during the preparative regimen became insulin free,” report the investigators. “Twelve patients maintained this status for a mean 31 months (range, 14–52 months) and 8 patients relapsed and resumed insulin use at low dose (0.1–0.3 IU/kg). In the continuous insulin–independent group, HbA1c levels were less than 7.0% and mean (SE) area under the curve (AUC) of C-peptide levels increased significantly from 225.0 (75.2) ng/mL per 2 hours pretransplantation to 785.4 (90.3) ng/mL per 2 hours at 24 months posttransplantation (P < .001) and to 728.1 (144.4) ng/mL per 2 hours at 36 months (P = .001). In the transient insulin–independent group, mean (SE) AUC of C-peptide levels also increased from 148.9 (75.2) ng/mL per 2 hours pretransplantation to 546.8 (96.9) ng/mL per 2 hours at 36 months (P = .001), which was sustained at 48 months.” (J. C. Voltarelli, jcvoltar@fmrp.usp.br)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 16, 2009 * Vol. 16, No. 72
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source: Apr. 16 issue of the New England Journal of Medicine (2009; 360).
Cognitive Function After Fetal Exposure to Antiepileptic Drugs: Risks of impaired cognitive function are increased at 3 years of age in children exposed in utero to valproate but not other antiepileptic medications, leading researchers to conclude that this drug should not be used for first-line treatment of women of childbearing age (pp. 1597–605). Among 309 children whose mothers had taken single antiepileptic drugs during pregnancy, these results were noted: “At 3 years of age, children who had been exposed to valproate in utero had significantly lower IQ scores than those who had been exposed to other antiepileptic drugs. After adjustment for maternal IQ, maternal age, antiepileptic-drug dose, gestational age at birth, and maternal preconception use of folate, the mean IQ was 101 for children exposed to lamotrigine, 99 for those exposed to phenytoin, 98 for those exposed to carbamazepine, and 92 for those exposed to valproate. On average, children exposed to valproate had an IQ score 9 points lower than the score of those exposed to lamotrigine (95% confidence interval [CI], 3.1 to 14.6; P = 0.009), 7 points lower than the score of those exposed to phenytoin (95% CI, 0.2 to 14.0; P = 0.04), and 6 points lower than the score of those exposed to carbamazepine (95% CI, 0.6 to 12.0; P = 0.04). The association between valproate use and IQ was dose dependent. Children’s IQs were significantly related to maternal IQs among children exposed to carbamazepine, lamotrigine, or phenytoin but not among those exposed to valproate.” (K. J. Meador, kimford.meador@emory.edu)
An editorialist notes that the time to change antiepileptic agents is long before pregnancy occurs (pp. 1667-9): “Because of the risks associated with a loss of seizure control during pregnancy, changes from valproate to another antiepileptic drug should be made and evaluated before conception. By the time a woman realizes that she is pregnant, switching drugs is unlikely to reduce the risk of birth defects. Because safe practice involves changing antiepileptic drugs only over a prolonged period (i.e., typically over a period of months, with the use of polytherapy during the transition period), a switch from valproate once pregnancy has been established is also unlikely to eliminate the risk of cognitive impairment in the child. For women taking high doses of valproate, dose reduction may be reasonable, but only after careful risk–benefit assessment by the physician.” (T. Tomson)
Valsartan for Atrial Fibrillation Prevention: In the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico–Atrial Fibrillation (GISSI-AF) trial, valsartan failed to reduce the incidence of recurrent atrial fibrillation among patients in sinus rhythm but with two or more documented episodes of atrial fibrillation within the past 6 months (pp. 1606–17). Study participants were also required to have underlying cardiovascular disease, diabetes, or left atrial enlargement, and results were assessed based on the primary end points of time to a first recurrence of atrial fibrillation and proportion of patients who had more than one recurrence of atrial fibrillation over the course of 1 year: “A total of 1,442 patients were enrolled in the study. Atrial fibrillation recurred in 371 of the 722 patients (51.4%) in the valsartan group, as compared with 375 of 720 (52.1%) in the placebo group (adjusted hazard ratio, 0.97; 96% confidence interval [CI], 0.83 to 1.14; P = 0.73). More than one episode of atrial fibrillation occurred in 194 of 722 patients (26.9%) in the valsartan group and in 201 of 720 (27.9%) in the placebo group (adjusted odds ratio, 0.89; 99% CI, 0.64 to 1.23; P = 0.34). The results were similar in all predefined subgroups of patients, including those who were not receiving angiotensin-converting–enzyme inhibitors.” (A. P. Maggioni, gissiaf@anmco.it)
Benefits and Risks of Inhaled Long-Acting Beta-Agonists: The controversies surrounding the effectiveness and safety of long-acting beta-agonists for treatment of asthma in various age groups is analyzed in a Perspective article (pp. 1592–5; J. M. Kramer).

>>>PNN NewsWatch
* Based reports of fatalities in neonates, the product labeling of ceftriaxone has been modified to warn of its interaction with calcium-containing products, FDA has announced.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 17, 2009 * Vol. 16, No. 73
Providing news and information about medications and their proper use

>>>Gastroenterology Report
Source: Apr. issue of Gastroenterology (2009; 136).
Preventing C. difficile Infection: A “simple, reliable, and accurate” clinical prediction rule can be used to prospectively identify patients at high risk of recurrence of Clostridium difficile infection (CDI), researchers report (pp. 1206–14). Using data from a previous study of 63 patients, the study authors developed a clinical prediction rule based on multivariate logistic regression analysis of patients’ age, presence of severe or fulminant illness, and additional antibiotic use after CDI therapy. Comparing the rule with a second rule that relied on concentrations of IgG against toxin A in a group of 89 patients, the investigators determined: “The clinical prediction rule discriminated between patients with and without recurrent CDI, with an area under the curve of the receiver-operating-characteristic curve of 0.83 (95% confidence interval [CI]: 0.70–0.95) in the derivation cohort and 0.80 (95% CI: 0.67–0.92) in the validation cohort. The rule correctly classified 77.3% (95% CI: 62.2%–88.5%) and 71.9% (95% CI: 59.2%–82.4%) of patients in the derivation and validation cohorts, respectively. The combined rule performed well in the derivation cohort but not in the validation cohort (area under the curve of the receiver-operating-characteristic curve, 0.89 vs 0.62; diagnostic accuracy, 93.8% vs 69.2%, respectively).” (C. P. Kelly, ckelly2@bidmc.harvard.edu)
Alcohol & Cancer: While risks of esophageal squamous cell carcinoma are increased in patients whose alcohol intake is above recommended U.S. dietary guidelines, no increased risk of esophageal adenocarcinoma or esophagogastric junction adenocarcinoma was seen in an analysis of nationwide samples of patients with the three conditions (pp. 1215–24). Comparing patients with controls sampled from a population register, the investigators found increased risk of esophageal squamous cell carcinoma with alcohol intake of more than 170 g/wk; modest alcohol users had lower risks of all three cancers. (N. Pandeya, Nirmala.Pandeya@qimr.edu.au)

>>>PNN NewsWatch
* A pharmacy technician yesterday shot and killed two outpatient pharmacy coworkers on the grounds of California’s Long Beach Memorial Hospital before killing himself, according to media reports. Police say that Mario Ramirez, 50, killed pharmacists Kelly Hales, 56, executive director of the outpatient pharmacy, and Hugo Bustamante, 46, supervisor in the department. While unclear, Ramirez’s motives may have related to recent rumors of layoffs in the outpatient pharmacy, the Long Beach Press–Telegram reports. Hales had practiced at the hospital for 21 years, according to the newspaper, and had four children, including two daughters in college at UCLA and Notre Dame. Bustamante coached a 10-year-old girls softball team that was to be honored at a Los Angeles Dodgers game this weekend, according to the Orange County Register. The team, given the opportunity to advance to the state finals when the team ahead of them could not afford the travel, instead raised money for the other team. The California Board of Pharmacy lists a second pharmacist at Bustamante’s home address, Jane Bustamante, presumably his wife.
* The Agency for Healthcare Research and Quality has released professional and consumer guides examining the effectiveness, safety, and adverse effects of treatments for osteoarthritis of the knee, including glucosamine/chondroitin, fluid injections, arthroscopic surgery, and pain medications. Among the guides’ conclusions are these: Evidence shows that some common treatments for osteoarthritis of the knee are not helpful and may have side effects. Glucosamine and chondroitin have not been shown to offer improvement and can cause upset stomach, diarrhea, and headache. Fluid injections do not reduce pain or improve movement and can cause swelling, minor infection, and pain. Arthroscopic surgery does little to reduce the pain of knee osteoarthritis and can result in more pain, swelling, infection, and blood clots in the legs.
* All Influend Cough and Cold products sold after May 29, 2008, are being recalled because of possible superpotency, ION Labs and FDA announced. Use of the products could lead to complications ranging from tachycardia, palpitations, arrhythmias, and cardiovascular collapse with hypotension to headaches, dizziness, anxiety, restlessness and nervousness.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 20, 2009 * Vol. 16, No. 74
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: Apr. 18 issue of Lancet (2009; 372).
Polypills & Cardiovascular Disease: In patients with cardiovascular disease, use of a polypill can assist patients in reducing multiple risk factors and cardiovascular risk, according to a study conducted at 50 centers in India (pp. 1341–51). The 2,053 study participants were assigned to one of nine groups receiving various medication combinations, including one in which patients received a daily Polycap containing thiazide 12.5 mg, atenolol 50 mg, ramipril 5 mg, simvastatin 20 mg, and aspirin 100 mg. Results showed: “Compared with groups not receiving blood-pressure-lowering drugs, the Polycap reduced systolic blood pressure by 7.4 mm Hg (95% CI 6.1—8.1) and diastolic blood pressure by 5.6 mm Hg (4.7—6.4), which was similar when three blood-pressure-lowering drugs were used, with or without aspirin. Reductions in blood pressure increased with the number of drugs used (2.2/1.3 mm Hg with one drug, 4.7/3.6 mm Hg with two drugs, and 6.3/4.5 mm Hg with three drugs). Polycap reduced LDL cholesterol by 0.70 mmol/L (95% CI 0.62—0.78), which was less than that with simvastatin alone (0.83 mmol/L, 0.72—0.93; p = 0.04); both reductions were greater than for groups without simvastatin (p < 0.0001). The reductions in heart rate with Polycap and other groups using atenolol were similar (7.0 beats per min), and both were significantly greater than that in groups without atenolol (p < 0.0001). The reductions in 11-dehydrothromboxane B2 were similar with the Polycap (283.1 ng/mmol creatinine, 95% CI 229.1—337.0) compared with the three blood-pressure-lowering drugs plus aspirin (350.0 ng/mmol creatinine, 294.6—404.0), and aspirin alone (348.8 ng/mmol creatinine, 277.6—419.9) compared with groups without aspirin. Tolerability of the Polycap was similar to that of other treatments, with no evidence of increasing intolerability with increasing number of active components in one pill.” (S. Yusuf, yusufs@mcmaster.ca)
Timing of Antiretroviral Initiation: Based on a collaborative analysis of data from 18 HIV cohort studies, researchers conclude that 350 cells/µL is the CD4 threshold at which antiretroviral therapy should be initiated in patients with HIV who have not developed AIDS symptoms (pp. 1352–63). “Data were obtained for 21,247 patients who were followed up during the era before the introduction of combination therapy and 24,444 patients who were followed up from the start of treatment,” the authors write. “Deferring combination therapy until a CD4 cell count of 251—350 cells per µL was associated with higher rates of AIDS and death than starting therapy in the range 351—450 cells per µL (hazard ratio [HR] 1.28, 95% CI 1.04—1.57). The adverse effect of deferring treatment increased with decreasing CD4 cell count threshold. Deferred initiation of combination therapy was also associated with higher mortality rates, although effects on mortality were less marked than effects on AIDS and death (HR 1.13, 0.80—1.60, for deferred initiation of treatment at CD4 cell count 251—350 cells per µL compared with initiation at 351—450 cells per µL).” (J. Sterne, jonathan.sterne@bristol.ac.uk)

>>>BMJ Highlights
Source: Early-release article from BMJ (2009; 337).
Secondary Drug Prevention of Stroke: Undertreatment of older people with stroke is not justified based on available evidence, according to results of a cohort study of 12,830 patients aged 50 years or more at 113 general practices in England with first strokes in 1995–2005 and survival to 30 days (b1279). Only one-fourth of men and one-fifth of women received poststroke medications to prevent recurrence, with significantly fewer patients of advanced age receiving treatment. Treated patients had significantly lower mortality in the year after the incident stroke, and no age-related effects were seen in reduction of mortality risk. (R. Raine, r.raine@ucl.ac.uk)

>>>PNN JournalWatch
* Effect of Calcium Dobesilate on Occurrence of Diabetic Macular Oedema (CALDIRET Study): Randomised, Double-Blind, Placebo-Controlled, Multicentre Trial, in Lancet, 2009; 373: 1364–71. (C. Haritoglou, christos.haritoglou@med.uni-muenchen.de)
* MAO-B Inhibitor Know-How: Back to the Pharm, in Neurology, 2009; 72: 1352–7. (P. A. LeWitt, palewitt@ameritech.net)
* Multiallergen Immunotherapy for Allergic Rhinitis and Asthma, in Journal of Allergy and Clinical Immunology, 2009; 123: 763–9. (H. S. Nelson, nelsonh@njc.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 © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 21, 2009 * Vol. 16, No. 75
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: Early-release article from and Apr. 21 issue of the Annals of Internal Medicine (2009; 150).
Glycemic Control in Type 2 Diabetes: With data accumulating that tight glycemic control is not the panacea once thought in patients with type 2 diabetes, authors call for “an evidence-based about-face” (early release): “Current best evidence requires a change in emphasis in our care for patients with type 2 diabetes. Clinicians should prioritize supporting well-being and healthy lifestyles, preventive care, and cardiovascular risk reduction for these patients. Randomized trial evidence that we reviewed do not strongly support tight glycemic control as a more beneficial than harmful approach to reduce the risk for diabetes complications. Although we should not dismiss potentially effective approaches (for example, early tight glycemic control for patients with newly diagnosed diabetes), we require additional research to confirm or refute such approaches before we impose them on patients, particularly given the unequivocal patient burden, cost, and harm of serious hypoglycemia associated with tight control.” (V. M. Montori, kerunit@mayo.edu)
Drug-Facts Box for Benefits, Harms: Presentation of information about prescription drugs in a boxed format similar to that used for OTC products improved consumers’ knowledge of drug benefits and adverse effects, resulted in better choices between drugs for current symptoms, and corrected overestimation of benefits for drugs used for prevention (pp. 516–27). Among 231 adults who viewed a drug box on heartburn medications or a direct-to-consumer advertisement for related products and 219 adults who viewed a drug box on prevention of cardiovascular events or a DTC ad, surveys revealed these results: “In the symptom drug box trial, 70% of the drug box group and 8% of the control group correctly identified the [proton pump inhibitor] as being ‘a lot more effective’ than the histamine-2 blocker (P < 0.001), and 80% and 38% correctly recognized that the side effects of the 2 drugs were similar (P < 0.001). When asked what they would do if they had bothersome heartburn and could have either drug for free, 68% of the drug box group and 31% of the control group chose the proton-pump inhibitor, the superior drug (P < 0.001). In the prevention drug box trial, the drug box improved consumers’ knowledge of the benefits and side effects of a statin and clopidogrel. For example, 72% of the drug box group and 9% of the control group correctly quantified the benefit (absolute risk reduction) of the statin (P < 0.001). Most of the control participants overestimated this benefit, and 65% did so by a factor of 10 or more.” (S. Woloshin, steven.woloshin@dartmouth.edu)
Peginterferon-Alpha-2a for Retreatment of Hepatitis C: Among 950 patients with hepatitis C who did not respond to treatment with peginterferon-alpha-2b plus ribavirin, 72 weeks of peginterferon-alpha-2a plus ribavirin significantly increased sustained virologic responses (SVRs), compared with 48 weeks of treatment (pp. 528–40). Adding that nonresponders to the 2a congener can generally be identified by week 12 of retreatment, the investigators add these details about those treated with ribavirin plus initially high doses of peginterferon-alpha-2a for 72 weeks (group A) or 48 weeks (group B) or lower doses throughout 72 weeks (group C) or 48 weeks (group D): “The SVR rates in groups A (n = 317), B (n = 156), C (n = 156), and D (n = 313) were 16%, 7%, 14%, and 9%, respectively (relative risk [RR] for group A vs. group D [the primary comparison], 1.80 [95% CI, 1.17 to 2.77]; P = 0.006). Extended treatment duration increased SVR rates (16% for 72 weeks [groups A and C] vs. 8% for 48 weeks [groups B and D]; RR, 2.00 [CI, 1.32 to 3.02]; P < 0.001). Complete viral suppression (HCV RNA level <50 IU/mL)at week 12 was achieved in 21% of patients in groups A and B and 13% of those in groups C and D. Rates of SVR were 49% (77 of 157 patients) and 4% (32 of 719 patients) among those with and without complete viral suppression at week 12, respectively.” (D. M. Jensen, djensen@medicine.bsd.uchicago.edu)
Tobacco Cessation Reaffirmed: Recommendations from 2003 regarding tobacco use are reaffirmed (pp. 551–5). All adult patients should be asked about tobacco use, the U.S. Preventive Services Task Force recommends, and cessation interventions should be offered to users. (USPSTF Web site, www.preventiveservices.ahrq.gov)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 22, 2009 * Vol. 16, No. 76
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source: Apr. 22/29 issue of JAMA (2009; 301).
Declining Continuity of Care: For Medicare beneficiaries, continuity of care between the outpatient and inpatient settings declined between 1996 and 2006, according to a retrospective cohort study of 3 million hospital admissions (pp. 1671–80). Analysis of a 5% national sample of beneficiaries older than 66 years of age showed these patterns based on the percentages of patients who during hospitalization were seen by any outpatient physician they had visited in the year before hospitalization (continuity with any outpatient physician) or by their primary care physician (PCP) (continuity with a PCP): “In 1996, 50.5% (95% confidence interval [CI], 50.3%–50.7%) of hospitalized patients were seen by at least 1 physician that they had visited in an outpatient setting in the prior year, and 44.3% (95% CI, 44.1%–44.6%) of patients with an identifiable PCP were seen by that physician while hospitalized. These percentages decreased to 39.8% (95% CI, 39.6%–40.0%) and 31.9% (95% CI, 31.6%–32.1%), respectively, in 2006. Greater absolute decreases in continuity with any outpatient physician between 1996 and 2006 occurred in patients admitted on weekends (13.9%; 95% CI, 12.9%–14.7%) and those living in large metropolitan areas (11.7%; 95% CI, 11.1%–12.3%) and in New England (16.2%; 95% CI, 14.4%–18.0%). In multivariable multilevel models, increasing involvement of hospitalists was associated with approximately one-third of the decrease in continuity of care between 1996 and 2006.” (G. Sharma, gulshan.sharma@utmb.edu)
Generic v. Brand-Name Cardiovascular Drugs: Responding to a recently published review and meta-analysis (see PNN, Dec. 3, 2008), a letter author writes that bioequivalence among young healthy volunteers may not always translate for older patients with cardiovascular disease (p. 1654): “It is impossible to predict the bioequivalence of generic medications for cardiovascular diseases in more vulnerable older persons with greater degrees of compromised metabolic function, who often take multiple interacting drugs. Until comparative bioequivalence studies are conducted using careful conditions that replicate the requirements of the Food and Drug Administration (FDA) in larger numbers of older patients (ideally older than 70 years), generic cardiovascular medications cannot simply be substituted for brand-name drugs. The clinician should be vigilant for possible changes in the pharmacodynamic effects whenever a generic is substituted, including switching between different generic products.” (B. L. Carter, barry.carter@uiowa.edu)
Authors of the original article respond (pp. 1655–6): “We disagree with the conclusion that generic cardiovascular medications cannot be substituted for brand-name drugs. First, there are inconsistencies with the findings. For example, in one study the generic formulation exhibiting an enhanced effect on one electrocardiographic measurement also demonstrated a slightly diminished effect on supine mean arterial pressure, as well as no significant effect on heart rate and standing mean arterial pressure. Second, none of the variations reported in the relevant studies showed meaningful effects on patient outcomes.” (A. S. Kesselheim, akesselheim@partners.org)

>>>PNN NewsWatch
* “Shared responsibility” is important to many Americans as they consider new financing mechanisms for health care, according to an article published yesterday on the Web by Health Affairs (doi: 10.1377/hlthaff.28.3.w501). In a telephone survey of 1,704 adults age 18 and older, 48% of respondents expressed support for an individual mandate on its own. However, a shared-responsibility approach with an individual mandate was considerably more popular than a stand-alone mandate. Overall, 59% of the public supported this approach. Spreading responsibility among government, employers, insurers, and individuals was more popular than a stand-alone mandate among all subgroups of respondents, and this shared-responsibility approach obtained 50% support or better in each subgroup except Republicans (44%). The biggest increases in support for a shared-responsibility approach, as compared to a stand-alone individual mandate, were found among those making $80,000 to $100,000 and among African Americans.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 23, 2009 * Vol. 16, No. 77
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source: Apr. 23 issue of the New England Journal of Medicine (2009; 360).
Genetic Basis of Stroke: A genomewide study associates a genetic locus with increased risk of stroke, researchers report (pp. 1718–28). Patients in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, including 19,602 whites who had had 1,544 incident strokes (1,164 ischemic strokes) over an average follow-up period of 11 years, were assessed for markers. Results were used in a replication cohort of 2,430 blacks with 215 strokes (191 ischemic strokes), another cohort of 574 black persons with 85 incident strokes (68 ischemic strokes), and 652 Dutch persons with ischemic stroke, and 3,613 unaffected persons. Results showed: “Two intergenic single-nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene NINJ2 were associated with stroke (P < 5 x 10–8). NINJ2 encodes an adhesion molecule expressed in glia and shows increased expression after nerve injury. Direct genotyping showed that rs12425791 was associated with an increased risk of total (i.e., all types) and ischemic stroke, with hazard ratios of 1.30 (95% confidence interval [CI], 1.19 to 1.42) and 1.33 (95% CI, 1.21 to 1.47), respectively, yielding population attributable risks of 11% and 12% in the discovery cohorts. Corresponding hazard ratios were 1.35 (95% CI, 1.01 to 1.79; P = 0.04) and 1.42 (95% CI, 1.06 to 1.91; P = 0.02) in the large cohort of black persons and 1.17 (95% CI, 1.01 to 1.37; P = 0.03) and 1.19 (95% CI, 1.01 to 1.41; P = 0.04) in the Dutch sample; the results of an underpowered analysis of the smaller black cohort were nonsignificant.” (S. Seshadri, suseshad@bu.edu)
Genomewide Association Studies & Human Disease: A review article assesses the current state of genomewide association studies, describes the process used in such research efforts, and provides a glossary of related terms (pp. 1759–68). The authors conclude: “The jigsaw puzzle of understanding the causes of disease lies before us: we now have the edges and corners in place. The identification of monogenic disease loci and the common genetic variability that contributes to disease risk is now a tractable problem. The techniques that are necessary for genomewide identification of such rare variants that contributes to disease risk are quickly being refined. There is an enormous amount of filling in to do (including the dissection of the interactions among different genes), and there are formidable challenges, which increased bioinformatic data will help to address. Undoubtedly, there will be surprises, but the boundaries of the task ahead have already been drawn.” (J. Hardy, jhardy@ion.ucl.ac.uk)
Struggling over Health Care Reform: Attempting to read the tea leaves regarding the prospects of health care reform this year in Congress, the Journal’s national correspondent provides these insights into the thinking of one key Democratic Senator, Finance Committee Chair Max Baucus (pp. 1693–5): “Because he is generally careful not to stray too far from the conservative views of many of his Montana constituents, Baucus’s passionate pursuit of health care reform has surprised some people. At a recent briefing, he said, ‘This is the most difficult legislative challenge of my life, and I relish it.’ Baucus has expressed a willingness to cap the tax-free amount of employer-provided health benefits, whose deductibility currently costs the federal treasury about $250 billion a year in forgone tax revenue. (The administration has signaled a willingness to accept such a measure even though during the presidential campaign Obama denounced a similar proposal as ‘the largest middle-class tax increase in history.&rsquo Baucus also proposed accelerating the pursuit of fraud, waste, and abuse in public programs; increasing the transparency of physician–industry relationships and physicians’ self-referral of patients; and addressing professional-liability issues.” (J. K. Iglehart)

>>>PNN NewsWatch
* ABC Beauty Supply and FDA yesterday announced a recall of 34 dietary supplement products because analysis indicates they contain sibutramine.
* FDA will not appeal a federal court order regarding the age at which women can purchase the emergency contraceptive Plan B (levonorgestrel, Barr) without a prescription. The company must submit an application for the change, which would lower the age for OTC purchase from 18 to 17.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 24, 2009 * Vol. 16, No. 78
Providing news and information about medications and their proper use

>>>Circulation Highlights
Source: Apr. 21 issue of Circulation (2009; 119).
Health-Seeking Behaviors & Adherence: Patients adherent to statin therapy are more likely to engage in other health-seeking behaviors, researchers report, making it difficult to determine the degree of protection provided by the medications (pp. 2051–7). A prospective cohort study of patients in British Columbia identified 141,086 individuals who were started on statins for primary prevention. Using multivariable-adjusted Cox proportional hazards models, the investigators determined: “The study population was 49% female and had an average age of 61 years. The results from our multivariable-adjusted models showed that more adherent patients were less likely to have accidents than less adherent patients. This effect was greatest for motor vehicle accidents (hazard ratio, 0.75; 95% confidence interval, 0.72 to 0.79) and workplace accidents (hazard ratio, 0.77; 95% confidence interval, 0.74 to 0.81). More adherent patients had a greater likelihood of using screening services (hazard ratio, 1.17; 95% confidence interval, 1.15 to 1.20) and a lower likelihood of developing other diseases likely to be unrelated to a biological [effect] of a statin (hazard ratio, 0.87; 95% confidence interval, 0.86 to 0.89).” (C. R. Dormuth, colin.dormuth@ti.ubc.ca)
Childhood Obesity: An executive summary (pp. 2114–23) and full report (e489–517) provide information and recommendations regarding childhood obesity. Based on an American Heart Association summit, the report notes that the prevalence of obesity has increased over the past 30 years by 4-fold for children 6–11 years of age and 3-fold for those 2–5 and 12–19.

>>>Allergy/Immunology Report
Source: Apr. issue of the Journal of Allergy and Clinical Immunology (2009; 123).
Asthma Self-management Education & Adherence: Individualized education designed to improve patients’ asthma self-management skills can help with adherence to medications and improve clinical markers of asthma control, authors of a 24-week, prospective trial report (pp. 840–6). Conducted to assess the impact of education on long-term adherence, the investigators report these results for 84 adults with moderate-to-severe asthma who received a 30-minute intervention followed by reinforcement at 2-week intervals: “Participants randomized to the self-management intervention maintained consistently higher ICS adherence levels and showed a 9-fold greater odds of more than 60% adherence to the prescribed dose compared with control subjects at the end of the intervention (P = .02) and maintained a 3-fold greater odds of higher than 60% adherence at the end of the study. Perceived control of asthma improved (P = .006), nighttime awakenings decreased (P = .03), and inhaled beta-agonist use decreased (P = .01) in intervention participants compared with control subjects.” (S. L. Janson, Susan.Janson@nursing.ucsf.edu)

>>>PNN NewsWatch
* A compounding error by an Ocala, FL, pharmacy may have caused the deaths of 21 Venezuelan polo horses, according to reports in the media. Franck’s Pharmacy offers compounding services for both human and veterinary products, its website promotes, along with community pharmacy services. According to a statement reported in lay media, the chief operations officer of the pharmacy, Jennifer Beckett, said that the strength of an ingredient in preparations administered to the horses was incorrect. The pharmacy was apparently trying to replicate an international product, Biodyl (Merial), that is not marketed in the U.S. According to Wikipedia, Biodyl is a dietary supplement product containing of ATP, selenium, magnesium, potassium, and cyanocobalamin; it is marketed in other countries as an oral supplement and for injection.
* CDC is investigating 7 human cases of swine influenza (H1N1) in San Diego and Imperial Counties, CA, and San Antonio, TX. The agency has set up a special website with updates on its investigation into unusual springtime influenza activity and is recommending the usual precautions for residents of California and Texas (cover nose and mouth with tissue during coughing and sneezing; throw tissue in trash after using; wash hands; avoid close contact with sick people; stay home when sick; and avoid touching eyes, nose, and mouth).

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 27, 2009 * Vol. 16, No. 79
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: Apr. 25 issue of Lancet (2009; 372).
Relaxin in Heart Failure: Among 234 patients with acute heart failure and normal-to-increased blood pressure, use of the natural human peptide relaxin produced relief of dyspnea and other favorable clinical effects with an acceptable safety profile, researchers report (pp. 1429–39). Compared with placebo in a dose-ranging study, relaxin produced these outcomes: “In the modified intention-to-treat population, 61 patients were assessed in the placebo group, 40 in the relaxin 10 µg/kg per day group, 42 in the relaxin 30 µg/kg per day group, 37 in the relaxin 100 µg/kg per day group, and 49 in the relaxin 250 µg/kg per day group. Dyspnoea improved with relaxin 30 µg/kg compared with placebo, as assessed by Likert scale (17 of 42 patients [40%] moderately or markedly improved at 6 h, 12 h, and 24 h vs 14 of 61 [23%]; p = 0.044) and visual analogue scale through day 14 (8214 mm X h [SD 8712] vs 4622 mm X h [9003]; p = 0.053). Length of stay was 10.2 days (SD 6.1) for relaxin-treated patients versus 12.0 days (7.3) for those given placebo, and days alive out of hospital were 47.9 (10.1) versus 44.2 (14.2). Cardiovascular death or readmission due to heart or renal failure at day 60 was reduced with relaxin (2.6% [95% CI 0.4—16.8] vs 17.2% [9.6—29.6]; p = 0.053). The number of serious adverse events was similar between groups.” (J. R. Teerlink, john.teerlink@ucsf.edu)

>>>PNN NewsWatch
* Responding to 20 U.S. cases of swine influenza A (H1N1), CDC has activated its Emergency Operations Center and is issuing frequent updates and recommendations to governmental authorities and clinicians. Patients with swine influenza are infectious from 1 day before to 7 days after onset of symptoms, CDC advises, and human-to-human transmission of the virus appears to be occurring. The possibility of swine influenza should be considered in those developing acute respiratory illness (defined as recent onset of at least two these symptoms—rhinorrhea or nasal congestion, sore throat, cough [with or without fever or feverishness]) after close contact with an identified case of swine influenza or after travel to affected areas (currently Mexico, southern California, San Antonio, Kansas, New York City) within 7 days of disease onset. In infected patients, zanamivir or oseltamivir can be used for 5 days of treatment. Those with suspected cases can receive either zanamivir alone or oseltamivir plus amantadine or rimantadine. Chemoprophylaxis with oseltamivir or zanamivir is recommended for health care workers with unprotected close contact with a case and several categories of patients who are at high risk of influenza complications, including close contacts and schoolmates of cases, those traveling to Mexico, and workers on the Mexican border.
* Approved on Friday by FDA was golimumab (Simponi, Centocor Ortho Biotech), a monthly treatment for adults with moderate-to-severe rheumatoid arthritis, active psoriatic arthritis, and active ankylosing spondylitis. Injected subcutaneously, this tumor necrosis factor-alpha blocker is used in combination with methotrexate in patients with rheumatoid arthritis; with or without methotrexate for psoriatic arthritis; and as monotherapy in patients with ankylosing spondylitis. In clinical trials (see first item in JournalWatch), patients who received golimumab for one of the three conditions showed improvements in the signs and symptoms common to their form of arthritis. The most common adverse reactions to golimumab include upper respiratory tract infection, sore throat, and nasal congestion. Like other TNF-alpha blockers, golimumab labeling includes a boxed warning alerting patients and health professionals to the risk of tuberculosis and invasive fungal infections with use of the drug. A risk evaluation mitigation strategy (REMS) for golimumab includes a Medication Guide for patients and a communication plan to help prescribers understand the drug’s risks.

>>>PNN JournalWatch
* Golimumab, A New Human Tumor Necrosis Factor Antibody, Administered Every Four Weeks as a Subcutaneous Injection in Psoriatic Arthritis: Twenty-Four-Week Efficacy and Safety Results of a Randomized, Placebo-Controlled Study, in Arthritis & Rheumatism, 2009; 60: 976–86–. (A. Kavanaugh, akavanaugh@ucsd.edu)
* Malignant Pleural Mesothelioma, in Journal of Clinical Oncology, 2009; 27: 2081–90–. (A. S. Tsao, astsao@mdanderson.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 © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 28, 2009 * Vol. 16, No. 80
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: Apr. 28 issue of the Archives of Internal Medicine (2009; 169).
Pharmacists’ Impact in Cardiovascular Disease: In a post-hoc analysis of data from two trials, interventions by pharmacists were shown to significantly decrease the risk of adverse drug events and medication errors (pp. 757–63). Study participants included 800 outpatients with hypertension, 535 of them with complicated cases. For 9 or 12 months, specially trained and equipped pharmacists communicated regularly with intervention patients to dispense medications and provide oral and written instructions, with these results: “Of the 800 participants (mean [SD] age, 59 [10] years), 484 (90.5%) and 258 (97.4%) participants remained in the complicated and uncomplicated strata, respectively, at 12 months. Compared with the control group, the risk of any event was 34% lower in the intervention group (risk ratio, 0.66; 95% confidence interval [CI], 0.50–0.88), including a lower risk of adverse drug events (risk ratio, 0.65; 95% CI, 0.47–0.90), preventable adverse drug events (risk ratio, 0.52; 95% CI, 0.25–1.09), potential adverse drug events (risk ratio, 0.70; 95% CI, 0.40–1.22), and medication errors (risk ratio, 0.63; 95% CI, 0.40–0.98).” (M. D. Murray, mick@unc.edu)
Describing this study, the below article, and another article in this issue as examples of the “change we need in health care,” editorialists write (pp. 737–9): “Although [Murray et al.] do not provide a thorough economic evaluation, they present reasonable assumptions that suggest that the cost savings related to prevention of adverse events might pay for the direct cost of the pharmacist. This source of potential cost savings would add to the net cost savings previously demonstrated in their trial in patients with heart failure. This alternative approach to enhancing health care quality encourages greater use of more cost-effective therapies and raises barriers to inappropriate prescribing in a more subtle manner than previously described approaches.
“While adding a pharmacist to the health care team may be more acceptable to providers and patients alike, challenges to widespread implementation exist. Standardization of the quality-related outcomes would require ongoing education of pharmacists and/or development of high-quality evidence-based decision support aids to pharmacy practice. The same high-quality evidence needed to support prior authorization and cost-sharing policies would be needed to implement the pharmacist approach.” (P. Greenland, p-greenland@northwestern.edu)
Cost Sharing & Drug Initiation in Chronic Illness: Especially in patients lacking experience with prescription drugs, high copayments decrease initiation of drug therapy for chronic diseases, researchers report, with lower rates of treatment stretching up to 5 years (pp. 740–8; M. D. Solomon, msolomon@stanford.edu)

>>>PNN NewsWatch
* The number of confirmed cases of swine influenza A (H1N1) doubled to 40 yesterday, CDC reports, with the increase the result of further testing of students at a New York school who traveled to Cancun, Mexico, on spring break. At the request of CDC, FDA has issued Emergency Use Authorizations (EUAs) for zanamivir (Relenza), oseltamivir (Tamiflu), and the rRT-PCR Swine Flu Panel diagnostic test. The FDA action allows use of the products for unapproved indications. The EUAs allow for oseltamivir to be used to treat and prevent influenza in children under 1 year and provide alternate dosing recommendations for children older than 1 year. In addition, under the EUAs, both medications may be distributed to large segments of the population without complying with the label requirements otherwise applicable to dispensed drugs, and accompanied by written information pertaining to the emergency use. They may also be distributed by a broader range of health care workers, including some public health officials and volunteers, in accordance with applicable state and local laws and/or public health emergency responses. The EUA also allows CDC to distribute the swine flu test to public health and other qualified laboratories that have the needed equipment and the personnel who are trained to perform and interpret the results. FDA cautioned that while a positive PCR test provides presumptive confirmation of swine influenza, a negative test by itself does not exclude infection with this viral strain.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 29, 2009 * Vol. 16, No. 81
Providing news and information about medications and their proper use

>>>Medical Care Highlights
Source: May issue of Medical Care (2009; 47).
Prescription Silos & Total Health Care Spending: Cost shifting to patients in the form of prescription medicine copayments increase the net expenditures for treatment of chronic lung diseases, report researchers who studied data from British Columbia (pp. 508–16). In an analysis of use of inhaled steroids, beta-2 agonists, and anticholinergics by patients older than 65 years, multivariable linear regression showed these patterns during a period when the benefit was changed from full coverage to copayments and then to income-based deductibles plus coinsurance (IBD): “Net health plan spending increased by C$1.98 million per year during the copay policy [95% confidence interval (CI): 0.10–4.34], and C$5.76 million per year during the first 10 months of the IBD policy (95% CI: 1.75–10.58). Out-of-pocket spending by older patients increased 30% during the copay policy (95% CI: 24–36) and 59% during the IBD policy (95% CI: 56–63).” (C. R. Dormuth, colin.dormuth@ti.ubc.ca)
Editorialists call on benefits managers to think “beyond the silos” (pp. 505–7): “Instead of deciding how to save money, we need to decide how to invest in health. Specifically, the health care system should promote use of high value services even if those services do not save money. It is incumbent upon benefit designers not to seek to reduce use of all services in the name of fiscal sustainability, but instead to strive to reduce the use of those services that do not provide good value. This is complex because the value of any given service depends on the characteristics of patients who use it, suggesting more sophistication in benefit design (and other managerial strategies) may be needed. On balance, purchasers must confront the question of how to finance benefits. They must seek to get the most health for any amount of spending and minimize spending for any amount of health. This will require the use of many strategies, of which benefit design is only one.” (M. E. Chernew, chernew@hcp.med.harvard.edu)
Integrated HIV Care: The structure, process, and functions of an integrated approach to HIV care significantly improved viral suppression among patients on combination antiretroviral therapy, according to a retrospective cohort study conducted at five VA facilities (pp. 560–7). The integrated HIV care (IHC) team included a nurse practitioner/physician assistant, clinical coordinator, HIV physician specialist, dedicated pharmacist, social worker, psychiatrist, and psychologist. For patients with at least 3 months of follow-up, these results were recorded: “The 1,018 HIV-infected patients eligible for analysis had substantial barriers to responding to cART: 93% had comorbidities with mean 3.2 comorbidities per patient (SD = 2.0); 52% achieved viral suppression in median 231 days (SD = 411.6). Patients visiting clinics that offered hepatitis, psychiatric, psychologic, and social services in addition to HIV primary care were 3.1 times more likely to achieve viral suppression than patients visiting clinics which offered only HIV primary care (hazard ratio = 3.1, P < 0.001).” (T. Hoang, Tuyen.Hoang@va.gov)

>>>PNN NewsWatch
* Improved warnings of adverse effects on nonprescription analgesic/antipyretic product labeling will be required under a final rule issued yesterday by FDA. Liver damage from acetaminophen and bleeding from aspirin and other NSAIDs will be “prominently displayed,” as will active ingredients. FDA noted in a news release that many but not all of the required changes have been already implemented voluntarily by manufacturers.
* The U.S. Substance Abuse and Mental Health Services Administration and FDA have launched an initiative to help ensure the safe use of methadone. The public outreach effort, Follow Directions: How to Use Methadone Safely, is designed to inform consumers, health professionals, and treatment clinics about the safe use and misuse of the drug for both pain relief and drug addiction treatment. An escalating number of poisoning deaths have been linked to the improper use of methadone.
* The number of U.S. cases of swine influenza has climbed to 64, including 1 death this morning, CDC reports. The agency issued a travel warning recommending that Americans avoid nonessential travel to Mexico as WHO raised the pandemic alert level to Phase 4.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 30, 2009 * Vol. 16, No. 82
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source: Apr. 30 issue of the New England Journal of Medicine (2009; 360).
Treatment of Chronic Hepatitis C Virus: Two research studies and an editorial examine use of telaprevir, a protease inhibitor specific to the hepatitis C virus nonstructural 3/4A serine protease, for treatment of chronic HCV infection.
While increased rates of adverse effects were noted, a telaprevir-based regimen significantly improved sustained virologic response rates in patients with genotype 1 HCV, researchers report (pp. 1827–38). A control group (PR48) received peginterferon alfa-2a plus ribavirin for 48 weeks, and their outcomes were compared with groups receiving the above agents plus telaprevir for 24 or 48 weeks. Using a primary outcome of sustained virologic response, defined as undetectable HCV RNA levels 24 weeks after the end of therapy, the investigators found: “The rate of sustained virologic response was 41% (31 of 75 patients) in the PR48 group, as compared with 61% (48 of 79 patients) in the T12PR24 group (P = 0.02), 67% (53 of 79 patients) in the T12PR48 group (P = 0.002), and 35% (6 of 17 patients) in the T12PR12 group (this group was exploratory and not compared with the control group). Viral breakthrough occurred in 7% of patients receiving telaprevir. The rate of discontinuation because of adverse events was higher in the three telaprevir-based groups (21%, vs. 11% in the PR48 group), with rash the most common reason for discontinuation.” (J. G. McHutchison, mchut001@mc.duke.edu)
In the second study, all intervention patients received telaprevir and peginterferon alfa-2a, with some groups receiving ribavirin, and it proved to be an important addition to therapy (pp. 1839–50). One group, T12PR24 (n = 81), received all three drugs for 12 weeks, followed by peginterferon alfa-2a and ribavirin for 12 more weeks. The T12PR12 group (n = 82) received all three drugs for 12 weeks. The T12P12 group (n = 78) received telaprevir and peginterferon alfa-2a without ribavirin for 12 weeks, while the control group, PR48 (n = 82), received peginterferon alfa-2a and ribavirin for 48 weeks. Results showed: “The rate of sustained virologic response for the T12PR12 and T12P12 groups combined was 48% (77 of 160 patients), as compared with 46% (38 of 82) in the PR48 (control) group (P = 0.89). The rate was 60% (49 of 82 patients) in the T12PR12 group (P = 0.12 for the comparison with the PR48 group), as compared with 36% (28 of 78 patients) in the T12P12 group (P = 0.003; P = 0.20 for the comparison with the PR48 group). The rate was significantly higher in the T12PR24 group (69% [56 of 81 patients]) than in the PR48 group (P = 0.004). The adverse events with increased frequency in the telaprevir-based groups were pruritus, rash, and anemia.” (J-M Pawlotsky, jean-michel.pawlotsky@hmn.aphp.fr)
Telaprevir is a “step forward in therapy for hepatitis C,” an editorialist claims, adding (pp. 1899–901): “Telaprevir appears to be a material advance in the therapy of hepatitis C, beginning a new era of treatment—an era of antiviral agents developed specifically to target this virus. Other HCV-specific agents, including other protease inhibitors, helicase and polymerase inhibitors, and molecular agents that interfere with viral replication, are likely to follow. Combinations of these new agents with drugs currently in use may ultimately provide effective therapy for all patients with hepatitis C, the promised goal of decades of research.” (J. H. Hoofnagle)
Rosuvastatin for VT Prevention: Among 17,802 healthy men and women, data from JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) show that rosuvastatin significantly reduced frequency of symptomatic venous thromboembolism (pp. 1851–61). During a median follow-up period of 1.9 years, symptomatic VT occurred in 34 patients in the rosuvastatin group and 60 participants in the placebo group (0.18 versus 0.32 event/100 person–years). (R. J. Glynn, rglynn@rics.bwh.harvard.edu)

>>>PNN NewsWatch
* CDC yesterday released interim treatment guidelines for managing swine influenza A (H1N1) virus infections in children and pregnant women. In the U.S., 91 cases and 1 death have been confirmed by CDC. For the second time this week, WHO raised its pandemic alert level, this time to Phase 5, the agency’s second highest level.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 1, 2009 * Vol. 16, No. 83
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source: May issue of Diabetes Care (2009; 32).
Tight Glycemic Control in Cardiac Surgery: An enhanced model predictive control (eMPC) algorithm provided the best tight glycemic control (TGC) among 120 consecutive patients in a surgical intensive care unit, compared with an absolute glucose (Matias) protocol and a relative glucose change (Bath) protocol, researchers report (pp. 757–61). Targeting a blood glucose range of 4.4 to 6.1 mmol/L and measuring levels at 1- to 4-h intervals, the investigators found: “The eMPC algorithm gave the best performance as assessed by time to target (8.8 ± 2.2 vs. 10.9 ± 1.0 vs. 12.3 ± 1.9 h; eMPC vs. Matias vs. Bath, respectively; P < 0.05), average blood glucose after reaching the target (5.2 ± 0.1 vs. 6.2 ± 0.1 vs. 5.8 ± 0.1 mmol/l; P < 0.01), time in target (62.8 ± 4.4 vs. 48.4 ± 3.28 vs. 55.5 ± 3.2%; P < 0.05), time in hyperglycemia >8.3 mmol/l (1.3 ± 1.2 vs. 12.8 ± 2.2 vs. 6.5 ± 2.0%; P < 0.05), and sampling interval (2.3 ± 0.1 vs. 2.1 ± 0.1 vs. 1.8 ± 0.1 h; P < 0.05). However, time in hypoglycemia risk range (2.9–4.3 mmol/l) in the eMPC group was the longest (22.2 ± 1.9 vs. 10.9 ± 1.5 vs. 13.1 ± 1.6; P < 0.05). No severe hypoglycemic episode (<2.3 mmol/l) occurred in the eMPC group compared with one in the Matias group and two in the Bath group.” (M. Haluzik, martin.haluzik@lf1.cuni.cz)
Exenatide v. Insulin Glargine: Compared with titrated insulin glargine in 69 metformin-treated patients with type 2 diabetes, exenatide significantly improved beta-cell function during 1 year of treatment (pp. 762–8). Beta-cell function was measured using an arginine-stimulated hyperglycemic clamp at weeks 0 and 52 and following a 4-week period with no drug. Results showed: “Treatment-induced change in combined glucose- and arginine-stimulated C-peptide secretion was 2.46-fold (95% CI 2.09–2.90, P < 0.0001) greater after a 52-week exenatide treatment compared with insulin glargine treatment. Both exenatide and insulin glargine reduced A1C similarly: –0.8 ± 0.1 and –0.7 ± 0.2%, respectively (P = 0.55). Exenatide reduced body weight compared with insulin glargine (difference –4.6 kg, P < 0.0001). Beta-cell function measures returned to pretreatment values in both groups after a 4-week off-drug period. A1C and body weight rose to pretreatment values 12 weeks after discontinuation of either exenatide or insulin glargine therapy.” (M. Diamant, m.diamant@vumc.nl)
Personal Trainer for Youth with Type 1 Diabetes: Six self-monitoring, goal-setting, and problem-solving sessions with trained nonprofessionals yielded positive 1-year results in 81 youths with type 1 diabetes, compared with usual care (pp. 807–9). Medical records obtained 2 years after the intervention showed: “An overall intervention effect on A1C (8.93% control vs. 8.43% intervention; F = 8.24, P = 0.05) and a significant intervention-by-age interaction (F = 9.88; P = 0.002) were observed, indicating a greater effect among older than younger youths. Subgroup analyses demonstrated no treatment group differences among pre-/early adolescents but a significant difference in A1C among middle adolescents (9.61% control vs. 8.46% intervention; F = 7.20, P = 0.011).” (T. Nansel, nanselt@mail.nih.gov)

>>>PNN NewsWatch
* Boxed warnings and a Risk Evaluation and Mitigation Strategy (REMS) are being required of botulinum toxin products, FDA announced yesterday. Following up on a 2008 warning (see PNN, Feb. 11, 2008), FDA is requiring more information be provided to clinicians about the risk for distant spread of botulinum toxin effects after local injection, as well as information to explain that botulinum toxin products cannot be interchanged. FDA is also requiring manufacturers to submit safety data after multiple administrations of the product in a specified number of children and adults with spasticity to assess the signal of serious risk regarding distant spread of toxin effects.
* Preparing for a possible H1N1 (swine) influenza pandemic, pharmacists and others in states where cases have been reported are gearing up to receive zanamivir, oseltamivir, and other medical supplies from the national stockpile, mobilized earlier this week by CDC. Strategies are being developed to prevent hoarding of medications and unnecessary redirection of supplies by employees of hospitals, pharmacies, and physician offices for personal and family 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 © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 4, 2009 * Vol. 16, No. 84
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: May 2 issue of Lancet (2009; 372).
Cetuximab for Advanced NSCLC: In the Phase III FLEX (First-Line ErbituX in lung cancer) trial, patients with non–small cell lung cancer had longer survival periods when cetuximab was added to platinum-based chemotherapy, researchers report (pp. 1525–31). “Between October, 2004, and January, 2006, 1.125 patients were randomly assigned to chemotherapy plus cetuximab (n = 557) or chemotherapy alone (n = 568),” authors of the open-label study write. “Patients given chemotherapy plus cetuximab survived longer than those in the chemotherapy-alone group (median 11.3 months vs 10.1 months; hazard ratio for death 0.871 [95% CI 0.762—0.996]; p = 0.044). The main cetuximab-related adverse event was acne-like rash (57 [10%] of 548, grade 3).” (R. Pirker, robert.pirker@meduniwien.ac.at)
ESAs & Cancer Mortality: A systematic review and meta-analysis of 53 trials of 13,933 patients with cancer confirms higher mortality in those receiving human recombinant erythropoiesis-stimulating agents (pp. 1532–42). The studies of epoetin alfa, epoetin beta, or darbepoetin alfa show: “1,530 patients died during the active study period and 4,993 overall. Erythropoiesis-stimulating agents increased mortality during the active study period (combined hazard ratio [cHR] 1.17, 95% CI 1.06—1.30) and worsened overall survival (1.06, 1.00—1.12), with little heterogeneity between trials (I2 0%, p = 0.87 for mortality during the active study period, and I2 7.1%, p = 0.33 for overall survival). 10,441 patients on chemotherapy were enrolled in 38 trials. The cHR for mortality during the active study period was 1.10 (0.98—1.24), and 1.04 (0.97—1.11) for overall survival. There was little evidence for a difference between trials of patients given different anticancer treatments (p for interaction = 0.42).” (A. Engert, a.engert@uni-koeln.de)

>>>BMJ Highlights
Source: Early-release article from BMJ (2009; 337).
BP Monitoring Needs Monitoring: True changes in patients’ blood pressure are not likely to be detected with currently used monitoring approaches in clinical practice, conclude authors of a trial conducted at 172 centers in Asia, Australasia, and Europe (b1492). Over a 33-month trial of perindopril (PROGRESS), mercury sphygmomanometer measurements of blood pressure showed the following: “There was no change in the mean blood pressure of the cohort during the 33 month follow-up. Six months after blood pressure was stabilised on treatment, if systolic blood pressure was measured as having increased by >10 mm Hg, six of those measurements would be false positives for every true increase of 10 mm Hg. The corresponding value for an increase of 20 mm Hg was over 200. Values for 5 mm Hg and 10 mm Hg increases in diastolic blood pressure were 3.5 and 39, respectively. The likelihood that observed increases in blood pressure reflected true increases rose with the time between measurements such that the ratio of true positives to false positives reached parity at 21 months.” (A. Hayen, ahayen@health.usyd.edu.au)

>>>PNN NewsWatch
* Serious cases of hepatic toxicities, some requiring liver transplant, have been reported in 23 patients using Hydroxycut products (lovate Health Sciences), FDA reported on Friday. Among the Hydroxycut products being recalled from the market are ones used for weight loss, fat burners, energy enhancers, low-carb diet aids, and diuresis.
* As the rise in cases of swine influenza A (H1N1) approaches the threshold at which WHO could declare a worldwide pandemic, FDA and the Federal Trade Commission are warning Americans to be alert to Internet sites and other promotions of fraudulent products with claims of preventing or treating influenza.

>>>PNN JournalWatch
* Prevention of Rotavirus Disease: Updated Guidelines for Use of Rotavirus Vaccine, in Pediatrics, 2009; 123: 1412–20. (Committee on Infectious Diseases)
* Genomewide Association Studies: History, Rationale, and Prospects for Psychiatric Disorders, in American Journal of Psychiatry, 2009; 166: 540–56. (Psychiatric GWAS Consortium Coordinating Committee)
* Insights from the Society of Infectious Diseases Pharmacists on Antimicrobial Stewardship Guidelines from the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America, in Pharmacotherapy, 2009; 29: 593–607. (R. H. Drew, richard.drew@duke.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 5, 2009 * Vol. 16, No. 85
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: Early-release article from and May 5 issue of the Annals of Internal Medicine (2009; 150).
Effectiveness of Renal Artery Stents: A 140-patient study conducted at 10 European medical centers supports a conservative approach to treatment of renal artery stenosis caused by atherosclerosis, as stents produced no clear benefit but several complications (early release). Medical treatment included antihypertensive treatment, a statin, and aspirin, and in comparison with renal artery stenting, these results were identified: “Forty-six of 64 patients assigned to stent placement underwent the procedure. Ten of the 64 patients (16%) in the stent placement group and 16 patients (22%) in the medication group reached the primary end point (hazard ratio, 0.73 [95% CI, 0.33 to 1.61]). Serious complications occurred in the stent group, including 2 procedure-related deaths (3%), 1 late death secondary to an infected hematoma, and 1 need for dialysis secondary to cholesterol embolism. The groups did not differ for other secondary end points.” (L. Bax)
Ultrasonography for Guiding Duration of Anticoagulation in DVT: Rates of recurrent venous thromboembolism (VTE) were reduced when ultrasonography was used to detect residual thrombi and guide the duration of anticoagulation, compared with fixed-duration treatment in adults with proximal deep-vein thrombosis (DVT), researchers report (pp. 577–85). At nine Italian centers, 538 consecutive patients with first episodes of acute proximal DVT who had completed 3 months of anticoagulation therapy uneventfully received either fixed-duration or flexible-duration, ultrasonography-guided anticoagulation, with these results: “Overall, 46 (17.2%) of 268 patients allocated to fixed-duration anticoagulation and 32 (11.9%) of 270 patients allocated to flexible-duration anticoagulation developed recurrent VTE (adjusted hazard ratio [HR], 0.64 [95% CI, 0.39 to 0.99]). For patients with unprovoked DVT, the adjusted HR was 0.61 (CI, 0.36 to 1.02) and 0.81 (CI, 0.32 to 2.06) for those with secondary DVT. Major bleeding occurred in 2 (0.7%) patients in the fixed-duration group and 4 (1.5%) patients in the flexible-duration group (P = 0.67).” (P. Prandoni, paoloprandoni@tin.it)
New GFR Equation: In comparison with the Modification of Diet in Renal Disease Study equation for estimation of glomerular filtration rate (GFR), the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation is “more accurate” and “could replace [the former] for routine clinical use,” authors of a study conclude (pp. 604–12). The investigators used data on 8,254 participants in 10 studies (equation development data set) and 3,896 participants in 16 studies (validation data set) and calculated prevalence estimates based on 16,032 participants in the National Health and Nutrition Examination Survey 1999–2006. Results were as follows: “In the validation data set, the CKD-EPI equation performed better than the Modification of Diet in Renal Disease Study equation, especially at higher GFR (P < 0.001 for all subsequent comparisons), with less bias (median difference between measured and estimated GFR, 2.5 vs. 5.5 mL/min per 1.73 m2), improved precision (interquartile range [IQR] of the differences, 16.6 vs. 18.3 mL/min per 1.73 m2), and greater accuracy (percentage of estimated GFR within 30% of measured GFR, 84.1% vs. 80.6%). In NHANES, the median estimated GFR was 94.5 mL/min per 1.73 m2 (IQR, 79.7 to 108.1) vs. 85.0 (IQR, 72.9 to 98.5) mL/min per 1.73 m2, and the prevalence of chronic kidney disease was 11.5% (95% CI, 10.6% to 12.4%) versus 13.1% (CI, 12.1% to 14.0%).” (A. S. Levey)
Potassium Homeostasis and Hypokalemia: The body has the capability of anticipating drops in potassium and activate feedforward responses, write authors of a narrative review (pp. 619–25). They note: “New data make clear that feedforward homeostatic responses activate when decreased potassium intake is sensed, even when plasma potassium concentration is still within the normal range and before frank hypokalemia ensues, in addition to the classic feedback activation of renal potassium conservation when plasma potassium concentration decreases. Given the clinical importance of dyskalemias in patients, these novel experimental paradigms invite renewed clinical inquiry into this important area.” (B. C. Kone, bkone@ufl.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 © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 6, 2009 * Vol. 16, No. 86
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source: May 6 issue of JAMA (2009; 301).
Health Care Reform: Commentaries discuss philosophies and ideologies framing the health care reform debate.
Two authors, one of them a physician–attorney with CVS Caremark, review the reasons behind health care reform before launching into a discussion of experiences with regulation of small-group and individual markets in Massachusetts and the possibility of an AmeriCare program that might create competition between Medicare and private insurers as part of a universal-coverage effort (pp. 1814–6). The pair conclude: “Reform proposals based on twinning Medicare expansions with connector-based oversight of the individual and small-group markets suggest an incremental approach to reform that does not abandon market competition, and hence may be more politically viable than fundamental reform has been in the past. But the reform’s passage is not imminent and indeed will be challenging. Because the goal is to cover more individuals while spending less, reform will involve losses for some, sparking resistance. Moreover, many who share the goal of universal access are nonetheless committed to market efficiencies and innovations and will fear these will be lost in a government-dominated approach. This philosophical/political difference will be the critical basis for debate even for an apparently incremental reform plan.” (T. A. Brennan, tabrennan@cvs.com)
The author of the second article outlines three ideology-influenced options for creating a federal program funded by payroll taxes and covering all Americans (pp. 1816–8): “First, the federal government could choose to employ or contract with hospitals, physicians, and other professionals to treat patients who need medical care. Under this model, the government acts not simply as an insurer but as a provider of health care. The Veterans Affairs health care system takes this approach.
“In the other 2 options for universal coverage, the federal government acts as insurer, but not as a provider, of health care. In one option, the government would provide health care coverage to everyone, paying hospital, physician, and pharmacy bills, but leaving it to individuals to choose their physicians and other health care professionals, who may be privately or publicly employed. Medicare follows this model.
“Alternatively, the government could provide a voucher to everyone for the purchase of health care insurance, and each person would then find a private plan for coverage. The private plans would be required to accept the voucher as payment in full. While such a program does not exist in the United States, it has been proposed.” (D. Orentlicher, dorentli@iupui.edu)

>>>Circulation Highlights
Source: May 5 issue of Circulation (2009; 119).
PAD & Bone Loss in Men: Community-dwelling older men with peripheral artery disease have increased risks of hip bone loss and nonspine fractures, report authors of a 5,781-patient study (pp. 2305–12). Over a mean follow-up period of 5.4 years, investigators found: “The mean annualized rate of bone loss at the total hip was –0.66% per year (95% confidence interval –0.78 to –0.54) in men with PAD compared with –0.34% per year (95% confidence interval –0.36 to –0.31) in men without PAD (P < 0.001). After further adjustment for multiple potential confounders, the difference was attenuated (–0.49% in men with PAD versus –0.35% in men without PAD) but remained significant (P = 0.02). Findings were similar at hip subregions. Twelve percent of men with PAD and 7.9% of those without PAD experienced an incident nonspine fracture (hazard ratio adjusted for age, race, and site = 1.47, 95% confidence interval 1.07 to 2.04); this association was not altered substantially by further adjustment for multiple confounders.” (T. C. Collins, tcc@umn.edu)

>>>PNN NewsWatch
* FDA yesterday issued an update on suicidal behavior and ideation associated with use of antiepileptic drugs, including class label changes and Medication Guides.
* While the number of cases of swine influenza A (H1N1) have topped 400 in the U.S., only one patient has died, and concerns about an immediate pandemic are subsiding. CDC reports that it has completed deployment of 25% of supplies in the national stockpile.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 7, 2009 * Vol. 16, No. 87
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source: May 7 issue of the New England Journal of Medicine (2009; 360).
Dealing with Patients About Vaccine Refusal: Some clinicians have ended relationships with patients/parents who refuse vaccines, but the “American Academy of Pediatrics Committee on Bioethics advises against this and recommends that clinicians address vaccine refusal by respectfully listening to parental concerns and discussing the risks of nonvaccination,” authors write in a Special Article (pp. 1981–8). “Vaccines are among the most effective prevention tools available to clinicians,” the group continues. “However, the success of an immunization program depends on high rates of acceptance and coverage. There is evidence of an increase in vaccine refusal in the United States and of geographic clustering of refusals that results in outbreaks. Children with exemptions from school immunization requirements (a measure of vaccine refusal) are at increased risk for measles and pertussis and can infect others who are too young to be vaccinated, cannot be vaccinated for medical reasons, or were vaccinated but did not have a sufficient immunologic response.” Supporting continued engagement of clinicians with reluctant parents, the authors note that “clinicians can play a crucial role in parental decision making” and “health care providers are cited as the most frequent source of immunization information by parents, including parents of unvaccinated children.” (S. B. Omer, somer@emory.edu)
Comparative-Effectiveness Research: Three Perspective articles debate aspects of comparative-effectiveness research efforts under way in Washington, including whether the resulting guidelines and algorithms threaten personalized medicine (pp. 1925–7; A. M. Garber); the effects of $1.1 billion in funding in the economic recovery law (pp. 1927–9; J. Avorn); and positive effects of CER when it has been implemented previously (pp. 1929–31; A. D. Naik). Avorn writes: “Fortunately, Congress did not let warnings of a dystopian scientific police state undercut the nation’s need to learn what works best in medicine. Given the quality and cost crises we face, preserving ignorance would have been a poor strategy for improving the effectiveness, safety, and affordability of health care. Although CER dodged a barrage of well-coordinated bullets this time, the debate is bound to continue. To engage in it responsibly, we must stay focused on the methodologic, practical, and ethical issues we will face in the new era of CER, while avoiding the disinformation and distractions that seek to equate generating new knowledge with denial of care.”

>>>PNN NewsWatch
* FDA has approved iloperidone tablets (Fanapt, Vanda Pharmaceuticals; Patheon Inc.) for treatment of adults with schizophrenia. Labeling for the second-generation (atypical) antipsychotic agent contain the boxed warning for this class alerting prescribers to an increased risk of death associated with off-label use of these drugs to treat behavioral problems in older people with dementia-related psychosis. In two placebo-controlled, short-term clinical trials, iloperidone was superior to placebo in reducing the symptoms of schizophrenia. The most common adverse reactions reported by patients on the drug were dizziness, dry mouth, fatigue, nasal congestion, orthostatic hypotension, drowsiness, tachycardia, and weight increase.
* A new Sanofi Pasteur influenza vaccine production facility has been approved by FDA, the agency announced yesterday. Fluzone will be manufactured there, FDA noted, adding that the facility could be used to make swine flu vaccine.
* Six pharmacy organizations met with high-level officials from the Obama administration on Tuesday regarding pharmacy’s role in a reformed health care system, APhA reports. Core messages delivered to the White House were: (1) Take advantage of health care’s most accessible professional. (2) Make medication therapy management (MTM) more widely available to patients who need help with the most commonly used modality of treatment. (3) More fully use and integrate the professional capabilities of all health care providers. (4) Through advances in health information technology, assure that all pharmacists have access to the clinical information needed for providing MTM services to patients. (5) Build upon pharmacy’s success with immunizations and recognize the role that pharmacists can play in prevention and wellness efforts.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 8, 2009 * Vol. 16, No. 88
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source: May issue of Pharmacotherapy (2009; 29).
QTc Intervals with Lofexidine/Methadone: ECG monitoring for prolonged QTc intervals may be needed when lofexidine and methadone are used concomitantly, according to a preliminary study of 14 adults with opioid dependence (pp. 495–502). After 3 weeks of methadone stabilization, the alpha-2 agonist lofexidine, an agent used in opioid detoxification, was added in escalating doses over the next 5 weeks, with these results: “Repeated-measures regression showed no significant changes in heart rate or PR, QRS, or QTc interval after methadone stabilization, but a significant decrease in heart rate (mean ± SD -8.0 ± 7.3 beats/min, p = 0.0006) after starting lofexidine. When data were analyzed by using maximal ECG response, again, no significant changes were noted during methadone induction compared with baseline, but significant changes did occur in all four ECG parameters when lofexidine was coadministered: decreased heart rate (mean ± SD -9.6 ± 5.8 beats/min, p < 0.0001) and increased PR interval (+11.1 ± 19.8 msec, p = 0.026), QRS interval (+3.7 ± 4.3 msec, p = 0.002), and QTc interval (+21.9 ± 40.8 msec, p = 0.018). In three female participants, the change in QTc interval from baseline was clinically significant (> 40 msec).”(K. L. Preston, kpreston@intra.nida.nih.gov)
Therapeutic Drug Monitoring in TB/HIV: Among 21 patients with advanced HIV infection who were treated for active tuberculosis, monitoring of antimycobacterial agents showed low concentrations suggestive of poor absorption, report researchers who concluded that monitoring of TB drugs may be needed (pp. 503–10). In a retrospective cohort study, serum concentrations following daily doses of isoniazid and rifamycins (rifamycin or rifabutin) showed these patterns: “Of the 21 patients, 18 (86%) had low serum concentrations of at least one drug 2 hours after ingestion: 2 (10%) had low isoniazid concentrations, 5 (24%) had low rifamycin concentrations, and 11 (52%) had low serum concentrations of both drugs. The median number of dosage adjustments to attain normal concentrations was 1 (range 0–4 adjustments). The median cost/patient for therapeutic drug monitoring was $619 (range $230–1948). The median final doses to achieve normal concentrations were isoniazid 600 mg/day (range 300–1500 mg/day), rifampin 1,050 mg/day (range 600–1200 mg/day), and rifabutin 300 mg (range 150–450 mg) 3 times/week. No patient demonstrated any adverse effects attributed to these higher doses.” (J. E. Stout, stout002@mc.duke.edu)

>>>PNN NewsWatch
* FDA yesterday officially approved delayed-release pancrelipase (Creon, Solvay), the first agent to reach this stage under the agency’s initiative aimed at dealing with previously marketed but unapproved drug products. FDA had required the manufacturer to submit a Risk Evaluation and Mitigation Strategy, which includes a Medication Guide, to advise patients on risks associated with high doses of Creon, and the theoretical risk of transmission of viral disease from pigs to patients as a result of using the porcine-derived enzyme. FDA’s Office of Compliance and Office of New Drugs continues to encourage the manufacturers of all other unapproved pancreatic enzyme products to work with the agency to obtain market approval. All such products must obtain FDA approval by April 28, 2010, or be removed from the marketplace, the agency noted in a news release.
* Two prescription topical testosterone gel products, AndroGel 1% and Testim 1%, are now required by FDA to include a black box on products’ labels warning of adverse effects in children who were inadvertently exposed to testosterone through contact with another person being treated with these products. Eight cases of such secondary exposure, occurring in children aged 9 months to 5 years, had been reported to FDA by Dec. 1, 2008. Adverse events included inappropriate enlargement of the genitalia (penis or clitoris), premature development of pubic hair, advanced bone age, increased libido, and aggressive behavior. In most cases, the signs and symptoms regressed when the child no longer was exposed to the product. However, in a few cases, enlarged genitalia did not fully return to age-appropriate size and bone age remained modestly greater than the child’s chronologic age.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 11, 2009 * Vol. 16, No. 89
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: May 9 issue of Lancet (2009; 372).
Voglibose for Diabetes Prevention: Combined with lifestyle modification, the alpha-glucosidase inhibitor voglibose reduced development of type 2 diabetes among 1,780 Japanese patients with impaired glucose tolerance (pp. 1607–14). The participants, at high risk of diabetes, received either oral voglibose 0.2 mg or placebo three times daily for 3 years, or until they developed type 2 diabetes or reverted to normoglycemia. Results showed: “In the interim analysis, voglibose was better than placebo (p = 0.0026) in individuals treated for an average of 48.1 weeks (SD 36.3). Patients treated with voglibose had a lower risk of progression to type 2 diabetes than did those on placebo (50 of 897 vs 106 of 881; hazard ratio 0.595, 95% CI 0.433—0.818; p = 0.0014). More people in the voglibose group achieved normoglycaemia than did those in the placebo group (599 of 897 vs 454 of 881; 1.539, 1.357—1.746; p < 0.0001). 810 (90%) of 897 patients in the voglibose group had adverse events versus 750 (85%) of 881 in the placebo group. Serious adverse events (all one each) in the voglibose group were cholecystitis, colonic polyp, rectal neoplasm, inguinal hernia, liver dysfunction, and subarachnoid haemorrhage, and in the placebo group were cerebral infarction and cholecystitis.” (R. Kawamori, kawamori@juntendo.ac.jp)
Questioning why this study was terminated early, an editorialist writes (pp. 1579–80): “Why the independent data-monitoring committee decided to end the voglibose study early is not known. One might be able to understand such a decision when the primary endpoint included major adverse cardiovascular events or mortality, but not when (as here) the endpoint is transition from impaired glucose tolerance to diabetes. This decision led to a much shorter follow-up (<1 year) in this study than in other trials. Additionally, early stopping of randomised trials for no overt efficacy can be problematic and can lead to an overestimation of the difference between the treatment arms. Whether these preventive approaches can slow the development of vascular complications of diabetes and ultimately reduce diabetes-related mortality remains an open question.” (A. J. Scheen, andre.scheen@chu.ulg.ac.be)

>>>BMJ Highlights
Source: Early-release article from BMJ (2009; 337).
POC Testing in Lower Respiratory Tract Infections: Point of care testing for C-reactive protein, a possible biomarker for lower respiratory tract infections, can reduce antibiotic prescribing without compromising recovery or satisfaction with care, researchers report (b1374). In a trial of POC testing plus enhanced communications skills for 40 general practitioners at 20 Dutch practices, these results were observed with 431 patients with lower respiratory tract infections: “General practitioners in the C reactive protein test group prescribed antibiotics to 31% of patients compared with 53% in the no test group (P = 0.02). General practitioners trained in enhanced communication skills prescribed antibiotics to 27% of patients compared with 54% in the no training group (P < 0.01). Both interventions showed a statistically significant effect on antibiotic prescribing at any point during the 28 days’ follow-up. Clinicians in the combined intervention group prescribed antibiotics to 23% of patients (interaction term was non-significant). Patients’ recovery and satisfaction were similar in all study groups.” (J. W. L. Cals, j.cals@hag.unimaas.nl)

>>>PNN NewsWatch
* FDA has approved bevacizumab (Avastin, Genentech) for use in treatment of glioblastoma multiforme.
* Confirmed and probable cases of swine influenza A (H1N1) are approaching 3,000 in the U.S., with 3 deaths now reported, 2 in Texas and 1 in Washington State. CDC said in a Saturday media briefing that an acceleration of cases can be expected and that this strain “is a very easily transmissible virus similar to the seasonal influenza viruses.”

>>>PNN JournalWatch
* Genomics, Transcriptional Profiling, and Heart Failure, in Journal of the American College of Cardiology, 2009; 53: 1752–9. (K. B. Margulies, ken.margulies@uphs.upenn.edu)
* Diagnosis and Management of Asthma in Older Adults, in Journal of the American Geriatrics Society, 2009; 57: 901–9. (S. H. Chotirmall, schotirmall@rcsi.ie)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 12, 2009 * Vol. 16, No. 90
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: May 11 issue of the Archives of Internal Medicine (2009; 169).
Pharmacist Care in Old–Old Adults: Addition of the pharmacist to the health care team caring for adults aged 80 years and older “would lead to major reductions in morbidity and health care costs,” authors of Swedish study conclude (pp. 894–900). At the University Hospital of Uppsala, 400 patients were randomized to control (standard care without direct involvement of ward pharmacists) or pharmacist intervention (comprehensive list of current medications compiled on admission with comparison to list compiled in emergency department; drug review with advice to physician on drug selection, dosages, and monitoring needs; education and monitoring of patients; discharge counseling; follow-up telephone call to patients 2 months after discharge) groups, with these results: “Three hundred sixty-eight patients (182 in the intervention group and 186 in the control group) were analyzed. For the intervention group, there was a 16% reduction in all visits to the hospital (quotient, 1.88 vs 2.24; estimate, 0.84; 95% confidence interval [CI], 0.72–0.99) and a 47% reduction in visits to the emergency department (quotient, 0.35 vs 0.66; estimate, 0.53; 95% CI, 0.37–0.75). Drug-related readmissions were reduced by 80% (quotient, 0.06 vs 0.32; estimate, 0.20; 95% CI, 0.10–0.41). After inclusion of the intervention costs, the total cost per patient in the intervention group was $230 lower than that in the control group.” (U. Gillespie, Ulrika.gillespie@farmbio.uu.se)
ALLHAT Redux: Combining data from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) with new information on heart failure (HF), authors reevaluate the association of drug treatment with new-onset diabetes mellitus (DM) and its cardiovascular disease (CVD) consequences (pp. 832–42): “Chlorthalidone was superior to (1) doxazosin mesylate in preventing combined CVD (CCVD) (risk ratio [RR], 1.20; 95% confidence interval [CI], 1.13–1.27), especially HF (RR, 1.80; 95% CI, 1.40–2.22) and stroke (RR, 1.26; 95% CI, 1.10–1.46); (2) lisinopril in preventing CCVD (RR, 1.10; 95% CI, 1.05–1.16), including stroke (in black persons only) and HF (RR, 1.20; 95% CI, 1.09–1.34); and (3) amlodipine besylate in preventing HF, overall (by 28%) and in hospitalized or fatal cases (by 26%). Central independent blinded reassessment of HF hospitalizations confirmed each comparison. Results were consistent by age, sex, race (except for stroke and CCVD), DM status, metabolic syndrome status, and renal function level. Neither amlodipine nor lisinopril was superior to chlorthalidone in preventing end-stage renal disease overall, by DM status, or by renal function level. In the chlorthalidone arm, new-onset DM was not significantly associated with CCVD (RR, 0.96; 95% CI, 0.88–2.42). Evidence from subsequent analyses of ALLHAT and other clinical outcome trials confirm that neither alpha-blockers, angiotensin-converting enzyme inhibitors, nor calcium channel blockers surpass thiazide-type diuretics (at appropriate dosage) as initial therapy for reduction of cardiovascular or renal risk. Thiazides are superior in preventing HF, and new-onset DM associated with thiazides does not increase CVD outcomes.” (S. L. Pressel, Sara.L.Pressel@uth.tmc.edu)
Syncope with Cholinesterase Inhibitors: Among older patients with dementia, rates of syncope, bradycardia, pacemaker insertion, and hip fracture are increased by cholinesterase inhibitors, a study shows (pp. 867–73). Population-based cohort analysis of Ontario databases in 2002–04 showed these patterns among 19,803 community-dwelling older adults with dementia who were prescribed cholinesterase inhibitors and 61,499 controls: “Hospital visits for syncope were more frequent in people receiving cholinesterase inhibitors than in controls (31.5 vs 18.6 events per 1,000 person–years; adjusted hazard ratio [HR], 1.76; 95% confidence interval [CI], 1.57–1.98). Other syncope-related events were also more common among people receiving cholinesterase inhibitors compared with controls: hospital visits for bradycardia (6.9 vs 4.4 events per 1000 person–years; HR, 1.69; 95% CI, 1.32–2.15), permanent pacemaker insertion (4.7 vs 3.3 events per 1000 person–years; HR, 1.49; 95% CI, 1.12–2.00), and hip fracture (22.4 vs 19.8 events per 1,000 person–years; HR, 1.18; 95% CI, 1.04–1.34). Results were consistent in additional analyses in which subjects were either matched on their baseline comorbidity status or matched using propensity scores.” (S. S. Gill)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 13, 2009 * Vol. 16, No. 91
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source: May 13 issue of JAMA (2009; 301).
Aspirin in Peripheral Artery Disease: While reducing the frequency of nonfatal stroke, aspirin has not provided a significant benefit in patients with peripheral artery disease with regard to prevention of cardiovascular disease, conclude authors of a meta-analysis of 18 trials (pp. 1909–19). The group writes: “Among 5,269 participants, cardiovascular events were experienced by 251 (8.9%) of 2,823 patients taking aspirin (alone or with dipyridamole) and by 269 (11.0%) of 2,446 in the control group (pooled relative risk [RR], 0.88; 95% confidence interval [CI], 0.76–1.04). Aspirin therapy was associated with a reduction in the secondary outcome of nonfatal stroke (52 of 2,823 vs 76 of 2,446; RR, 0.66; 95% CI, 0.47–0.94) but was not associated with significant reductions in all-cause or cardiovascular mortality, MI, or major bleeding. In the subset of 3,019 participants taking aspirin alone vs control, aspirin was associated with a nonsignificant reduction in cardiovascular events (125 of 1,516 vs 144 of 1,503; RR, 0.75; 95% CI, 0.48–1.18), a significant reduction in nonfatal stroke (32 of 1,516 vs 51 of 1,503; RR, 0.64; 95% CI, 0.42–0.99), but no statistically significant reductions in all-cause or cardiovascular mortality, MI, or major bleeding.” (W. R. Hiatt, will.hiatt@UCDenver.edu)
Editorialists counter that aspirin should still be recommended in patients with PAD, as the available evidence is from less-than-optimal trials that lack statistical power (pp. 1927–8): “Based on the limitations of data available, the findings should not alter recommendations for aspirin as an important therapeutic tool for secondary prevention in patients with PAD. To best inform evidence-based clinical practice guidelines, more high-quality clinical trials are needed. Achieving this will require greater resources for research and a larger critical mass of clinical investigators dedicated to the study of PAD.” (M. McGrae McDermott, mdm608@northwestern.edu)
Estradiol Levels in Men with HF: High and low serum estradiol concentrations are associated with increased mortality in men with systolic chronic heart failure, compared with midrange values, researchers report (pp. 1892–901). The study was based on two facts that lead to the conclusion that abnormal estrogen metabolism might be expected in these patients: androgen deficiency is common among men with HF, and estrogens are formed by aromatization of androgens. In a prospective observational study in Poland, 501 men with chronic HF were assessed based on quintiles of serum estradiol levels: “171 deaths (34%) occurred during the 3-year follow-up. Compared with quintile 3, men in the lowest and highest estradiol quintiles had increased mortality (adjusted hazard ratio [HR], 4.17; 95% confidence interval [CI], 2.33–7.45 and HR, 2.33; 95% CI, 1.30–4.18; respectively; P < .001). These 2 quintiles had different clinical characteristics (quintile 1: increased serum total testosterone, decreased serum DHEA-S, advanced NYHA class, impaired renal function, and decreased total fat tissue mass; and quintile 5: increased serum bilirubin and liver enzymes, and decreased serum sodium; all P < .05 vs quintile 3). For increasing estradiol quintiles, 3-year survival rates adjusted for clinical variables and androgens were 44.6% (95% CI, 24.4%–63.0%), 65.8% (95% CI, 47.3%–79.2%), 82.4% (95% CI, 69.4%–90.2%), 79.0% (95% CI, 65.5%–87.6%), and 63.6% (95% CI, 46.6%–76.5%); respectively (P < .001).” (E. A. Jankowska, ewa.jankowska@antro.pan.wroc.pl)
HCR & Commitment to Care: The JAMA Editor explores the “commitment to care for the community” in an editorial on health care reform (pp. 1929–30): “With the variety of proposed solutions to the problem of so many Americans not having access to care, in this case primary care, the common theme is commitment to care for the community. This includes commitment by physicians and other clinicians to provide the kind of care they know is best for patients, commitment by all payers—private or public—to provide the resources needed for this care, and commitment by patients to pay for what they can and not to misuse the system that provides care for them. Some individuals might believe this effort to be a pipe dream, but without the commitments by all those involved, there will never be a health system in the United States to care for all who truly need it.” (C. D. DeAngelis, cathy.deangelis@jama-archives.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 © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 14, 2009 * Vol. 16, No. 92
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source: May 14 issue of the New England Journal of Medicine (2009; 360).
Adjuvant Breast Cancer Chemotherapy in Older Women: Among women with early-stage breast cancer and 65 years of age or older, standard adjuvant chemotherapy proved superior to capecitabine, according to results from the CALGB (Cancer and Leukemia Group B) trial (pp. 2055–65). Standard chemotherapy (cyclophosphamide, methotrexate, and fluorouracil; or cyclophosphamide plus doxorubicin) or capecitabine was used to treat the stage I, II, IIIA, or IIIB breast cancer tumors in patients. Researchers report: “When the 600th patient was enrolled, the probability that, with longer follow-up, capecitabine therapy was highly likely to be inferior to standard chemotherapy met a prescribed level, and enrollment was discontinued. After an additional year of follow-up, the hazard ratio for disease recurrence or death in the capecitabine group was 2.09 (95% confidence interval, 1.38 to 3.17; P < 0.001). Patients who were randomly assigned to capecitabine were twice as likely to have a relapse and almost twice as likely to die as patients who were randomly assigned to standard chemotherapy (P = 0.02). At 3 years, the rate of relapse-free survival was 68% in the capecitabine group versus 85% in the standard-chemotherapy group, and the overall survival rate was 86% versus 91%. Two patients in the capecitabine group died of treatment-related complications; as compared with patients receiving capecitabine, twice as many patients receiving standard chemotherapy had moderate-to-severe toxic effects (64% vs. 33%).” (H. B. Muss, hyman.muss@gmail.com)
Clopidogrel plus Aspirin in Atrial Fibrillation: For patients with atrial fibrillation unable to take vitamin K antagonists, clopidogrel plus aspirin provides a useful alternative, lowering the risk of stroke and other major vascular events, report ACTIVE (Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events) investigators (pp. 2066–78). Among 7,554 patients, clopidogrel 75 mg or placebo daily, with aspirin therapy, produced these results: “At a median of 3.6 years of follow-up, major vascular events had occurred in 832 patients receiving clopidogrel (6.8% per year) and in 924 patients receiving placebo (7.6% per year) (relative risk with clopidogrel, 0.89; 95% confidence interval [CI], 0.81 to 0.98; P = 0.01). The difference was primarily due to a reduction in the rate of stroke with clopidogrel. Stroke occurred in 296 patients receiving clopidogrel (2.4% per year) and 408 patients receiving placebo (3.3% per year) (relative risk, 0.72; 95% CI, 0.62 to 0.83; P < 0.001). Myocardial infarction occurred in 90 patients receiving clopidogrel (0.7% per year) and in 115 receiving placebo (0.9% per year) (relative risk, 0.78; 95% CI, 0.59 to 1.03; P = 0.08). Major bleeding occurred in 251 patients receiving clopidogrel (2.0% per year) and in 162 patients receiving placebo (1.3% per year) (relative risk, 1.57; 95% CI, 1.29 to 1.92; P < 0.001).” (S. J. Connolly, stuart.connolly@phri.ca)
An editorialist describes these next steps in stroke prevention in patients with atrial fibrillation (pp. 2127–9): “First, we need to identify more robust methods to predict the individual risk of ischemic stroke and bleeding—especially intracranial hemorrhage. Second, efforts should focus on delivering high-quality vitamin K–antagonist therapy to patients at increased risk for ischemic stroke. Third, physicians should consistently apply existing data to identify patients eligible for vitamin K–antagonist or antiplatelet therapy and should present a complete and balanced picture of the absolute risks and benefits of each approach to the patient for more effective decision making.” (A. S. Go)
Antivenom for Scorpion Stings: Intravenous administration of scorpion-specific F(ab&rsquo2 antivenom to 15 critically ill children with neurotoxicity from scorpion envenomation resolved the clinical syndrome within 4 hours, reduced the need for concomitant sedation with midazolam, and reduced levels of circulating unbound venom (pp. 2090–8). In a randomized, double-blind study, investigators note: “More midazolam was administered in the placebo recipients than in the antivenom recipients (mean cumulative dose, 4.61 vs. 0.07 mg per kilogram of body weight; P = 0.01). Plasma venom concentrations were undetectable in all eight antivenom recipients but in only one placebo recipient 1 hour after treatment (P = 0.001).” (L. V. Boyer , boyer@pharmacy.arizona.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 15, 2009 * Vol. 16, No. 93
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source: May 19 issue of the Journal of the American College of Cardiology (2009; 53).
Statins in Rheumatic Valve Stenosis: Progression of degenerative aortic valve stenosis (AS) is slowed by statin therapy, report authors who studied patients with rheumatic heart disease (pp. 1874–9). Retrospective identification of patients with echocardiographic evidence of AS showed these patterns in their histories: “The study population consisted of 164 patients (30 treated with statins) followed up for 8.5 ± 4.2 years. Peak aortic velocity at baseline was not different in patients treated with statins versus untreated patients (2.3 ± 0.8 m/s vs. 2.3 ± 0.7 m/s, p = 0.84). There were no significant differences in sex, age, or follow-up duration between the 2 groups. Progression of AS severity was slower in patients receiving statins compared with untreated patients (annual change of peak aortic velocity: 0.05 ± 0.07 m/s/year vs. 0.12 ± 0.11 m/s/year, p = 0.001). An annual rate of peak velocity progression 0.1 m/s was found in 10% of statin-treated patients and in 49% of untreated patients (p < 0.0001).” (F. Antonini-Canterin, cardiologia@aopn.fvg.it)
Editorialists provide interim advice for clinicians interpreting this study for their patients with rheumatic heart disease until better evidence is available from currently ongoing trials (pp. 1880–2): “For some patients, the presence of concomitant indications for statin therapy makes the decision easy. For the rest, the decision to initiate treatment is more complex. Women have a higher incidence of progression to valvular RHD than men. Unfortunately, the progression of RHD is likely to occur during childbearing years for women. Statins are contraindicated in pregnancy and in women who are likely to become pregnant. Therefore, this not-fully-proven option is not appropriate for many at risk of RHD.” (O. Ben-Yehuda)
RAAS Genotypes & Cardiac Transplant Rejection: While more study is needed, inhibitors of the renin–angiotensin–aldosterone system (RAAS) may be useful following cardiac transplantation for decreasing rejection in patients with certain high-risk genotypes associated with RAAS upregulation (pp. 1909–17). Patients, all under 25 years of age, were genotyped for polymorphisms in genes associated with RAAS upregulation: AGT-G, ACE-D, AGTR1-C, CYP11B2-G, and CMA-A, with these results: “A total of 145 patients were studied, 103 primary cohort and 42 replication cohort; 81% had rejection, 51% had graft dysfunction, and 13% had vasculopathy, 7% died, and 8% underwent re-transplantation. A higher number of homozygous high-risk RAAS genotypes was associated with a higher risk of graft dysfunction (hazard ratio [HR]: 1.5, p = 0.02) and a higher probability of death (HR: 2.5, p = 0.04). The number of heterozygous high-risk RAAS genotypes was associated with frequency of rejection (+0.096 events/year, p < 0.001) and rejection-associated graft dysfunction (+0.37 events/year, p = 0.002). IL-6 and TGF-beta were markedly upregulated during rejection in patients with 2 high-risk RAAS genotypes.” (S. Mital, seema.mital@sickkids.ca)
Prevention of Infective Endocarditis: Differing with newly updated American College of Cardiology/American Heart Association Guidelines for the Management of Patients With Valvular Heart Disease, an author provides his viewpoint on use of antibiotic prophylaxis in such patients (pp. 1852–4): “The new recommendations represent a dramatic shift with regard to which patients should receive antibiotic prophylaxis for prevention of [infective endocarditis (IE)] and for what procedures. The shift in recommendations is striking in that the recommendations are based not on new data, but on no data. (There are no large, prospective, randomized double-blind trials testing the efficacy of IE prophylaxis.) However, available data suggest that there may be no real risk associated with IE prophylaxis. Even if few cases of IE are successfully prevented using antibiotic prophylaxis, those few cases may represent a favorable risk–benefit ratio. On an individual basis, patients with organic heart valve disease who are trying to delay or avoid surgical intervention have something very real to risk if they develop IE, and a very real benefit if they avoid it. Pending data from prospective randomized trials, a strategy of individual decision-making by informed patients may be best.” (D. S. Bach, dbach@umich.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 18, 2009 * Vol. 16, No. 94
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: May 16 issue of Lancet (2009; 372).
Rivaroxaban After Total Knee Arthroplasty: For prevention of venous thromboembolism after total knee arthroplasty in 3,148 patients, oral rivaroxaban 10 mg once daily for 10—14 days proved significantly superior to subcutaneous enoxaparin 30 mg given every 12 h, RECORD4 (Regulation of Coagulation in Orthopaedic Surgery to Prevent Deep Vein Thrombosis and Pulmonary Embolism) investigators report (pp. 1673–80). Looking at a composite outcome of any deep-vein thrombosis, nonfatal pulmonary embolism, or death from any cause up to day 17 after surgery, the researchers found: “The primary efficacy outcome occurred in 67 (6.9%) of 965 patients given rivaroxaban and in 97 (10.1%) of 959 given enoxaparin (absolute risk reduction 3.19%, 95% CI 0.71—5.67; p = 0.0118). Ten (0.7%) of 1,526 patients given rivaroxaban and four (0.3%) of 1,508 given enoxaparin had major bleeding (p = 0.1096).” (A. G. G. Turpie, turpiea@mcmaster.ca)
Sequential Docetaxel for Early Breast Cancer: If sequential docetaxel has any advantage over standard anthracycline chemotherapy for adjuvant chemotherapy of early breast cancer, it must be in subgroups of patients, conclude investigators who found no differences in an overall population of 4,162 women in TACT (Taxotere as Adjuvant Chemotherapy Trial) (pp. 1681–92). Intention-to-treat analysis of trial results showed: “With a median follow-up of 62 months, disease-free survival events were seen in 517 of 2,073 patients in the experimental group compared with 539 of 2,089 controls (hazard ratio [HR] 0.95, 95% CI 0.85—1.08; p = 0.44). 75.6% (95% CI 73.7—77.5) of patients in the experimental group and 74.3% (72.3—76.2) of controls were alive and disease-free at 5 years. The proportion of patients who reported any acute grade 3 or 4 adverse event was significantly greater in the experimental group than in the control group (p < 0.0001); the most frequent events were neutropenia (937 events vs 797 events), leucopenia (507 vs 362), and lethargy (456 vs 272).” (P. Ellis, paul.ellis@gstt.nhs.uk)

>>>BMJ Highlights
Source: Early-release article from BMJ (2009; 337).
Congenital Heart Disease After Folic Acid Food Fortification: In Quebec, mandatory fortification of flour and pasta products with folate was associated with a decrease in severe congenital heart defects among newborns (b1673). Using a time-trend analysis of administrative databases, researchers found these patterns among infants born between 1990 and 2005 with tetralogy of Fallot, endocardial cushion defects, univentricular hearts, truncus arteriosus, or transposition complexes: “Among the 1,324,440 births in Quebec in 1990–2005 there were 2,083 infants born with severe congenital heart defects, corresponding to an average birth prevalence of 1.57/1,000 births. Time trend analysis showed no change in the birth prevalence of severe birth defects in the nine years before fortification (rate ratio 1.01, 95% confidence interval 0.99 to 1.03), while in the seven years after fortification there was a significant 6% decrease per year (0.94, 0.90 to 0.97).” (L. Pilote, louise.pilote@mcgill.ca)

>>>PNN JournalWatch
* Cryptococcosis in Solid-Organ, Hematopoietic Stem Cell, and Tissue Transplant Recipients: Evidence-Based Evolving Trends, in Clinical Infectious Diseases, 2009; 48: 1566–76. (N. Singh, nis5@pitt.edu)
* Should Patients with Rheumatoid Arthritis Receive Statin Therapy [editorial]?, in Arthritis & Rheumatism, 2009; 60: 1205–9. (P. M. Ridker, pridker@partners.org)
* Health Literacy and Kidney Disease, in American Journal of Kidney Diseases, 2009; 53: 884–9. (R. Devraj, rdevraj@siue.edu)
* Thrombolytic Therapy for Acute Pulmonary Embolism: A Critical Appraisal, in Chest, 2009; 135: 1321–9. (V. F. Tapson, Tapso001@mc.duke.edu)
* Statin Use and the Risk of Cholecystectomy in Women, in Gastroenterology, 2009; 136: 1593–600. (C. J. Tsai, hpcjt@channing.harvard.edu)
* MRI Features of Benign Multiple Sclerosis: Toward a New Definition of this Disease Phenotype, in Neurology, 2009; 72: 1693–701. (M. Filippi, filippi.massimo@hsr.it)
* Medication Interventions for Fall Prevention in the Older Adult, in Journal of the American Pharmacists Association, 2009; 49: e70–84. (J. W. Cooper, jcooper@mail.rx.uga.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 © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 19, 2009 * Vol. 16, No. 95
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: Early-release articles from and May 19 issue of the Annals of Internal Medicine (2009; 150–1).
Telmisartan & Diabetic Renal Outcomes: In 5,927 adults with known cardiovascular disease or diabetes with end-organ damage but without macroalbuminuria or heart failure who could not tolerate ACE inhibitors, telmisartan was no more effective than placebo for stopping the progression of advanced diabetic nephropathy, according to results of the TRANSCEND (Telmisartan Randomised Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease) trial (early release). Comparing 80-mg daily doses of telmisartan with placebo over a mean of 56 months, the investigators found: “No important difference was found in the composite renal outcome with telmisartan (58 patients [1.96%]) versus placebo (46 patients [1.55%]) (hazard ratio, 1.29 [95% CI, 0.87 to 1.89]; P = 0.20). Among the telmisartan and placebo groups, 7 and 10 patients had dialysis and 56 and 36 patients had doubling of serum creatinine, respectively (hazard ratio, 1.59 [CI, 1.04 to 2.41]; P = 0.031). Albuminuria increased less with telmisartan than with placebo (32% [CI, 23% to 41%] vs. 63% [CI, 52% to 76%]; P < 0.001). Declines in estimated GFR were greater with telmisartan than with placebo (mean change in estimated GFR, –3.2 mL/min per 1.73 m2 (SD, 18.3) vs. –0.26 mL/min per 1.73 m2 (SD, 18.0); P < 0.001).” (ONTARGET Office, ntarget@phri.ca">ontarget@phri.ca),
Candesartan & Kidney Function in Diabetes: In three randomized trials of the DIRECT (Diabetic Retinopathy Candesartan Trials) program, candesartan 32 mg/day failed to prevent microalbuminuria in 3,326 and 1,905 patients with type 1 and type 2 diabetes, respectively (early release). These results were noted over a median of 4.7 years in the mostly normotensive patient population: “Individual and pooled results of the 3 trials showed that candesartan had little effect on risk for microalbuminuria (pooled hazard ratio, 0.95 [95% CI, 0.78 to 1.16]; P = 0.60). Pooled results showed that the annual rate of change in albuminuria was 5.53% lower (CI, 0.73% to 10.14%; P = 0.024) with candesartan than with placebo.” (R. Bilous, rudy.bilous@stees.nhs.uk)
Angiotensin Blockade in Older Adults: The evidence base for use of ACE inhibitors and angiotensin II receptor blockers in older adults with chronic kidney disease is insufficient, authors of a review article conclude (pp. 717–24). A journal summary notes: “Angiotensin-converting enzyme inhibitors and angiotensin II–receptor antagonists are recommended for patients with chronic kidney disease because these drugs can slow disease progression. Older adults account for a large and growing number of patients with chronic kidney disease. The authors evaluated the relevance to adults older than 70 years of the evidence base for major U.S. practice guidelines for the use of these agents in chronic kidney disease. The authors first examined the representation of older adults in randomized trials that underpin these guidelines, then compared the characteristics of participants in these trials with those of a representative sample of older adults with chronic kidney disease in the general population. The authors found that current guidelines for the use of angiotensin-converting enzyme inhibitors and angiotensin II–receptor antagonists in chronic kidney disease are based on evidence with limited relevance to most persons older than 70 years with this condition.” (A. M. O’Hare, ann.ohare@va.gov)

>>>PNN NewsWatch
* Margaret A. Hamburg, MD, was confirmed yesterday by the Senate as FDA Commissioner. Hamburg, former commissioner of health in New York City, is the daughter of two physicians and was on the board of directors of Henry Schein. Hamburg most recently was senior scientist for the Nuclear Threat Initiative/Global Health and Security Initiative, and she served as principal policy advisor to HHS Secretary Donna Shalala in the second term of the Clinton administration.
* On the health care reform front, the Senate Finance Committee yesterday released a list of financing options. The choices will serve as the basis of a “walk through” at a full committee meeting on Wednesday. Options include various ways of achieving cost savings, modifying payments, and taxing lifestyle choices such as alcoholic beverages and sugar-sweetened drinks.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 20, 2009 * Vol. 16, No. 96
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source: May 20 issue of JAMA (2009; 301).
Adverse Events with Tamsulosin After Cataract Surgery: Tamsulosin, used commonly for benign prostatic hyperplasia in older men, produces serious postoperative ophthalmic adverse events when restarted within 14 days of cataract surgery, researchers report (pp. 1991–6). Noting that other alpha-adrenergic blockers did not cause these problems, the investigators reported these results of a nested case–control analysis of health care databases from Ontario: “Overall, 3,550 patients (3.7%) in the cohort had recent exposure to tamsulosin and 7,426 patients (7.7%) had recent exposure to other alpha-blockers. Two hundred eighty-four patients (0.3%) had an adverse event. We randomly matched 280 of the cases to 1,102 controls according to their age, surgeon, and year of surgery. Adverse events were significantly more common among patients with recent tamsulosin exposure (7.5% vs 2.7%; adjusted odds ratio [OR], 2.33; 95% confidence interval [CI], 1.22–4.43) but were not associated with recent exposure to other alpha-blockers (7.5% vs 8.0%; adjusted OR, 0.91; 95% CI, 0.54–1.54) or to previous exposure to either tamsulosin (1.8% vs 1%; adjusted OR, 0.94; 95% CI, 0.27–3.34) or other alpha-blockers (2.9% vs 2.1%; adjusted OR, 1.08; 95% CI, 0.47–2.48). This corresponds to an estimated number needed to harm (NNH) of 255 (95% CI, 99–1666).” (C. M. Bell, mbellc@smh.toronto.on.ca)
An editorialist emphasizes this link between tamsulosin and intraoperative floppy iris syndrome (IFIS) (pp. 2044–5): “Cataract surgery is the most commonly performed operation in the United States today. With nearly 2 million cataract operations performed in the United States each year, the magnitude of IFIS associated with tamsulosin cannot be underestimated. Although the prescribing information for tamsulosin includes IFIS as a ‘general precaution,’ the data on the risk of this complication should be reassessed to determine whether a ‘black box’ warning should be issued to caution the ophthalmic surgeon and the general public (men in particular) of danger to the eye of taking alpha-1-adrenergic blocking agents before cataract surgery.” (A. H. Friedman, alan.friedman@mssm.edu)
Medication Plus CBT for Insomnia: In 160 adults with persistent insomnia, addition of medication to cognitive–behavioral therapy (CBT) proved beneficial during the acute phase of treatment but “long-term outcome was optimized when medication [was] discontinued during maintenance CBT,” investigators conclude (pp. 2005–15). These results were noted with zolpidem 10 mg/d and CBT in this randomized controlled trial: “Cognitive behavioral therapy used singly or in combination with zolpidem produced significant improvements in sleep latency, time awake after sleep onset, and sleep efficiency during initial therapy (all P < .001); a larger increase of sleep time was obtained with the combined approach (P = .04). Both CBT alone and CBT plus zolpidem produced similar rates of treatment responders (60% [45/75] vs 61% [45/74], respectively; P = .84) and treatment remissions (39% [29/75] vs 44% [33/74], respectively; P = .52) with the 6-week acute treatment, but combined therapy produced a higher remission rate compared with CBT alone during the 6-month extended therapy phase and the 6-month follow-up period (56% [43/74 and 32/59] vs 43% [34/75 and 28/68]; P = .05). The best long-term outcome was obtained with patients treated with combined therapy initially, followed by CBT alone, as evidenced by higher remission rates at the 6-month follow-up compared with patients who continued to take zolpidem during extended therapy (68% [20/30] vs 42% [12/29]; P = .04).” (C. M. Morin, cmorin@psy.ulaval.ca)
Regulating Safety of Pharmaceuticals: Reflecting on the recent Wyeth v Levine Supreme Court decision (see PNN, Mar. 5), a Commentary author writes (pp. 2036–7): “Should FDA approval set a regulatory ceiling for product safety or can states enforce higher safety standards? Wyeth will not be the death knell of the preemption doctrine. The Supreme Court strongly hinted that it would preempt tort litigation if the FDA takes an active role and pays close attention to a particular safety risk, and the manufacturer fully discloses all the pertinent facts.” (L. O. Gostin, gostin@law.georgetown.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 © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 21, 2009 * Vol. 16, No. 97
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source: May 21 issue of the New England Journal of Medicine (2009; 360).
Early Use of Eptifibatide in Acute Coronary Syndromes: Among 9,492 patients who had acute coronary syndromes without ST-segment elevation, use of eptifibatide 12 hours or more before angiography failed to provide significant benefits over provisional use of the drug after angiography, researchers report, adding that “the early use of eptifibatide was associated with an increased risk of non–life-threatening bleeding and need for transfusion” (pp. 2176–90). The Early Glycoprotein IIb/IIIa Inhibition in Non–ST-Segment Elevation Acute Coronary Syndrome (EARLY ACS) trial compared early eptifibatide (two boluses of 180 mcg/kg, administered 10 minutes apart, and a standard infusion 12 hours before angiography) with a matching placebo infusion with provisional use of eptifibatide after angiography (delayed eptifibatide). Based on a primary end point of composite of death, myocardial infarction, recurrent ischemia requiring urgent revascularization, or thrombotic complication during percutaneous coronary intervention that required “thrombotic bailout” at 96 hours, results showed: “The primary end point occurred in 9.3% of patients in the early-eptifibatide group and in 10.0% in the delayed-eptifibatide group (odds ratio, 0.92; 95% confidence interval [CI], 0.80 to 1.06; P = 0.23). At 30 days, the rate of death or myocardial infarction was 11.2% in the early-eptifibatide group, as compared with 12.3% in the delayed-eptifibatide group (odds ratio, 0.89; 95% CI, 0.79 to 1.01; P = 0.08). Patients in the early-eptifibatide group had significantly higher rates of bleeding and red-cell transfusion. There was no significant difference between the two groups in rates of severe bleeding or nonhemorrhagic serious adverse events.” (R. P. Giugliano, rgiugliano@partners.org)
Commenting on this and a second study showing lack of benefits with early intervention in patients with ACS (pp. 2165–75; S. R. Mehta, smehta@mcmaster.ca), editorialists write (pp. 2237–40): “Independent of [an] initial risk assessment [using the Thrombolysis in Myocardial Infarction (TIMI) risk score and the Global Registry of Acute Coronary Events (GRACE) risk model], the patient’s general medical and cognitive status, anticipated life expectancy, personal preferences, and risk of treatment-related complications should be evaluated. Since intensive medical therapy and invasive management are associated with bleeding complications, the patient’s risk of such events should be assessed before these therapies are administered. Female sex, older age, renal insufficiency, low body weight, tachycardia, high or low systolic arterial pressure, low hematocrit, and a history of diabetes mellitus predict an increased risk of major bleeding, often due to the administration of excessive doses of antiplatelet or anticoagulant agents. The bleeding risk can be estimated with the tool available at www.crusadebleedingscore.org.” (L. D. Hillis)
Dipyridamole plus Aspirin & Hemodialysis Graft Patency: A “significant but modest” benefit was seen when dipyridamole plus aspirin were used for maintaining patency of newly created hemodialysis grafts, a 649-patient study shows (pp. 2191–201). After placement of a new arteriovenous graft, extended-release dipyridamole 200 mg and aspirin 25 mg were given twice daily until the primary outcome (loss of primary unassisted patency) was reached, with these results over 4.5 years: “The incidence of primary unassisted patency at 1 year was 23% (95% confidence interval [CI], 18 to 28) in the placebo group and 28% (95% CI, 23 to 34) in the dipyridamole–aspirin group, an absolute difference of 5 percentage points. Treatment with dipyridamole plus aspirin significantly prolonged the duration of primary unassisted patency (hazard ratio, 0.82; 95% CI, 0.68 to 0.98; P = 0.03) and inhibited stenosis. The incidences of cumulative graft failure, death, the composite of graft failure or death, and serious adverse events (including bleeding) did not differ significantly between study groups.” (B. S. Dixon, bradley-dixon@uiowa.edu)
Fomepizole for Ethylene Glycol & Methanol Poisoning: Use of the alcohol dehydrogenase inhibitor fomepizole in treatment of ethylene glycol and methanol poisoning is reviewed in a Clinical Therapeutics article (pp. 2216–23). The case of a 35-year-old man provides the springboard to discussion of options in this situation. (J. Brent, jeffrey.brent@ucdenver.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 © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 22, 2009 * Vol. 16, No. 98
Providing news and information about medications and their proper use

>>>Allergy/Immunology Report
Source: May issue of the Journal of Allergy and Clinical Immunology (2009; 123).
Characteristics of Preschool Children Benefitting from Inhaled Steroids: Children with recurrent wheezing who have aeroallergen sensitization, are boys and/or white, or have been seen in the emergency department or as inpatients are most likely to benefit from inhaled corticosteroid therapy, researchers report (pp. 1077–82.e5). In a randomized trial, 285 children aged 2 and 3 years old received placebo or fluticasone propionate 88 mcg twice daily, and these characteristics were identified as predicting improved outcomes: “Multivariate analysis demonstrated significantly greater improvement with fluticasone than placebo in terms of episode-free days among boys, white subjects, participants with an emergency department (ED) visit or hospitalization within the past year, and those who experienced more symptomatic days at baseline. Children with aeroallergen sensitization experienced greater benefits in terms of oral corticosteroid use, urgent care and ED visits, and use of supplemental controller medications.” (L. B. Bacharier, bacharier_L@kids.wustl.edu)
Re-evaluation in Nonallergic Rhinitis: Patients with nonallergic rhinitis should be re-evaluated periodically for asthma, conjunctivitis, and/or sensitization to aeroallergens, according to researchers who analyzed a representative sample of 180 individuals (pp. 1098–102). Study patients had been diagnosed with NAR in 2000–04 and were re-evaluated in 2007 using sociodemographic and clinical questionnaires, spirometry, skin prick testing, and measurement of specific IgE to common aeroallergens, with these results: “Patients with NAR generally experienced worsening disease (52%), with an increase in the persistence (12%) and severity of nasal symptoms (9%) and new comorbidities (24%) over time. The most frequent comorbidities at the re-evaluation were asthma (increasing from 32% to 55%) and conjunctivitis (from 28% to 43%), followed by chronic rhinosinusitis. Sensitization to aeroallergens not present at the initial evolution was detected by means of skin prick testing, serum specific IgE measurement, or both in 24% of the patients.” (C. Rondon, carmenrs61@gmail.com)

>>>JAPhA Highlights
Source: May/June issue of the Journal of the American Pharmacists Association (2009; 49).
Patient Perceptions of Medicare Part D MTM: Patients at four chain pharmacies in Maryland and Delaware had “very limited knowledge of the core elements of [a medication therapy management] service,” but they were “supportive of and believe[d] that MTM services can improve communication and relationship with their pharmacist and improve medication use” (pp. 392–8). Surveys of adults aged 18 or older yielded these insights: “49 of 81 patients (60%) had never heard of MTM services. A total of 65 patients (80%) had never had or received a medication therapy review, 63 (78%) never had or received a personal medication record, and 70 (86%) never had or received a medication action plan. Some 56% of participants (n = 45) thought that pharmacist provision of medication therapy reviews, personal medication records, medication action plans, recommendations about medications, and referral to other health care providers was very important. At least 70% of participants (n = 57) thought that having one-on-one consultation sessions with pharmacists to improve communication and relationships with their pharmacists and to improve their medication use and overall health was very important. More than 50% of participants indicated that they would like to receive brochures or talk to their pharmacist to learn more about MTM services.” (H-A Troung, htroung@rx.umaryland.edu)

>>>PNN NewsWatch
* Legislation that would authorize FDA to regulate tobacco products is nearing passage in Congress. The House previously passed a bill, and, using nearly identical language, the Senate Health, Education, Labor and Pensions Committee this week advanced a bill to the floor in a bipartisan 15–8 vote.
* Recommendations for use of oseltamivir and zanamivir against the H1N1 influenza virus now circulating were issued this week by FDA along with Emergency Use Authorizations and fact sheets.
* PNN will not be published on Mon., May 25, Memorial Day.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 26, 2009 * Vol. 16, No. 99
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: May 23 issue of Lancet (2009; 372).
Intensive Glucose Control in Diabetes: Compiling the divergent data on effectiveness of intensive glucose control in patients with type 2 diabetes, investigators used a meta-analysis to determine that intensive control significantly reduces coronary events without an increased risk of death, compared with standard therapy (pp. 1765–73). “The five trials provided information on 1,497 events of non-fatal myocardial infarction, 2,318 of coronary heart disease, 1,127 of stroke, and 2,892 of all-cause mortality during about 163,000 person–years of follow-up,.” the authors wrote of the 33,040 participants. “The mean haemoglobin A1c concentration (HbA1c) was 0.9% lower for participants given intensive treatment than for those given standard treatment. Intensive glycaemic control resulted in a 17% reduction in events of non-fatal myocardial infarction (odds ratio 0.83, 95% CI 0.75–0.93), and a 15% reduction in events of coronary heart disease (0.85, 0.77–0.93). Intensive glycaemic control had no significant effect on events of stroke (0.93, 0.81–1.06) or all-cause mortality (1.02, 0.87–1.19).” (K. K. Ray, kkr25@medschl.cam.ac.uk)
Type 2 Diabetes After Gestational Diabetes: Based on a 7.5-fold increase in risk of type 2 diabetes among women with gestational diabetes, investigators make these recommendations, “Increased awareness of the magnitude and timing of the risk of type 2 diabetes after gestational diabetes among patients and clinicians could provide an opportunity to test and use dietary, lifestyle, and pharmacological interventions that might prevent or delay the onset of type 2 diabetes in affected women” (pp. 1773–9). Using cohort studies published since 1960, the investigators identified these relationships: “Women with gestational diabetes had an increased risk of developing type 2 diabetes compared with those who had a normoglycaemic pregnancy (RR 7.43, 95% CI 4.79–11.51). Although the largest study (659,164 women; 9,502 cases of type 2 diabetes) had the largest RR (12.6, 95% CI 12.15–13.19), RRs were generally consistent among the subgroups assessed.” (D. Williams, d.j.williams@ucl.ac.uk)

>>>PNN NewsWatch
* Tolvaptan (Samsca, Otsuka) has been approved by FDA as the only oral selective vasopressin V2 antagonist indicated for treatment of patients with clinically significant hypervolemic and euvolemic hyponatremia (serum sodium less than 125 meq/L, or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction), including patients with heart failure, cirrhosis, and the syndrome of inappropriate anti-diuretic hormone. Because of the risk of overly rapid correction of hyponatremia, a boxed warning in the product labeling cautions that tolvaptan treatment should be initiated and re-initiated in patients only in a hospital where serum sodium concentrations can be monitored closely. Too rapid correction of hyponatremia (e.g., increase of greater than 12 meq/L/24 hours) can cause osmotic demyelination syndrome, resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and death. In susceptible patients, including those with severe malnutrition, alcoholism or advanced liver disease, slower rates of correction may be advisable. FDA is also requiring a Risk Evaluation and Mitigation Strategy that requires a patient Medication Guide be given out when the drug is dispensed. The most common adverse reactions with use of tolvaptan reported by patients in clinical trials include thirst, dry mouth, asthenia, constipation, pollakiuria, polyuria, and hyperglycemia.

>>>PNN JournalWatch
* Diabetes: Finding “A Clean Well-Lighted Place,” in Lancet, 2009; 373: 1746–7. (A. M. Jacobson, Alan.Jacobson@joslin.harvard.edu)
* Use of Blood Pressure Lowering Drugs in the Prevention of Cardiovascular Disease: Meta-analysis of 147 Randomised Trials in the Context of Expectations from Prospective Epidemiological Studies, in BMJ, 2009; 338: b1665. (M. R. Law, m.r.law@qmul.ac.uk)
* Adult Liver Transplantation: What Non-specialists Need to Know, in BMJ, 2009; 338: b1670. (G. M. Hirschfield, gideon.hirschfield@uhn.on.ca)
* Association of Obesity with IgE Levels and Allergy Symptoms in Children and Adolescents: Results from the National Health and Nutrition Examination Survey 2005–2006, in Journal of Allergy and Clinical Immunology, 2009; 123: 1163–9.e4. (C. M. Visness, cindy_visness@rhoworld.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 © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 27, 2009 * Vol. 16, No. 100
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: May 25 issue of the Archives of Internal Medicine (2009; 169).
Prescription Errors with CPOE: Just under 1% of medication orders issued using computerized provider order entry contained inconsistent communication, according to a study conducted at a tertiary care facility (pp. 982–9). Over a 4-month period, pharmacists reported problematic prescriptions, and 500 randomly selected orders with comments in a free-text field were examined for inconsistencies with structured fields. Results showed: “Of 55,992 new prescriptions, 532 (0.95%) were reported to contain inconsistent communication, a rate comparable to that obtained from the unreported group. Drug dosage was the most common inconsistent element among both groups. Certain medications were more likely associated with errors, as was the inpatient setting (odds ratio, 3.30; 95% confidence interval, 2.18–5.00) and surgical subspecialty (odds ratio, 2.45; 95% confidence interval, 1.57–3.82). About 20% of errors could have resulted in moderate to severe harm, for which significant independent predictors were found.” (H. Singh, hardeeps@bcm.tmc.edu)

>>>JAMA Highlights
Source: May 27 issue of JAMA (2009; 301).
Self-management of Pain by Patients with Depression: Both depression and pain were better controlled when patients received optimized antidepressant therapy and underwent a pain self-management program, researchers report (pp. 2099–110). In the Stepped Care for Affective Disorders and Musculoskeletal Pain (SCAMP) trial, 250 patients with low back, hip, or knee pain for 3 months or longer and at least moderate depression severity received usual care or an intervention of 12 weeks of optimized antidepressant therapy (step 1) followed by 6 sessions of a pain self-management program over 12 weeks (step 2), and a continuation phase of therapy for 6 months (step 3). Results showed: “At 12 months, 46 of the 123 intervention patients (37.4%) had a 50% or greater reduction in depression severity from baseline compared with 21 of 127 usual care patients (16.5%) (relative risk [RR], 2.3; 95% confidence interval [CI], 1.5–3.2), corresponding to a much lower number of patients with major depression (50 [40.7%] vs 87 [68.5%], respectively; RR, 0.6 [95% CI, 0.4–0.8]). Also, a clinically significant (30%) reduction in pain was much more likely in intervention patients (51 intervention patients [41.5%] vs 22 usual care patients [17.3%]; RR, 2.4 [95% CI, 1.6–3.2]), as was global improvement in pain (58 [47.2%] vs 16 [12.6%], respectively; RR, 3.7 [95% CI, 2.3–6.1]). More intervention patients also experienced benefits in terms of the primary outcome, which was a combined improvement in both depression and pain (32 intervention patients [26.0%] vs 10 usual care patients [7.9%]; RR, 3.3 [95% CI, 1.8–5.4]).” (K. Kroenke, kkroenke@regenstrief.org)
Acid Suppression & Pneumonia: The risk of hospital-acquired pneumonia was 30% greater among inpatients receiving acid-suppressive medications in a prospective pharmacoepidemiologic cohort study (pp. 2120–8). Included in the analysis were patients admitted to non–intensive care areas of an academic medical center for 3 days or more in 2004–07 who received either proton-pump inhibitors or histamine-2 antagonists. The investigators found: “The final cohort comprised 63,878 admissions. Acid-suppressive medication was ordered in 52% of admissions and hospital-acquired pneumonia occurred in 2,219 admissions (3.5%). The unadjusted incidence of hospital-acquired pneumonia was higher in the group exposed to acid-suppressive medication than in the unexposed group (4.9% vs 2.0%; odds ratio [OR], 2.6; 95% confidence interval [CI], 2.3–2.8). Using multivariable logistic regression, the adjusted OR of hospital-acquired pneumonia in the group exposed to acid-suppressive medication was 1.3 (95% CI, 1.1–1.4). The matched propensity-score analyses yielded identical results. The association was significant for proton-pump inhibitors (OR, 1.3; 95% CI, 1.1–1.4) but not for histamine-2 receptor antagonists (OR, 1.2; 95% CI, 0.98–1.4).” (S. J. Herzig, sherzig@bidmc.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 © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 28, 2009 * Vol. 16, No. 101
Providing news and information about medications and their proper use

>>>Oncology Highlights
Source: May 20 issue of the Journal of Clinical Oncology (2009; 27).
Radiopharmaceuticals/Chemotherapy in Castration-Resistant Prostate Cancer: Two research studies and an editorial focus on treatment and relief of symptoms with metastatic castration-resistant prostate cancer (CRPC).
Docetaxel plus samarium-153–ethylene diamine tetramethylene phosphonic acid (EDTMP) was well tolerated and relieved pain from bone metastases in 43 patients with CRCP, according to results of a Phase II trial (pp. 2429–35). Following responses or stabilization with four cycles of docetaxel/estramustine, study participants received docetaxel plus EDTMP, with these effects on prostate-specific antigen (PSA) response, pain assessed using a visual analog scale (VAS), and PSA–progression-free survival (PFS): “A PSA response was obtained in 77% (95% CI, 61% to 82%). The pain response rate was 69% (95% CI, 49% to 85%). At least five of the six planned weekly injections of docetaxel were administered to 34 patients (81%). The consolidation docetaxel–samarium-153–EDTMP regimen was well tolerated; there was no febrile neutropenia, and only two episodes (5%) of rapidly reversible grade 3 thrombocytopenia occurred. Although a serum PSA relapse eventually occurred in all patient cases, this regimen resulted in pain control in the long-term. The median PSA-PFS was 6.4 months (95% CI, 6 to 7 months). The median survival was 29 months (95% CI, 22 to 31); the 1-year survival rate was 77% (62% to 87%); and the 2-year survival rate was 56% (41% to 70%).” (K. Fizazi, fizazi@igr.fr)
A Phase I dose-ranging study of docetaxel and EDTMP produced these results (pp. 2436–42): “Twenty-eight men were treated in six cohorts. Maximum-tolerated dose was not reached, because full doses of both agents were well tolerated, even using an every-6-week dosing schedule of 153Sm-EDTMP. Patients received an average of 5.6 docetaxel doses (range, one to 13 doses) and 2.9 153Sm-EDTMP doses (range, one to six doses). Fifteen patients demonstrated a more than 50% decline in prostate-specific antigen. Treatment significantly reduced indices of bone deposition and resorption.” (M. J. Morris, morrism@mskcc.org)
Describing this combination approach as a possible “new beginning” in management of CRPC, an editorialist writes (pp. 2417–8): “Given these two trials, what is needed next? First, efficacy of combined-modality therapy is difficult to ascertain in the absence of randomized trials. Second, it seems unlikely that a dosing regimen other than 75 mg/m2 every 3 weeks of docetaxel monotherapy will be accepted by medical oncologists, thus this docetaxel dosing regimen may be the best point to start the next series of trials. Third, the entry criteria and end points for the next trial must be well defined. Is the focus to be on the chemotherapy-naive population or the taxane-refractory? Trials in both CRPC populations will be needed to fully understand response and progression-free survival rates. The exact regimen used will be subject to debate.” (O. Sartor)

>>>Health Affairs Report
Source: May issue of Health Affairs (2009; 28).
Antidepressant Reformulations: Examining use and benefits of antidepressants reformulated by manufacturers to provide less frequent dosing and also obtain extensions of patent life, authors conclude (pp. 734–45): “Our results provide some evidence of benefit for reformulations, although the benefit varies across reformulations and may differ by diagnosis. We also documented racial disparities in receipt of reformulated antidepressants, as blacks were significantly less likely to receive reformulations than whites. The fact that some of these medications confer benefits for at least certain subpopulations makes these disparities troubling and highlights the need for research to understand the factors driving them.” (H. Huskamp, huskamp@hcp.med.harvard.edu)
Antidepressant Use After Suicidality Warnings: FDA’s communications strategies for warning of adverse drug effects need to be refined, conclude authors who found reduced levels of antidepressant prescribing for both pediatric and adult patients after the 2004 addition of black-box warnings concerning pediatric suicidality (pp. 724–33). Despite FDA’s emphasis on the proven efficacy of fluoxetine, the researchers found no “dramatic” changes in the drug’s prescribing patterns. (S. H. Busch)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 29, 2009 * Vol. 16, No. 102
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source: June issue of Diabetes Care (2009; 32).
Factors Affecting Intensification of Glycemic Control: Over an 18-month period, antihyperglycemic therapy was intensified with beneficial results and no worsening of anxiety, depression, or health status among patients with type 2 diabetes, including elderly, lower-income, and minority patients (pp. 971–6). The Translating Research into Action for Diabetes (TRIAD) trial included patients who at baseline were using diet/exercise and oral hypoglycemic agents and had A1C levels greater than 7.2%, and results showed: “Of 1,093 patients, 520 intensified therapy with oral medications or insulin. Patients intensifying therapy were aged 58 ± 12 years, had diabetes duration of 11 ± 9 years, and had A1C of 9.1 ± 1.5%. Younger age and higher A1C were associated with therapy intensification. Compared with patients who did not intensify therapy, those who intensified therapy experienced a 0.49% reduction in A1C (P < 0.0001), a 3-pound increase in weight (P = 0.003), and no change in anxiety/depression (P = 0.5) or health status (P = 0.2). Among those who intensified therapy, improvement in A1C was associated with higher baseline A1C, older age, black race/ethnicity, lower income, and more physician visits.” (L. N. McEwen, lmattei@med.umich.edu)
Effects of Fiber on Calcium, Phosphorous Balance: High-fiber diets have a “small impact on calcium and phosphorus balance in subjects with type 2 diabetes,” researchers report, making it “prudent to ensure adequate intake of calcium and other minerals in individuals consuming a high-fiber diet” (pp. 990–5). Among 13 patients fed high- or moderate-fiber diets, these changes were noted over 6 weeks: “Compared with the moderate-fiber diet, the high-fiber diet increased stool weight (165 ± 53 vs. 216 ± 63 g/day, P = 0.02) and reduced 24-h urinary calcium (3.3 ± 1.7 vs. 2.4 ± 1.2 mmol/day, P = 0.003) and phosphorus (29.2 ± 5.5 vs. 26.0 ± 3.2 mmol/day, P = 0.003) excretion and serum calcium concentration (2.33 ± 0.06 vs. 2.29 ± 0.07 mmol/l, P = 0.04). Calcium absorption, stool calcium, magnesium, and phosphorus content and serum phosphorus concentration were not significantly different with the two diets.” (A. Garg, abhimanyu.garg@utsouthwestern.edu)
Insulin Resistance in Utero: Babies of obese women develop insulin resistance in utero and are born with greater body fat and other indicators of metabolic compromise, according to a study of 53 lean and 68 obese pregnant women (pp. 1076–80). Researchers conclude that, with a goal of preventing obesity, the perinatal period may be “an important focus of future research.” (P. M. Catalano, pcatalano@metrohealth.org)

>>>PNN NewsWatch
* Besifloxacin ophthalmic suspension 0.6% (Besivance, Bausch & Lomb) has been approved by FDA for topical treatment of bacterial conjunctivitis. Patients using the drug in clinical trials had a faster rate of resolution of the infection than those treated with a solution containing only a preservative. The eyedrops were effective in treating patients age 1 year and older. Adverse reactions, reported in less than 3% of clinical trial participants, included redness of the eyes, blurred vision, eye pain, irritation and itching, and headache.
* Centocor Ortho Biotech and FDA are reminding health professionals of the risk of serious fungal infections associated with use of TNF-alpha blockers, including golimumab (Simponi). FDA has reported that histoplasmosis and other invasive fungal infections are not consistently recognized in patients taking other TNF-alpha blockers, resulting in delays in appropriate antifungal treatment and in some cases death.
* FDA yesterday wrapped up 2 days of hearings on a class Risk Mitigation and Mitigation Strategy (REMS) for opioid drug products. The agency has previously proposed action for selected products, specifically those formulated with fentanyl, hydromorphone, methadone, morphine, oxycodone, and oxymorphone. During the hearings, FDA heard testimony from a variety of stakeholders in this arena, and the nature of its final action is not yet clear. In a news conference at the end of the hearings, FDA officials indicated that the agency will proceed with consideration of new drug applications in the interim. Various techniques for preventing diversion were discussed, both in the supply chain and after dispensing.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 1, 2009 * Vol. 16, No. 103
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: May 30 issue of Lancet (2009; 372).
Aspirin for Primary Prevention: The risk of major bleeds makes the use of aspirin for primary cardiovascular prevention of uncertain value, according to the Antithrombotic Trialists’ (ATT) Collaboration (pp. 1849–60). A meta-analyses of serious vascular events (myocardial infarction, stroke, or vascular death) and major bleeds in six primary prevention trials of aspirin (95,000 individuals at low average risk, 660,000 person–years, 3,554 serious vascular events) and 16 secondary prevention trials (17,000 individuals at high average risk, 43,000 person–years, 3,306 serious vascular events) showed the following: “In the primary prevention trials, aspirin allocation yielded a 12% proportional reduction in serious vascular events (0.51% aspirin vs 0.57% control per year, p = 0.0001), due mainly to a reduction of about a fifth in non-fatal myocardial infarction (0.18% vs 0.23% per year, p < 0.0001). The net effect on stroke was not significant (0.20% vs 0.21% per year, p = 0.4: haemorrhagic stroke 0.04% vs 0.03%, p = 0.05; other stroke 0.16% vs 0.18% per year, p = 0.08). Vascular mortality did not differ significantly (0.19% vs 0.19% per year, p = 0.7). Aspirin allocation increased major gastrointestinal and extracranial bleeds (0.10% vs 0.07% per year, p < 0.0001), and the main risk factors for coronary disease were also risk factors for bleeding. In the secondary prevention trials, aspirin allocation yielded a greater absolute reduction in serious vascular events (6.7% vs 8.2% per year, p < 0.0001), with a non-significant increase in haemorrhagic stroke but reductions of about a fifth in total stroke (2.08% vs 2.54% per year, p = 0.002) and in coronary events (4.3% vs 5.3% per year, p < 0.0001). In both primary and secondary prevention trials, the proportional reductions in the aggregate of all serious vascular events seemed similar for men and women.” (Antithrombotic Trialists’ Collaboration, colin.baigent@ctsu.ox.ac.uk)
Worldwide Antituberculosis Drug Resistance: In China and countries of the former Soviet Union, antituberculosis drug resistance threatens efforts to control tuberculosis, researchers report, adding that for many countries (especially in Africa), no data are available (pp. 1861–73). Analysis of information from 90,726 patients in 83 countries in 2002–07 shows these patterns: “The median prevalence of resistance to any drug in new cases of tuberculosis was 11.1% (IQR 7.0—22.3). The prevalence of multidrug resistance in new tuberculosis cases ranged from 0% in eight countries to 7% in two provinces in China, 11.1% in Northern Mariana Islands (although reporting only two cases), and between 6.8% and 22.3% in nine countries of the former Soviet Union, including 19.4% in Moldova and 22.3% in Baku, Azerbaijan (median for countries surveyed 1.6%, IQR 0.6—3.9). Trend analysis showed that between 1994 and 2007, the prevalence of multidrug-resistant (MDR) tuberculosis in new cases increased substantially in South Korea and in Tomsk Oblast and Orel Oblast, Russia, but was stable in Estonia and Latvia. The prevalence of MDR tuberculosis in all tuberculosis cases decreased in Hong Kong and the USA. 37 countries and territories reported representative data on extensively drug-resistant (XDR) tuberculosis. Five countries, all from the former Soviet Union, reported 25 cases or more of XDR tuberculosis each, with prevalence among MDR-tuberculosis cases ranging between 6.6% and 23.7%.” (A. Wright, wrighta@who.int)

>>>PNN JournalWatch
* Recognition and Assessment of Coeliac Disease in Children and Adults: Summary of NICE Guidance, in BMJ, 2009; 338: b1684. (P. Howdle, p.d.howdle@leeds.ac.uk)
* Improving Diabetes Care: The Model for Health Care Reform, in Diabetes Care, 2009; 32: 1115–8. (R. Kahn, rkahn@diabetes.org)
* Genetic Architecture of Type 2 Diabetes: Recent Progress and Clinical Implications, in Diabetes Care, 2009; 32: 1107–14. (R. W. Grant, rgrant@partners.org)
* Efficacy of Pneumococcal Vaccination in Children Younger Than 24 Months: A Meta-analysis, in Pediatrics, 2009; 123: e1103–10. ( I. F. Angelillo, italof.angelillo@unina2.it)
* Attention-Deficit–Hyperactivity Disorder: An Update, in Pharmacotherapy, 2009; 29: 656–79. (J. A. Dopheide)
* Effects of Web- and Computer-Based Smoking Cessation Programs: Meta-analysis of Randomized Controlled Trials, in Archives of Internal Medicine, 2009; 169: 929–37. (S-K Myung, msk@ncc.re.kr)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 2, 2009 * Vol. 16, No. 104
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: June 2 issue of the Annals of Internal Medicine (2009; 150).
Aldosterone in Metabolic Syndrome and Resistant Hypertension: Aldosterone administration may be contributing to the development of metabolic syndrome and resistant hypertension, write authors of a narrative review (pp. 776–83): “Emerging evidence supports a paradigm shift in our understanding of the renin–angiotensin–aldosterone system and in aldosterone’s ability to promote insulin resistance and participate in the pathogenesis of the metabolic syndrome and resistant hypertension. Recent data suggest that excess circulating aldosterone promotes the development of both disorders by impairing insulin metabolic signaling and endothelial function, which in turn leads to insulin resistance and cardiovascular and renal structural and functional abnormalities. Indeed, hyperaldosteronism is associated with impaired pancreatic beta-cell function, skeletal muscle insulin sensitivity, and elevated production of proinflammatory adipokines from adipose tissue, which results in systemic inflammation and impaired glucose tolerance.
“Accumulating evidence indicates that the cardiovascular and renal abnormalities associated with insulin resistance are mediated in part by aldosterone acting on the mineralocorticoid receptor. Although we have known that mineralocorticoid receptor blockade attenuates cardiovascular and renal injury, only recently have we learned that mineralocorticoid receptor blockade improves pancreatic insulin release, insulin-mediated glucose utilization, and endothelium-dependent vasorelaxation. In summary, aldosterone excess has detrimental metabolic effects that contribute to the metabolic syndrome and endothelial dysfunction, which in turn contribute to the development of resistant hypertension as well as cardiovascular disease and chronic kidney disease.” (M. Epstein, murraye@gate.net)
Dose v. Heart Rate with Beta-Blockers: Reduction in heart rate is better than drug dose in gauging of the survival benefit of beta-blockers in patients with heart failure, according to a meta-analysis of trials reporting all-cause deaths (pp. 784–94): “The mean left ventricular ejection fraction in the 23 beta-blocker trials ranged from 0.17 to 0.36, and more than 95% of the 19,209 patients had systolic dysfunction. The overall risk ratio for death was 0.76 (95% CI, 0.68 to 0.84); however, heterogeneity testing revealed moderate heterogeneity among trials (I2 = 30%), which was associated with the magnitude of heart rate reduction achieved within each trial (P for meta-regression = 0.006). For every heart rate reduction of 5 beats/min with beta-blocker treatment, a commensurate 18% reduction (CI, 6% to 29%) in the risk for death occurred. No significant relationship between all-cause mortality and beta-blocker dosing was observed (risk ratio for death, 0.74 [CI, 0.64 to 0.86]) in high-dose beta-blocker trials vs. 0.78 [CI, 0.63 to 0.96] in low-dose beta-blocker trials; P for meta-regression = 0.69).” (F. A. McAlister, finlay.mcalister@ualberta.ca)
Paradigm Shift in Diabetes: Rather than focusing on tight glycemic control in patients with type 2 diabetes, the time has arrived for an evidence-based about-face, authors of a Perspective article write, with more attention to lifestyle, prevention, and risk reduction (pp. 803–8): “Some diabetes guidelines set low glycemic control goals for patients with type 2 diabetes mellitus (such as a hemoglobin A1c level as low as 6.5% to 7.0%) to avoid or delay complications. Our review and critique of recent large randomized trials in patients with type 2 diabetes suggest that tight glycemic control burdens patients with complex treatment programs, hypoglycemia, weight gain, and costs and offers uncertain benefits in return. We believe clinicians should prioritize supporting well-being and healthy lifestyles, preventive care, and cardiovascular risk reduction in these patients. Glycemic control efforts should individualize hemoglobin A1c targets so that those targets and the actions necessary to achieve them reflect patients’ personal and clinical context and their informed values and preferences.” (V. M. Montori, kerunit@mayo.edu)
Hormone Suspension & Breast Density: Brief suspensions of hormone-replacement therapy can reduce breast density, but the intervention failed to affect recall rates after mammography significantly in a study of 1,704 postmenopausal women (pp. 752–65; D. S. M. Buist, buist.d@ghc.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 © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 3, 2009 * Vol. 16, No. 105
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source: June 3 issue of JAMA (2009; 301).
Depression Prevention in Adolescents: Group cognitive behavioral (CB) therapy prevented depression in 316 at-risk adolescents, but teens with a currently depressed parent had a muted response (pp. 2215–24). The program included 8 weekly, 90-minute group sessions followed by 6 monthly continuation sessions. Compared with usual care alone, the intervention produced these responses: “Through the postcontinuation session follow-up, the rate and HR of incident depressive episodes were lower for those in the CB prevention program than for those in usual care (21.4% vs 32.7%; HR, 0.63; 95% confidence interval [CI], 0.40–0.98). Adolescents in the CB prevention program also showed significantly greater improvement in self-reported depressive symptoms than those in usual care (coefficient, –1.1; z = –2.2; P = .03). Current parental depression at baseline moderated intervention effects (HR, 5.98; 95% CI, 2.29–15.58; P = .001). Among adolescents whose parents were not depressed at baseline, the CB prevention program was more effective in preventing onset of depression than usual care (11.7% vs 40.5%; HR, 0.24; 95% CI, 0.11–0.50), whereas for adolescents with a currently depressed parent, the CB prevention program was not more effective than usual care in preventing incident depression (31.2% vs 24.3%; HR, 1.43; 95% CI, 0.76–2.67).” (J. Garber, judy.garber@vanderbilt.edu)
Pentavalent Rotavirus Vaccine Effectiveness in Nicaragua: Vaccination of Nicaraguan children with pentavalent rotavirus vaccine (RV5) significantly reduced the risk of severe rotavirus diarrhea but not to the extent observed in studies in developed countries (pp. 2243–51). A case–control evaluation of 285 children hospitalized or requiring intravenous hydration for laboratory-confirmed rotavirus diarrhea showed these results in comparison with neighborhood and hospital cohorts: “Of the 285 rotavirus cases, 265 (93%) required hospitalization; 251 (88%) received intravenous hydration. A single rotavirus strain (G2P[4]) was identified in 88% of the cases. Among cases and controls, respectively, 18% and 12% were unvaccinated, 12% and 15% received 1 dose of RV5, 15% and 17% received 2 doses, and 55% and 57% received 3 doses. Vaccination with 3 doses was associated with a lower risk of rotavirus diarrhea requiring overnight admission or intravenous hydration (odds ratio [OR], 0.54; 95% confidence interval [CI], 0.36–0.82). Of the 285 rotavirus cases, 191 (67%) were severe and 54 (19%) were very severe. A progressively lower risk of severe (OR, 0.42; 95% CI, 0.26–0.70) and very severe rotavirus diarrhea (OR, 0.23; 95% CI, 0.08–0.61) was observed after RV5 vaccination. Thus, effectiveness of 3 doses of RV5 against rotavirus disease requiring admission or treatment with intravenous hydration was 46% (95% CI, 18%–64%); against severe rotavirus diarrhea, 58% (95% CI, 30%–74%); and against very severe rotavirus diarrhea, 77% (95% CI, 39%–92%).” (M. Patel, aul3@cdc.gov)

>>>PNN NewsWatch
* FDA on Tuesday announced formation of a transparency task force and scheduled a June 24 public meeting to discuss ways the agency “can make more available, useful and understandable information on its activities and decisions.” Recently confirmed FDA Commissioner Margaret A. Hamburg, MD, named Principal Deputy Commissioner Joshua Sharfstein, MD, to chair the panel.
* The White House Council of Economic Advisors yesterday issued a 51-page report outlining the Obama administration’s “economic case for health care reform.” The advisors emphasize that expanding coverage would have three beneficial effects: increase economic well-being of the 46 million currently uninsured Americans by substantially more than the cost of insuring them, increasing the labor supply by reducing disability and absenteeism, and improving the functioning of the labor market by eliminating restrictions on pre-existing conditions and thereby removing a major barrier to changing jobs.
* Deloitte Consulting is claiming that “community pharmacists can and should be at the core of disease management programs,” according to a Drug Topics article republished in Modern Medicine. Linking the pharmacy database with patients’ medical records will result in improved care, the report notes.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 4, 2009 * Vol. 16, No. 106
Providing news and information about medications and their proper use

>>>NEJM Highlights