Sep 2008

PNN Quarterly File—Third Quarter 2008

PNN Pharmacotherapy Line
July 1, 2008 * Vol. 15, No. 127
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
July 1 issue of the Annals of Internal Medicine (www.annals.org/current.shtml; 2008; 149).
Hearing Impairment in Diabetes: Diabetes appears to be an independent risk factor for hearing impairment in adults, according to an analysis of the National Health and Nutrition Examination Survey, 1999 to 2004 (pp. 1-10). Data on 5,140 noninstitutionalized people aged 20–69 years show: “Hearing impairment was more prevalent among adults with diabetes. Age-adjusted prevalence of low- or mid-frequency hearing impairment of mild or greater severity in the worse ear was 21.3% (95% CI, 15.0% to 27.5%) among 399 adults with diabetes compared with 9.4% (CI, 8.2% to 10.5%) among 4,741 adults without diabetes. Similarly, age-adjusted prevalence of high-frequency hearing impairment of mild or greater severity in the worse ear was 54.1% (CI, 45.9% to 62.3%) among those with diabetes compared with 32.0% (CI, 30.5% to 33.5%) among those without diabetes. The association between diabetes and hearing impairment was independent of known risk factors for hearing impairment, such as noise exposure, ototoxic medication use, and smoking (adjusted odds ratios for low- or mid-frequency and high-frequency hearing impairment were 1.82 [CI, 1.27 to 2.60] and 2.16 [CI, 1.47 to 3.18], respectively).” (K. E. Bainbridge, Social & Scientific Systems, Silver Spring, MD; kbainbridge@s-3.com)
An editorialist points out that “you might not know what you’re missing” when it comes to hearing loss (pp. 54-5): “Counseling patients with mild to moderate hearing loss to avoid loud, prolonged noise exposure and ototoxic medications can be helpful in eliminating other sources of progressive hearing loss. We have few current therapeutic options for progressive hearing loss from any cause, and the study of hearing loss in diabetic patients could lead to important progress in new techniques of studying and treating microvascular disease of the inner ear. In many cases of mild to moderate hearing loss, patients are not aware of what they cannot hear; thus, screening for hearing loss in individuals at risk could lead to interventions that would affect their ability to communicate, their productivity, and their safety.” (K. Hirose,
HiroseK@ent.wustl.edu)
Assessing Intensive Glucose Control in Older Patients: Compared with age alone, presence of multiple comorbid illnesses or functional impairments is a more important predictor of limited life expectancy and diminishing expected benefits of intensive glucose control, concludes a decision analysis that relied on data from major clinical studies in diabetes and geriatrics (pp. 11-9). Taking the perspective of the health care system and using a lifetime horizon, the researchers found these benefits of intensive versus moderate glucose control: “Healthy older patients of different age groups had expected benefits of intensive glucose control ranging from 51 to 116 quality-adjusted days. Within each age group, the expected benefits of intensive control steadily declined as the level of comorbid illness and functional impairment increased (mortality index score, 1 to 26 points). For patients 60 to 64 years of age with new-onset diabetes, the benefits declined from 106 days at baseline good health (life expectancy, 14.6 years) to 44 days with 3 additional index points (life expectancy, 9.7 years) and 8 days with 7 additional index points (life expectancy, 4.8 years). A similar decline in benefits occurred among patients with prolonged duration of diabetes.” Sensitivity analysis showed: “With alternative model assumptions (such as Framingham models), expected benefits of intensive control declined as mortality index scores increased.” (E. S. Huang, ehuang@medicine.bsd.uchicago.edu)
Safety of Salmeterol: Commenting on a meta-analysis that assessed severe asthma-related events with salmeterol plus inhaled corticosteroids versus inhaled corticosteroids alone (pp. 33-42; E. Bateman, U. Cape Town Lung Inst., Cape Town, South Africa; eric.bateman@uct.ac.za), an editorialist explains that “the controversy continues” (pp. 56-7). “Ultimately, nearly all drugs have therapeutic windows within which physicians and patients must function. Like insulin and oral anticoagulation, long-acting beta-agonists have a narrow therapeutic window. They deserve the same caution and meticulous attention to detail that physicians expect of themselves when they prescribe potentially harmful drugs.” (K. B. Weiss, Am. Board of Med. Specialties, Evanston, IL)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
July 2, 2008 * Vol. 15, No. 128
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
July 2 JAMA (http://jama.ama-assn.org/current.dtl; 2008; 300).
Mortality in Treated HIV Infection: Since advent of antiretroviral agents, mortality rates among HIV-infected persons have declined and are approaching those of the general population, researchers report (pp. 51-9). Using data from a large group of HIV seroconverter cohorts, the investigators found: “Of 16,534 individuals with median duration of follow-up of 6.3 years (range, 1 day to 23.8 years), 2,571 died, compared with 235 deaths expected in an equivalent general population cohort. The excess mortality rate (per 1,000 person–years) decreased from 40.8 (95% confidence interval [CI], 38.5–43.0; 1,275.9 excess deaths in 31,302 person–years) before the introduction of highly active antiretroviral therapy (pre-1996) to 6.1 (95% CI, 4.8–7.4; 89.6 excess deaths in 14,703 person-years) in 2004–2006 (adjusted excess hazard ratio, 0.05 [95% CI, 0.03–0.09] for 2004–2006 vs pre-1996). By 2004–2006, no excess mortality was observed in the first 5 years following HIV seroconversion among those infected sexually, though a cumulative excess probability of death remained over the longer term (4.8% [95% CI, 2.5%–8.6%] in the first 10 years among those aged 15–24 years).” (K. Porter, MRC Clinical Trials Unit, London; kp@ctu.mrc.ac.uk)
Analgesia During Painful Neonatal Procedures: Painful and stressful medical procedures in neonates are often performed without analgesia, according to data collected in Paris-area neonatal units (pp. 60-70). In the Epidemiology of Procedural Pain in Neonates (EPIPPAIN) study, procedures performed during the first 14 days of life in 430 infants in tertiary-care neonatal units showed these patterns: “Neonates experienced 60,969 first-attempt procedures, with 42,413 (69.6%) painful and 18,556 (30.4%) stressful procedures; 11,546 supplemental attempts were performed during procedures including 10,366 (89.8%) for painful and 1,180 (10.2%) for stressful procedures. Each neonate experienced a median of 115 (range, 4–613) procedures during the study period and 16 (range, 0–62) procedures per day of hospitalization. Of these, each neonate experienced a median of 75 (range, 3–364) painful procedures during the study period and 10 (range, 0–51) painful procedures per day of hospitalization. Of the 42,413 painful procedures, 2.1% were performed with pharmacological-only therapy; 18.2% with nonpharmacological-only interventions, 20.8% with pharmacological, nonpharmacological, or both types of therapy; and 79.2% without specific analgesia, and 34.2% were performed while the neonate was receiving concurrent analgesic or anesthetic infusions for other reasons. Prematurity, category of procedure, parental presence, surgery, daytime, and day of procedure after the first day of admission were associated with greater use of specific preprocedural analgesia, whereas mechanical ventilation, noninvasive ventilation and administration of nonspecific concurrent analgesia were associated with lower use of specific preprocedural analgesia.” (R. Carbajal, Hôpital d’enfants Armand Trousseau, Paris; ricardo.carbajal@trs.aphp.fr)
Treatment Strategies in ACS: Invasive strategies for non-ST-segment elevation acute coronary syndromes are more effective in men and high-risk women than conservative approaches to treatment, but available data differ for low-risk women, authors who reviewed eight articles conclude (pp. 71-80): “The odds ratio (OR) for the composite of death, MI, or ACS for invasive vs conservative strategy in women was 0.81 (95% confidence interval [CI], 0.65–1.01; 21.1% vs 25.0%) and in men was 0.73 (95% CI, 0.55–0.98; 21.2% vs 26.3%) without significant heterogeneity between sexes (P for interaction = .26). Among biomarker-positive women, an invasive strategy was associated with a 33% lower odds of death, MI, or ACS (OR, 0.67; 95% CI, 0.50–0.88) and a nonsignificant 23% lower odds of death or MI (OR, 0.77; 95% CI, 0.47–1.25). In contrast, an invasive strategy was not associated with a significant reduction in the triple composite end point in biomarker-negative women (OR, 0.94; 95% CI, 0.61–1.44; P for interaction = .36) and was associated with a nonsignificant 35% higher odds of death or MI (OR, 1.35; 95% CI, 0.78–2.35; P for interaction = .08). Among men, the OR for death, MI, or ACS was 0.56 (95% CI, 0.46–0.67) if biomarker-positive and 0.72 (95% CI, 0.51–1.01) if biomarker-negative (P for interaction = .09).” (M. O’Donoghue, modonoghue@partners.org)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
July 3, 2008 * Vol. 15, No. 129
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
July 3 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2008; 359).
Treatment of Out-of-Hospital Cardiac Arrest: Addition of vasopressin to epinephrine treatment of patients with out-of-hospital cardiac arrest provided no added benefits, according to a study with a primary endpoint of survival to hospital admission (pp. 21-30). During advanced cardiac life support, patients were randomized to either epinephrine 1 mg plus vasopressin 40 IU or epinephrine 1 mg plus placebo, with these results: “A total of 1,442 patients were assigned to receive a combination of epinephrine and vasopressin, and 1, 452 to receive epinephrine alone. The treatment groups had similar baseline characteristics except that there were more men in the group receiving combination therapy than in the group receiving epinephrine alone (P = 0.03). There were no significant differences between the combination-therapy and the epinephrine-only groups in survival to hospital admission (20.7% vs. 21.3%; relative risk of death, 1.01; 95% confidence interval [CI], 0.97 to 1.05), return of spontaneous circulation (28.6% vs. 29.5%; relative risk, 1.01; 95% CI, 0.97 to 1.06), survival to hospital discharge (1.7% vs. 2.3%; relative risk, 1.01; 95% CI, 1.00 to 1.02), 1-year survival (1.3% vs. 2.1%; relative risk, 1.01; 95% CI, 1.00 to 1.02), or good neurologic recovery at hospital discharge (37.5% vs. 51.5%; relative risk, 1.29; 95% CI, 0.81 to 2.06).” (P-Y Gueugniaud, Pôle Urgence, CHU Lyon-Sud, Lyon, France; pierre-yves.gueugniaud@chu-lyon.fr)
Motesanib for Thyroid Cancer: Partial responses were observed in patients with progressive advanced or metastatic differentiated thyroid cancer when they received motesanib diphosphate, a novel oral inhibitor of vascular endothelial growth factor receptors (pp. 31-42). “Of the 93 patients, 57 (61%) had papillary thyroid carcinoma,” the authors wrote of their open-label, single-group, Phase II study. “The objective response rate was 14%. Stable disease was achieved in 67% of the patients, and stable disease was maintained for 24 weeks or longer in 35%; 8% had progressive disease as the best response. The Kaplan–Meier estimate of the median duration of the response was 32 weeks (the lower limit of the 95% confidence interval [CI] was 24; the upper limit could not be estimated because of an insufficient number of events); the estimate of median progression-free survival was 40 weeks (95% CI, 32 to 50). Among the 75 patients in whom thyroglobulin analysis was performed, 81% had decreased serum thyroglobulin concentrations during treatment, as compared with baseline levels. The most common treatment-related adverse events were diarrhea (in 59% of the patients), hypertension (56%), fatigue (46%), and weight loss (40%).” (S. I. Sherman, sisherma@mdanderson.org)
Electronic Health Records in Ambulatory Care: The small proportion of early-adopter physicians who are using electronic health records in the ambulatory setting are satisfied with the systems and believe they improve care, according to results of a national survey of 2,758 physicians (pp. 50-60). Based on responses from 62% of the sample, the investigators found these trends in the late 2007/early 2008 survey: “Four percent of physicians reported having an extensive, fully functional electronic-records system, and 13% reported having a basic system. In multivariate analyses, primary care physicians and those practicing in large groups, in hospitals or medical centers, and in the western region of the United States were more likely to use electronic health records. Physicians reported positive effects of these systems on several dimensions of quality of care and high levels of satisfaction. Financial barriers were viewed as having the greatest effect on decisions about the adoption of electronic health records.” (C. M. DesRoches, cdesroches@partners.org)

>>>PNN NewsWatch
* Cardiovascular safety concerns are not being adequately addressed in agency reviews of new antidiabetic drugs, an FDA advisory panel concluded yesterday. The group suggested that long-term studies be required to monitor cardiovascular safety of investigational agents, and these could add 5 years or more to the development time of new drugs for this disease.
*
PNN will not be published on Fri., July, Independence 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 © 2008, 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
July 7, 2008 * Vol. 15, No. 130
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
July 5 issue of Lancet (www.thelancet.com; 2008; 372).
Rivaroxaban for VT Prophylaxis After Surgery: Providing additional data from the RECORD2 (REgulation of Coagulation in ORthopedic surgery to prevent Deep-vein thrombosis and pulmonary embolism 2) trial (see PNN, June 26), investigators conclude that extended use of the oral agent rivaroxaban is significantly better than short-term injectable enoxaparin for prevention of venous thromboembolism following total hip arthroplasty (pp. 31-9). Patients received either oral rivaroxaban 10 mg once daily for 31–39 days or enoxaparin 40 mg once daily subcutaneously for 10–14 days, with these results: “The modified intention-to-treat population for the analysis of the primary efficacy outcome consisted of 864 patients in the rivaroxaban group and 869 in the enoxaparin group. The primary outcome occurred in 17 (2.0%) patients in the rivaroxaban group, compared with 81 (9.3%) in the enoxaparin group (absolute risk reduction 7.3%, 95% CI 5.2–9.4; p < 0.0001). The incidence of any on-treatment bleeding was much the same in both groups (81 [6.6%] events in 1,228 patients in the rivaroxaban safety population vs 68 [5.5%] of 1,229 patients in the enoxaparin safety population; p = 0.25).” (A. K. Kakkar, Barts and the London Sch. of Med. and Dentistry, London; akkakkar@tri-london.ac.uk)
Treating Depression in Patients with Cancer: A nurse-delivered complex intervention in patients with cancer and major depressive disorder was feasible, acceptable, and potentially cost-effective, according to a 200-patient study (pp. 40-8). Depression Care for People with Cancer provided an average of seven sessions with a nurse to patients assigned to the intervention group. Compared with those receiving usual care, the intervention provided these differences in outcomes: “For 196 patients for whom we had data at 3 months, the adjusted difference in mean Symptom Checklist-20 depression score, between those who received the intervention and those who did not, was 0.34 (95% CI 0.13–0.55). This treatment effect was sustained at 6 and 12 months. The intervention also improved anxiety and fatigue but not pain or physical functioning. It cost an additional £5,278 (US$10,556) per quality-adjusted life–year gained.” (M. Sharpe, U. Edinburgh, Edinburgh, Scotland; Michael.Sharpe@ed.ac.uk)

>>>BMJ Highlights
Source:
July 5 issue of BMJ (www.bmj.org; 2008; 337).
Vaccine Adverse Reactions & Recall Bias: A study of U.K. military personnel shows that adverse health consequences associated by patients with vaccine administration often are not supported by immunization records (pp. a220). A subset of 378 military personnel deployed to Iraq reported how many vaccinations they received on a single day, and their medical records were checked to verify the administrations and symptoms such as psychological distress, fatigue, symptoms of posttraumatic stress disorder, health perception, and multiple physical symptoms. Results showed: “Personnel who reported receiving two or more vaccinations on a single day were more likely to report symptoms of fatigue (adjusted risk ratio 1.17, 95% confidence interval 1.05 to 1.30), show caseness according to the general health questionnaire (1.31, 1.13 to 1.53), and have multiple physical symptoms (1.32, 1.08 to 1.60). These associations were no longer significant when number of vaccinations recorded in individuals’ medical records was used as the independent variable.” (D. Murphy, King’s College, London; dominic.murphy@iop.kcl.ac.uk)

>>>PNN JournalWatch
* Protecting Public Trust in Immunization, in Pediatrics, 2008; 122: 149–53. Reprints: L. Z. Cooper, Columbia U., New York
* Efficacy, Safety, and Tolerability of Pregabalin Treatment for Painful Diabetic Peripheral Neuropathy, in
Diabetes Care, 2008; 31: 1448–54. Reprints: R. Freeman, rfreeman@bidmc.harvard.edu
* Rosiglitazone and Risk of Cancer: A Meta-analysis of Randomized Clinical Trials, in
Diabetes Care, 2008; 31: 1455–60. Reprints: E. Mannucci, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy; edoardo.mannucci@unifi.it
* Sleep Disturbance in Bipolar Disorder: Therapeutic Implications, in
American Journal of Psychiatry, 2008; 165: 830–43. Reprints: D. T. Plante.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
July 8, 2008 * Vol. 15, No. 131
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
July issue of Diabetes Care (http://care.diabetesjournals.org/current.shtml; 2008; 31).
UTIs in Women with Diabetes: Urinary tract infections recur more frequently in women with diabetes both before and after menopause, a research study shows, despite treatment with longer courses of antibiotics and use of more potent agents in those with diabetes (pp. 1380-5). A Dutch registration database of pharmacy dispensing records showed these patterns among 10,366 women with and 200,258 women without diabetes who received short (5 days or fewer) or long courses of norfloxacin and other antibiotics: “Premenopausal women with diabetes more often received a long (26.5 vs. 19.2%; P < 0.001) treatment with norfloxacin (10.7 vs. 6.2%; P < 0.001) but still had a higher recurrence rate (16.1 vs. 12.2%; P = 0.003) compared with those without diabetes. Similarly, postmenopausal women with diabetes more often received a longer (32.8 vs. 28.8%; P < 0.001) treatment with norfloxacin (15.2 vs. 12.7%; P < 0.001) but had a higher recurrence rate (19.1 vs. 16.4%; P < 0.001) compared with those without diabetes.” (S. Geerlings, U. Med. Ctr. Groningen, Amsterdam; s.e.geerlings@amc.nl)
Glucagon, Insulin Patterns in Early Type 1 Diabetes: Increased levels of glucagon after meals are common among children with type 1 diabetes and may provide a useful therapeutic target, a study of 23 children concludes (pp. 1403-4). Based on responses to standard mixed meals within 6 weeks of diagnosis and every 3 months thereafter for 1 year, the researchers determined: “Glucagon secretion in response to a physiologic stimulus (mixed meal) increased by 37% over 12 months, while C-peptide secretion declined by 45%. Fasting glucagon concentrations remained within the normal (nondiabetic) reference range.” The group concludes: “Fasting glucagon values may underestimate the severity of hyperglucagonemia. The opposing directions of abnormal glucagon and C-peptide secretion over time support the link between dysregulated glucagon secretion and declining beta-cell function.” (R. J. Brown, brownrebecca@mail.nih.gov)
CHD Risk in Metabolic Syndrome: While individuals with metabolic syndrome have varying degrees of coronary heart disease risk factors, about half have moderate or high risks, and all should have their risks determined and addressed as appropriate, authors conclude (pp. 1405-9). The investigators used the National Cholesterol Education Program/Third Adult Treatment Panel definition to categorize 4,293 U.S. adults aged 20–79 years in the National Health and Nutrition Examination Survey 2003–2004 in low, moderate, moderately high, and high risk categories (<6, 6 to <10, 10–20, and >20% probability of CHD in 10 years). Results showed: “The weighted prevalence of metabolic syndrome by NCEP criteria in our study was 29.0% overall (30.0% in men and 27.9% in women, P = 0.28): 38.5% (30.7% men and 46.9% women) were classified as low risk, 8.5% (7.9% men and 9.1% women) were classified as moderate risk, 15.8% (23.4% men and 7.6% women) were classified as moderately high risk, and 37.3% (38.0% men and 36.5% women) were classified as high risk. The proportion at high risk increased with age but was similar among Hispanics, non-Hispanic whites, and non-Hispanic blacks.” (N. D. Wong, ndwong@uci.edu)

>>>PNN NewsWatch
* FDA has concluded that antiepileptic drugs increase suicidality among patients taking the drugs and that this class effect should be detailed in a black-box warning. In briefing documents for two FDA advisory committees meeting later this week, the agency writes: “It is our intention to ask sponsors to include a description of these findings in a Boxed Warning, as well as in the Warnings and Precautions sections [of product labeling]. In addition, we expect that patients will receive a medication guide describing this risk each time a prescription for an AED is filled.” Data compiled by FDA show that 8 of 11 AEDs had numeric increases in reports of suicidality, but statistical significance was reached for only 2 drugs. FDA argued that small numbers of reports were responsible for the lack of increases and statistical significance and that it could not “ignore what appears to be a very clear empirical finding of an increase in suicidality.”

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
July 9, 2008 * Vol. 15, No. 132
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
July 9 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2008; 300).
Androgen Deprivation in Localized Prostate Cancer: Patients receiving primary androgen deprivation therapy had similar survival rates as did those who received surgery, radiation, or conservative management for the treatment of localized prostate cancer, a research study concludes (pp. 173-81). Authors of the population-based cohort study report: “Among patients with localized prostate cancer (median age, 77 years), 7,867 (41%) received PADT, and 11,404 were treated with conservative management, not including PADT. During the follow-up period, there were 1,560 prostate cancer deaths and 11,045 deaths from all causes. Primary androgen deprivation therapy was associated with lower 10-year prostate cancer–specific survival (80.1% vs 82.6%; hazard ratio [HR], 1.17; 95% confidence interval [CI], 1.03–1.33) and no increase in 10-year overall survival (30.2% vs 30.3%; HR, 1.00; 95% CI, 0.96–1.05) compared with conservative management. However, in a prespecified subset analysis, PADT use in men with poorly differentiated cancer was associated with improved prostate cancer–specific survival (59.8% vs 54.3%; HR, 0.84; 95% CI, 0.70–1.00; P = .049) but not overall survival (17.3% vs 15.3%; HR, 0.92; 95% CI, 0.84–1.01).” (S-L Yao, syao@aya.yale.edu)
Medicare Part D & Chemotherapy Treatments: No differences in travel distance or patient wait times were evident following implementation of the Medicare Modernization Act of 2003, according to an analysis of claims data submitted to CMS in 2003–06 (pp. 189-96). “There were 5,082 incident cases of breast cancer, colorectal cancer, leukemia, lung cancer, or lymphoma in 2003; 5,379 cases in 2004; 5,116 cases in 2005; and 5,288 cases in 2006,” report the authors. “Approximately 70% of patients received treatment in physician office settings in each year. Although the distribution of treatment settings in 2004 and 2005 was not significantly different from 2003 (P = .24 and P = .72, respectively), there was a small but significant change from 2003 to 2006 (P = .02). The proportion of patients receiving chemotherapy in inpatient settings decreased from 10.2% in 2003 to 8.8% in 2006 (P = .03), and the proportion in institutional outpatient settings increased from 21.1% to 22.5% (P = .004). The proportion in physician offices remained at 68.7% (P = .29). The median time from diagnosis to initial chemotherapy visit was 28 days in 2003, 27 days in 2004, 29 days in 2005, and 28 days in 2006. In multivariate analyses, average wait times for chemotherapy were 1.96 days longer in 2005 than in 2003 (95% confidence interval [CI], 0.11–3.80 days; P = .04) but not significantly different in 2006 (0.88 days; 95% CI, –0.96 to 2.71 days; P = .35). Median travel distance was 7 miles (11.2 km) in 2003 and 8 miles (12.8 km) in 2004 through 2006. After adjustment, average travel distance remained slightly longer in 2004 … compared with 2003.” (L. H. Curtis, lesley.curtis@duke.edu)

>>>PNN NewsWatch
* A black-box warning about increased risk of tendinitis and tendon rupture is being added to product labeling of fluoroquinolone antibiotics, FDA announced yesterday. In addition, a Medication Guide for distribution with prescriptions for the agents will be required for oral and injectable dosage forms (but not for products used locally, such as ophthalmic or otic drops). Based on a new analysis of the available literature and postmarketing adverse event reports, FDA concluded that use of fluoroquinolones is associated with an increased risk of tendon rupture. The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is further increased in people older than 60, in those taking corticosteroid drugs, and in kidney, heart, and lung transplant recipients. Patients experiencing pain, swelling, inflammation of a tendon or tendon rupture should be advised to stop taking their fluoroquinolone medication and to contact their health care professional promptly about changing their antimicrobial therapy. Patients should also avoid exercise and using the affected area at the first sign of tendon pain, swelling, or inflammation.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
July 10, 2008 * Vol. 15, No. 133
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
July 10 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2008; 359).
Reducing HIV Transmission During Breast-feeding: Postnatal transmission of HIV-1 was significantly reduced through use of extended antiretroviral prophylaxis in a Phase III trial in Malawi (pp. 119-29). Researchers compared single-dose nevirapine plus 1 week of zidovudine (control regimen) or the control regimen plus daily extended prophylaxis either with nevirapine (extended nevirapine) or with nevirapine plus zidovudine (extended dual prophylaxis) until the age of 14 weeks, with these results: “Among 3,016 infants in the study, the control group had consistently higher rates of HIV-1 infection from the age of 6 weeks through 18 months. At 9 months, the estimated rate of HIV-1 infection (the primary end point) was 10.6% in the control group, as compared with 5.2% in the extended-nevirapine group (P < 0.001) and 6.4% in the extended-dual-prophylaxis group (P = 0.002). There were no significant differences between the two extended-prophylaxis groups. The frequency of breast-feeding did not differ significantly among the study groups. Infants receiving extended dual prophylaxis had a significant increase in the number of adverse events (primarily neutropenia) that were deemed to be possibly related to a study drug.” (T. E. Taha, ttaha@jhsph.edu)
Commenting on this and a second study on abrupt cessation of breast-feeding (pp. 130-41; L. Kuhn,
lk24@columbia.edu), editorialists write of the choices facing researchers and mothers: “Indeed, current research is already examining the benefits of extending antiretroviral prophylaxis through the entire breast-feeding period. Similarly, efforts to tailor breast-feeding options to obtain optimal HIV-free survival continue. Ultimately, as the two studies reported here show, caregivers and mothers in low-resource settings will continue to select options that best suit their own cultural, economic, and psychological needs, and science will need to adapt and design strategies to meet their needs, rather than the other way around.” (G. E. Gray, U. Witwatersrand, Johannesburg, South Africa)
E-Prescribing: Writing about trends in electronic prescribing of medications, the author of a Perspective article notes these upcoming milestones in Medicare Part D (pp. 115-7): “When a prescription being paid for under Medicare Part D is entered in an electronic system, certain standards must be followed. For example, an exemption that allows prescriptions that are otherwise electronic to be sent by fax will be eliminated in January 2009. The Centers for Medicare and Medicaid Services (CMS) announced e-prescribing standards that will go into effect in April 2009. The regulations cover such matters as the provision of information about generics and lower-cost options and about medication history, including medicines prescribed by others (which could contribute to adverse drug events). They also cover electronic notification from the pharmacy about whether a prescription has been picked up, partially filled, or left unfilled, which could help physicians to monitor compliance. And they require the use of the National Provider Identifier, which identifies the writer of a prescription and should obviate the need for some phone calls from pharmacies to medical offices.” (R. Steinbrook, rsteinbrook@attglobal.net)

>>>PNN NewsWatch
* APhA and other pharmacy groups are applauding yesterday’s 69–30 Senate vote to end debate in support of the Medicare Improvements for Patients and Providers Act of 2008 (H.R. 6331). This legislation, which would delay physician payment cuts in the Medicare program, also includes many critical pharmacy provisions that will better ensure patient access to pharmacist services. The Senate passed the legislation by voice vote, and the veto-proof cloture margin should assure that the bill will become law even if President Bush continues to oppose it.
* FDA will begin working with its counterparts in the European Union and Australia to jointly plan, allocate for, and conduct
inspections of drug-manufacturing facilities, HHS Secretary Mike Leavitt announced yesterday. The project will initially focus on makers of active pharmaceutical ingredients. If successful, this program could expand to include other types of manufacturing facilities.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
July 11, 2008 * Vol. 15, No. 134
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
July 15 issue of the Journal of the American College of Cardiology (http://content.onlinejacc.org/current.dtl; 2008; 52).
Beta-Blockers During HF Hospitalization: Patients fare better when beta-blockers are continued after hospitalization for heart failure, a study shows (pp. 190-9). In the OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure) program, lower postdischarge mortality risk and improved treatment rates were evident among those continued on the drug, while withdrawal of beta-blockers put patients at increased risk for adverse outcomes, including death. Specific results showed: “Among 2,373 patients eligible for beta-blockers at discharge, there were 1,350 (56.9%) who were receiving beta-blockers before admission and continued on therapy, 632 (26.6%) newly started, 79 (3.3%) in which therapy was withdrawn, and 303 (12.8%) eligible but not treated. Continuation of beta-blockers was associated with a significantly lower risk and propensity adjusted post-discharge death (hazard ratio [HR]: 0.60; 95% confidence interval [CI]: 0.37 to 0.99, p = 0.044) and death/rehospitalization (odds ratio: 0.69; 95% CI: 0.52 to 0.92, p = 0.012) compared with no beta-blocker. In contrast, withdrawal of beta-blocker was associated with a substantially higher adjusted risk for mortality compared with those continued on beta-blockers (HR: 2.3; 95% CI: 1.2 to 4.6, p = 0.013), but with similar risk as HF patients eligible but not treated with beta-blockers.” (G. C. Fonarow, gfonarow@mednet.ucla.edu)
Nitroprusside for Advanced Low-Output HF: Favorable long-term clinical outcomes were noted when the vasodilator sodium nitroprusside was added to optimal current medical therapy during hospitalization for advanced low-output heart failure (pp. 200-7). Among consecutive patients admitted with this diagnosis between 2000 and 2005, the researchers found: “Compared with control patients (n = 97), cases treated with SNP (n = 78) had significantly higher mean central venous pressure (15 vs. 13 mm Hg; p = 0.001), pulmonary capillary wedge pressure (29 vs. 24 mm Hg; p = 0.001), but similar demographics, medications, and renal function at baseline. Use of SNP was not associated with higher rates of inotropic support or worsening renal function during hospitalization. Patients treated with SNP achieved greater improvement in hemodynamic measurements during hospitalization, had higher rates of oral vasodilator prescription at discharge, and had lower rates of all-cause mortality (29% vs. 44%; odds ratio: 0.48; p = 0.005; 95% confidence interval: 0.29 to 0.80) without increase in rehospitalization rates (58% vs. 56%; p = NS).” (W. H. Wilson Tang, tangw@ccf.org)
Leptin & Coronary Artery Calcification: The fat-secreted adipokine leptin was a significant predictor of coronary artery calcification among 860 asymptomatic, nondiabetic participants in SIRCA (Study of Inherited Risk of Coronary Atherosclerosis; pp. 231-6). “Plasma adiponectin and leptin levels had opposite and distinct associations with adiposity, insulin resistance, and inflammation,” the researchers report. “Plasma leptin was positively (top vs. bottom quartile) associated with higher CAC after adjustment for age, gender, traditional risk factors, and Framingham risk scores....” (M. P. Reilly, muredach@spirit.gcrc.upenn.edu)

>>>PNN NewsWatch
* Genentech reports an increased number of complaints of damaged and broken vials of the breast cancer agent Herceptin (trastuzumab) 440 mg and BWFI (bacteriostatic water for injection) diluent. The affected vials are NDC no. 50242-0134-68, list no. 15534. Health professionals should inspect cartons of the product for signs of leakage, cracks, and other damage to the vials, observe the vials during reconstitution, and check for loss of vacuum in the vials.
* Two FDA advisory panels, meeting jointly, yesterday rejected agency staff’s call for a black-box warning regarding suicidality with
antiepileptic drugs. The vote was 14–4 with three abstentions. Panelists agreed that the risk of suicidality is increased with the drugs, by a vote of 20–1, and supported 17–4 the issuance of a Medication Guide for the drugs for distribution to patients.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
July 14, 2008 * Vol. 15, No. 135
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
July 12 issue of Lancet (www.thelancet.com; 2008; 372).
Pegylated Interferon Alfa-2b for Resected Melanoma: Adjuvant treatment of patients with stage III melanoma with pegylated interferon alfa-2b significantly improves recurrence-free survival, report investigators from the European Organisation for Research and Treatment of Cancer (EORTC) Melanoma Group (pp. 117-26). In trial 18991, 1,256 patients with the condition received either observation or pegylated interferon alfa-2b 6 mcg/kg/wk for 8 weeks (induction) followed by 3 mcg/kg/wk (maintenance), with these results: “The median length of treatment with pegylated interferon alfa-2b was 12 (IQR 3.8–33.4) months. At 3.8 (3.2–4.2) years median follow-up, 328 recurrence events had occurred in the interferon group compared with 368 in the observation group (hazard ratio 0.82, 95% CI 0.71–0.96; p = 0.01); the 4-year rate of recurrence-free survival was 45.6% (SE 2.2) in the interferon group and 38.9% (2.2) in the observation group. There was no difference in overall survival between the groups. Grade 3 adverse events occurred in 246 (40%) patients in the interferon group and 60 (10%) in the observation group; grade 4 adverse events occurred in 32 (5%) patients in the interferon group and 14 (2%) in the observation group. In the interferon group, the most common grade 3 or 4 adverse events were fatigue (97 patients, 16%), hepatotoxicity (66, 11%), and depression (39, 6%). Treatment with pegylated interferon alfa-2b was discontinued because of toxicity in 191 (31%) patients.” (A. M. M. Eggermont, Erasmus U. Med. Ctr., Rotterdam, the Netherlands; a.m.m.eggermont@erasmusmc.nl)
Preventive Malaria Treatment in Schoolchildren: Intermittent preventive treatment (IPT) of malaria improved health and cognitive abilities among 4,906 children and adolescents in western Kenya (pp. 127-38). Administration of three treatments of sulfadoxine–pyrimethamine in combination with amodiaquine or dual placebo at 4-month intervals produced these 12-month data: “Prevalence of anaemia at 12 months averaged 6.3% in the IPT group and 12.6% in the placebo group (adjusted risk ratio 0.52, 95% CI 0.29–0.93; p = 0.028). Significant improvements were also seen in two of the class-based tests of sustained attention, with a mean increase in code transmission test score of 6.05 (95% CI 2.83–9.27; p = 0.0007) and counting sounds test score of 1.80 (0.19–3.41; p = 0.03), compared with controls.” (S. Clarke, London Sch. of Hygiene and Tropical Med., London; sian.clarke@lshtm.ac.uk)
Therapeutic Vaccine After Renal Cell Carcinoma Nephrectomy: Use of the therapeutic vaccine vitespen (autologous, tumor-derived heat-shock protein [glycoprotein 96]–peptide complex (HSPPC-96]) had no effect on recurrence-free survival in 818 patients who had undergone nephrectomy for renal cell carcinoma (pp. 145-54). In the open-label trial, only patients with early-stage disease showed possible benefits, as noted in these results: “After a median follow-up of 1.9 years (IQR 0.9–2.5) in the [intent to treat] population, recurrence events were reported in 136 (37.7%) patients in the vitespen group and 146 (39.8%) in the observation group (hazard ratio 0.923, 95% CI 0.729–1.169; p = 0.506). After continued follow-up until March, 2007, there had been 70 deaths in the vitespen group and 72 in the observation group (p = 0.896); however, overall survival data were not mature, and patients continue to be followed up for survival. In predefined exploratory analyses by [American Joint Committee on Cancer] stage, recurrence events in patients with stage I or II disease were reported in 19 (15.2%) patients in the vitespen group and 31 (27.0%) in the observation group (hazard ratio 0.576, 95% CI 0.324–1.023; p = 0.056).” (C. Wood, cgwood@mdanderson.org)

>>>PNN JournalWatch
* Gastric Mucosal Defense and Cytoprotection: Bench to Bedside, in Gastroenterology, 2008; 135: 41–60. Reprints: L. Laine, llaine@usc.edu
* Overweight, Obesity, and the Development of Stage 3 CKD: The Framingham Heart Study, in
American Journal of Kidney Diseases, 2008; 52: 39–48. Reprints: C. S. Fox, foxca@nhlbi.nih.gov
* Effect of Intensive Insulin Therapy and Pentastarch Resuscitation on Acute Kidney Injury in Severe Sepsis, in
American Journal of Kidney Diseases, 2008; 52: 13–7. Reprints: B. L. Jaber, Caritas St. Elizabeth’s Med. Ctr., Boston; bertrand.jaber@caritaschristi.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 © 2008, 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
July 15, 2008 * Vol. 15, No. 136
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
July 15 issue of the Annals of Internal Medicine (www.annals.org/current.shtml; 2008; 149).
Thromboprophylaxis After Knee Arthroscopy: Compared with graduated compression stockings, low molecular weight heparins were significantly more effective for prevention of a composite of adverse outcomes in a study of 1,761 consecutive patients undergoing knee arthroscopy in 2002–06 (pp. 73-82). Seven days of stockings were compared with 7 or 14 days of nadroparin (3800 anti-Xa IU), and these results were recorded for a composite end point of asymptomatic proximal deep venous thrombosis, symptomatic venous thromboembolism, and all-cause mortality: “The 3-month cumulative incidence of asymptomatic proximal deep venous thrombosis, symptomatic venous thromboembolism, and all-cause mortality was 3.2% (21 of 660 patients) in the stockings group, 0.9% (6 of 657 patients) in the 7-day LMWH group (absolute difference, 2.3 percentage points [95% CI, 0.7 to 4.0 percentage points]; P = 0.005), and 0.9% (4 of 444 patients) in the prematurely stopped 14-day LMWH group. The cumulative incidence of major or clinically relevant bleeding events was 0.3% (2 of 660 patients) in the stockings group, 0.9% (6 of 657 patients) in the 7-day LMWH group (absolute difference, –0.6 percentage point [CI, –1.5 to 0.2 percentage points]), and 0.5% (2 of 444 patients) in the 14-day LMWH group.” (G. Camporese, U. Hosp., Padua, Italy; giuseppe.camporese@sanita.padova.it)
Empirical Fluconazole in Intensive Care: Among 270 adult patients in intensive care units at 26 facilities, empirical fluconazole “did not clearly improve a composite outcome more than placebo,” researchers conclude (pp. 83-90). Assessing patients using a primary outcome that included all of four potential events (resolution of fever; absence of invasive fungal infection; no discontinuation because of toxicity; and no need for a nonstudy, systemic antifungal medication), the investigators found: “Only 44 of 122 (36%) fluconazole recipients and 48 of 127 (38%) placebo recipients had a successful outcome (relative risk, 0.95 [95% CI, 0.69 to 1.32; P = 0.78]). The main reason for failure was lack of resolution of fever (51% for fluconazole and 57% for placebo). Documented invasive candidiasis occurred in 5% of fluconazole recipients and 9% of placebo recipients (relative risk, 0.57 [CI, 0.22 to 1.49]). Seven (5%) fluconazole recipients and 10 (7%) placebo recipients had adverse events resulting in discontinuation of the study drug. Discontinuation because of abnormal liver test results occurred in 3 (2%) fluconazole recipients and 5 (4%) placebo recipients.” (M. G. Schuster, schustem@mail.med.upenn.edu)

>>>Internal Medicine Report
Source:
July 14 Archives of Internal Medicine (http://archinte.ama-assn.org/current.dtl; 2008; 168).
Physician Performance & Certification Scores: Physician scores on the American Board of Internal Medicine examination were predictive of the quality of their care to Medicare patients, with higher scores associated with higher rates of processes of care, a study shows (pp. 1396-403). Researchers grouped physicians into quartiles based on their certification scores and then assessed their use of A1C measurement, lipid testing, retinal screening in patients with diabetes; mammography; and lipid testing in those with cardiovascular diseases. Results were as follows: “Physicians scoring in the top quartile were more likely to perform processes of care for diabetes (composite measure odds ratio [OR], 1.17; 95% confidence interval [CI], 1.07–1.27) and mammography screening (OR, 1.14; 95% CI, 1.08–1.21) than physicians in the lowest physician quartile, even after adjustment for multiple factors. There was no significant difference among the groups in lipid testing of patients with cardiovascular disease (OR, 1.00; 95% CI, 0.91–1.10).” (E. S. Holmboe, American Board of Internal Medicine, Philadelphia; eholmboe@abim.org)
Medical Visit Companions: Companions who accompany older adults to medical appointments should be more systematically recognized and integrated into care processes, an analysis shows (pp. 1409-15). Nearly 40% of 12,018 community-dwelling elderly had companions with them at such appointments, and the study shows they were often actively engaged in the patient’s care and influential in terms of the patient’s satisfaction with physician care. (J. L. Wolff, jwolff@jhsph.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
July 16, 2008 * Vol. 15, No. 137
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
July 16 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2008; 300).
Simvastatin Effects on Cognition in Pediatric Neurofibromatosis: In 62 children with neurofibromatosis type 1, simvastatin was statistically similar to placebo in terms of improvement of scores on most cognition tests, researchers report (pp. 287-94). The trial, developed based on statin restoration of the genetic defects in an NF1 mouse model, showed these effects after 12 weeks of treatment: “No significant differences were observed between the simvastatin and placebo groups on any primary outcome measure: Rey complex figure test (beta = 0.10; 95% confidence interval [CI], –0.36 to 0.56); cancellation test (beta = –0.19; 95% CI, –0.67 to 0.29); prism adaptation (odds ratio = 2.0; 95% CI, 0.55 to 7.37); and mean brain apparent diffusion coefficient (beta = 0.06; 95% CI, –0.07 to 0.20). In the secondary outcome measures, we found a significant improvement in the simvastatin group in object assembly scores (beta = 0.54; 95% CI, 0.08 to 1.01), which was specifically observed in children with poor baseline performance (beta = 0.80; 95% CI, 0.29 to 1.30). Other secondary outcome measures revealed no significant effect of simvastatin treatment.” (Y. Elgersma, Erasmus Med. Ctr., Rotterdam, the Netherlands; y.elgersma@erasmusmc.nl)
Opiate Addiction: Two case reports explore aspects of addiction to heroin and other opiates.
A 50-year-old woman who wished to be switched from methadone to buprenorphine maintenance forms the basis for the first article (pp. 314-21): “Ms W should be congratulated for all of the progress that she has made in struggling against a very powerful addiction. It could be argued that she should be discouraged from stopping methadone because she has done so well and because of the risks of relapse and possible overdose. However, I have treated patients who, after being fully informed of the risks, succeed in the plan that Ms W has chosen. Therefore, I would warn her of the potential problems and explain that tapering off methadone may be difficult and that she should not feel like a failure if she changes her mind. She should be informed that persons with her history have been successfully maintained on methadone for decades and that the risk of relapse is high. After providing this information, if Ms W continues to wish to transfer her maintenance treatment to buprenorphine, her methadone dose could be gradually reduced over several months to an eventual dose of 40 mg or less. She should be treated by a physician familiar with the intricacies of switching from methadone to buprenorphine because adding buprenorphine too soon after the last dose of methadone could precipitate opiate withdrawal.” (C. P. O’Brien,
brien@mail.trc.upenn.edu">obrien@mail.trc.upenn.edu)
A Clinical Crossroads Update article checks in on a 35-year-old physician who is 4.5 years post-rehab for hydrocodone addiction (p. 322): “What advice do I have for other physicians? Looking back on this, the biggest thing that I would say is that you can’t do any of this alone. Physicians can feel very isolated. One thing this program has taught me is that there are plenty of ways to reach out to other physicians if you choose to do that. You don’t have to be a martyr when it comes to this. Admitting mistakes is part of life, but it’s something we as physicians are not very good at doing, and we never admit that we are wrong because of fear; maybe it’s fear of malpractice, maybe it is a different fear. But once you do it, you realize that nobody is going to beat you over the head. Another piece of advice would be not relying on yourself so much and asking for help and admitting when you’ve done something wrong. This program is not so much about being a better physician; it’s about figuring out that there are a lot of better strategies for dealing with life than the way we have dealt with it thus far.” (N. Farag)

>>>PNN NewsWatch
* Several cases of microangiopathic hemolytic anemia (MAHA) have been reported in patients with solid tumors receiving bevacizumab (Avastin) with sunitinib malate, an unapproved combination, Genentech and FDA are warning. In a Phase I dose-escalation study combining the drugs, five patients had laboratory findings consistent with MAHA. Two of these patients had laboratory values that were considered severe; abnormalities reversed within 3 weeks after discontinuation.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
July 17, 2008 * Vol. 15, No. 138
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
July 17 issue of and early-release article from the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2008; 359).
Desensitization with IG, Rituximab: A combination of intravenous immune globulin and rituximab showed promise as a desensitization regimen for 20 patients awaiting transplants from living or deceased donors (pp. 242-51). Concluding that the regimen should be tested further in larger and longer trials, the researchers report: “The mean panel-reactive antibody level was 44 ± 30% after the second infusion of intravenous immune globulin (P < 0.001 for the comparison with the pretreatment level). At study entry, the mean time on dialysis among recipients of a transplant from a deceased donor was 144 ± 89 months (range, 60 to 324). However, the time to transplantation after desensitization was 5 ± 6 months (range, 2 to 18). Sixteen of the 20 patients (80%) received a transplant. At 12 months, the mean serum creatinine level was 1.5 ± 1.1 mg per deciliter (133 ± 97 µmol per liter), and the mean survival rates of patients and grafts were 100% and 94%, respectively. There were no infusion-related adverse events or serious adverse events during the study. Long-term monitoring for infectious complications and neurologic problems revealed no unanticipated events.” (A. A. Vo, ashley.vo@cshs.org)
An editorialist expresses excitement about this approach to desensitization of patients awaiting transplantation (pp. 305-6): “As the authors note, their observations need to be confirmed and validated by other centers and in larger numbers of patients and during longer periods of follow-up. However, their approach may represent a breakthrough in the care of sensitized patients awaiting transplantation and may have the potential to help thousands of patients who are languishing on waiting lists around the world.” (R. Shapiro, U. Pittsburgh, Pittsburgh)
Acetylcysteine for Acetaminophen Poisoning: The difficulties of determining whether and how to use acetylcysteine in patients with liver injury but not failure secondary to acetaminophen poisoning are explored through discussion of a case involving a 25-year-old man who took prescription and nonprescription products containing acetaminophen 12 g/day for 5 days (pp. 285-92). “Although in many cases acute acetaminophen poisoning is a straightforward problem, the vignette illustrates a common situation for which there are no clear answers. Published protocols have focused on patients with acetaminophen poisoning who present with a toxic acetaminophen concentration and without liver injury. These patients will do well as long as they receive timely acetylcysteine therapy. Patients who present with liver failure have a less favorable prognosis, but it is clear that acetylcysteine treatment improves their chance of surviving. The best treatment for the patient who cannot be risk-stratified with the use of the Rumack–Matthew nomogram, or who has hepatic injury without hepatic failure, is less well defined.” (K. J. Heard, kennon.heard@rmpdc.org)
Veto Override of Medicare Bill: This week’s votes in the House and Senate to override President Bush’s veto of a Medicare bill are analyzed in an early-release Perspective article (doi: 10.1056/NEJMp0805760; J. K. Iglehart).

>>>PNN NewsWatch
* Roxane Laboratories has recalled two lots of Sodium Polystyrene Sulfonate Suspension, USP, 15 g/60 mL unit dose bottles (NDC 0054-0165-51; lot 856396A Exp April 2010, and lot 856693A Exp May 2010) because a sample of one of the affected lots tested positive for a strain of yeast. Pharmacists should determine if any of the referenced product has been dispensed and retrieve it. Additionally, pharmacists and wholesalers of the product should discontinue distribution and use of the referenced lots immediately and contact the manufacturer regarding returning the product.
* X-rays used during CT examinations may cause some implanted and external electronic medical devices, including
infusion pumps, to malfunction, FDA is warning. The agency has received a small number of reports of adverse events in which CT scans may have interfered with electronic medical devices, including pacemakers, defibrillators, neurostimulators, and implanted or externally worn drug infusion pumps.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
July 18, 2008 * Vol. 15, No. 139
Providing news and information about medications and their proper use

>>>Pediatrics Highlights
Source:
July issue of Pediatrics (http://pediatrics.aappublications.org/current.shtml - ARTICLES; 2008; 122).
Lamotrigine During Breastfeeding: A highly variable portion of serum lamotrigine levels reaches breastfed infants, a research study shows, and mild thrombocytosis was observed in seven of eight infants tested for this adverse effect (e223-31). Among 30 women and their nursing infants in the study of this antiepileptic drug, these patterns were noted in sera and 210 assayed breast milk samples: “The mean milk/plasma ratio was 41.3%. There was a nonsignificant trend for higher lamotrigine concentrations in breast milk 4 hours after the maternal dose. Infant plasma concentrations were 18.3% of maternal plasma concentrations. The theoretical infant lamotrigine dose was 0.51 mg/kg per day, and the relative infant lamotrigine dose was 9.2%. Mild thrombocytosis was present in 7 of 8 infants at the time of serum sampling. No other adverse events were observed or reported in the breastfed infants.” (D. J. Newport, Emory U., Atlanta)
Risk of Papillomavirus Infection: Trying to figure out which adolescents should receive human papillomavirus vaccine based on behavioral risk factors is “unlikely to be an effective implementation strategy,” investigators conclude (pp. 1-7). Looking at data on 3,181 females older than 12 years in waves I and III of the National Longitudinal Study of Adolescent Health, the researchers found: “Although nearly one half (43%) of the female adolescents were sexually active in wave I, adolescent sexual activity status was not associated with future detection of vaccine-specific human papillomavirus infection. Furthermore, for both virginal and sexually active adolescents, none of the assessed risk factors was associated with increased odds of future vaccine-specific human papillomavirus infection in multivariate models. Similar results were obtained when all high-risk human papillomavirus types were assessed as the outcome measure.” (A. F. Dempsey, U. Mich., Ann Arbor)

>>>Gastroenterology Report
Source:
July issue of Gastroenterology (www.gastrojournal.org/current; 2008; ).
Hormonal Therapy & GER: Estrogens used alone are associated with symptoms of gastroesophageal reflux, a 10,739-patient study shows, but the relationship is not present when the hormones are used with progestins (pp. 72-81). Other findings from the randomized controlled trial show an increased risk of GER symptoms with increasing weight and girth, as described in study results: “After 1 year, there was a trend toward a higher incidence of symptomatic GER among women randomly assigned to the estrogen treatment (4.2%) than with placebo (3.1%). The estrogen plus progestin treatment did not affect this risk. Neither treatment affected the progression of existing GER symptom. There was a dose–response association between baseline obesity, particularly as measured by waist circumference, with more than double the risk of incident symptomatic GER at 1 year among women with the largest waist circumference (114 cm) compared with a normal waist circumference (70–80 cm). Weight gain at 1 year was associated with elevated risk of incident symptomatic GER. Weight loss at 1 year alleviated existing GER symptoms. No interaction between hormone therapy and obesity on symptomatic GER was observed.” (Z. Zheng, Karolinska Inst., Stockholm; zongli.zheng@ki.se)
Rosiglitazone for Nonalcoholic Steatohepatitis: Among 63 patients with nonalcoholic steatohepatitis (NASH), rosiglitazone improved steatosis and transaminase levels despite weight gain, researchers report (pp. 100-10). One year of treatment with rosiglitazone 4 and later 8 mg/day or placebo followed by liver biopsy showed: “More patients treated with rosiglitazone than receiving placebo had improved steatosis (47% vs 16%; P = .014) and normalized transaminase levels (38% vs 7%; P = .005), although only half of patients responded.… Improvement of steatosis correlated with reduction of transaminase levels (r = 0.36; P < .005), improvement in insulin sensitivity (r = 0.34; P = .008), and increase in adiponectin levels (r = −0.54; P < .01) but not with weight variations. Independent predictors of response were rosiglitazone treatment, the absence of diabetes, and massive steatosis.” (V. Ratziu, Hôpital Pitié-Salpetriére, Paris; vratziu@teaser.fr)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
July 21, 2008 * Vol. 15, No. 140
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
July 19 issue of Lancet (www.thelancet.com; 2008; 372).
Dimebon for Alzheimer’s Disease: An orally active drug approved in Russia as a nonselective antihistamine proved useful for improving the clinical course of Alzheimer’s disease among 183 patients with mild to moderate symptoms (pp. 207-15). Scores on the cognitive subscale of the Alzheimer’s disease assessment scale showed these patterns during 26 weeks of treatment with placebo or dimebon 20 mg three times daily: “155 (85%) patients completed the trial (78 [88%] in dimebon group, 77 [82%] in placebo group). Treatment with dimebon resulted in significant benefits in ADAS-cog compared with placebo (ITT-LOCF) at week 26 (mean drug-placebo difference −4·0 [95% CI −5·73 to −2·28]; p < 0·0001). Results of the ITT-LOCF and the evaluable population analyses were much the same for all measures. Patients given dimebon were significantly improved over baseline for ADAS-cog (mean difference −1·9 [−2·92 to −0·85]; p = 0·0005). Dimebon was well tolerated: dry mouth and depressed mood or depression were the most common adverse events associated with dimebon (12 [14%] patients for each symptom by week 26). The percentage of patients who had adverse events in the two groups did not differ.” (R. S. Doody, Baylor Coll. of Med., Houston; rdoody@bcm.tmc.edu)
Apolipoproteins v. Lipoproteins for MI Risk: The nonfasting apolipoprotein B/apolipoprotein A1 ratio should replace cholesterol-based measures of risk for acute myocardial infarction, authors of a research study conclude (pp. 224-33). Results of a case–control study of 12,461 cases and 14,637 age- and sex-matched controls in 52 countries showed: “The non-fasting ApoB/ApoA1 ratio was superior to any of the cholesterol ratios for estimation of the risk of acute myocardial infarction in all ethnic groups, in both sexes, and at all ages, and it should be introduced into worldwide clinical practice.” (M. McQueen, Hamilton Genl. Hosp., Hamilton, ON, Canada; mcquemat@hhsc.ca)

>>>BMJ Highlights
Source:
Early-release article from BMJ (www.bmj.org; 2008; 337).
Human Papillomavirus Vaccine: Vaccination of schoolgirls for human papillomavirus—including catch-up doses—is likely to be cost-effective in the U.K. , an article concludes (doi:10.1136/bmj.a769). An analysis of costs, quality-adjusted life–years, and incremental cost effectiveness ratios for a range of vaccination options shows these results: “Vaccinating 12 year old schoolgirls with a quadrivalent vaccine at 80% coverage is likely to be cost effective at a willingness to pay threshold of £30,000 (37,700 euros; $59,163) per QALY gained, if the average duration of protection from the vaccine is more than 10 years. Implementing a catch-up campaign of girls up to age 18 is likely to be cost effective. Vaccination of boys is unlikely to be cost effective. A bivalent vaccine with the same efficacy against human papillomavirus types 16 and 18 costing £13–£21 less per dose (depending on the duration of vaccine protection) may be as cost effective as the quadrivalent vaccine although less effective as it does not prevent anogenital warts.” (M. Jit, Health Protection Agency, London; mark.jit@hpa.org.uk)

PNN JournalWatch
* Case Series Report of a Linezolid-Containing Regimen for Extensively Drug-Resistant Tuberculosis, in Chest, 2008; 134: 187–92. Reprints: R. Condos, NYU Sch. of Med., New York; Rany.Condos@nyumc.org
* New Drugs and Technologies: Myocardial Contrast Echocardiography: A 25-Year Retrospective, in
Circulation, 2008; 118: 291–308. Reprints: S. Kaul.
* Diagnostic Accuracy of the Physical Examination and Imaging Tests for Osteomyelitis Underlying Diabetic Foot Ulcers: Meta-Analysis, in
Clinical Infectious Diseases, 2008; 47: 519–27. Reprints: M. T. Dinh, U. Wisconsin, Madison.
* Workshop on HIV Infection and Aging: What Is Known and Future Research Directions, in
Clinical Infectious Diseases, 2008; 47: 542–53. Reprints: R. B. Effros, U. Calif., Los Angeles.
* Critical Issues in Mucosal Immunity for HIV-1 Vaccine Development, in
Journal of Allergy and Clinical Immunology, 2008; 122: 3–9. Reprints: B. F. Haynes, hayne002@mc.duke.edu
* Viral Reservoirs, Residual Viremia, and the Potential of Highly Active Antiretroviral Therapy to Eradicate HIV Infection, in
Journal of Allergy and Clinical Immunology, 2008; 122: 22–8. Reprints: Robert F. Siliciano, rsiliciano@jhmi.edu

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
July 22, 2008 * Vol. 15, No. 141
Providing news and information about medications and their proper use

>>>Rheumatology Highlights
Source:
July issue of Arthritis & Rheumatism (www3.interscience.wiley.com/journal/76509746/home; 2008; 58).
Etanercept Dosing Frequency: Increasing the dosing frequency of etanercept to twice weekly failed to provide significantly increased responses among a group of 201 patients with rheumatoid arthritis who did not respond to standard once-weekly doses of the drug (pp. 1921-30). Patients received once-weekly methotrexate and were randomized to either once- or twice-weekly etanercept 50 mg, with these results: “At week 12 (double-blind period), the DAS28 response in the 50 mg twice weekly and the 50 mg once weekly groups was not significantly different (45.6% versus 35.0%; P = 0.285), and similar proportions of patients in the groups taking 100 mg and 50 mg experienced adverse events (34.4% versus 37.5%; P = 0.711). Serious adverse events occurred in 7 of 160 of the 50 mg twice weekly group and 0 of 40 of the 50 mg once weekly group (P = 0.387), and serious infectious events occurred in 3 of 160 patients in the 50 mg twice weekly group (P = 0.884).” (M. E. Weinblatt; mweinblatt@partners.org)
Adalimumab in Axial Spondylarthritis: In a study of 46 patients, adalimumab became the first tumor necrosis factor antagonist to have good efficacy and safety in treatment of axial spondylarthritis (SpA) without radiographically defined sacroiliitis (pp. 1981-91). Testing 40-mg subcutaneous doses of the drug against placebo and looking for 40% improvement on the Assessment of Spondyloarthritis International Society scale (ASAS40), the researchers found: “All 46 patients (22 receiving adalimumab and 24 receiving placebo) completed the 12-week trial; 38 patients completed the extension period to week 52. At week 12, an ASAS40 response was achieved by 54.5% of the adalimumab-treated patients, as compared with 12.5% of the placebo-treated patients (P = 0.004). After switching to adalimumab, a similar degree of efficacy was also achieved by the patients who were initially treated with placebo. Efficacy was maintained in all patients until week 52. Young age at study entry and an elevated C-reactive protein concentration were the best predictors of achieving an ASAS40 response. Serious adverse events occurred in 5 patients, none of which was related to the study drug.” (J. Sieper, Charité Med. U. Hosp., Berlin; joachim.sieper@charite.de)

>>>Neurology Highlights
Source:
July 22 issue of Neurology (www.neurology.org/current.shtml; 2008; 71).
IVIG in MS:
A dose-ranging study of intravenous immunoglobulin calls into question the effectiveness of the product for treating remitting–remitting multiple sclerosis (RRMS) (pp. 265-71). The study included 127 patients with RRMS who received placebo or a new formulation of IVIG 0.2 or 0.4 g/kg every 4 weeks for 48 weeks. Results showed: “Baseline variables were similar in IVIG- and placebo-treated groups. After 1 year, the proportion of relapse-free patients did not differ statistically according to treatment (IVIG 0.2 g/kg: 57%; IVIG 0.4 g/kg: 60%; placebo: 68%), and there was no difference regarding the cumulative number of unique newly active MRI lesions (median numbers: IVIG 0.2 g/kg: 8.0; IVIG 0.4 g/kg: 5.0; placebo: 7.2) after 48 weeks. There were no significant between-group differences in the rates of adverse events.” (F. Fazekas, Medical U. Graz, Graz, Austria; franz.fazekas@meduni-graz.at)
Topiramate in Pregnancy: While the overall rate of fetal abnormalities observed in a study of women taking topiramate during pregnancy was low, the rate of major congenital malformation raises concern (pp. 272-6). “Full outcome data are available on 203 pregnancies,” write the authors. “Of these, 178 resulted in live birth; 16 had an MCM (9.0%; 95% CI 5.6% to 14.1%). Three [major congenital malformations] were observed in 70 monotherapy exposures (4.8%; 95% CI 1.7% to 13.3%) and 13 in cases exposed to topiramate as part of a polytherapy regimen (11.2%; 95% CI 6.7% to 18.2%). Four of the [major congenital malformations] were oral clefts (2.2%; 95% CI 0.9% to 5.6%). Four cases of hypospadias were reported (5.1%; 95% CI 0.2% to 10.1%) among 78 known live male births of which two were classified as major malformations.” (J. Craig, Royal Group of Hospitals, Belfast, U.K.; john.craig@belfasttrust.hscni.net)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
July 23, 2008 * Vol. 15, No. 142
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
July 23/30 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2008; 300).
Sildenafil for Antidepressant-Associated Sexual Dysfunction in Women: Sexual dysfunction among 49 women taking SSRIs improved when sildenafil 50–100 mg was taken before sexual activity, researchers report (pp. 395-404): “In an intention-to-treat analysis, women treated with sildenafil had a mean Clinical Global Impression–sexual function score of 1.9 (95% confidence interval [CI], 1.6–2.3) compared with those taking placebo (1.1; 95% CI, 0.8–1.5), with a mean end point difference of 0.8 (95% CI, 0.6–1.0; P = .001). Assigning baseline values carried forward to the 22% of patients who prematurely discontinued resulted in a mean end point in the sexual function score of 1.5 (95% CI, 1.1–1.9) among women taking sildenafil compared with 0.9 (95% CI, 0.6–1.3) among women taking placebo with a mean end point difference of 0.6 (95% CI, 0.3–0.8; P = .03). Baseline endocrine levels were within normal limits and did not differ between groups. The mean (SD) Hamilton scores for depression remained consistent with remission in both groups (4.0 [3.6]; P = .90). Headache, flushing, and dyspepsia were reported frequently during treatment, but no patients withdrew because of serious adverse effects.” (H. G. Nurnberg, gnurnberg@salud.unm.edu)
CMV Reactivation in Critical Illness: Reactivation of cytomegalovirus occurs frequently and is associated with prolonged hospitalizations and increased mortality among immunocompetent patients in intensive care units, according to a study of 120 patients (pp. 413-22). Between 2004 and 2006, patients admitted to six ICUs at two academic medical centers who were seropositive for CMV were studied and these results noted: “The primary composite end point of continued hospitalization (n = 35) or death (n = 10) by 30 days occurred in 45 (35%) of the 120 patients. Cytomegalovirus viremia at any level occurred in 33% (39/120; 95% confidence interval [CI], 24%–41%) at a median of 12 days (range, 3–57 days) and CMV viremia greater than 1,000 copies/mL occurred in 20% (24/120; 95% CI, 13%–28%) at a median of 26 days (range, 9–56 days). By logistic regression, CMV infection at any level (adjusted odds ratio [OR], 4.3; 95% CI, 1.6–11.9; P = .005) and at greater than 1,000 copies/mL (adjusted OR, 13.9; 95% CI, 3.2–60; P < .001) and the average CMV area under the curve (AUC) in log-10 copies per milliliter (adjusted OR, 2.1; 95% CI, 1.3–3.2; P < .001) were independently associated with hospitalization or death by 30 days. In multivariable partial proportional odds models, both CMV 7-day moving average (OR, 5.1; 95% CI, 2.9–9.1; P < .001) and CMV AUC (OR, 3.2; 95% CI, 2.1–4.7; P < .001) were independently associated with a hospital length of stay of at least 14 days.” (A. P. Limaye, limaye@u.washington.edu)
HIV, TB Epidemics: The epidemic of tuberculosis combined with emergence of multidrug-resistant strains of its causative pathogen represent major challenges to HIV care in resource-limited environments, writers maintain (pp. 423-30). “Tuberculosis is a major cause of mortality among patients with HIV and poses a risk throughout the course of HIV disease, even after successful initiation of antiretroviral therapy (ART),” the group notes. “Progress in the implementation of activities directed at reducing TB burden in the HIV population lags far behind global targets. HIV programs designed for longitudinal care are ideally suited to implement TB control measures and have no option but to address TB vigorously to save patient lives, to safeguard the massive investment in HIV treatment, and to curb the global TB burden. We propose a framework of strategic actions for HIV care programs to optimally integrate TB into their services. The core activities of this framework include intensified TB case finding, treatment of TB, isoniazid preventive treatment, infection control, administration of ART, TB recording and reporting, and joint efforts of HIV and TB programs at the national and local levels.” (D. V. Havlir, dhavlir@php.ucsf.edu)

>>>PNN NewsWatch
* At the upcoming Olympics in Beijing, respiratory illnesses and dog bites should be the concerns of visitors rather than exotic diseases, according to an article by CDC staff in the American Journal of Tropical Medicine and Hygiene. Respiratory infections, skin problems, injuries, and diarrhea are other potentially common health problems.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
July 24, 2008 * Vol. 15, No. 143
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
July 24 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2008; 359).
Raltegravir for HIV Infection: Two research articles and an editorial examine the utility of raltegravir for treatment of HIV infection.
In two identical trials conducted in different geographic areas, raltegravir provided viral suppression in patients infected with multidrug-resistant HIV-1 who had failed antiretroviral therapy (pp. 339-54). Study participants received optimized background therapy supplemented with raltegravir or placebo in a 2:1 ratio, with these results: “In the combined studies, 699 of 703 randomized patients (462 and 237 in the raltegravir and placebo groups, respectively) received the study drug. Seventeen of the 699 patients (2.4%) discontinued the study before week 16. Discontinuation was related to the study treatment in 13 of these 17 patients: 7 of the 462 raltegravir recipients (1.5%) and 6 of the 237 placebo recipients (2.5%). The results of the two studies were consistent. At week 16, counting noncompletion as treatment failure, 355 of 458 raltegravir recipients (77.5%) had HIV-1 RNA levels below 400 copies per milliliter, as compared with 99 of 236 placebo recipients (41.9%, P < 0.001). Suppression of HIV-1 RNA to a level below 50 copies per milliliter was achieved at week 16 in 61.8% of the raltegravir recipients, as compared with 34.7% of placebo recipients, and at week 48 in 62.1% as compared with 32.9% (P < 0.001 for both comparisons). Without adjustment for the length of follow-up, cancers were detected in 3.5% of raltegravir recipients and in 1.7% of placebo recipients. The overall frequencies of drug-related adverse events were similar in the raltegravir and placebo groups.” (H. Teppler,
hedy_teppler@merck.com)
Similar conclusions are reached in a subgroup analysis of the above two trials, with researchers noting that patients in several difficult-to-treat categories responded to raltegravir, including those with high HIV-1 RNA level, low CD4 cell count, and low genotypic or phenotypic sensitivity score (pp. 355-65): “Virologic responses to raltegravir were consistently superior to responses to placebo, regardless of the baseline values of HIV-1 RNA level; CD4 cell count; genotypic or phenotypic sensitivity score; use or nonuse of darunavir, enfuvirtide, or both in optimized background therapy; or demographic characteristics. Among patients in the two studies combined who were using both enfuvirtide and darunavir for the first time, HIV-1 RNA levels of less than 50 copies per milliliter were achieved in 89% of raltegravir recipients and 68% of placebo recipients. HIV-1 RNA levels of less than 50 copies per milliliter were achieved in 69% and 80% of the raltegravir recipients and in 47% and 57% of the placebo recipients using either darunavir or enfuvirtide for the first time, respectively. At 48 weeks, 105 of the 462 raltegravir recipients (23%) had virologic failure. Genotyping was performed in 94 raltegravir recipients with virologic failure. Integrase mutations known to be associated with phenotypic resistance to raltegravir arose during treatment in 64 patients (68%). Forty-eight of these 64 patients (75%) had two or more resistance-associated mutations.” (B-Y Nguyen,
bachyen_nguyen@merck.com)
While cautioning that raltegravir has a “low genetic barrier to drug resistance,” an editorialist is upbeat in her assessment of current research (pp. 416-8): “The fact that integrase inhibitors are emerging out of the pipeline and into the clinic shows that persistence and investment in new agents can shed light on basic science, open new doors for research, and most importantly, transform approaches to HIV treatment.” (D. V. Havlir, UCSF)
Sorafenib in Hepatocellular Carcinoma: Median survival and the time to radiologic progression increased by nearly 3 months in 602 patients with advanced heptocellular carcinoma who were treated with sorafenib 400 mg twice daily, investigators report (pp. 378-90): “Median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group (hazard ratio in the sorafenib group, 0.69; 95% confidence interval, 0.55 to 0.87; P < 0.001). There was no significant difference between the two groups in the median time to symptomatic progression (4.1 months vs. 4.9 months, respectively, P = 0.77). The median time to radiologic progression was 5.5 months in the sorafenib group and 2.8 months in the placebo group (P < 0.001).” (J. M. Llovet Barcelona Clínic Liver Cancer Group, Barcelona; jmllovet@clinic.ub.es)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
July 25, 2008 * Vol. 15, No. 144
Providing news and information about medications and their proper use

>>>JAPhA Highlights
Source:
July/August issue of the Journal of the American Pharmacists Association (www.japha.org; 2008; 48).
Iron for Chemotherapy-Induced Anemia: Patients commonly received erythropoiesis-stimulating agent therapy without sufficient iron availability or supplementation, according to an analysis of 50 patients with a nonmyeloid malignancy who were receiving chemotherapy and had hemoglobin levels of less than 11 g/dL, a research study shows (pp. 487-93). In a review of medical records, the investigators found: “A total of 174 medical records were reviewed, and 50 patients met study criteria. Of these, 38 patients were treated with darbepoetin alfa, 11 patients were treated with epoetin alfa, and 1 patient was not treated with either agent. 20 patients achieved the target Hb level of 12 grams/dL within a median of 7 weeks (range 1–24 weeks). Only five patients treated with an ESA received iron supplementation, one responder and four nonresponders. Iron indices were measured in 20 patients (40%); 14 patients were candidates for iron therapy based on transferrin saturation, and 3 of these 14 patients received oral iron supplementation. Six responders and six nonresponders received a transfusion (25%).” (S. S. Shord, sshord@uic.edu)
Editorialists, noting that iron therapy is much better used by nephrologists than oncologists, use the phrase “opportunity lost” in describing intravenous iron as a standard of care in oncology (pp. 455-7): “Currently, in most states, no limitations are placed on nephrologist’s use of ESAs. In most regions of the country, nephrologists can treat to Hb levels of 12 grams/dL. CMS dictates that oncologists must stop ESA therapy in chemotherapy-induced anemia at 10 grams/dL. CMS has eliminated cancer- related (not chemotherapy-related) anemia as an indication for ESAs, and [the Oncology Drug Advisory Committee] recommends restricting ESA use in all adjuvant therapy, metastatic breast, and head and neck cancer patients. If total ESA exposure is indeed causing morbidity in oncology patients, is it not reasonable to ask that I.V. iron, which in all existing studies has improved the magnitude of response, time to maximal response, and cost of therapy by decreasing ESA exposure, becomes routine in the treatment algorithm for anemic patients with cancer? The study by Shord and Cuellar, albeit with small numbers of patients and no comparative treatment data, provides us with a strong reminder that we have been remiss by our inadequate monitoring of iron parameters in our patients and by our continued underuse of I.V. iron.” (M. Auerbach, Georgetown U., Washington, DC;
mauerbachmd@aol.com)
Pharmacist Vitamin D Intervention: A pharmacist-developed and -administered educational intervention with 80 elderly patients increased the proportion with sufficient vitamin D levels, increased self-reported intake of the vitamin, and lowered serum parathyroid hormone concentrations (pp. 501-7). Study data show that intake of more than the recommended amounts of vitamin D is likely needed to achieve target serum concentrations. (J. P. Vande Griend, joseph.vandegriend@ucdenver.edu)

>>>PNN NewsWatch
* Serious and sometimes fatal hypersensitivity reactions (HSR) caused by abacavir therapy are significantly more common in patients with a particular human leukocyte antigen (HLA) allele, HLA-B*5701, FDA warned yesterday. Abacavir HSR is a multiorgan syndrome characterized by two or more clinical signs or symptoms that can include fever, rash, gastrointestinal symptoms, respiratory symptoms, and constitutional symptoms. Based on data from two studies, FDA recommended that HLA-B*5701-positive patients not be treated with an abacavir-containing regimen except in exceptional circumstances where the potential benefit outweighs the risk. Development of clinically suspected abacavir HSR requires immediate and permanent discontinuation of abacavir therapy in all patients, including those negative for HLA-B*5701.
* At
FDA’s request, U.S. Marshalls have seized nearly $74,000 worth of Xiadafil VIP tablets, Lots 6K029 and 6K209-SEI, distributed by SEI Pharmaceuticals, Inc. of Miami, FL. The company had refused to comply with a May 27 FDA request to recall the product, which the agency says contains hydroxyhomosildenafil, chemically similar to sildenafil.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
July 28, 2008 * Vol. 15, No. 145
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
July 26 issue of Lancet (www.thelancet.com; 2008; 372).
Life Expectancy with HIV Treatment: Patients who have HIV at age 20 years in high-income countries can expect to live about two-thirds of the years expected for the general population, according to an analysis performed by the Antiretroviral Therapy Cohort Collaboration (pp. 293-9). Since the introduction of highly active antiretroviral therapy in the mid-1990s, life expectancy has climbed as follows: “18,587, 13,914, and 10,854 eligible patients initiated combination antiretroviral therapy in 1996–99, 2000–02, and 2003–05, respectively. 2,056 (4.7%) deaths were observed during the study period, with crude mortality rates decreasing from 16.3 deaths per 1,000 person–years in 1996–99 to 10.0 deaths per 1,000 person–years in 2003–05. Potential years of life lost per 1,000 person–years also decreased over the same time, from 366 to 189 years. Life expectancy at age 20 years increased from 36.1 (SE 0.6) years to 49.4 (0.5) years. Women had higher life expectancies than did men. Patients with presumed transmission via injecting drug use had lower life expectancies than did those from other transmission groups (32.6 [1.1] years vs 44.7 [0.3] years in 2003–05). Life expectancy was lower in patients with lower baseline CD4 cell counts than in those with higher baseline counts (32.4 [1.1] years for CD4 cell counts below 100 cells per µL vs 50.4 [0.4] years for counts of 200 cells per µL or more).” (R. Hogg, bobhogg@cfenet.ubc.ca)
Protecting Infants with Extended Nevirapine Therapy: Infants receiving an extended course of nevirapine had less HIV transmission at 6 weeks of age, according to a clinical trial of prenatal nevirapine followed by a single dose or a 6-week course of the drug after delivery (pp. 300-13). Concluding that “a longer course of daily infant nevirapine to prevent HIV transmission via breast milk might be more effective where access to affordable and safe replacement feeding is not yet available and where the risks of replacement feeding are high,” the investigators report: “2,024 liveborn infants randomised in the study had at least one specimen tested before 6 months of age (1,047 infants in the single-dose group and 977 infants in the extended-dose group). The modified intention-to-treat population included 986 infants in the single-dose group and 901 in the extended-dose group. At 6 months, 87 children in the single-dose group and 62 in the extended-dose group were infected with HIV (relative risk 0.80, 95% CI 0.58–1.10; p = 0.16). At 6 weeks of age, 54 children in the single-dose group and 25 in the extended-dose group were HIV positive (0.54, 0.34–0.85; p = 0.009). 393 infants in the single-dose group and 346 in the extended-dose group experienced grade 3 or 4 serious adverse events during the study (p = 0.54).” (R. C. Bollinger, rcb@jhmi.edu)

>>>BMJ Highlights
Source:
Early-release article from BMJ (www.bmj.org; 2008; 337).
Mortality Rates Among Problem Drug Users: A 12-fold higher mortality rate among people with problem drug use and the higher prevalence of this condition in Scotland accounts for one-third of that country’s higher overall mortality rate, compared with England (doi:10.1136/bmj.a478). In a study that has implications for variances in health parameters in the U.S., the researchers note: “Excluding estimated numbers of deaths in drug users would bring down age standardised mortality at ages 15–54 years from 196 to 162 per 100,000 in Scotland and from 138 to 122 per 100,000 in England; 32.0% (22.3% to 43.0%) of the excess mortality in Scotland is due to drug use.” (M. Bloor, M.Bloor@socsci.gla.ac.uk)

>>>PNN JournalWatch
* Results, Rhetoric, and Randomized Trials: The Case of Donepezil, in Journal of the American Geriatrics Society, 2008; early publication. Reprints: T. E. Finucane, tfinucan@jhmi.edu
* The Health Of Aging Populations In China And India, in
Health Affairs, 2008; 27: 1052-63–. Reprints: S. Chatterji.
* Validating Diagnostic Information on the Minimum Data Set in Ontario Hospital-Based Long-Term Care, in
Medical Care, 2008; 46: 882–7. Reprints: W. P. Wodchis.
* Risk Factors for Cardiovascular Complications Following Total Joint Replacement Surgery, in
Arthritis & Rheumatism, 2008; 58: 1915–20. Reprints: J. N. Katz, jnkatz@partners.org

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
July 29, 2008 * Vol. 15, No. 146
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
August issue of Diabetes Care (http://care.diabetesjournals.org/current.shtml; 2008; 31).
Costs of Preventing Cardiovascular Disease: While nationally recommended prevention activities could prevent much of the cardiovascular disease that would otherwise ensue, the cost of doing so far outweighs the cost of most of the diseases themselves, according to a cost analysis conducted using the Archimedes model (pp. 1686-96). Only smoking cessation prevention proved cost-effective, the authors note, adding these details: “Approximately 78% of adults aged 20–80 years alive today in the U.S. are candidates for at least one prevention activity. If everyone received the activities for which they are eligible, myocardial infarctions and strokes would be reduced by 63% and 31%, respectively. If more feasible levels of performance are assumed, myocardial infarctions and strokes would be reduced 36% and 20%, respectively. Implementation of all prevention activities would add 221 million life–years and 244 million quality-adjusted life–years to the U.S. adult population over the coming 30 years, or an average of 1.3 years of life expectancy for all adults. Of the specific prevention activities, the greatest benefits to the U.S. population come from providing aspirin to high-risk individuals, controlling pre-diabetes, weight reduction in obese individuals, lowering blood pressure in people with diabetes, and lowering LDL cholesterol in people with existing coronary artery disease (CAD). As currently delivered and at current prices, most prevention activities are expensive when considering direct medical costs; smoking cessation is the only prevention strategy that is cost-saving over 30 years.” (R. Kahn, rkahn@diabetes.org)
Editorialists add this perspective to the problem of many people receiving preventive therapies to prevent illness in a few (pp. 1708-9): “In an ideal world, critical health care–spending decisions would be informed by directly applicable randomized clinical trial results. Because logistical and ethical constraints make such evidence unavailable in many cases, information must be synthesized and extrapolated across time and to populations not directly studied. As the analysis by Kahn et al. demonstrates, the results are not always consistent with intuition; in this case, it turns out that prevention generally does not save money. The analysis does, however, identify interventions that efficiently produce health improvements and, hence, suggests programs that policy makers should target to increase population compliance. Given the substantial health implications and health care resources involved, using tools like the Archimedes model can help ensure that we are making the best use of available information to identify measures to improve public health.” (P. J. Neumann,
pneumann@tuftsmedicalcenter.org)
Colesevelam in Type 2 Diabetes: The LDL cholesterol–lowering agent colesevelam hydrochloride provided the additional benefit of improved glycemic control when used in 461 patients with type 2 diabetes that was being treated with sulfonylureas (pp. 1479-84). The 26-week trial showed these effects of colesevelam and placebo: “The least squares (LS) mean change in A1C from baseline to week 26 was –0.32% in the colesevelam group and +0.23% in the placebo group, resulting in a treatment difference of –0.54% (P < 0.001). The LS mean percent change in LDL cholesterol from baseline to week 26 was –16.1% in the colesevelam group and +0.6% in the placebo group, resulting in a treatment difference of –16.7% (P < 0.001). Furthermore, significant reductions in fasting plasma glucose, fructosamine, total cholesterol, non–HDL cholesterol, and apolipoprotein B were demonstrated in the colesevelam relative to placebo group at week 26.” (V. Fonseca, vfonseca@tulane.edu)
Calculating Average Blood Glucose from A1Cs: An equation is determined for converting A1C values into estimated average glucose levels using data from 507 patients with type 1 or type 2 diabetes (pp. 1473-8): “Approximately 2,700 glucose values were obtained by each subject during 3 months. Linear regression analysis between the A1C and AG values provided the tightest correlations (AGmg/dL = 28.7 x A1C – 46.7, R2 = 0.84, P < 0.0001), allowing calculation of an estimated average glucose (eAG) for A1C values. The linear regression equations did not differ significantly across subgroups based on age, sex, diabetes type, race/ethnicity, or smoking status.” (D. M. Nathan, dnathan@partners.org)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
July 30, 2008 * Vol. 15, No. 147
Providing news and information about medications and their proper use

>>>Chest Highlights
Source:
July issue of Chest (www.chestjournal.org/current.shtml; 2008; 134).
Comorbid Asthma, COPD: Substantially more medical services are required when patients with asthma develop chronic obstructive pulmonary disease, conclude authors who analyzed a Medicaid population of patients 40–64 years of age (pp. 14-9). Using data from 2001–03, the researchers showed: “The analysis included a total of 3,072 asthma, 3,455 COPD, and 2,604 COPD/asthma patients. COPD/asthma co-occurring disease has higher utilization of any service type than either disease alone. Compared with asthma patients, COPD patients were 16% and 51% more likely to use physician (odds ratio [OR], 1.16; 95% confidence interval [CI], 1.01 to 1.34) and inpatient services (OR, 1.51; 95% CI, 1.31 to 1.74), respectively; and 60% less likely to use outpatient services (OR, 0.40; 95% CI, 0.35 to 0.46). Compared with asthma patients, COPD patients and COPD/asthma co-occurring patients cost 50% (OR, 1.50; 95% CI, 1.3 to 1.74) and five times (OR, 5.25; 95% CI, 4.59 to 6.02) more for total medical services, respectively.” (F. T. Shaya, fshaya@rx.umaryland.edu)
Treprostinil for PAH: Patients with mild or moderate pulmonary arterial hypertension benefited from treprostinil therapy, including some who required combination therapy with bosentan (pp. 139-45). The subcutaneous long-acting prostacyclin analogue provided these effects in 38 patients who were followed for a mean of 984 days: “Mean pulmonary artery pressure decreased from 59.7 to 50.5 mm Hg (p < 0.001). Significant and sustained improvement in [6-minute walk] distance (p = 0.022) and Borg dyspnea score (p = 0.023) were observed. At the final observation, the mean dose of treprostinil was 37.8 ng/kg/min (range, 7.5 to 115 ng/kg/min). At baseline, 5% of patients were in [New York Heart Association] functional class 2 or lower vs 58% at the last follow-up. Bosentan was added to the regimens of 19 patients. In those patients, significant additional improvement occurred in the pulmonary arterial pressure (p < 0.001), [6-minute walk] distance (p = 0.001), and Borg dyspnea scale (p = 0.020) compared to baseline.” (R. L. Benza, rbenza@uab.edu)

>>>Infectious Diseases Report
Source:
Early-release article from Clinical Infectious Diseases (www.journals.uchicago.edu/toc/cid/0/0; 2008).
Increasing Incidence of Legionellosis in U.S.: Cases of legionellosis have increased suddenly in the U.S., researchers report, noting an abrupt climb beginning in 2003 and occurring especially among middle-aged persons (doi: 10.1086/590557). Concluding that the disease should be considered in the differential diagnosis of any patient with pneumonia, the authors write: “A total of 23,076 cases of legionellosis were reported to the Centers for Disease Control and Prevention from 1990 through 2005. The number of reported cases increased by 70% from 1,310 cases in 2002 to 2,223 cases in 2003, with a sustained increase to >2,000 cases per year from 2003 through 2005. The eastern United States showed most of the increases in age-adjusted incidence rates after 2002, with the mean rate in the Middle Atlantic states during 2003–2005 exceeding that during 1990–2002 by 96%. During 2000–2005, legionellosis cases were most commonly reported in persons aged 45–64 years. Persons aged <65 years comprised 63% of total cases in 2000–2005. Age-adjusted incidence rates in males exceeded those in females for all age groups and years. Legionellosis incidence showed marked seasonality in eastern states, with most cases reported in the summer or fall.” (K. Neil, Karen.Neil@cdc.hhs.gov)

>>>PNN NewsWatch
* FDA yesterday reminded health professionals who treat patients with mitoxantrone about 2005 recommendations that left ventricular ejection fraction (LVEF) be evaluated before initiating treatment and before administering each dose of the drug. FDA offered additional recommendations for cardiac monitoring to detect late-occurring cardiac toxicity and provided information for patients with multiple sclerosis who receive mitoxantrone. The agency noted that postmarketing research shows poor adherence to its original advice regarding mitoxantrone.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
July 31, 2008 * Vol. 15, No. 148
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
July 31 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2008; 359).
Cellulose Sulfate Gel for Preventing HIV Transmission: The HIV-entry inhibitor cellulose sulfate failed to prevent transmission of the virus—and may have increased the number of women infected—in a trial conducted in Africa and India (pp. 463-72). Formulated as a vaginal gel, cellulose sulfate produced these outcomes in this randomized double-blind trial: “A total of 1,398 women were enrolled and randomly assigned to receive cellulose sulfate gel (706 participants) or placebo (692 participants) and had follow-up HIV test data. There were 41 newly acquired HIV infections, 25 in the cellulose sulfate group and 16 in the placebo group, with an estimated hazard ratio of infection for the cellulose sulfate group of 1.61 (P = 0.13). This result, which is not significant, is in contrast to the interim finding that led to the trial being stopped prematurely (hazard ratio, 2.23; P = 0.02) and the suggestive result of a preplanned secondary (adherence-based) analysis (hazard ratio, 2.02; P = 0.05). No significant effect of cellulose sulfate as compared with placebo was found on the risk of gonorrheal infection (hazard ratio, 1.10; 95% confidence interval [CI], 0.74 to 1.62) or chlamydial infection (hazard ratio, 0.71; 95% CI, 0.47 to 1.08).” (L. Van Damme, FHI, Arlington, VA; lvandamme@fhi.org)
Cyclosporine for Reperfusion Injury in AMI: Administered at the time of percutaneous coronary intervention, cyclosporine reduced the size of reperfusion infarcts among 58 patients with acute ST-elevation myocardial infarction (pp. 473-81). Concluding that these preliminary data require confirmation in larger clinical trials, the investigators report these results with cyclosporine 2.5 mg/kg or normal saline: “The cyclosporine and control groups were similar with respect to ischemia time, the size of the area at risk, and the ejection fraction before PCI. The release of creatine kinase was significantly reduced in the cyclosporine group as compared with the control group (P = 0.04). The release of troponin I was not significantly reduced (P = 0.15). On day 5, the absolute mass of the area of hyperenhancement (i.e., infarcted tissue) on MRI was significantly reduced in the cyclosporine group as compared with the control group, with a median of 37 g (interquartile range, 21 to 51) versus 46 g (interquartile range, 20 to 65; P = 0.04). No adverse effects of cyclosporine administration were detected.” (M. Ovize, Hôpital L. Pradel, Lyon, France; vize@sante.univ-lyon1.fr">ovize@sante.univ-lyon1.fr)
Editorialists provide this perspective on the mechanism of cyclosporine action (pp. 518-20): “[These] findings … confirm the existence of myocardial reperfusion injury in humans and suggest that the mitochondrial permeability-transition pore is a new target for protecting the heart against this form of injury and reducing the size of the myocardial infarct in patients who are undergoing primary PCI. Large, multicenter studies are required to determine whether this new treatment strategy is able to influence the clinical outcomes after ST-elevation myocardial infarction. Targeting the opening of the mitochondrial permeability-transition pore may also offer protection in other clinical contexts, such as stroke, cardiac surgery, and organ transplantation. We believe it is now time to take myocardial reperfusion injury seriously, since it provides a new target for reducing the size of a myocardial infarct and potentially improving the clinical outcomes in patients with ST-elevation myocardial infarction.” (D. J. Hausenloy, U. College, London)
ACS After Smokefree Legislation: Hospitalizations for acute coronary syndrome fell after implementation of a countrywide ban on smoking in enclosed public places in Scotland in Mar. 2006, and two-thirds of the decrease was in nonsmokers, researchers report (pp. 482-91): “Overall, the number of admissions for acute coronary syndrome decreased from 3,235 to 2,684—a 17% reduction (95% confidence interval, 16 to 18)—as compared with a 4% reduction in England (which has no such legislation) during the same period and a mean annual decrease of 3% (maximum decrease, 9%) in Scotland during the decade preceding the study…. There was a 14% reduction in the number of admissions for acute coronary syndrome among smokers, a 19% reduction among former smokers, and a 21% reduction among persons who had never smoked.” (J. Pell, U. Glasgow, Glasgow, U.K.; j.pell@clinmed.gla.ac.uk)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
Aug. 1, 2008 * Vol. 15, No. 149
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Aug. issue of Pharmacotherapy (www.pharmacotherapy.org; 2008; 28).
PPIs & Hip Fractures: Contrary to prior research, a nested case–control study finds no increase in the risk of hip fractures among patients taking proton-pump inhibitors (pp. 951-9). Phase I of the study sought to identify major risk factors for hip fracture among 4,414 case patients in the U.K. General Practice Research Database who had incident hip fractures in 1995–2005 and up to 10 control patients per case. Phase II included 1,098 case patients with no identified risk factors and 10,923 control patients. Results showed: “The relative risk (RR) for hip fracture among patients who received any PPI prescription was 0.9 (95% confidence interval 0.7–1.1) compared with those with no PPI prescription. We found no evidence of an increased risk of hip fracture with increased PPI use. The RR estimates were similar in both sexes and in all age subgroups. No specific PPI was associated with an increased risk of hip fracture.” (J. A Kaye, jkaye@bu.edu)
Thromboembolism During Subtherapeutic Warfarin Dosing: A low risk of thromboembolism was found during the 90-day period following a subtherapeutic international normalized ratio value among 2,597 adults who were otherwise stabilized on warfarin therapy (pp. 960-7). Study participants had two INR values in the therapeutic range and a third value at least 0.5 units below their therapeutic range. Compared with patients with INRs within 0.2 units of their therapeutic range, those with lower values had these outcomes: “Four thromboembolic events (0.4%) occurred in the low INR cohort and one event (0.1%) in the therapeutic INR cohort (p = 0.214). The differences in the proportions of thromboembolism, bleeding, or death were not significant between the cohorts (p > 0.05). No significant differences were noted in the hazard of thromboembolism, bleeding, or death between the cohorts (p > 0.05).” (N. P. Clark, nathan.clark@kp.org)
Inappropriate Continuation of Stress Ulcer Prophylaxis: Among 248 consecutive adult patients admitted to a surgical intensive care unit over a 6-month period, acid-suppressive therapy (AST) was often inappropriately continued after discharge from the unit, a study shows (pp. 968-76). “In most patients (237 [95.6%] of 248), initiation of AST was associated with one or more risk factors for gastrointestinal bleeding,” report the researchers. “Continuation of AST during hospitalization outside the SICU occurred in 215 patients (86.7%). Sixty patients (24.2%) were discharged from the hospital receiving AST: 52 patients (21.0%) went to skilled nursing facilities or rehabilitation centers, and eight (3.2%) were discharged home. Compared with those whose AST was discontinued in the hospital, patients who continued to receive AST after hospital discharge required extended mechanical ventilation (p = 0.001), had twice as many risk factors for gastrointestinal bleeding (p < 0.001), were frequently discharged with anticoagulant therapy (p < 0.001), exhibited longer hospital and SICU stays (p < 0.001), and more frequently demonstrated Glasgow Coma Scale scores of 8 or lower and/or had head injury (p < 0.001), hepatic failure (p = 0.004), and major trauma (p = 0.049). Evaluation of continuation of AST during hospitalization revealed that only 7.4% (16/215) of patients at SICU transfer and 5.0% (3/60) of patients at hospital discharge had a compelling risk factor to continue AST as demonstrated by a coagulopathy at discharge; no patients required mechanical ventilation at hospital discharge.” (J. A. Rebuck, jarebuck@lancastergeneral.org)

>>>PNN NewsWatch
* FDA and Amgen have completed discussions regarding labeling changes for erythropoiesis-stimulating agents, and FDA has issued a letter ordering the additional changes. Specific wording on two points remains unresolved: a warning statement that ESAs are not intended for use in patients receiving myelosuppressive therapy when the expected outcome is cure and statements regarding when to initiate and discontinue ESA dosing.
* Consumers and health professionals should not to buy or use
Viapro 375 mg Capsules, EG Labs is warning, because one lot of the product was found to contain a potentially harmful undeclared ingredient, thiomethisosildenafil, an analogue of sildenafil.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
Aug. 4, 2008 * Vol. 15, No. 150
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Aug. 2 issue of Lancet (www.thelancet.com; 2008; 372).
Treating Early Severe Rheumatoid Arthritis: A combination of etanercept plus methotrexate was effective for achieving clinical remission and radiographic nonprogression among 542 patients with moderate or severe symptoms of rheumatoid arthritis early in the course of the disease, according to results from the Combination of Methotrexate and Etanercept in Early Rheumatoid Arthritis (COMET) trial (pp. 375-82). Patients, who were methotrexate-naive and had had symptoms for 3–24 months at study entry, received either methotrexate alone titrated up from 7.5 mg/week to a maximum of 20 mg/week by week 8 or methotrexate (same titration) plus etanercept 50 mg/week, with these results: “274 participants were randomly assigned to receive combined treatment and 268 methotrexate alone. 132 of 265 (50%, 95% CI 44–56%) patients who took combined treatment and were available for assessment achieved clinical remission compared with 73 of 263 (28%, 23–33%) taking methotrexate alone (effect difference 22.05%, 95% CI 13.96–30.15%, p < 0.0001). 487 evaluable patients had severe disease ([disease activity score in 28 joints] > 5.1). 196 of 246 (80%, 75–85%) and 135 of 230 (59%, 53–65%), respectively, achieved radiographic non-progression (20.98%, 12.97–29.09%, p < 0.0001). Serious adverse events were similar between groups.” (P. Emery, U. Leeds, Leeds, U.K.; p.emery@leeds.ac.uk)
Abatacept for Juvenile Rheumatoid Arthritis: In 122 children and adolescents with juvenile rheumatoid arthritis, abatacept modulation of T-cell costimulation with abatacept significantly reduced the number of flares without increasing adverse events, compared with placebo (pp. 383-91). During an open-label phase, 190 patients received abatacept, and 122 of those responding were randomized to intravenous abatacept 10 mg/kg every 28 days for 6 months or placebo. Flares were defined as worsening of 30% or more on at least three of six core variables, and results showed: “Flares of arthritis occurred in 33 of 62 (53%) patients who were given placebo and 12 of 60 (20%) abatacept patients during the double-blind treatment (p = 0.0003).… The risk of flare in patients who continued abatacept was less than a third of that for controls during that double-blind period (hazard ratio 0.31, 95% CI 0.16–0.95). During the double-blind period, the frequency of adverse events did not differ in the two treatment groups.” (N. Ruperto, IRCCS Istituto G Gaslini Pediatria II—PRINTO, Genova, Italy; nicolaruperto@ospedale-gaslini.ge.it)
Influenza Vaccine & Risk of Pneumonia: Among older patients, influenza vaccination is less effective for prevention of pneumonia than previously believed, researchers conclude (pp. 398-405). In a population-based, nested case–control study in immunocompetent elderly people aged 65–94 years, investigators found these patterns among cases with community-acquired pneumonia: “1,173 cases and 2,346 controls were included in the study. After we adjusted for the presence and severity of comorbidities, as defined by chart review, influenza vaccination was not associated with a reduced risk of community-acquired pneumonia (odds ratio 0.92, 95% CI 0.77–1.10) during the influenza season.” (M. L. Jackson, mlj3@cornell.edu)

>>>PNN JournalWatch
* Management of Hypothyroidism in Adults, in BMJ, 2008; doi: 10.1136/bmj.a801. Reprints: B. Vaidya, Royal Devon and Exeter Hosp., Exeter, U.K.; bijay.vaidya@pms.ac.uk
* Is the Combination of Sulfonylureas and Metformin Associated with an Increased Risk of Cardiovascular Disease or All-Cause Mortality?, in
Diabetes Care, 2008; 31: 1672–8. Reprints: V. Fonseca, vfonseca@tulane.edu
* Vitamin D Deficiency in Children and Its Management: Review of Current Knowledge and Recommendations, in
Pediatrics, 2008; 122: 398–417. Reprints: M. Misra.
* Asperger’s Syndrome: Diagnosis and Treatment, in
American Journal of Psychiatry, 2008; 165: 958–63. Reprints: K. Toth.
* The Evolution of the Cognitive Model of Depression and Its Neurobiological Correlates, in
American Journal of Psychiatry, 2008; 165: 969–77. Reprints: A. T. Beck.
* Aspirin Resistance: Disparities and Clinical Implications, in
Pharmacotherapy, 2008; 28: 999–1018. Reprints: A. Airee, aairee@utmem.edu
* Extended- and Continuous-Cycle Oral Contraceptives, in
Pharmacotherapy, 2008; 28: 1033–40. Reprints: S. P. Shrader, shrader@musc.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 © 2008, 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
Aug. 5, 2008 * Vol. 15, No. 151
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Aug. 5 issue of the Annals of Internal Medicine (www.annals.org/current.shtml; 2008; 149).
Behavioral plus Drug Therapy for Urge Incontinence: In women with urge-predominant incontinence, an 8-month trial shows that addition of behavioral therapy enhances outcomes but does not replace drug therapy (pp. 161-9). At nine university-affiliated outpatient clinics, women with this condition received 10 weeks of open-label, extended-release tolterodine alone (n = 153) or combined with behavioral training (n = 154), followed by discontinuation of therapy and follow-up at 8 months. Results were as follows: “237 participants completed the trial. According to life-table estimates, the rate of successful discontinuation of therapy at 8 months was the same in the combination therapy and drug therapy alone groups (41% in both groups; difference, 0 percentage points [95% CI, –12 to 12 percentage points]). A higher proportion of participants who received combination therapy than drug therapy alone achieved a 70% or greater reduction in incontinence at 10 weeks (69% vs. 58%; difference, 11 percentage points [CI, –0.3 to 22.1 percentage points]). Combination therapy yielded better outcomes over time on the Urogenital Distress Inventory and the Overactive Bladder Questionnaire (both P < 0.001) at both time points for patient satisfaction and perceived improvement but not health-related quality of life. Adverse events were uncommon (12 events in 6 participants [3 in each group]).” (K. L. Burgio, kburgio@aging.uab.edu)
Screening for Prostate Cancer: The U.S. Preventive Services Task Force has concluded that “current evidence is insufficient to assess the balance of benefits and harms of screening for prostate cancer in men younger than age 75 years” and that men aged 75 years and older should not be screened for these tumors (pp. 185-91). For younger men, “The results of 2 ongoing trials, the U.S. Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial and the European Study of Screening for Prostate Cancer, should help to clarify the potential benefits of screening,” the authors note. The recommendation against screening older men was rated Grade D, which indicates “moderate or high certainty that the service has no benefit or that the harms outweigh the benefits.” (www.preventiveservices.ahrq.gov)
In a Clinical Guidelines article, evidence from a systematic review of prostate-specific antigen screening for prostate cancer shows (pp. 192-9): “No good-quality randomized, controlled trials of screening for prostate cancer have been completed. In 1 cross-sectional and 2 prospective cohort studies of fair to good quality, false-positive PSA screening results caused psychological adverse effects for up to 1 year after the test. The natural history of PSA-detected prostate cancer is poorly understood.” (K. Lin,
kenneth.lin@ahrq.hhs.gov)

>>>PNN NewsWatch
* Clevidipine butyrate (Cleviprex Injectable Emulsion 0.5 mg/mL, The Medicines Company), an intravenous fourth-generation dihydropyridine calcium-channel blocker, has been approved by FDA for marketing in the U.S. for reduction of blood pressure when the use of oral therapy is not feasible or desirable. Six Phase III trials of 1,406 patients medical and surgical patients established efficacy and safety of the drug. Clevidipine may produce systemic hypotension and reflex tachycardia. The most common adverse reactions (greater than 2%) seen with the agent are headache, nausea, and vomiting. Initial therapy with clevidipine is administered as infusions of 1–2 mg/hr, after which the dose doubled every 90 seconds until the blood pressure goal is approached. Doses are then increased by less than doubled doses that are adjusted every 5–10 minutes. Product labeling advises that 1–2 mg/hr dose increases produce an additional 2–4 mm Hg decrease in systolic blood pressure.
*
FDA announced yesterday announced plans to strengthen its policies and procedures for management of FDA advisory committees. Described in a final guidance document published in the Federal Register, the changes include stricter limits on financial conflicts of interest for committee members, improved voting procedures, and improvements to the processes for disclosing information pertaining both to advisory committee members and to specific matters considered at advisory committee meetings, FDA noted in a news release.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
Aug. 6, 2008 * Vol. 15, No. 152
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Aug. 6 issue of JAMA, a theme issue on HIV (http://jama.ama-assn.org/current.dtl; 2008; 300).
Low-Dose Growth Hormone in HIV: Small physiologic doses of human growth hormone administered to patients with HIV and abdominal fat accumulation had beneficial effects on visceral fat and truncal obesity, triglycerides, and diastolic blood pressure, but serum glucose tests were increased (pp. 509-19). Researchers used starting doses of 2 mcg/kg/day of GH, increasing those to a maximum of 6 mcg/kg/day during the 18-month trial. Results showed: “Fifty-five patients (26 with GH and 29 with placebo) were included in the safety analyses and 52 patients (25 with GH and 27 with placebo) were included in the efficacy analyses. Visceral adipose tissue area (treatment effect [last-value-carried-forward analysis {n = 56}, –19 cm2; 95% confidence interval {CI}, –37 to –0.3 cm2], –19 cm2; 95% CI, –38 to –0.5 cm2; P = .049); trunk fat (–0.8 kg; 95% CI, –1.5 to –0.04 kg; P = .04); diastolic BP (–7 mm Hg; 95% CI, –11 to –2 mm Hg; P = .006); and triglycerides (–7 mg/dL, P = .002) improved but 2-hour glucose levels on glucose tolerance testing increased in the GH group vs the placebo group (treatment effect, 22 mg/dL; 95% CI, 6–37 mg/dL; P = .009). The [insulinlike growth factor 1] levels increased (treatment effect, 129 ng/mL; 95% CI, 95–164 ng/mL; P < .001). Adverse events were not increased for GH vs placebo (23%; 95% CI, 9%-44% vs 28%; 95% CI, 13%–47%; P = .70).” (S. Grinspoon, sgrinspoon@partners.org)
HIV Therapy During Antitubercular Treatment: Efavirenz-based antiretroviral regimens worked better than those using nevirapine in patients who were on concomitant rifampin-based antitubercular therapy, according to results of a study that included 2,035 individuals on efavirenz (1,074 with concurrent tuberculosis) and 1,935 taking nevirapine (209 with concurrent tuberculosis) (pp. 530-9). “Patients starting nevirapine with concurrent tuberculosis were at a higher risk of elevated viral load most notably at 6 months (16.3%; 95% confidence interval [CI], 10.6%–23.5%) than those without tuberculosis (8.3%; 95% CI, 6.7%–10.0%; adjusted odds ratio [OR], 2.1; 95% CI, 1.2–3.4; and in the combined estimate, adjusted OR, 1.7; 95% CI, 1.2–2.6),” authors of this cohort analysis report. “In the time-to-event analysis of confirmed virological failure (2 consecutive values of 5,000 copies/mL), patients starting nevirapine with concurrent tuberculosis developed virological failure sooner (adjusted hazard ratio [HR] 2.2; 95% CI, 1.3–3.7). There were no differences between patients starting efavirenz with and without concurrent tuberculosis (adjusted OR, 1.1; 95% CI, 0.8–1.5 [combined estimate] and adjusted HR, 1.1; 95% CI, 0.6–2.0, respectively). There was no difference in time to virological rebound in patients free of tuberculosis and those developing tuberculosis during follow-up while taking nevirapine (adjusted HR, 1.0; 95% CI, 0.5–2.0) or efavirenz (adjusted HR, 0.8; 95% CI, 0.4–1.7).” (A. Boulle, U. Cape Town, Cape Town, South Africa; andrew.boulle@uct.ac.za)
Injection Drug Use and HIV Outcomes: Survival rates were similar among injection drug users and other patients infected with HIV in a population-based, prospective cohort study of 3,116 antiretroviral-naive patients (pp. 550-4). During a median follow-up period of 5.3 years among IDUs and 4.3 years among non-IDUs, the investigators found: “Overall, 622 individuals died (20.0%) during the study period (232 IDUs and 390 non-IDUs), for a crude mortality rate of 20.0% (95% confidence interval [CI], 18.4%–21.5%). At 84 months after the initiation of HAART, the product limit estimate of the cumulative all-cause mortality rate was similar between the 915 IDUs (26.5%; 95% CI, 23.2%–29.8%) and 2,201 non-IDUs (21.6%; 95% CI, 16.9%–26.2%) (Wilcoxon P = .47). In multivariate time-updated Cox regression, the hazard ratio of mortality was similar between IDUs and non-IDUs (1.09; 95% CI, 0.92–1.29).” (J. S. G. Montaner, jmontaner@cfenet.ubc.ca)

>>>PNN NewsWatch
* FDA yesterday announced that it has licensed six influenza vaccines for use during the 2008–09 season: Afluria (CSL Limited), Fluarix (GlaxoSmithKline Biologicals); FluLaval (ID Biomedical); FluMist (MedImmune); Fluvirin (Novartis Vaccines and Diagnostics); and Fluzone (Sanofi Pasteur). All three strains in the vaccines are new this year.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
Aug. 7, 2008 * Vol. 15, No. 153
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Aug. 7 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2008; 359).
Treating Extensively Drug-Resistant Tuberculosis: Successful outpatient treatment of extensively drug-resistant tuberculosis is described in a study from Peru that included 651 non–HIV-infected patients who had isolates tested (pp. 563-74). Treatment was individualized for each patient and included drug treatment, resective surgery, adverse-event management, and nutritional and psychosocial support. Results showed: “Of the 651 patients tested, 48 (7.4%) had extensively drug-resistant tuberculosis; the remaining 603 patients had multidrug-resistant tuberculosis. The patients with extensively drug-resistant tuberculosis had undergone more treatment than the other patients (mean [±SD] number of regimens, 4.2 ± 1.9 vs. 3.2 ± 1.6; P < 0.001) and had isolates that were resistant to more drugs (number of drugs, 8.4 ± 1.1 vs. 5.3 ± 1.5; P < 0.001). None of the patients with extensively drug-resistant tuberculosis were coinfected with the human immunodeficiency virus (HIV). Patients with extensively drug-resistant tuberculosis received daily, supervised therapy with an average of 5.3 ± 1.3 drugs, including cycloserine, an injectable drug, and a fluoroquinolone. Twenty-nine of these patients (60.4%) completed treatment or were cured, as compared with 400 patients (66.3%) with multidrug-resistant tuberculosis (P = 0.36).” (C. D. Mitnick, Harvard Med. Sch., Boston)
The hope and the challenge involved in treating extensively drug-resistant tuberculosis are addressed by an editorialist (pp. 636-8): “Can [the above] model be scaled up to cover the entire country, and can it be replicated in other countries with different economic and social conditions? How can a rigorous approach to a high standard of individual care be expanded to a programmatic scale and become routine public health practice? In 2008, scaling up is indeed the major challenge faced by most complex health interventions worldwide, especially when health systems and services are not optimal. What is required is action that is borne out of clear planning, financial commitment and adequate resources, technical capacity, and partnership. Ultimately, the effectiveness of a complex intervention depends on coordinated work among all forces. The Peru experience is a clear example that, in this spirit, even the most difficult objectives can be reached. The challenge is to make this approach a sustainable reality worldwide.” (M. C. Raviglione, World Health Organization, Geneva)
Malaria Prevention in Short-Term Travelers: In a Clinical Practice article, a family of three—a young father, pregnant mother, and 7-year-old child—traveling to southern Africa illustrates the decisions that must reached in providing antimalarial regimens to travelers going to endemic areas for short time periods (pp. 603-12): “Resources that are readily accessible to nonspecialist clinicians indicate that the family members in the vignette face a risk of chloroquine-resistant malaria during the portion of their visit in Kruger National Park and Victoria Falls. For the husband, I would recommend daily atovaquone–proguanil. (Mefloquine is contraindicated because of his history of depression. The side effects of doxycycline, including photosensitivity and vaginal yeast infections in women, are drawbacks for its use in travelers in the tropics, although its lower cost may balance this risk for some travelers.) Atovaquone–proguanil should be started on the second day in Cape Town, 2 days before the first possible exposure to malaria, and continued for 7 days after his departure from the areas where malaria is endemic. The 7-year-old child should also receive atovaquone–proguanil on the same schedule, but tablets containing pediatric doses should be used. The pregnant wife should be advised not to travel, but if she insists (as is common once someone has planned a trip and come for pretravel counseling), I would prescribe mefloquine according to the usual regimen and advise diligent precautions against mosquitoes including repellents containing 20% DEET, protective clothing, and air-conditioned or well-screened sleeping quarters. Since no chemoprophylactic regimen is 100% effective, this family should receive clear instructions about what to do if fever develops on their return home.” (D. O. Freedman, U. Alabama, Birmingham)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
Aug. 8, 2008 * Vol. 15, No. 154
Providing news and information about medications and their proper use

>>>Psychiatry Highlights
Source:
Aug. issue of the American Journal of Psychiatry (http://ajp.psychiatryonline.org/current.dtl; 2008; 165).
Novel Cholinergic Agents for Schizophrenia: Two research studies and an editorial present information on use of new cholinergic agents for treatment of schizophrenia.
Xanomeline, a relatively selective muscarinic type 1 and type 4 (M1 and M4) receptor agonist, provided sufficient evidence of efficacy in a 4-week trial to merit larger trials, researchers report (pp. 1033-9). In a double-blind, placebo-controlled trial, 20 patients with schizophrenia showed these outcomes with xanomeline: “Subjects treated with xanomeline did significantly better than subjects in the placebo group on total [Brief Psychiatric Rating Scale] scores and total [Positive and Negative Syndrome Scale for schizophrenia] scores. In the cognitive test battery, subjects in the xanomeline group showed improvements most robustly in measures of verbal learning and short-term memory function.” (A. Shekhar)
A partial alpha-7 nicotinic agonist, 3-(2,4-dimethoxybenzylidene) anabaseine (DMXB-A), improved clinical ratings of negative symptoms that are generally resistant to treatment with dopamine antagonist antipsychotic drugs, according to results of a Phase II trial (pp. 1040-7). The 4-week crossover trial recorded these results on the MATRICS Consensus Cognitive Battery, and Scale for the Assessment of Negative Symptoms (SANS), and Brief Psychiatric Rating Scale (BPRS): “There were no significant differences in the MATRICS cognitive measures between DMXB-A and placebo over the three treatment arms, but the patients experienced significant improvement at the higher DMXB-A dose on the SANS total score and nearly significant improvement on the BPRS total score. Improvement was most notable on the SANS anhedonia and alogia subscales. Examination of the first treatment arm showed effects of DMXB-A on the attention/vigilance and working memory MATRICS domains, compared to baseline. Five subjects developed mild tremor, and nearly half had mild nausea while taking DMXB-A.” (R. Freedman)
Concluding that these data are encouraging, editorialists reach these conclusions about cholinergic agents for treatment of schizophrenia (pp. 931-6): “These studies provide an important signal of the potential of cholinergic agonists as novel therapeutic agents in schizophrenia. Moreover, they follow the recent publication of positive findings on the use of a metabotropic glutamate receptor 2/3 agonist monotherapy, a treatment based on the glutamate hypothesis of schizophrenia. This augurs well for the field. Only further pursuit of these targets and replication of these results will confirm the validity of these novel strategies. Nevertheless, the encouraging results with these cholinergic agonists suggest that the tide may be turning in experimental therapeutics for schizophrenia and that rational drug development for the field of psychiatry may have finally arrived.” (J. A. Lieberman,
jlieberman@columbia.edu)

>>>Pediatrics Highlights
Source:
Aug. issue of Pediatrics (http://pediatrics.aappublications.org/current.shtml; 2008; 122).
Adherence Video Game: A video-game intervention improved medication adherence and self-efficacy and knowledge parameters among 375 adolescents and young adults with cancer (e305-17). At 34 medical centers in the U.S., Canada, and Australia in 2004–05, patients in the intervention group had access to a video game that addressed issues of cancer care and treatment. Based on measures of adherence and psychologic health, results showed: “Adherence to trimethoprim-sulfamethoxazole and 6-mercaptopurine was greater in the intervention group. Self-efficacy and knowledge also increased in the intervention group compared with the control group. The intervention did not affect self-report measures of adherence, stress, control, or quality of life.” (P. M. Kato, Stanford Hosp., Stanford, CA)
Cough/Cold Medicine Use in U.S. Children: A telephone survey of U.S. households quantifies use of cough and cold medications in children during 1999–2006, showing that 1 in 10 children receives these products in a given week (e323-9). Highest use was among 2–5-year-olds, followed by those under 2 years—the groups of most current concern about efficacy and safety. (L. Vernacchio)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
Aug. 11, 2008 * Vol. 15, No. 155
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Aug. 9 issue of Lancet (www.thelancet.com; 2008; 372).
Everolimus for Advanced Renal Cell Carcinoma: Among patients with renal cell carcinoma that had advanced during treatment with sunitinib and/or sorafenib, everolimus prolonged progression-free survival, compared with placebo (pp. 449-56). Researchers recorded these effects of everolimus 10 mg once daily (n = 272) and placebo (n = 138): “The results of the second interim analysis indicated a significant difference in efficacy between arms and the trial was thus halted early after 191 progression events had been observed (101 [37%] events in the everolimus group, 90 [65%] in the placebo group; hazard ratio 0.30, 95% CI 0.22–0.40, p < 0.0001; median progression-free survival 4.0 [95% CI 3.7–5.5] vs 1.9 [1.8–1.9] months). Stomatitis (107 [40%] patients in the everolimus group vs 11 [8%] in the placebo group), rash (66 [25%] vs six [4%]), and fatigue (53 [20%] vs 22 [16%]) were the most commonly reported adverse events, but were mostly mild or moderate in severity. Pneumonitis (any grade) was detected in 22 (8%) patients in the everolimus group, of whom eight had pneumonitis of grade 3 severity.” (R. J. Motzer, motzerr@mskcc.org)
Pediatric Febrile Seizures: Children with febrile seizures have no increase in long-term mortality but do experience a small increase in mortality during the 2 years following complex episode, researchers report (pp. 457-63). Based on experiences of 1.7 million Danish children born in 1977–2004, the investigators note: “We identified 8,172 children who died, including 232 deaths in 55,215 children with a history of febrile seizures. The mortality rate ratio was 80% higher during the first year (adjusted mortality rate ratio 1.80 [95% CI 1.31–2.40]) and 90% higher during the second year (1.89 [1.27–2.70]) after the first febrile seizure; thereafter it was close to that noted for the general population. 132 of 100,000 children (95% CI 102–163) died within 2 years of a febrile seizure compared with 67 (57–76) deaths per 100,000 children without a history of this disorder. In the nested case–control study, children with simple (15 min and no recurrence within 24 h) febrile seizure had a mortality rate similar to that of the background population (adjusted mortality rate ratio 1.09 [95% CI 0.72–1.64]), whereas mortality was increased for those with complex (>15 min or recurrence within 24 h) febrile seizures (1.99 [1.24–3.21]). This finding was partly explained by pre-existing neurological abnormalities and subsequent epilepsy.” (M. Vestergaard, Aarhus U., Aarhus, Denmark; mogens.vestergaard@alm.au.dk)

>>>BMJ Highlights
Source:
Early-release article from BMJ (www.bmj.org; 2008; 337).
Treating Unexplained Infertility: Among couples with unexplained infertility for more than 2 years, neither clomiphene citrate nor unstimulated intrauterine insemination provided superior live birth rates compared with expectant management (doi: 10.1136/bmj.a716). Couples in the study had confirmed ovulation, patent fallopian tubes, and motile sperm, the investigators note, adding these results: “580 women were randomised to expectant management (n = 193), oral clomifene citrate (n = 194), or unstimulated intrauterine insemination (n = 193) for six months. The three randomised groups were comparable in terms of age, body mass index, duration of infertility, sperm concentration, and motility. Live birth rates were 32/193 (17%), 26/192 (14%), and 43/191 (23%), respectively. Compared with expectant management, the odds ratio for a live birth was 0.79 (95% confidence interval 0.45 to 1.38) after clomifene citrate and 1.46 (0.88 to 2.43) after unstimulated intrauterine insemination. More women randomised to clomifene citrate (159/170, 94%) and unstimulated intrauterine insemination (155/162, 96%) found the process of treatment acceptable than those randomised to expectant management (123/153, 80%) (P = 0.001 and P < 0.001, respectively).” (S. Bhattacharya, U. Aberdeen, Aberdeen, U.K.; s.bhattacharya@abdn.ac.uk)

>>>PNN JournalWatch
* Evidence Mandating Earlier and More Aggressive Treatment of Hypercholesterolemia, in Circulation, 2008; 118: 672–7. Reprints: D. Steinberg.
* Blepharoptosis and External Ophthalmoplegia Associated with Long-Term Antiretroviral Therapy, in
Clinical Infectious Diseases, doi: 10.1086/591202. Reprints: D. M. Peterson, Dolores.Peterson@UTSouthwestern.edu

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
Aug. 12, 2008 * Vol. 15, No. 156
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Aug. 11/25 issue of the Archives of Internal Medicine (http://archinte.ama-assn.org/current.dtl; 2008; 168).
Metabolically Benign Obesity: Researchers identify a metabolically benign form of obesity in a study of 314 people, concluding that the presence of ectopic fat in the liver may be a more important harbinger of beneficial effects than visceral fat (pp. 1609-16). Magnetic resonance tomography, proton MR spectroscopy, and oral glucose tolerance tests showed these patterns with respect to insulin sensitivity and resistance (IS and IR, respectively) among the diverse group of patients: “Total body and visceral fat were higher in the overweight and obese groups compared with the normal-weight group (P < .05); however, no differences were observed between the obese groups. In contrast, ectopic fat in skeletal muscle (P < .001) and particularly the liver (4.3% ± 0.6% vs 9.5% ± 0.8%) and the intima-media thickness of the common carotid artery (0.54 ± 0.02 vs 0.59 ± 0.01 mm) were lower and insulin sensitivity was higher (17.4 ± 0.9 vs 7.3 ± 0.3 arbitrary units) in the obese-IS vs the obese-IR group (P < .05). Unexpectedly, the obese-IS group had almost identical insulin sensitivity and the intima-media thickness was not statistically different compared with the normal-weight group (18.2 ± 0.9 AU and 0.51 ± 0.02 mm, respectively).” (N. Stefan, U. Tübingen, Tübingen, Germany; norbert.stefan@med.uni-tuebingen.de)
Vitamin D Levels & Mortality: Patients with the lowest levels of 25-hydroxyvitamin D are at greatest risk of mortality, according to an analysis of 13,331 nationally representative adults whose data were collected in the Third National Health and Nutrition Examination Survey (pp. 1629-37). Figures from the 1998–94 time period show the following: “In cross-sectional multivariate analyses, increasing age, female sex, nonwhite race/ethnicity, diabetes, current smoking, and higher body mass index were all independently associated with higher odds of 25(OH)D deficiency (lowest quartile of 25(OH)D level, <17.8 ng/mL [to convert to nanomoles per liter, multiply by 2.496]), while greater physical activity, vitamin D supplementation, and nonwinter season were inversely associated. During a median 8.7 years of follow-up, there were 1,806 deaths, including 777 from [cardiovascular disease]. In multivariate models (adjusted for baseline demographics, season, and traditional and novel CVD risk factors), compared with the highest quartile, being in the lowest quartile (25[OH]D levels <17.8 ng/mL) was associated with a 26% increased rate of all-cause mortality (mortality rate ratio, 1.26; 95% CI, 1.08–1.46) and a population attributable risk of 3.1%. The adjusted models of CVD and cancer mortality revealed a higher risk, which was not statistically significant.” (M. L. Melamed, mmelamed@aecom.yu.edu)
Cost of PPIs with Prophylactic Aspirin: Proton-pump inhibitors are cost-effective at nonprescription prices for patients taking long-term, low-dose aspirin with average risk of upper gastrointestinal bleeding and at prescription prices for those at highest risk of this complication, a study concludes (pp. 1684-90). Using a Markov model, researchers compared lifelong ASA therapy alone with therapy with ASA plus PPI in patients with coronary heart disease aged 50 years and older from the perspective of a long-term payer such as Medicare, with these results: “In the base-case analysis, ASA plus PPI resulted in fewer lifetime UGIB events (3.1% vs 9.5%) and UGIB-related deaths (0.4% vs 1.4%). At over-the-counter (OTC) PPI cost, ASA plus PPI was cost-effective, with an incremental cost-effectiveness ratio (ICER) of $40,090 per life–year saved (LYS). Varying PPI effectiveness from 75% to 25% resulted in ICERs of $35,315 to $94,578 per LYS. Varying the starting age of the cohort from 80 to 50 years resulted in ICERs of $16,887 to $79,955 per LYS. At prescription PPI cost, the ICER for average-risk patients was over $100,000 per LYS across all modeled age groups and assumptions of PPI effectiveness, but the ICER for high-risk patients was $10,433 to $51,505 per LYS.” (S. D. Saini, sdsaini@umich.edu)

>>>PNN NewsWatch
* FDA is warning of rhabdomyolysis when simvastatin is used with amiodarone. The agency said the risk is dose-related and increases when a dose of simvastatin greater than 20 mg per day is given with amiodarone.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
Aug. 13, 2008 * Vol. 15, No. 157
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Aug. 13 violence-theme issue of JAMA (http://jama.ama-assn.org/current.dtl; 2008; 300).
Alcohol Use & Military Deployment: Alcohol-use problems increase in frequency after deployed reserve and National Guard personnel encounter combat situations, report Millennium Cohort Study researchers (pp. 663-75). Among 48,481 active-duty and reserve personnel, these experiences were noted among 5,510 individuals deployed with combat exposures, 5,661 deployed without combat exposures, and 37,310 who did not deploy: “Baseline prevalence of heavy weekly drinking, binge drinking, and alcohol-related problems among Reserve or National Guard personnel who deployed with combat exposures was 9.0%, 53.6%, and 15.2%, respectively; follow-up prevalence was 12.5%, 53.0%, and 11.9%, respectively; and new-onset rates were 8.8%, 25.6%, and 7.1%, respectively. Among active-duty personnel, new-onset rates were 6.0%, 26.6%, and 4.8%, respectively. Reserve and National Guard personnel who deployed and reported combat exposures were significantly more likely to experience new-onset heavy weekly drinking (odds ratio [OR], 1.63; 95% confidence interval [CI], 1.36–1.96), binge drinking (OR, 1.46; 95% CI, 1.24–1.71), and alcohol-related problems (OR, 1.63; 95% CI, 1.33–2.01) compared with nondeployed personnel. The youngest members of the cohort were at highest risk for all alcohol-related outcomes.” (I. G. Jacobson, Isabel.Jacobson@med.navy.mil)
Substance use disorders, traumatic brain injury (TBI), and posttraumatic stress disorder (PTSD) in military and civilian populations should be researched more extensively, editorialists write (pp. 720-1): “The co-occurrence of behavioral health problems may place additional demands on treatments designed for one of these conditions in isolation. What is not clear is whether simple accommodations (eg, compensatory strategies in the case of co-occurring TBI) or other minor adaptations to treatment are all that is needed, or whether a fundamentally different treatment approach is required. For example, the treatment demands for individuals dually diagnosed with substance use disorders and severe mental illness spawned Integrated Dual Disorders Treatment (IDDT). This treatment approach introduced ideas such as holistic case conceptualization and individualized staging of treatment components to better address the complexity of the clinical manifestation of co-occurring disorders. The complexity of substance use disorders co-occurring with PTSD, TBI, or both may necessitate that new treatment concepts be developed to successfully address these combined disorders. A systematic program of research and, if indicated, treatment development is a high priority, particularly for formerly deployed military personnel who are experiencing TBI, PTSD, and substance use disorders.” (T. B. Cole,
JAMA, Chicago; tbcole@bellsouth.net)
Chronic Pain After Traumatic Brain Injury: A systematic review provides this summary of chronic pain after traumatic brain injury in 1,670 participants in 12 studies (pp. 711-9): “Of these, 966 complained of chronic headache, yielding a prevalence of 57.8% (95% confidence interval [CI], 55.5%–60.2%). Among civilians, the prevalence of chronic pain was greater in patients with mild TBI (75.3% [95% CI, 72.7%–77.9%]) compared with moderate or severe TBI (32.1% [95% CI, 29.3%–34.9%]). Twenty studies including 3289 civilian patients with TBI yielded a chronic pain prevalence of 51.5% (95% CI, 49.8%–53.2%). Three studies assessed TBI among 917 veterans and yielded a pain prevalence of 43.1% (95% CI, 39.9%–46.3%). PTSD may mediate chronic pain, but brain injury appears to have an independent correlation with chronic pain.” (D. E. Nampiaparampil, VA, Fresno, CA; devichechi@gmail.com)

>>>PNN NewsWatch
* Adverse injection site reactions in patients receiving naltrexone are the subject of an FDA alert issued yesterday. Naltrexone should be administered as an intramuscular gluteal injection and not administered intravenously, subcutaneously, or inadvertently into fatty tissue, FDA noted. Physicians should instruct patients to monitor the injection site and contact them if they develop pain, swelling, tenderness, induration, bruising, pruritus, or redness at the injection site that does not improve or worsens within 2 weeks.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
Aug. 14, 2008 * Vol. 15, No. 158
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Aug. 14 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2008; 359).
Bivalirudin During PCI: Among patients with stable or unstable angina undergoing percutaneous coronary intervention, bivalirudin provided no additional clinical benefit, compared with heparin, but it increased reduced the incidence of major bleeding (pp. 688-96). The study included 4,570 patients who were pretreated with clopidogrel 600 mg at least 2 hours before PCI, followed by randomization to bivalirudin or unfractionated heparin, with these results on a primary end point of the composite of death, myocardial infarction, urgent target-vessel revascularization due to myocardial ischemia within 30 days after randomization, or major bleeding during the index hospitalization: “The incidence of the primary end point was 8.3% (190 patients) in the bivalirudin group as compared with 8.7% (199 patients) in the unfractionated-heparin group (relative risk, 0.94; 95% confidence interval [CI], 0.77 to 1.15; P = 0.57). The secondary end point [composite of death, myocardial infarction, or urgent target-vessel revascularization] occurred in 134 patients (5.9%) in the bivalirudin group and 115 patients (5.0%) in the unfractionated-heparin group (relative risk, 1.16; 95% CI, 0.91 to 1.49; P = 0.23). The incidence of major bleeding was 3.1% (70 patients) in the bivalirudin group and 4.6% (104 patients) in the unfractionated-heparin group (relative risk, 0.66; 95% CI, 0.49 to 0.90; P = 0.008).” (A. Kastrati, Deutsches Herzzentrum, Lazarettstr. Munich, Germany; kastrati@dhm.mhn.de)
Tibolone in Older Postmenopausal Women: In a study of 4,538 women aged 60–85 years with osteoporosis, the synthetic gonadal hormone analogue tibolone reduced the risk of fracture and breast cancer and possibly colon cancer but increased the risk of stroke, researchers report (pp. 697-708). Once-daily doses of tibolone 1.25 mg produced these results in comparison with placebo: “During a median of 34 months of treatment, the tibolone group, as compared with the placebo group, had a decreased risk of vertebral fracture, with 70 cases versus 126 cases per 1,000 person–years (relative hazard, 0.55; 95% confidence interval [CI], 0.41 to 0.74; P < 0.001), and a decreased risk of nonvertebral fracture, with 122 cases versus 166 cases per 1,000 person–years (relative hazard, 0.74; 95% CI, 0.58 to 0.93; P = 0.01). The tibolone group also had a decreased risk of invasive breast cancer (relative hazard, 0.32; 95% CI, 0.13 to 0.80; P = 0.02) and colon cancer (relative hazard, 0.31; 95% CI, 0.10 to 0.96; P = 0.04). However, the tibolone group had an increased risk of stroke (relative hazard, 2.19; 95% CI, 1.14 to 4.23; P = 0.02), for which the study was stopped in February 2006 at the recommendation of the data and safety monitoring board. There were no significant differences in the risk of either coronary heart disease or venous thromboembolism between the two groups.” (S. R. Cummings, California Pacific Med. Ctr. Res. Inst., San Francisco)
Commenting on clinical use of tibolone—an agent approved for use in 90 countries but not the U.S.—an editorialist writes (pp. 753-5): “The long-term safety and efficacy of tibolone on major health outcomes in younger postmenopausal women are unknown. In older, mostly white women with osteoporosis, tibolone at a dose of 1.25 mg daily for 3 years seemed to have a beneficial effect on the breast and skeleton and did not appear to have a deleterious effect on cardiovascular outcomes or thrombosis. However, the study was not adequately powered to evaluate the effect of tibolone on these outcomes. The use of tibolone should be avoided in older women, those at a high risk for stroke, and those who have breast cancer or are at high risk for the disease.
“The ideal postmenopausal hormonal therapy, which has yet to be identified, should achieve several benefits, minimize risks, and enhance adherence in the individual patient while optimizing cost-effectiveness—a formidable medical and societal challenge. The health risks and needs of a woman vary greatly during her 30 years of expected life after menopause, and health-risk profiles among women also differ. Therein lies the conundrum in searching for an ideal hormonal therapy.” (G. El-Hajj Fuleihan, American U., Beirut, Lebanon)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
Aug. 15, 2008 * Vol. 15, No. 159
Providing news and information about medications and their proper use

>>>Chest Highlights
Source:
Aug. issue of Chest (www.chestjournal.org/current.shtml; 2008; 228).
Long-term Sildenafil in Pulmonary Hypertension: In a small trial of 19 patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH), long-term treatment with sildenafil provided beneficial effects for several secondary measures of efficacy, in comparison with placebo (pp. 229-36). Looking at a primary end point of change in 6-min walking distance (6MWD) and secondary end points that included changes in World Health Organization (WHO) class, cardiopulmonary hemodynamics, quality of life (QOL) scores, and N-terminal pro brain natriuretic peptide (NT-proBNP), the investigators found: “There were no significant differences between the two groups with respect to change in exercise capacity. However significant improvements were seen in WHO class and pulmonary vascular resistance (PVR). Seventeen subjects were eligible for reassessment at 12 months and demonstrated significant improvements in 6MWD, activity and symptom components of QOL, cardiac index, PVR, and NT-proBNP.” (J. Pepke-Zaba, joanna.pepkezaba@papworth.nhs.uk)
Managing Yellow Nail Syndrome: Antibiotics, oral vitamin E, corticosteroids, and surgery proved effective means of managing 41 consecutive patients with yellow nail syndrome, a rare condition defined by the presence of yellow nails associated with lymphedema and/or chronic respiratory manifestations (pp. 375-81). For 20 men and 21 women with a median age at diagnosis was 61 years (range 18–82 years), the investigators report these experiences: “All but one patient had chronic respiratory manifestations that included pleural effusions (46%), bronchiectasis (44%), chronic sinusitis (41%), and recurrent pneumonias (22%); 26 patients (63%) had lymphedema. Treatment included rotating antibiotic therapy for bronchiectasis, thoracenteses, oral vitamin E, and corticosteroid therapy. Eight patients underwent surgical management of recurrent pleural effusions including pleurodesis and decortication; two additional patients underwent pleurodesis via tube thoracostomy. The yellow nails improved or resolved in 14 of 25 patients (56%) for whom relevant data were available. Median survival of this cohort using the Kaplan–Meier method was 132 months, significantly lower than (P = 0.01) the control population. Among those still alive (20 patients), the disease appeared stable.” (F. Maldonado, ryu.jay@mayo.edu)

>>>Cardiology Highlights
Source:
Aug. 19 issue of the Journal of the American College of Cardiology (http://content.onlinejacc.org/current.dtl; 2008; 52).
Effects of Statins on ApoB: Support of more aggressive statin therapy for primary prevention comes from the MERCURY II (Measuring Effective Reductions in Cholesterol Using Rosuvastatin therapY II) trial (pp. 626-32). Patients had high coronary heart disease (CHD) risk, LDL-C levels of 130–250 mg/dL, and triglyceride levels less than 400 mg/dL. Rosuvastatin 10 or 20 mg, atorvastatin 10 or 20 mg, or simvastatin 20 or 40 mg produced these changes in apolipoprotein B and other markers: “In untreated patients, the apoB target of <90 mg/dl was roughly equivalent to an LDL-C level <100 mg/dl and a non–HDL-C level <130 mg/dl, which is consistent with existing apoB and lipoprotein guidelines. However, during statin therapy, to reach an apoB target of <90 mg/dl it was necessary to reduce non–HDL-C to <100 mg/dl or to reduce LDL-C to <70 mg/dl (in high-triglyceride patients) or <80 mg/dl (in lower-triglyceride patients). The tight correlation seen for non–HDL-C with apoB while on statin therapy (R2 = 0.92) implies that non–HDL-C may be an acceptable surrogate for direct apoB measurement.” (C. M. Ballantyne, cmb@bcm.edu)

>>>PNN NewsWatch
* Watson Pharmaceuticals, Inc., issued a voluntary recall of one lot of Fentanyl Transdermal System 75 mcg/hr patches (lot 92461850; expiration date, 8/31/2009) because of leakage.
*
Correction: In yesterday’s article on use of bivalirudin and unfractionated heparin in patients with stable or unstable angina undergoing percutaneous coronary intervention, PNN should have reported that the incidence of major bleeding was reduced, not increased, with bivalirudin.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
Aug. 18, 2008 * Vol. 15, No. 160
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Aug. 16 issue of Lancet (www.thelancet.com; 2008; 372).
Prehospital Tirofiban in STEMI: Early administration of the glycoprotein IIb/IIIa blocker tirofiban at first medical contact improves ST-segment resolution and clinical outcomes after primary coronary angioplasty, report researchers who studied patients with acute ST-elevation myocardial infarction (pp. 537-46). At 24 centers in the Netherlands, Germany, and Belgium, 984 patients with STEMI who were candidates to undergo PCI received either high-bolus dose tirofiban or placebo in addition to aspirin 500 mg, heparin 5,000 IU, and clopidogrel 600 mg, with these results: “936 (95%) patients were randomly assigned to treatment after a prehospital diagnosis of myocardial infarction in the ambulance. Median time from onset of symptoms to diagnosis was 76 min (IQR 35–150). Mean residual ST deviation before PCI (10.9 mm [SD 9.2] vs 12.1 mm [9.4], p = 0.028) and 1 h after PCI (3.6 mm [4.6] vs 4.8 mm [6.3], p = 0.003) was significantly lower in patients pretreated with high-bolus dose tirofiban than in those assigned to placebo. The rate of major bleeding did not differ significantly between the two groups (19 [4%] vs 14 [3%]; p = 0.36).” (A. W. J. van ‘t Hof, Isala Klinieken, Zwolle, the Netherlands v.r.c.derks@isala.nl)
Renal Effects of Combined ACEIs, ARBs: Among patients aged 55 years or older with established atherosclerotic vascular disease or with diabetes with end-organ damage, combination therapy with ramipril and telmisartan reduced proteinuria but worsened major renal outcomes, report investigators in ONTARGET, the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (pp. 547-53). These results were recorded among 25,620 patients on the ACE inhibitor ramipril 10 mg/day, the angiotensin II receptor blocker telmisartan 80 mg/day, or both over a median of 56 months: “784 patients permanently discontinued randomised therapy during the trial because of hypotensive symptoms (406 on combination therapy, 149 on ramipril, and 229 on telmisartan). The number of events for the composite primary outcome was similar for telmisartan (n = 1,147 [13.4%]) and ramipril (1,150 [13.5%]; hazard ratio [HR] 1.00, 95% CI 0.92–1.09), but was increased with combination therapy (1,233 [14.5%]; HR 1.09, 1.01–1.18, p = 0.037). The secondary renal outcome, dialysis or doubling of serum creatinine, was similar with telmisartan (189 [2.21%]) and ramipril (174 [2.03%]; HR 1.09, 0.89–1.34) and more frequent with combination therapy (212 [2.49%]: HR 1.24, 1.01–1.51, p = 0.038). Estimated glomerular filtration rate (eGFR) declined least with ramipril compared with telmisartan (−2.82 [SD 17.2] mL/min/1.73 m2 vs −4.12 [17.4], p < 0.0001) or combination therapy (−6.11 [17.9], p < 0.0001). The increase in urinary albumin excretion was less with telmisartan (p = 0.004) or with combination therapy (p = 0.001) than with ramipril.” (J. F. E. Mann, McMaster U., Hamilton, ON, Canada; tbn02ab@mail.lrz-muenchen.de)

>>>BMJ Highlights
Source:
Early-release article from BMJ (www.bmj.org; 2008; 337).
Effects of Electronic Systems on Resource Usage: Computerized physician order entry systems and picture archiving and communications systems were associated with both increases and decreases in repeat orders for laboratory tests, a study concludes (a939). At four U.K. National Health Service hospitals in England, a reduction was observed in the proportion of outpatient appointments at which full blood count (odds ratio 0.25, 95% confidence interval 0.16 to 0.40), urea and electrolytes (0.55, 0.39 to 0.77), and urine culture (0.30, 0.17 to 0.51) tests were ordered, and at which full blood count tests were repeated (0.73, 0.53 to 0.99) were ordered, but use of urea and electrolytes tests among day case patients increased nearly fourfold (3.63, 1.66 to 7.94) (B. C. Reeves, U. Bristol, Bristol, U.K.; barney.reeves@bristol.ac.uk)

>>>PNN JournalWatch
* New Drugs and Technologies: Aliskiren, in Circulation, 2008; 118: 773–84. Reprints: M. J. Brown, Addenbrookes Hosp., Cambridge, U.K.; m.j.brown@cai.cam.ac.uk
* The Changing Face of Heart Transplantation, in
Journal of the American College of Cardiology, 2008; 52: 587–98. Reprints: S. A. Hunt, shunt@cvmed.stanford.edu
* Illnesses at High Altitude, in
Chest, 2008; 134: 402–16. Reprints: R. B. Schoene, rschoene@ucsd.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 © 2008, 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
Aug. 19, 2008 * Vol. 15, No. 161
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Aug. 19 issue of the Annals of Internal Medicine (www.annals.org/current.shtml; 2008; 149).
Vitamin D & Hip Fractures: Among 400 case–patients with incident hip fracture and 400 control participants, lower levels of serum 25(OH) vitamin D were associated with higher risk for hip fracture, researchers report (pp. 242-50). Followed for a median of 7.1 years in a study of postmenopausal women who were not taking estrogens or other bone-active therapies and who had not had a previous hip fracture, the study participants showed these trends: “Mean serum 25(OH) vitamin D concentrations were lower in case-patients than in control participants (55.95 nmol/L [SD, 20.28] vs. 59.60 nmol/L [SD, 18.05]; P = 0.007), and lower serum 25(OH) vitamin D concentrations increased hip fracture risk (adjusted odds ratio for each 25-nmol/L decrease, 1.33 [95% CI, 1.06 to 1.68]). Women with the lowest 25(OH) vitamin D concentrations (47.5 nmol/L) had a higher fracture risk than did those with the highest concentrations (70.7 nmol/L) (adjusted odds ratio, 1.71 [CI, 1.05 to 2.79]), and the risk increased statistically significantly across quartiles of serum 25(OH) vitamin D concentration (P for trend = 0.016). This association was independent of number of falls, physical function, frailty, renal function, and sex-steroid hormone levels and seemed to be partially mediated by bone resorption.” (J. A. Cauley, jcauley@edc.pitt.edu)
Drug Company–Sponsored Seeding Trials: ADVANTAGE, Assessment of Differences between Vioxx and Naproxen To Ascertain Gastrointestinal Tolerability and Effectiveness, was an example of “marketing framed as science,” authors conclude (pp. 251-8). Using internal Merck documents and presentations made during Vioxx litigation, the investigators looked into whether ADVANTAGE was a seeding trial, that is, a clinical study conducted by pharmaceutical companies designed to seem as if it answered a scientific question but primarily fulfilling marketing objectives: “Review of the documents revealed 3 key themes: The trial was designed by Merck’s marketing division to fulfill a marketing objective; Merck’s marketing division handled both the scientific and the marketing data, including collection, analysis, and dissemination; and Merck hid the marketing nature of the trial from participants, physician investigators, and institutional review board members. Although the systematic review of the literature identified 6 articles that focused on the practice of seeding trials, none provided documentary evidence of their existence or conduct.” (K. P. Hill, kphill@partners.org)
Furosemide for Hypercalcemia: The unproven practice of using furosemide for hypercalcemia should be stopped, according to authors of a review article (pp. 259-63): “Although primary hyperparathyroidism is the most common cause of hypercalcemia, cancer is the most common cause requiring inpatient intervention. An estimated 10% to 20% of all patients with cancer have hypercalcemia at some point in their disease trajectory, particularly in advanced disease. Aggressive saline hydration and varying doses of furosemide continue to be the standard of care for emergency management. However, a review of the evidence for the use of furosemide in the medical management of hypercalcemia yields only case reports published before the introduction of bisphosphonates, in contrast to multiple randomized, controlled trials supporting the use of bisphosphonates. The use of furosemide in the management of hypercalcemia should no longer be recommended.” (S. B. LeGrand, legrans@ccf.org)

>>>PNN NewsWatch
* Tetrabenazine (Xenazine, Prestwick Pharmaceuticals) has been approved by FDA for treatment of chorea in Huntington’s disease. The new drug is the first approved treatment for any symptom of Huntington’s disease.
*
FDA has received reports of 6 cases of hemorrhagic or necrotizing pancreatitis in patients taking exenatide (Byetta, Amylin). All patients required hospitalization, two patients died, and four patients were recovering at time of reporting. Exenatide and other potentially suspect drugs should be promptly discontinued if pancreatitis is suspected, FDA advised. If pancreatitis is confirmed, initiate appropriate treatment and carefully monitor the patient until recovery. Exenatide should not be restarted.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
Aug. 20, 2008 * Vol. 15, No. 162
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Aug. 20 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2008; 300).
B Vitamins for Secondary Coronary Prevention: Use of B vitamins for lowering homocysteine had no significant effect on total mortality or cardiovascular events among 3,096 adults participants undergoing coronary angiography for cardiovascular disease (pp. 795-804). Daily oral folic acid 0.8 mg, vitamin B12 0.4 mg, plus vitamin B6 40 mg; folic acid plus vitamin B12; vitamin B6 alone; or placebo, yielded these results: “Mean plasma total homocysteine concentration was reduced by 30% after 1 year of treatment in the groups receiving folic acid and vitamin B12. The trial was terminated early because of concern among participants due to preliminary results from a contemporaneous Norwegian trial suggesting adverse effects from the intervention. During a median 38 months of follow-up, the primary end point was experienced by a total of 422 participants (13.7%): 219 participants (14.2%) receiving folic acid/vitamin B12 vs 203 (13.1%) not receiving such treatment (hazard ratio, 1.09; 95% confidence interval, 0.90–1.32; P = .36) and 200 participants (13.0%) receiving vitamin B6 vs 222 (14.3%) not receiving vitamin B6 (hazard ratio, 0.90; 95% confidence interval, 0.74–1.09; P = .28).” (M. Ebbing, Haukeland U. Hosp., Bergen, Norway; marta.ebbing@helse-bergen.no)
Pharmaceutical Promotions & Physician Education: Authors of a historical perspective on the interrelationship between pharmaceutical promotion and physician education reach this conclusion (pp. 831-3): “The problem of pharmaceutical promotion in the continuing education of practicing physicians presents an enduring dilemma. Arguments from academia, industry, and organized medicine articulated in 1958 persist in almost untouched form in 2008. Technological and regulatory solutions intended to defend professional control over knowledge circulation—such as [continuing medical education]—have instead provided novel sites of intersection between pharmaceutical marketing and physician education. At the same time, the stakes of the debate have continued to increase: by 2006, the worldwide sales of the pharmaceutical industry had increased to more than $600 billion, and estimates of the amount of money spent promoting new drugs to US physicians range from $27.7 billion to $57.5 billion.
“As advertising executive Pierre Garai noted in 1963: ‘The drug business is today, and will be tomorrow, what the doctors cause it to be. Drug advertising too.’ Any responsible analysis of the role of pharmaceutical promotion in CME must account for the process by which individual physicians, organized medicine, and the regulatory state allowed and even encouraged this process to take place. Garai1 finished with the question: ‘We know what the doctors are today. What will they be tomorrow?’ This question continues to define the important and precarious project of CME: a project with values, goals, and tools that remain very much at play between commercial and professional interests.” (S. H. Podolsky,
scott_podolsky@hms.harvard.edu)
Patient-Centered Medical Home: The patient-centered medical home, proposed by medical groups in 2006, needs to be tested, the author of a Commentary argues (pp. 834-5): “The pace of activity and attention the PCMH has received from the public and private sectors speaks to the desire and need to find alternative models of health care delivery and reimbursement that are responsive to the well-documented shortcomings of the US health care system. Those individuals and organizations involved in these efforts understand that the PCMH model needs to be tested in a robust way and continually improved based on lessons learned through the accumulation of data from multiple demonstration projects. However, the PCMH is only one potential method of addressing some of the ills of the US health care system. Even assuming that the demonstration projects will improve quality, reduce cost, and satisfy the needs of patients and families, unless other major policy changes occur, the PCMH cannot significantly improve the plight of the uninsured, reduce pervasive health disparities, or solve the primary care and geriatric workforce issues. However, the PCMH model may provide a pathway for revitalization of primary care and become an essential part of a new approach to health care delivery in the United States.” (M. S. Barr, mbarr@acponline.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 © 2008, 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
Aug. 21, 2008 * Vol. 15, No. 163
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Aug. 21 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2008; 359).
Pharmacogenetics & Statin-Induced Myopathy: Patients with common variants of a gene for an anion-transporting peptide have significantly increased risk of statin-induced myopathy, concludes a research effort that screened approximately 300,000 markers in 85 patients with myopathy and 90 control patients (pp. 789-99). Study participants were identified from among 12,000 patients who were taking simvastatin 80 mg daily, and results were retested in a 20,000-patient study of simvastatin 40 mg daily. The authors report: “The genomewide scan yielded a single strong association of myopathy with the rs4363657 single-nucleotide polymorphism (SNP) located within SLCO1B1 on chromosome 12 (P = 4 x 10–9). SLCO1B1 encodes the organic anion–transporting polypeptide OATP1B1, which has been shown to regulate the hepatic uptake of statins. The noncoding rs4363657 SNP was in nearly complete linkage disequilibrium with the nonsynonymous rs4149056 SNP (r2 = 0.97), which has been linked to statin metabolism. The prevalence of the rs4149056 C allele in the population was 15%. The odds ratio for myopathy was 4.5 (95% confidence interval [CI], 2.6 to 7.7) per copy of the C allele, and 16.9 (95% CI, 4.7 to 61.1) in CC as compared with TT homozygotes. More than 60% of these myopathy cases could be attributed to the C variant. The association of rs4149056 with myopathy was replicated in the trial of 40 mg of simvastatin daily, which also showed an association between rs4149056 and the cholesterol-lowering effects of simvastatin. No SNPs in any other region were clearly associated with myopathy.” (SEARCH Collaborative Group, U. Oxford, Oxford, U.K.; search@ctsu.ox.ac.uk)
Pondering whether the findings in these studies can be extended to rhabdomyolysis, an editorialist notes the difficulty of conducting sound research on rare adverse drug events (pp. 856-8): “The degree of myopathy that occurred in these two trials was mild and reversible, in stark contrast to a form of statin-induced rhabdomyolysis that involves severe muscle damage accompanied by toxic effects in other organs such as the kidney.
SLCO1B1 variants must be tested for an association with this adverse drug reaction as soon as possible. However, severe adverse drug reactions are very rare, and the incidence of statin-induced rhabdomyolysis is reported to be as low as 0.000044 event per person per year. Hence, a global network for the collection of data on persons with statin-induced rhabdomyolysis would be required to test for the association with a variant in SLCO1B1. Indeed, a global mechanism for collecting data on patients with severe adverse drug reactions would benefit the field of pharmacogenetics enormously and encourage the development of new technologies.” (Y. Nakamura, U. Tokyo, Tokyo)
Adalimumab in Juvenile Rheumatoid Arthritis: Administered with or without methotrexate to children and adolescents with juvenile rheumatoid arthritis, adalimumab was an effective means of reducing symptoms of the disease, researchers report (pp. 810-20). Adalimumab was administered subcutaneously every other week for 16 weeks in doses of 24 mg/sq m up to maximum doses of 40 mg, with these results: “Seventy-four percent of patients not receiving methotrexate (64 of 86) and 94% of those receiving methotrexate (80 of 85) had an ACR Pedi 30 response at week 16 and were eligible for double-blind treatment. Among patients not receiving methotrexate, disease flares (the primary outcome) occurred in 43% of those receiving adalimumab and 71% of those receiving placebo (P = 0.03). Among patients receiving methotrexate, flares occurred in 37% of those receiving adalimumab and 65% of those receiving placebo (P = 0.02). At 48 weeks, the percentages of patients treated with methotrexate who had ACR Pedi 30, 50, 70, or 90 responses were significantly greater for those receiving adalimumab than for those receiving placebo; the differences between patients not treated with methotrexate who received adalimumab and those who received placebo were not significant. Response rates were sustained after 104 weeks of treatment. Serious adverse events possibly related to adalimumab occurred in 14 patients.” (D. J. Lovell, daniel.lovell@cchmc.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 © 2008, 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
Aug. 22, 2008 * Vol. 15, No. 164
Providing news and information about medications and their proper use

>>>Gastroenterology Report
Source:
Aug. issue of Gastroenterology (www.gastrojournal.org/current; 2008; 135).
Peginterferon/Ribavirin for Hepatitis C: In patients with hepatitis C virus infections of genotype 1 or 4 strains, a 24-week regimen of peginterferon alfa-2a plus ribavirin 1000/1200 mg/day is appropriate when they have a low baseline HCV RNA level and rapid virologic response to therapy, defined as response by week 4 of treatment, researchers report (pp. 451-8). “A total of 150 of 516 patients (29%) had an RVR, 143 of whom completed 24 weeks of treatment,” the article explains. “Younger patients, leaner patients, and those with an HCV RNA level 400,000 IU/mL and HCV genotype 4 infection were more likely to achieve an RVR; however, among patients with an RVR, no baseline factor predicted [sustained virologic response (SVR)]. The SVR rate was 80.4% (115/143; 95% confidence interval [CI], 72.9–86.6) in patients who completed 24 weeks of treatment. The SVR rate was 86.7% (26/30; 95% CI, 69.3%–96.2%) in patients infected with genotype 4 and 78.8% in those infected with genotype 1 (89/113; 95% CI, 70.1%–85.9%; intent to treat: 89/120; 74.2%; 65.4–81.7%). Treatment was well tolerated.” (P. Ferenci, Med. U., Vienna; peter.ferenci@meduniwien.ac.at)
Peginterferon/Lamivudine for Hepatitis B: In a long-term follow-up (LTFU) study, pegylated interferon alfa-2b (PEG-IFN) proved important in loss of hepatitis B antigens regardless of whether it was administered alone or in combination with lamivudine (pp. 459-67). Patients were treated with PEG-IFN 100 mcg/wk alone or in combination with lamivudine 100 mg/day for 52 weeks, with initial response defined as HBeAg negativity at 26 weeks posttreatment. During a mean follow-up period of 3.0 years, these results were noted based on one additional visits after the initial study: “Of 266 patients enrolled in the initial study, 172 (65%) participated in the LTFU study. At LTFU, HBeAg and hepatitis B surface antigen (HBsAg) negativity were observed in 37% and 11% of 172 patients, respectively. Sixty-four patients were classified as initial responders and 108 as nonresponders. Among the initial responders, sustained HBeAg negativity and HBsAg loss were observed in 81% and 30%, respectively. Significantly higher rates of HBeAg negativity were observed in genotype A–infected initial responders compared with those with genotype non-A (96% vs 76%; P = .06) as well as HBsAg loss (58% vs 11%; P < .001).” (H. L. A. Janssen, Erasmus MC U. Med. Ctr., Rotterdam, the Netherlands; h.janssen@erasmusmc.nl)

>>>Allergy/Immunology Report
Source:
Aug. issue of the Journal of Allergy and Clinical Immunology (www.jacionline.org/current; 2008; 122).
Beta-2 Agonist Use in Elite Athletes: A summary of an Olympic Committee Consensus Conference explores the requirement that elite athletes demonstrate presence of asthma, exercise-induced bronchoconstriction, or airways hyperresponsiveness (AHR) to be approved to inhale beta-2 agonists (pp. 254-60): “Asthma management in elite athletes should follow established treatment guidelines (eg, Global Initiative for Asthma) and should include education, an individually tailored treatment plan, minimization of aggravating environmental factors, and appropriate drug therapy that must meet the requirements of the World Anti-Doping Agency. Asthma control can usually be achieved with inhaled corticosteroids and inhaled beta-2 agonists to minimize exercise-induced bronchoconstriction and to treat intermittent symptoms. The rapid development of tachyphylaxis to beta-2 agonists after regular daily use poses a dilemma for athletes. Long-term intense endurance training, particularly in unfavorable environmental conditions, appears to be associated with an increased risk of developing asthma and AHR in elite athletes. Globally, the prevalence of asthma, exercise-induced bronchoconstriction, and AHR in Olympic athletes reflects the known prevalence of asthma symptoms in each country. The policy of requiring Olympic athletes to demonstrate the presence of asthma, exercise-induced bronchoconstriction, or AHR to be approved to inhale beta-2 agonists will continue.” (K. D. Fitch, U. Western Australia, Crawley, Western Australia; kfitch@cyllene.uwa.edu.au)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
Aug. 25, 2008 * Vol. 15, No. 165
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Aug. 23 issue of Lancet (www.thelancet.com; 2008; 372).
Treatment of Antiretroviral-Naive Patients with HIV: In a 48-week study of patients with HIV-1 infection who had not received prior antiretroviral therapy, atazanavir/ritonavir once daily had similar antiviral efficacy as lopinavir/ritonavir twice daily, with less gastrointestinal toxicity but a higher rate of hyperbilirubinemia, researchers report (pp. 646-55). Results from the open-label, noninferiority study of 883 patients showed the following: “At week 48, 343 (78%) of 440 patients receiving atazanavir/ritonavir and 338 (76%) of 443 patients receiving lopinavir/ritonavir had achieved a viral load of less than 50 copies per mL (difference 1.7%, 95% CI −3.8 to 7.1). Mean increases from baseline in CD4 cell count were similar (203 cells per µL in the atazanavir/ritonavir group vs 219 cells per µL in the lopinavir/ritonavir group). 25 (6%) patients in the atazanavir/ritonavir group and 26 (6%) in the lopinavir/ritonavir group were virological failures by week 48. Only two patients, both in the atazanavir/ritonavir group, had non-polymorphic protease inhibitor resistance mutations emerge on treatment, which conferred phenotypic resistance to atazanavir in one patient. Serious adverse events were noted in 51 (12%) of 441 patients in the atazanavir/ritonavir group and in 42 (10%) of 437 patients in the lopinavir/ritonavir group. Fewer patients in the atazanavir/ritonavir group than in the lopinavir/ritonavir group experienced grade 2–4 treatment-related diarrhoea (10 [2%] vs 50 [11%]) and nausea (17 [4%] vs 33 [8%]). Grade 2–4 jaundice was seen in 16 (4%) of 441 patients in the atazanavir/ritonavir group versus none of 437 patients in the lopinavir/ritonavir group; grade 3–4 increases in total bilirubin were seen in 146 (34%) of 435 patients on atazanavir/ritonavir and in one (<1%) of 431 patients on lopinavir/ritonavir.” (J-M Molina, Hopital Saint-Louis, Paris; jean-michel.molina@sls.aphp.fr)

>>>BMJ Highlights
Source:
Early-release article from BMJ (www.bmj.org; 2008; 337).
HRT Long After Menopause: Women started on combination hormone-replacement therapy at ages 50–69 had significantly improved health-related quality of life after 1 year on the agents, compared with placebo, in a 3,721-patient study (a1190). Data from 1,043 women on estrogen/progestin and 1,087 women taking placebo showed: “After one year small but significant improvements were observed in three of nine components of the women’s health questionnaire for those taking combined HRT compared with those taking placebo: vasomotor symptoms (P < 0.001), sexual functioning (P < 0.001), and sleep problems (P < 0.001). Significantly fewer women in the combined HRT group reported hot flushes (P < 0.001), night sweats (P < 0.001), aching joints and muscles (P = 0.001), insomnia (P < 0.001), and vaginal dryness (P < 0.001) than in the placebo group, but greater proportions reported breast tenderness (P < 0.001) or vaginal discharge (P < 0.001). Hot flushes were experienced in the combined HRT and placebo groups by 30% and 29% at trial entry and 9% and 25% at one year, respectively. No significant differences in other menopausal symptoms, depression, or overall quality of life were observed at one year.” (A. H. MacLennan, U. Adelaide, Adelaide, Australia; alastair.maclennan@adelaide.edu.au)

>>>PNN NewsWatch
* FDA has approved romiplostim (Nplate, Amgen) for treatment of thrombocytopenia in splenectomized and nonsplenectomized adults with chronic immune thrombocytopenic purpura. Romiplostim is a fusion protein with characteristics of both peptides and antibodies; it is the first “peptibody protein” approved by FDA. It works by stimulating thrombopoietin receptors, thereby raising platelet counts.

>>>PNN JournalWatch
* Human Facial Allotransplantation: A 2-Year Follow-up Study, in Lancet, 2008; 372: 631–8. Reprints: S. Guo, Fourth Military Med. U., Shaanxi, China; mzf0709@fmmu.edu.cn
* Repair of the Lower and Middle Parts of the Face by Composite Tissue Allotransplantation in a Patient with Massive Plexiform Neurofibroma: A 1-Year Follow-up Study, in
Lancet, 2008; 372: 639–45. Reprints: L. Lantieri, CHU Henri Mondor, Créteil, France; laurent.lantieri@hmn.aphp.fr
* Antimicrobial Peptides and the Skin Immune Defense System, in
Journal of Allergy and Clinical Immunology, 2008; 122: 261–6. Reprints: R. L. Gallo, rgallo@ucsd.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 © 2008, 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
Aug. 26, 2008 * Vol. 15, No. 166
Providing news and information about medications and their proper use

>>>Rheumatology Highlights
Source:
Aug. issue of Arthritis & Rheumatism (www3.interscience.wiley.com/journal/76509746/home; 2008; 58).
Abetimus for SLE: Among 317 patients with systemic lupus erythematosus, abetimus reduced anti-dsDNA antibody levels and other renal end points but failed to delay the time to renal flare, compared with placebo (pp. 2470-80). Testing 100 mg/wk doses of the drug for up to 22 months, investigators found these trends in SLE parameters: “Abetimus did not significantly prolong time to renal flare, time to initiation of high-dose corticosteroid and/or cyclophosphamide treatment, or time to major SLE flare. However, there were 25% fewer renal flares in the abetimus group compared with the placebo group (17 of 145 abetimus-treated patients [12%] versus 24 of 153 placebo-treated patients [16%]). Abetimus treatment decreased anti-dsDNA antibody levels (P < 0.0001), and reductions in anti-dsDNA levels were associated with increases in C3 levels (P < 0.0001). More patients in the abetimus group experienced 50% reductions in proteinuria at 1 year, compared with the placebo group (nominal P = 0.047). Trends toward reduced rates of renal flare and major SLE flare were noted in patients treated with abetimus who had impaired renal function at baseline. Treatment with abetimus for up to 22 months was well tolerated.” (M. D. Linnik, La Jolla Pharmaceutical Co., San Diego; linnik@ljpc.com)
Economic Burden of Arthritis: Expenditures for treatment of arthritis—both out of pocket (OOP) and through Medicare and other payers—climbed substantially between 1998 and 2004, researchers report, concluding that “high prescription drug expenditures are likely to continue to be an issue” (pp. 2236-40). Using nationally representative data from seven panels of the Medical Expenditures Panel Survey, the investigators assessed 1998–2004 expenditures and extrapolated trends through 2006 in an effort to simulate the impact of the Medicare Part D benefit: “Median total OOP expenditures for persons with arthritis showed an increase of 52.4% between 1998 and 2004 (7.3% annually beyond inflation). Median OOP expenditures for prescription medication showed larger growth, at 72.0%. Medicare Part D was predicted to lower both total and prescription OOP expenditures and return them close to 2003 levels. Simulation limitations included exclusive use of the standard Medicare Part D benefit structure and the assumption of stable prescribing trends during this period.” (L. M. Manheim, l-manheim@northwestern.edu)

>>>Oncology Report
Source:
Aug. 20 issue of the Journal of Clinical Oncology (http://jco.ascopubs.org/current.dtl; 2008; 26).
Treating Metastatic Breast Cancer: Gemcitabine proved useful in advanced breast cancer after anthracycline-based adjuvant therapy, a research study reports, making “GT … a reasonable choice for women who require cytoreduction with manageable toxicities” (pp. 3950-7). Among 529 patients who relapsed after adjuvant anthracyclines, the unblinded study showed these results: “Median survival on GT was 18.6 months versus 15.8 months on paclitaxel (log-rank P = . 0489), with an adjusted Cox hazard ratio of 0.78 (95% CI, 0.64 to 0.96; P = .0187). The [time to progression] was longer (6.14 v 3.98 months; log-rank P = .0002) and the [response rate] was better (41.4% v 26.2%; P = .0002) on GT. There was more grade 3 to 4 neutropenia on GT and grade 2 to 4 fatigue and neuropathy were slightly more prevalent on GT.” (K. S. Albain, Loyola U., Maywood, IL; kalbain@lumc.edu)

>>>PNN NewsWatch
* Two cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients receiving natalizumab (Tysabri, Biogen Idec, Elan) monotherapy for multiple sclerosis in Europe, FDA announced yesterday. Both patients had received natalizumab for more than 1 year. PML, which is usually fatal, is a known risk of natalizumab treatment, but previous cases in patients with multiple sclerosis were seen in combination with other immunomodulatory therapies. While the two patients who developed PML were on monotherapy, FDA still believes that natalizumab monotherapy may confer a lower risk of PML than when natalizumab is used together with other immunomodulatory medications.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
Aug. 27, 2008 * Vol. 15, No. 167
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Aug. 27 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2008; 300).
Tight Glucose Control in Critically Ill Adults: Risk of hypoglycemia is increased when strategies for tight glucose control are used in critically ill adults, a meta-analysis concludes, and this increased risk is not accompanied by a reduction in hospital mortality (pp. 933-44). Based on 29 randomized controlled trials of 8,432 patients, the investigators determined: “Hospital mortality did not differ between tight glucose control and usual care overall (21.6% vs 23.3%; RR, 0.93; 95% confidence interval [CI], 0.85–1.03). There was also no significant difference in mortality when stratified by glucose goal ([1] very tight: 110 mg/dL; 23% vs 25.2%; RR, 0.90; 95% CI, 0.77–1.04; or [2] moderately tight: <150 mg/dL; 17.3% vs 18.0%; RR, 0.99; 95% CI, 0.83–1.18) or intensive care unit setting ([1] surgical: 8.8% vs 10.8%; RR, 0.88; 95% CI, 0.63–1.22; [2] medical: 26.9% vs 29.7%; RR, 0.92; 95% CI, 0.82–1.04; or [3] medical-surgical: 26.1% vs 27.0%; RR, 0.95; 95% CI, 0.80–1.13). Tight glucose control was not associated with significantly decreased risk for new need for dialysis (11.2% vs 12.1%; RR, 0.96; 95% CI, 0.76–1.20), but was associated with significantly decreased risk of septicemia (10.9% vs 13.4%; RR, 0.76; 95% CI, 0.59–0.97), and significantly increased risk of hypoglycemia (glucose 40 mg/dL; 13.7% vs 2.5%; RR, 5.13; 95% CI, 4.09–6.43).” (R. S. Wiener, renda.s.wiener@dartmouth.edu)
Noting that a 42-site study is under way using a Web-based algorithm (the NICE SUGAR study), editorialists provide this direction to researchers (pp. 963-5): “Those investigating tight glycemic control should take a step back and address the fundamental questions of defining quality standards for tight glycemic control, finding affordable methods of frequent and highly accurate measurement of blood glucose in the ICU, and conduct[ing] multicenter efficacy studies to determine if tighter glycemic control can reduce mortality under optimal conditions.” (S. Finfer, George Inst. for International Health, Sydney;
sfinfer@george.org.au)
Metal Content in Ayurvedic Medicines: Detectable lead, mercury, or arsenic is present in one-fifth of Ayurvedic medicines manufactured in the U.S. or India, researchers report (pp. 915-23). Among 193 products identified and purchased on the Internet, the researchers found these contents: “The prevalence of metal-containing products was 20.7% (95% confidence interval [CI], 15.2%–27.1%). The prevalence of metals in US-manufactured products was 21.7% (95% CI, 14.6%–30.4%) compared with 19.5% (95% CI, 11.3%–30.1%) in Indian products (P = .86). Rasa shastra compared with non–rasa shastra medicines had a greater prevalence of metals (40.6% vs 17.1%; P = .007) and higher median concentrations of lead (11.5 µg/g vs 7.0 µg/g; P = .03) and mercury (20,800 µg/g vs 34.5 µg/g; P = .04). Among the metal-containing products, 95% were sold by US Web sites and 75% claimed Good Manufacturing Practices. All metal-containing products exceeded 1 or more standards for acceptable daily intake of toxic metals.” (R. B. Saper, robert.saper@bmc.org)
Allopurinol for Hypertension: In 30 adolescents with newly diagnosed, never-treated stage 1 essential hypertension and elevated serum uric acid levels, allopurinol 200 mg twice daily proved effective for blood pressure reduction in a 4-week study (pp. 924-32). Allopurinol reduced systolic and diastolic blood pressures by means of 6.9 and 5.1 mm Hg, significantly more than the respective 2.0 and 2.4 mm Hg reductions seen with placebo. (D. I. Feig, dfeig@bcm.tmc.edu)

>>>PNN NewsWatch
* Confusion surrounding last week’s FDA warning (see PNN, Aug. 19) about exenatide injection (Byetta; Lilly, Amylin) was clarified yesterday in a company media briefing. In addition to the two deaths reported last week, four other deaths of patients who developed pancreatitis while taking exenatide have surfaced, but company officials emphasized that these fatalities did not appear directly attributable to exenatide exposure. The cause of one death is unknown, while the other three were caused by postoperative complications several weeks after pancreatitis, relapse of leukemia 2.5 months after pancreatitis, and gastrointestinal bleeding after surgical removal of the gallbladder.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
Aug. 28, 2008 * Vol. 15, No. 168
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Aug. 28 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2008; 359).
Magnesium Sulfate for Preventing Cerebral Palsy: Administered to mothers at imminent risk for preterm delivery, magnesium sulfate failed to reduce a composite end point of stillbirth or infant death by 1 year of corrected age or moderate or severe cerebral palsy at or beyond 2 years of corrected age, researchers report (pp. 895-905). However, the agent, administered as a 6-g bolus followed by a constant infusion of 2 g/h, did reduce the risk of cerebral palsy among infants who survived, as detailed in these study results: “A total of 2,241 women underwent randomization. The baseline characteristics were similar in the two groups. Follow-up was achieved for 95.6% of the children. The rate of the primary outcome was not significantly different in the magnesium sulfate group and the placebo group (11.3% and 11.7%, respectively; relative risk, 0.97; 95% confidence interval [CI], 0.77 to 1.23). However, in a prespecified secondary analysis, moderate or severe cerebral palsy occurred significantly less frequently in the magnesium sulfate group (1.9% vs. 3.5%; relative risk, 0.55; 95% CI, 0.32 to 0.95). The risk of death did not differ significantly between the groups (9.5% vs. 8.5%; relative risk, 1.12; 95% CI, 0.85 to 1.47). No woman had a life-threatening event.” (D. J. Rouse, drouse@uab.edu)
Editorialists address the question of whether magnesium sulfate can be recommended for prevention of cerebral palsy among preterm infants (pp. 962-4): “Although promising, we would advise caution because of the differences between the populations that were eligible for entry into the individual studies and the different protocols used. Better understanding is needed of factors that might influence the likelihood that offspring will benefit from maternal magnesium sulfate treatment, such as the reason for imminent preterm birth, the dose of magnesium sulfate, and the timing of administration relative to birth and gestational age.” (F. J. Stanley, University of Western Australia, Perth, Australia)
Bortezomib for Multiple Myeloma: In a study of 682 patients, bortezomib plus melphalan–prednisone was superior to melphalan–prednisone alone in patients with newly diagnosed myeloma who were ineligible for high-dose therapy (pp. 906-17). Following nine 6-week cycles of the drugs, the investigators found these outcomes: “The time to progression among patients receiving bortezomib plus melphalan–prednisone (bortezomib group) was 24.0 months, as compared with 16.6 months among those receiving melphalan–prednisone alone (control group) (hazard ratio for the bortezomib group, 0.48; P < 0.001). The proportions of patients with a partial response or better were 71% in the bortezomib group and 35% in the control group; complete-response rates were 30% and 4%, respectively (P < 0.001). The median duration of the response was 19.9 months in the bortezomib group and 13.1 months in the control group. The hazard ratio for overall survival was 0.61 for the bortezomib group (P = 0.008). Adverse events were consistent with established profiles of toxic events associated with bortezomib and melphalan–prednisone. Grade 3 events occurred in a higher proportion of patients in the bortezomib group than in the control group (53% vs. 44%, P = 0.02), but there were no significant differences in grade 4 events (28% and 27%, respectively) or treatment-related deaths (1% and 2%).” (J. F. San Miguel, Hospital Universitario de Salamanca, Salamanca, Spain; sanmigiz@usal.es)
An editorialist provides this perspective (pp. 964-6): “The important new results associated with bortezomib combination therapy very much encourage a broad exploration of the drug in the initial therapy of patients with myeloma regardless of their transplantation status. A particularly exciting combination is bortezomib plus lenalidomide and low-dose dexamethasone, which is currently being compared with lenalidomide and low-dose dexamethasone alone in a Southwest Oncology Group trial (S0777)…. For the foreseeable future, we are fortunate to have so many options both in the clinic and in development. Our challenge will be to assess each patient on an individual basis and to identify and customize therapy for maximum long-term benefit.” (B. G. M. Durie, Cedars–Sinai Outpatient Cancer Center, Los Angeles)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
Aug. 29, 2008 * Vol. 15, No. 169
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Sept. issue of Diabetes Care (http://care.diabetesjournals.org/current.shtml; 2008; 31).
Telephonic Care in Diabetes: Among 2,598 patients with diabetes enrolled for at least 2 years in Florida: A Healthy State (FAHS), those who received telephonic care management more frequently began treatment and had better adherence to oral hypoglycemic drugs and recommended tests than did those receiving usual care (pp. 1717-22). Adherence to insulin also significantly improved among those using insulin at baseline, the researchers report, adding these details about their analysis of this Medicaid disease management program: “Changes in utilization were evaluated separately for those who were characterized as adherent to treatment at baseline (‘users&rsquoWinking and those who were not (‘nonusers&rsquoWinking. Both groups achieved significant improvement in adherence between baseline and follow-up. Nonusers increased their overall hypoglycemic use by 0.7 script (P < 0.001), by 0.7 script for ACEIs and statins (both P < 0.001), by 0.8 test for A1C (P < 0.001), and by 0.7 test for lipids (P < 0.001). Users increased hypoglycemic use by 1.5 scripts (P < 0.001) and insulin use by 0.9 script (P < 0.001).” (P. Thiebaud, Pfizer, New York; ptrck_thbd@yahoo.com)
Adherence in Adolescents with Type 1 Diabetes: Multisystemic therapy (MST), in the form of an intensive home-based psychotherapy, significantly decreased the occurrence of diabetic ketoacidosis among 127 adolescents with poorly controlled type 1 diabetes (pp. 1746-7). Compared with standard medical care for those assigned to the control group, the MST intervention produced these results: “Youth who received MST had significantly fewer hospital admissions than control subjects (chi square = 11.77, 4 d.f., n = 127; P = 0.019). MST-treated youth had significantly fewer admissions versus their baseline rate at 6-month (P = 0.004), 12-month (P = 0.021), 18-month (P = 0.046), and 24-month follow-up (P = 0.034). Cost to provide MST was 6,934 USD per youth; however, substantial cost offsets occurred from reductions in DKA admissions.” (D. Ellis, dellis@med.wayne.edu)
Prescribing & Early Mortality in Type 2 Diabetes: Early mortality in men and women with type 2 diabetes has declined recently, and investigators report that better prescribing of agents to control lipids, blood glucose, and blood pressure may be responsible for the improved outcomes (pp. 1761-6). In a cohort study of 197 general practices in the U.K. General Practice Research Database, 48,579 participants were identified with type 2 diabetes first diagnosed between 1996 and 2006. Looking at all-cause mortality and prescription of hypoglycemic, lipid-lowering, and antihypertensive drugs, the researchers determined: “From 1996 to 2006, incidence of type 2 diabetes increased and the mean age at diagnosis declined in women. Prescription of statins within 12 months of diagnosis increased (1996, women 4.9%, men 5.1%; 2005, women 63.5%, men 71.0%), as did drugs acting on the renin-angiotensin system (1996, women 19.4%, men 21.5%; 2005, women 45.5%, men 54.6%) and metformin (1996, women 19.1%, men 15.8%; 2005, women 45.5%, men 42.8%), whereas prescription of sulfonylureas declined. All-cause mortality in the first 24 months after diabetes diagnosis declined in men from 47.9 per 1,000 person–years for subjects with diabetes diagnosed in 1996 to 25.2 for subjects with diabetes diagnosed in 2006 and in women from 37.4 in 1996 to 27.6 in 2006. In a multiple regression model adjusting for age and comorbidity, prescription of statins before or after diagnosis, renin-angiotensin system drugs before or after diagnosis, and metformin after diagnosis were associated with lower mortality.” (M. Gulliford, King’s College, London; martin.gulliford@kcl.ac.uk)

>>>PNN NewsWatch
* Medication Safety Technologies: What Is and Is Not Working is a Cardinal-sponsored teleconference that features two prominent experts in the field of medication errors: David W. Bates, MD, MSc, of Brigham and Women’s Hospital, Boston, and Robert M. Wachter, MD, of UCSF. Tim Vanderveen, PharmD, MS, of Cardinal Health, will also participate in the Sept. 26 event, which begins at 12 noon EDT. To register, access www.att-rsvp.com and enter access code 958179.
*
PNN will not be published on Mon., Sept. 1, Labor 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 © 2008, 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
Sept. 2, 2008 * Vol. 15, No. 170
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from BMJ (www.bmj.org; 2008; 337).
Low-Dose Aspirin & Cognitive Function: Among middle-aged to elderly men and women at moderately increased cardiovascular risk, low doses of aspirin had no significant effect on cognitive function in a 5-year trial (a1198). Compared with placebo, aspirin 100 mg daily produced these outcomes in 3,350 participants in Aspirin for Asymptomatic Atherosclerosis (AAA) trial: “At baseline, mean vocabulary scores (an indicator of previous cognitive ability) were similar in the aspirin (30.9, SD 4.7) and placebo (31.1, SD 4.7) groups. In the primary intention to treat analysis, there was no significant difference at follow-up between the groups in the proportion achieving over the median general factor cognitive score (32.7% and 34.8% respectively, odds ratio 0.91, 95% confidence interval 0.79 to 1.05, P = 0.20) or in mean scores on the individual cognitive tests. There were also no significant differences in change in cognitive ability over the five years in a subset of 504 who underwent detailed cognitive testing at baseline.” (J. F. Price, U. Edinburgh, Edinburgh; Jackie.Price@ed.ac.uk)
Influence of U.S. Drug Advertising on Canadian Prescribing: Direct-to-consumer advertising in the U.S. increased prescribing of tegaserod by Canadian prescribers, a controlled longitudinal study concludes (a1055). Data from 2,700 Canadian pharmacies and Medicaid programs in 50 states showed these prescribing patterns for etanercept, mometasone, and tegaserod: “Spending on direct to consumer advertising for study drugs ranged from $194m to $314m (£104m–£169m; 131m–212m euros) over the study period. Prescription rates for etanercept and mometasone did not increase in English speaking provinces relative to French speaking controls after the start of direct to consumer advertising. In contrast, tegaserod prescriptions increased 42% (0.56 prescriptions/10,000 residents, 95% confidence interval 0.37 to 0.76) in English speaking provinces immediately after the start of US direct to consumer advertising. Uncontrolled analysis of US Medicaid data showed a larger 56% increase in tegaserod prescriptions. However, this increase did not persist over time in either country, despite continued advertising.” (M. R. Law, mlaw@post.harvard.edu)

>>>Lancet Highlights
Source:
Aug. 30 issue of Lancet (www.thelancet.com; 2008; 372).
Small-Molecule Treatment of Cystic Fibrosis: Oral administration of a small molecule, PTC124, that suppresses nonsense mutations in some patients with cystic fibrosis can reduce epithelial electrophysiological abnormalities caused by cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction, researchers report (pp. 719-27). A nonsense mutation that causes premature termination during mRNA translation is present in 10% of patients with CF worldwide and about 50% of patients in Israel, the investigators explain. In a Phase II trial of PTC124, these changes in transepithelial nasal potential difference (PD) were noted during two 28-day cycles that tested 16 and 40 mg/kg/day dosages: “Transepithelial nasal PD was evaluated in 23 patients in the first cycle and in 21 patients in the second cycle. Mean total chloride transport increased in the first treatment phase, with a change of −7.1 (SD 7.0) mV (p < 0.0001), and in the second, with a change of −3.7 (SD 7.3) mV (p = 0.032). We recorded a response in total chloride transport (defined as a change in nasal PD of −5 mV or more) in 16 of the 23 patients in the first cycle’s treatment phase (p < 0.0001) and in eight of the 21 patients in the second cycle (p < 0.0001). Total chloride transport entered the normal range for 13 of 23 patients in the first cycle’s treatment phase (p = 0.0003) and for nine of 21 in the second cycle (p = 0.02). Two patients given PTC124 had constipation without intestinal obstruction, and four had mild dysuria. No drug-related serious adverse events were recorded.” (E. Kerem, Hadassah Hebrew U. Hosp., Jerusalem; ek@cc.huji.ac.il)

>>>PNN JournalWatch
* The Controversial Role of Tumor Necrosis Factor in Fibrotic Diseases, in Arthritis & Rheumatism, 2008; 58: 2228–35. Reprints: O. Distler, U. Hosp., Zurich, Switzerland; Oliver.Distler@usz.ch
* Medication Errors in Pediatric Inpatients: Prevalence and Results of a Prevention Program, in
Pediatrics, 2008; 122: e737–43. Reprints: P. Otero.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
Sept. 3, 2008 * Vol. 15, No. 171
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Early-release articles from the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2008; 359).
Simvastatin/Ezetimibe in Aortic Stenosis: In one of two research reports released yesterday in advance of publication, the combination of simvastatin and ezetimibe failed to reduce the incidence of events related to aortic stenosis among 1,873 patients with mild to moderate asymptomatic changes in this valve (doi: 10.1056/NEJMoa0804602). Assessing a primary composite outcome of major cardiovascular events, including death from cardiovascular causes, aortic-valve replacement, nonfatal myocardial infarction, hospitalization for unstable angina pectoris, heart failure, coronary-artery bypass grafting, percutaneous coronary intervention, and nonhemorrhagic stroke, Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) investigators determined: “During a median follow-up of 52.2 months, the primary outcome occurred in 333 patients (35.3%) in the simvastatin–ezetimibe group and in 355 patients (38.2%) in the placebo group (hazard ratio in the simvastatin–ezetimibe group, 0.96; 95% confidence interval [CI], 0.83 to 1.12; P = 0.59). Aortic-valve replacement was performed in 267 patients (28.3%) in the simvastatin–ezetimibe group and in 278 patients (29.9%) in the placebo group (hazard ratio, 1.00; 95% CI, 0.84 to 1.18; P = 0.97). Fewer patients had ischemic cardiovascular events in the simvastatin–ezetimibe group (148 patients) than in the placebo group (187 patients) (hazard ratio, 0.78; 95% CI, 0.63 to 0.97; P = 0.02), mainly because of the smaller number of patients who underwent coronary-artery bypass grafting. Cancer occurred more frequently in the simvastatin–ezetimibe group (105 vs. 70, P = 0.01).” (A. B. Rossebø, Aker U. Hosp., Oslo, Norway; anne@rossebo.net)
Ezetimibe & Cancer: No evidence of significantly increased rates of cancer were found among those receiving ezetimibe in pooled data from three large trials: SEAS, Study of Heart and Renal Protection (SHARP), and Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) (doi: 10.1056/NEJMsa0806603). However, cancer mortality was higher with drug use and approached statistical significance, a finding that will likely lead to further scrutiny of this drug and its effects on absorption in the gastrointestinal tract: “In the SEAS trial, assignment to ezetimibe was associated with an increase in any new onset of cancer (101 patients in the active-treatment group vs. 65 in the control group) from several cancer sites. In SHARP and IMPROVE-IT combined, there was no overall excess of cancer (313 active-treatment vs. 326 control; risk ratio, 0.96; 95% confidence interval, 0.82 to 1.12; P = 0.61) and no significant excess at any particular site. Among patients assigned to ezetimibe, there were more, albeit not significantly more, deaths from cancer (97, vs. 72 in the control group; P = 0.07), but there were also fewer, although not significantly fewer, other cases of cancer (216, vs. 254 in the control group; P = 0.08). There was no evidence of a trend in the risk ratio for incidence of or death from cancer with increasing duration of follow-up.” (Clinical Trial Service Unit & Epidemiological Studies Unit, U. Oxford, Oxford, U.K.; secretary@ctsu.ox.ac.uk)

>>>Internal Medicine Report
Source:
Sept. 3 issue of the Annals of Internal Medicine (www.annals.org/current.shtml; 2008; 149).
Opportunistic Disease and Death with HAART: Reinstating continuous highly active antiretroviral therapy after a period of episodic therapy reduced but did not eliminate an increased risk of opportunistic infections and death associated with prior episodic use of the drugs, researchers report (pp. 289-99). Based on data covering 18 months of continuous therapy, the investigators found: “Participants who reinitiated continuous therapy experienced rapid suppression of HIV RNA levels (89.7% with HIV RNA levels 400 copies/mL after 6 months), but CD4+ cell counts after 6 months remained 0.140 x 109 cells/L below baseline. The hazard ratio (episodic versus continuous treatment) for opportunistic disease or death decreased after the recommendation to reinitiate continuous therapy (from 2.5 [CI, 1.8 to 3.5] to 1.4 [CI, 1.0 to 2.0]; P = 0.033 for difference). The residual excess risk was attributable to failure to reinitiate therapy by some participants and slow recovery of CD4+ cell counts for those who reinitiated therapy.” (J. D. Neaton, jim@ccbr.umn.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 © 2008, 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
Sept. 4, 2008 * Vol. 15, No. 172
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Sept. 4 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2008; 359).
Defibrillator Therapy in Heart Failure: Implantable cardioverter–defibrillator therapy provided a quality of life similar to that with amiodarone therapy in a group of 2,521 patients with heart failure (pp. 999-1008). Based on assessments using the Duke Activity Status Index and the Medical Outcomes Study 36-Item Short-Form Mental Health Inventory 5, the investigators found these results during a 30-month trial: “Psychological well-being in the ICD group, as compared with medical therapy alone, was significantly improved at 3 months (P = 0.01) and at 12 months (P = 0.003) but not at 30 months. No clinically or statistically significant differences in physical functioning among the study groups were observed. Additional quality-of-life measures were improved in the ICD group at 3 months, 12 months, or both, but there was no significant difference at 30 months. ICD shocks in the month preceding a scheduled assessment were associated with a decreased quality of life in multiple domains. The use of amiodarone had no significant effects on the primary quality-of-life outcomes.” (D. B. Mark, Duke U. Med. Ctr., Durham, NC)
Commenting on this and another defibrillator study in this issue (pp. 1009-17; J. E. Poole,
jpoole@u.washington.edu), editorialists write (pp. 1058-9): “These two reports show that modern ICD therapy is prolonging survival in patients with heart failure, with relatively little compromise in the quality of life. It is somewhat disturbing to realize that actually receiving a shock is such an important predictor of death (commonly in association with progressive heart failure). However, it should not be surprising that many patients in whom sudden death from arrhythmia is averted by an ICD ultimately die from heart failure. In severe chronic conditions, most worthwhile interventions only modestly delay death. If a specific therapy is effective against only one cause of death and does not address the underlying disease process, then death from competing causes is inevitable. Several randomized trials of ICD therapy have shown that a reduction in deaths from arrhythmia is offset either partially or completely by an increase in deaths from other causes. Nevertheless, [the Sudden Cardiac Death in Heart Failure Trial] has shown us that a prophylactic ICD does buy some time and that this time is worthwhile to patients.” (J. Healey, McMaster U., Hamilton, ON, Canada)
Data-Poor Drug Warnings: The FDA Amendments Act may help the situation somewhat, but the author of a Perspective article bemoans the lack of data that supports many of the drug warnings being issued by FDA (pp. 991-4): “[A] solution will require collecting more complete data about benefits and harms in preapproval trials, confirming risk signals through rigorous postmarketing assessments, and rapidly transforming such data into balanced, comprehensible recommendations communicated effectively to prescribers and patients.” (J. Avorn, Harvard Med. Sch., Boston)

>>>JAMA Highlights
Source:
Sept. 3 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2008; 300).
Hydration in Contrast Medium Nephropathy: Sodium bicarbonate, suggested for hydration in patients with contrast medium–induced nephropathy, performed no better than sodium chloride in a 353-patient trial (pp. 1038-46). Tested in a randomized, controlled, single-blind study in 2006–07, the two agents were infused at 3 mL/kg for 1 hour before coronary angiography and at 1.5 mL/kg/h during and for 4 hours after the procedure, with these results: “Median patient age was 71 (interquartile range, 65–76) years, and 45% had diabetes mellitus. The groups were well matched for baseline characteristics. The primary end point was met in 13.3% of the sodium bicarbonate group and 14.6% of the sodium chloride group (relative risk, 0.94; 95% confidence interval, 0.55–1.60; P = .82). In patients randomized to receive sodium bicarbonate vs sodium chloride, the rates of death, dialysis, myocardial infarction, and cerebrovascular events did not differ significantly at 30 days (1.7% vs 1.7%, 0.6% vs 1.1%, 0.6% vs 0%, and 0% vs 2.2%, respectively) or at 30 days to 6 months (0.6% vs 2.3%, 0.6% vs 1.1%, 0.6% vs 2.3%, and 0.6% vs 1.7%, respectively) (P > .10 for all).” (S. S. Brar, Columbia U., New York; sbrar@cvri.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 © 2008, 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
Sept. 5, 2008 * Vol. 15, No. 173
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Sept. issue of Pharmacotherapy (www.pharmacotherapy.org; 2008; 28).
Need for Genetic Testing with Warfarin: Routine use of pharmacogenetic testing before warfarin therapy is begun is not supported by available evidence, conclude authors of a review article (pp. 1084-97). Looking at the effects of the cytochrome P450 2C9 gene, CYP2C9, and the vitamin K epoxide reductase complex 1 gene, VKORC1, on warfarin response, the authors report: “The influence of CYP2C9 and VKORC1 genotypes on warfarin dose requirements has been consistently demonstrated in diverse racial and ethnic patient groups in observational studies and randomized clinical trials. Dosing algorithms have been developed that incorporate clinical, demographic, and genetic information to help select a warfarin starting dose. Furthermore, CYP2C9 variant genotypes have been associated with a significantly increased risk of serious bleeding events. However, evidence to date from prospective, controlled studies has not demonstrated an added benefit of incorporating genotype-guided therapy in improving anticoagulation control or in preventing or reducing the risk of hemorrhagic or thromboembolic complications. Research efforts designed to evaluate the effectiveness of genotype-guided therapy in improving outcomes are under way. However, the routine use of CYP2C9 and VKORC1 genotyping in the general patient population who begin warfarin therapy is not supported by evidence currently available.” (N. A. Limdi, nlimdi@uab.edu)
An editorialist agrees with the authors’ bottom line (pp. 1081-3): “Clearly, genetics plays an important role in defining the interpatient variability in dose requirement to achieve a therapeutic INR. However, it is less clear that prospective use of genetic information will lead to clinical improvements in terms of risk of thromboembolism or bleeding, time outside the therapeutic range, time required to achieve dose stability, or other parameters that might be viewed as clinically relevant.” (J. A. Johnson,
johnson@cop.ufl.edu)
Defining Major Bleeding Events with Warfarin: A standardized definition for major bleeding is needed to assure more comparability among clinical studies of warfarin, according to a retrospective cohort study of 120 patients on long-term warfarin therapy who experienced a nonminor bleeding event in 2001–06 (pp. 1098-103). Comparing a subjective definition of major bleeding (criteria A) with two objective definitions, the International Society on Thrombosis and Haemostasis ([ISTH] criteria B) and the Italian Study of Complications of Anticoagulant Therapy ([ISCOAT] criteria C), the authors find that the ISTH criteria might be best in clinical practice: “One hundred thirty-eight bleeding events in the 120 patients met at least one of the definitions of major bleeding and thus were included in the analysis. Level of agreement among the definitions was determined by the kappa statistic. The level of agreement between criteria B and C was excellent; no discrepancies were found; however, the level of agreement between criteria A and criteria B or C was poor, with a kappa statistic value of –0.134 (95% confidence interval –0.196 to –0.071). Use of criteria A resulted in underreporting of 31 major bleeding events by excluding events that were managed on an outpatient basis.” (A. K. Wittkowsky, akwitt@u.washington.edu)

>>>PNN NewsWatch
* The product labeling for tumor necrosis factor alpha blockers must be strengthened to warn of the risk of developing opportunistic fungal infections, including invasive conditions that can be fatal, FDA ruled yesterday. FDA has reviewed 240 reports of histoplasmosis, an infection caused by Histoplasma capsulatum, in patients being treated with etanercept (Enbrel, Wyeth/Amgen), adalimumab (Humira, Abbott), or infliximab (Remicade, Centocor). The majority of the reports involved people in the Ohio River and Mississippi River valleys (the fungus is commonly found in those areas). In at least 21 of the reports, histoplasmosis was initially not recognized by health care professionals, and antifungal treatment was delayed. Twelve of those patients died. The labeling for certolizumab (Cimzia, USB) is also subject to the FDA action, which was enabled by the 2007 amendments to the agency’s statutory authority.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
Sept. 8, 2008 * Vol. 15, No. 174
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Sept. 6 issue of Lancet (www.thelancet.com; 2008; 372).
Ivabradine in Coronary Disease: While not advantageous for improving cardiac outcomes in all patients with stable coronary artery disease and left-ventricular systolic dysfunction, ivabradine did lower the incidence of coronary artery disease outcomes in a subgroup of patients with heart rates of 70 bpm or greater, a study shows (pp. 807-16). One of two papers in this issue from the BEAUTIFUL (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left-ventricULar dysfunction) trial, this report provides these results on 5,479 patients who received ivabradine 5 mg, with the intention of increasing to the target dose of 7.5 mg twice a day, and 5,438 on matched placebo in addition to appropriate cardiovascular medication: “Mean heart rate at baseline was 71.6 (SD 9.9) beats per minute (bpm). Median follow-up was 19 months (IQR 16–24). Ivabradine reduced heart rate by 6 bpm (SE 0.2) at 12 months, corrected for placebo. Most (87%) patients were receiving beta blockers in addition to study drugs, and no safety concerns were identified. Ivabradine did not affect the primary composite endpoint (hazard ratio 1.00, 95% CI 0.91–1.1, p = 0.94). 1,233 (22.5%) patients in the ivabradine group had serious adverse events, compared with 1,239 (22.8%) controls (p = 0.70). In a prespecified subgroup of patients with heart rate of 70 bpm or greater, ivabradine treatment did not affect the primary composite outcome (hazard ratio 0.91, 95% CI 0.81–1.04, p = 0.17), cardiovascular death, or admission to hospital for new-onset or worsening heart failure. However, it did reduce secondary endpoints: admission to hospital for fatal and non-fatal myocardial infarction (0.64, 95% CI 0.49–0.84, p = 0.001) and coronary revascularisation (0.70, 95% CI 0.52–0.93, p = 0.016).” (K. Fox, Royal Brompton Hosp., London; k.fox@rbht.nhs.uk)

>>>BMJ Highlights
Source:
Early-release article from BMJ (www.bmj.org; 2008; 337).
Ibuprofen and Acetaminophen for Pediatric Fever: Ibuprofen should be used alone in initial treatment of febrile children, a research study concludes, and despite possible clinical advantages, acetaminophen (referred to in the article by its British name, paracetamol) should be considered for supplemental therapy only after its benefits and risks are considered (a1302). Investigators randomly assigned children aged 6 months to 6 years with fever to paracetamol plus ibuprofen, paracetamol alone, or ibuprofen alone, with these results: “On an intention to treat basis, paracetamol plus ibuprofen were superior to paracetamol for less time with fever in the first four hours (adjusted difference 55 minutes, 95% confidence interval 33 to 77; P < 0.001) and may have been as good as ibuprofen (16 minutes, –7 to 39; P = 0.2). For less time with fever over 24 hours, paracetamol plus ibuprofen were superior to paracetamol (4.4 hours, 2.4 to 6.3; P < 0.001) and to ibuprofen (2.5 hours, 0.6 to 4.4; P = 0.008). Combined therapy cleared fever 23 minutes (2 to 45; P = 0.025) faster than paracetamol alone but no faster than ibuprofen alone (–3 minutes, 18 to –24; P = 0.8). No benefit was found for discomfort or other symptoms, although power was low for these outcomes. Adverse effects did not differ between groups.” (A. D. Hay, alastair.hay@bristol.ac.uk)

>>>PNN NewsWatch
* FDA has posted the first of its new quarterly reports of medications with potential safety issues. Listed are 20 drugs or drug products with safety issues that arose in January through March of this year. FDA emphasized that this report contains potential problems and that patients should not stop taking medications unless they have been advised by the prescriber to do so.

>>>PNN JournalWatch
* Contrast Medium–Induced Nephropathy: Strategies for Prevention, in Pharmacotherapy, 2008; 28: 1140–50. Reprints: A. Massicotte, Ottawa Hosp., Ottawa, ON, Canada.
* A Sea Change in the Treatment of Alcoholism [editorial], in
American Journal of Psychiatry, 2008; 165: 1093–5. Reprints: J. Westermeyer, weste010@umn.edu
* Mentalization: Ontogeny, Assessment, and Application in the Treatment of Borderline Personality Disorder, in
American Journal of Psychiatry, 2008; 165: 1127–35. Reprints: L. W. Choi-Kain.
* Advances in Neutrophil Biology: Clinical Implications, in
Chest, 2008; 134: 606–12. Reprints: E. R. Chilvers, erc24@cam.ac.uk

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
Sept. 9, 2008 * Vol. 15, No. 175
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Sept. 8 issue of the Archives of Internal Medicine (http://archinte.ama-assn.org/current.dtl3; 2008; 168).
Hormonal Therapy & GERD: Women taking prescription or nonprescription postmenopausal hormone (PMH) therapy are more likely to have symptoms of gastroesophageal reflux disease, concludes a prospective cohort study of 51,637 postmenopausal women (pp. 1798-804). Data from the Nurses’ Health Study show the following trends based on GERD symptoms in 2002 and product use since 1976: “Among eligible participants, 12,018 women (23%) reported GERD symptoms. Compared with women who never used PMHs, the multivariate odds ratio (OR) for the risk of GERD symptoms was 1.46 (95% confidence interval [CI], 1.36–1.56) for past hormone users, 1.66 (95% CI, 1.54–1.79) for current users of estrogen only, and 1.41 (95% CI, 1.29–1.54) for current users of combined estrogen and progesterone. The risk of GERD symptoms increased significantly with increasing estrogen dosage (P < .001) and increasing duration of estrogen use (P < .001). Moreover, current selective estrogen receptor modulator users experienced an OR of 1.39 (95% CI, 1.22–1.59) for GERD symptoms, and women currently using OTC hormone preparations had an OR of 1.37 (95% CI, 1.16–1.62).” (B. C. Jacobson, brian.jacobson@bmc.org)
Dalteparin Use in Renal Insufficiency: Prophylaxis against deep-vein thrombosis in critically ill patients with severe renal insufficiency may be feasible using the low molecular weight heparin dalteparin, researchers report (pp. 1805-12). In a multicenter, single-arm clinical trial of DVT prophylaxis with dalteparin sodium 5000 IU once daily, bioaccumulation and pharmacodynamic tests showed the following: “We enrolled 156 patients with a mean (SD) creatinine clearance of 18.9 (6.5) mL/min; 18 were excluded because they died or were discharged before testing (n = 3) or had prevalent DVT (n = 15). Of 138 patients included, the median (interquartile range [IQR]) duration of dalteparin exposure was 7 (4–12) days. In 120 patients who had at least 1 trough anti-Xa level (427 total measurements), no patient had bioaccumulation (0%; 95% confidence interval [CI]: 0%–3.0%); the median (IQR) trough anti-Xa level was undetectable (<0.10 IU/mL [<0.10 to <0.10 IU/mL]). Based on serial measurements, peak anti-Xa levels were 0.29 to 0.34 IU/mL and trough levels were lower than 0.06 IU/mL. Deep vein thrombosis occurred in 7 of 138 patients (5.1%; 95% CI, 2.5%–10.1%); major bleeding occurred in 10 patients (7.2%; 95% CI, 4.0%–12.8%), all with trough anti-Xa levels of 0.18 IU/mL or lower.” (J. Douketis, jdouket@mcmaster.ca)
CAD Guideline Adherence: American Heart Assoc. guidelines for management of patients with coronary artery disease were more closely followed during a Get With the Guidelines (GWTG) campaign, with results going beyond improvements associated with public reporting of hospital performance (pp. 1813-9). Comparing 223 GWTG_CAD hospitals with 3,407 nonparticipating institutions, the investigators found: “Adherence to the overall Hospital Compare composite measure was higher in GWTG-CAD hospitals than in non–GWTG-CAD hospitals (mean [SD], 89.7% [10.0%] vs 85.0 [15.0%]; absolute increase, 4.7%; P < .001). Adherence to the GWTG-CAD performance measures (PM) composite was also higher (89.5% [11.0%] vs 83.0% [18.0%]; P < .001). In multivariate analysis, GWTG-CAD participation was associated with a modest absolute increase in adherence to the PM composite by 2.52% (95% confidence interval [CI], 0.19%–4.85%). Larger acute myocardial infarction volume by quartile (absolute increase, 14.2%; 95% CI, 12.2%–16.3%), geographic location in the Northeast, and teaching hospital status (absolute increase, 2.87%; 95% CI, 0.43–5.32) were also associated with improved adherence to the PM composite. As a control, evaluation of unrelated quality measures for pneumonia, showed lower adherence among GWTG-CAD participating hospitals (74.8% [7.3%] vs 76.1% [9.7%]; P = .005).” (W. R. Lewis, wlewis@metrohealth.org)
Cold-Pressor Test for Hypertension: The cold-pressor test, historically used to detect a propensity for hypertension among normotensive individuals, may also be useful in identifying candidates for dietary interventions for hypertension, a study shows. (pp. 1740-6; J. Chen, jchen@tulane.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
Sept. 10, 2008 * Vol. 15, No. 176
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Sept. 10 issue of JAMA, a theme issue on medical education (http://jama.ama-assn.org/current.dtl; 2008; 300).
Need for Medical-Student Diversity: Medical students graduating from schools with greater racial and ethnic diversity in their student bodies felt they were better prepared to meet the needs of a diverse patient population, compared with those from homogeneous programs (pp. 1135-45). Results of a Web-based survey of 20,112 graduating medical students at 118 U.S. medical schools showed: “White students within the highest quintile for student body racial and ethnic diversity, measured by the proportion of underrepresented minority (URM) students, were more likely to rate themselves as highly prepared to care for minority populations than those in the lowest diversity quintile (61.1% vs 53.9%, respectively; P < .001; adjusted odds ratio [OR], 1.33; 95% confidence interval [CI], 1.13–1.57). This association was strongest in schools in which students perceived a positive climate for interracial interaction. White students in the highest URM quintile were also more likely to have strong attitudes endorsing equitable access to care (54.8% vs 44.2%, respectively; P < .001; adjusted OR, 1.42; 95% CI, 1.15–1.74). For nonwhite students, after adjustment there were no significant associations between student body URM proportions and diversity-related outcomes. Student body URM proportions were not associated with white or nonwhite students’ plans to practice in underserved communities, although URM students were substantially more likely than white or nonwhite/non-URM students to plan to serve the underserved (48.7% vs 18.8% vs 16.2%, respectively; P < .001).” (S. Saha, sahas@ohsu.edu)
MD/PhD Workforce: Future physician–scientists—with MD/PhD degrees—are a less demographically diverse population than general medical students, a research study shows (pp. 1165-73). They also end their formal education with lower debt burdens and prefer different medical specialties and greater involvement in research, data on 80,575 medical graduates show: “Of the 79,104 respondents with complete data (71.7% of all 2000–2006 graduates), 1,833 (2.3%) were MD/PhD program graduates. Variables associated with greater likelihood of MD/PhD program graduation included planned substantial career involvement in research (OR, 10.30; 95% confidence interval [CI], 8.89–11.93); lower educational debt (compared with $150,000: $100,000–$149,999, OR, 1.85; 95% CI, 1.35–2.52; $50,000–$99,999, OR, 5.50; 95% CI, 4.14–7.29; $1–$49 999, OR, 17.50; 95% CI, 13.30–23.03; no debt, OR, 17.41; 95% CI, 13.22–22.92); and receipt of medical school scholarships or grants (OR, 3.22; 95% CI, 2.82–3.69). Compared with planned training in internal medicine, MD/PhD graduation was positively associated with planned training in dermatology, neurology, ophthalmology, pathology, pediatrics, or radiology. Variables associated with lower likelihood of MD/PhD graduation included female sex (OR, 0.68; 95% CI, 0.60–0.77); race/ethnicity underrepresented in medicine (OR, 0.64; 95% CI, 0.52–0.80); and, compared with internal medicine, planned training in emergency medicine (OR, 0.58; 95% CI, 0.40–0.84) or surgery (OR, 0.70; 95% CI, 0.57–0.85).” (D. A. Andriole, andrioled@wustl.edu)
Internet-Based Learning: In the health professions, Internet-based learning opportunities are associated with large positive effects, compared with no interventions, a meta-analysis of 201 studies concludes (pp. 1181-96). But overall effects are heterogeneous and generally small, indicating that their effectiveness is likely similar to traditional educational methods: “Heterogeneity in results across studies was large (I2 79%) in all analyses. Effect sizes were pooled using a random effects model. The pooled effect size in comparison to no intervention favored Internet-based interventions and was 1.00 (95% confidence interval [CI], 0.90–1.10; P < .001; n = 126 studies) for knowledge outcomes, 0.85 (95% CI, 0.49–1.20; P < .001; n = 16) for skills, and 0.82 (95% CI, 0.63–1.02; P < .001; n = 32) for learner behaviors and patient effects. Compared with non–Internet formats, the pooled effect sizes (positive numbers favoring Internet) were 0.10 (95% CI, –0.12 to 0.32; P = .37; n = 43) for satisfaction, 0.12 (95% CI, 0.003 to 0.24; P = .045; n = 63) for knowledge, 0.09 (95% CI, –0.26 to 0.44; P = .61; n = 12) for skills, and 0.51 (95% CI, –0.24 to 1.25; P = .18; n = 6) for behaviors or patient effects.” (D. A. Cook, cook.david33@mayo.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
Sept. 11, 2008 * Vol. 15, No. 177
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Sept. 11 New England Journal of Medicine (http://content.nejm.org/current.shtml; 2008; 359).
Surgery for Knee Osteoarthritis: Compared with optimized physical and medical therapy for osteoarthritis of the knee, arthroscopic surgery provided no additional benefit, researchers report (pp. 1097-107). Assessing benefits with the total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at 2 years and the Short Form-36 (SF-36) Physical Component Summary, the investigators found: “Of the 92 patients assigned to surgery, 6 did not undergo surgery. Of the 86 patients assigned to control treatment, all received only physical and medical therapy. After 2 years, the mean (± SD) WOMAC score for the surgery group was 874 ± 624, as compared with 897 ± 583 for the control group (absolute difference [surgery-group score minus control-group score], –23 ± 605; 95% confidence interval [CI], –208 to 161; P = 0.22 after adjustment for baseline score and grade of severity). The SF-36 Physical Component Summary scores were 37.0 ± 11.4 and 37.2 ± 10.6, respectively (absolute difference, –0.2 ± 11.1; 95% CI, –3.6 to 3.2; P = 0.93). Analyses of WOMAC scores at interim visits and other secondary outcomes also failed to show superiority of surgery.” (R. B. Litchfield, rlitchf@uwo.ca)
Platinum Chemo/Cetuximab in Head and Neck Cancer: Cetuximab plus platinum–fluorouracil chemotherapy improved overall survival when given as first-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck, compared with platinum-based chemotherapy plus fluorouracil alone, a 442-patient study reports (pp. 1116-27). Using up to six every-3-week cycles, the researchers found these trends: “Adding cetuximab to platinum-based chemotherapy with fluorouracil (platinum–fluorouracil) significantly prolonged the median overall survival from 7.4 months in the chemotherapy-alone group to 10.1 months in the group that received chemotherapy plus cetuximab (hazard ratio for death, 0.80; 95% confidence interval, 0.64 to 0.99; P = 0.04). The addition of cetuximab prolonged the median progression-free survival time from 3.3 to 5.6 months (hazard ratio for progression, 0.54; P < 0.001) and increased the response rate from 20% to 36% (P < 0.001). The most common grade 3 or 4 adverse events in the chemotherapy-alone and cetuximab groups were anemia (19% and 13%, respectively), neutropenia (23% and 22%), and thrombocytopenia (11% in both groups). Sepsis occurred in 9 patients in the cetuximab group and in 1 patient in the chemotherapy-alone group (P = 0.02). Of 219 patients receiving cetuximab, 9% had grade 3 skin reactions and 3% had grade 3 or 4 infusion-related reactions. There were no cetuximab-related deaths.” (J. B. Vermorken, jan.b.vermorken@uza.be)
GnRH Agonists for Endometriosis: The case of a 36-year-old woman with long-standing pelvic pain, including dysmenorrhea and painful intercourse, highlights proper use of gonadotropin-releasing hormone agonists (pp. 1136-42): “Empirical treatment with a GnRH agonist is reasonable, provided that a careful evaluation has failed to show any other cause of her pain, including nongynecologic sources. The choice of GnRH agonist should be based on cost, availability, and the patient’s preference with respect to the delivery method. Norethindrone acetate should be administered concomitantly as add-back therapy at a dose of 2.5 mg daily, at first, with an increase in the dose if side effects of the GnRH agonist are still noted. If pain relief occurs, the therapy could be discontinued at 6 months, with continued treatment with oral contraceptives, a progestogen-based intrauterine device, or depot medroxyprogesterone to achieve a long-term decrease in menstrual volume and to minimize the risk of recurrent pain. If the patient is reluctant to undergo these long-term therapies, she could continue to receive a GnRH agonist with add-back therapy. However, with long-term treatment, the amount of norethindrone acetate would need to be increased to 5 mg daily to ensure minimal loss of bone mineral density. Should this add-back regimen prove to have unacceptable adverse effects, switching to low-dose estrogen–progestin combination therapy may result in greater acceptability and compliance. If no relief occurs with any of these medical approaches, surgical investigation of the pelvis and abdomen, by means of laparoscopy, could be considered.” (D. L. Olive, dlolive1@aol.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 © 2008, 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
Sept. 12, 2008 * Vol. 15, No. 178
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
Sept. 16 issue of the Journal of the American College of Cardiology (http://content.onlinejacc.org/; 2008; 52).
Omega-3 Fatty Acids & Cardiovascular Diseases: Increased consumption of dietary omega-3 polyunsaturated fatty acids (PUFA) can protect against heart failure, JACC (Japan Collaborative Cohort Study for Evaluation of Cancer Risk) concludes (pp. 988-96). A prospective study of 57,972 Japanese men and women, JACC analyzed the dietary intakes of fish and omega-3 PUFA by food frequency questionnaire and followed participants for 12.7 years, finding the following: “We observed generally inverse associations of fish and omega-3 PUFA intakes with risks of mortality from heart failure (multivariable hazard ratio [95% confidence interval] for highest versus lowest quintiles = 0.76 [0.53 to 1.09] for fish and 0.58 [0.36 to 0.93] for omega-3 PUFA). Associations with ischemic heart disease or myocardial infarction were relatively weak and not statistically significant after adjustment for potential risk factors. Neither fish nor omega-3 PUFA dietary intake was associated with mortality from total stroke, its subtypes, or cardiac arrest. For mortality from total cardiovascular disease, intakes of fish and omega-3 PUFA were associated with 18% to 19% lower risk.” (H. Iso, iso@pbhel.med.osaka-u.ac.jp)
Stratifying HF Using Categories of Natriuretic Peptide: Serial determinations of N-terminal pro-brain natriuretic peptide (NT-proBNP) concentrations and classification into few categories of changes based on threshold levels provided what researchers termed “a superior strategy for risk stratification of patients with chronic and stable” heart failure (pp. 997-1003). Analyzing data from Val-HeFT (Valsartan Heart Failure Trial), the investigators found these trends in 1,742 patients enrolled in the placebo arm of the trial: “A single determination of NT-proBNP (area under the curve at 4 months: 0.702, 95% confidence interval [CI]: 0.669 to 0.735) showed a higher prognostic discrimination than continuous changes of concentrations, expressed either as absolute (0.592, 95% CI: 0.549 to 0.634) or relative changes (0.602, 95% CI: 0.566 to 0.639). A Cox proportional hazards model showed that stratification of patients into 4 categories according to NT-proBNP levels at 2 time points 4 months apart with respect to a threshold concentration provided prognostic information in patients with chronic HF beyond that of a single determination.” (S. Masson, masson@marionegri.it)
Myocardial Benefits of Caloric Restriction: Among 12 obese, insulin-treated patients with type 2 diabetes, caloric restriction decreased levels of myocardial triglyceride stores and improved diastolic heart function (pp. 1006-12). Patients followed a very-low-calorie diet (VLCD; 450 kcal/day) for 16 weeks in an effort to reduce weight, a period during which insulin was stopped. Results showed: “The [body mass index] decreased from 35.6 ± 1.2 kg/m2 (baseline, mean ± SEM) to 27.5 ± 1.3 kg/m2 (after the VLCD, p < 0.001) and was associated with an improvement in hemoglobin A1c from 7.9 ± 0.4% (baseline) to 6.3 ± 0.3% (after the VLCD, p = 0.006). Myocardial TG content decreased from 0.88 ± 0.12% to 0.64 ± 0.14%, respectively (p = 0.019), and was associated with improved diastolic function (reflected by the ratio between the early and atrial filling phase) from 1.02 ± 0.08 to 1.18 ± 0.06, respectively (p = 0.019).” (S. Hammer, S.Hammer@LUMC.nl)
Industry Support of CE: The JACC editor-in-chief, calling for reason during a time of change, describes proposals to eliminate all industrial support of continuing medical education as “throwing the baby out with the bath water.” (A. N. DeMaria, ademaria@acc.org)

>>>PNN NewsWatch
* Product labeling for rituximab (Rituxan) now describes a case of progressive multifocal leukoencephalopathy (PML) leading to death in a patient with rheumatoid arthritis who received rituximab in a long-term safety extension clinical study, Genentech reports. The patient developed a JC virus infection with resultant PML and death 18 months after taking the last dose of rituximab. Health care professionals treating patients with rituximab should consider PML in any patient presenting with new onset neurologic manifestations. Additionally, consultation with a neurologist, brain imaging, and lumbar puncture should be considered as clinically indicated.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
Sept. 15, 2008 * Vol. 15, No. 179
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Sept. 13 issue of Lancet (www.thelancet.com; 2008; 372).
Cognitive–Behavioral Therapy for Perinatal Depression: Community-based health workers successfully delivered a cognitive–behavioral therapeutic intervention to 40 clusters of women in rural Pakistan who had perinatal depression during the third trimester of pregnancy (pp. 902-9). Compared with sham visits to those in the control groups, the intervention produced these outcomes: “The number of clusters per group was 20, with 463 mothers in the intervention group and 440 in the control group. At 6 months, 97 (23%) of 418 and 211 (53%) of 400 mothers in the intervention and control groups, respectively, met the criteria for major depression (adjusted odds ratio (OR) 0.22, 95% CI 0.14 to 0.36, p < 0.0001). These effects were sustained at 12 months (111/412 [27%] vs 226/386 [59%], adjusted OR 0.23, 95% CI 0.15 to 0.36, p < 0.0001). The differences in weight-for-age and height-for-age Z scores for infants in the two groups were not significant at 6 months (−0.83 vs −0.86, p=0.7 and −2.03 vs −2.16, p = 0.3, respectively) or 12 months (−0.64 vs −0.8, p = 0.3 and −1.10 vs −1.36, p = 0.07, respectively).” (A. Rahman, U. Liverpool, Liverpool, U.K.; Atif.Rahman@liverpool.ac.uk)

>>>BMJ Highlights
Source:
Early-release articles from BMJ (www.bmj.org; 2008; 337).
Heath Benefits with Mediterranean Diet: Significant health benefits were associated with adherence to a Mediterranean diet in a meta-analysis of 12 studies of 1.6 million participants, including reductions in overall mortality (9%), mortality from cardiovascular diseases (9%), incidence of or mortality from cancer (6%), and incidence of Parkinson’s disease and Alzheimer’s disease (13%) (a1344). The investigators report: “The cumulative analysis among eight cohorts (514,816 subjects and 33,576 deaths) evaluating overall mortality in relation to adherence to a Mediterranean diet showed that a two point increase in the adherence score was significantly associated with a reduced risk of mortality (pooled relative risk 0.91, 95% confidence interval 0.89 to 0.94). Likewise, the analyses showed a beneficial role for greater adherence to a Mediterranean diet on cardiovascular mortality (pooled relative risk 0.91, 0.87 to 0.95), incidence of or mortality from cancer (0.94, 0.92 to 0.96), and incidence of Parkinson’s disease and Alzheimer’s disease (0.87, 0.80 to 0.96).” (F. Sofi, U. Florence, Florence, Italy; francescosofi@gmail.com)

>>>PNN NewsWatch
* FDA on Friday announced the approval of Human Papillomavirus Quadrivalent (Types 6, 11, 16, 18) Vaccine, Recombinant (Gardasil, Merck) for prevention of vaginal and vulvar cancer caused by HPV types 16 and 18 in girls and women ages 9 to 26. The agency noted that these two HPV types cause 70% of cervical cancers, and are known to also cause some vulvar and vaginal cancers, but the percentages are not well defined. FDA originally licensed Gardasil in 2006 for girls and women ages 9 to 26 for the prevention of cervical cancer caused by HPV types 16 and 18, precancerous genital lesions caused by HPV types 6, 11, 16, and 18 ,and genital warts caused by HPV types 6 and 11. The new indications were approved based on 2-year follow-up data for more than 15,000 participants from the original studies. Among females who tested negative for HPV types 16 or 18 at the start of the study, Gardasil was highly effective in preventing these types of HPV-related precancerous vulvar and vaginal lesions, which are considered to be the precursors for cancer. In the control group that did not receive the vaccine, 10 individuals developed precancerous vulvar lesions and nine developed precancerous vaginal lesions, all related to HPV types 16 or 18. No one in the Gardasil group developed either kind of precancerous lesion due to HPV types 16 or 18.

>>>PNN JournalWatch
* Hemoxygenase-1 in Cardiovascular Disease, in Journal of the American College of Cardiology, 2008; 52: 971–8. Reprints: G. Y. H. Lip, City Hosp., Birmingham, U.K.; g.y.h.lip@bham.ac.uk
* Hospital Staffing and Health Care–Associated Infections: A Systematic Review of the Literature, in
Clinical Infectious Diseases, 2008; 47: 937–44. Reprints: P. W. Stone, ps2024@columbia.edu

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
Sept. 16, 2008 * Vol. 15, No. 180
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release article from and Sept. 16 issue of the Annals of Internal Medicine (www.annals.org/current.shtml; 2008; 149).
Effectiveness and Safety of Premixed Insulin Analogues: Premixed insulin analogues—mixtures of rapid- and intermediate-acting insulin analogues— provide glycemic control similar to that of premixed human insulin with tighter better results than those provided by long-acting insulin analogues and noninsulin antidiabetic agents, according to a systematic review of available literature and unpublished data (early release). The authors write: “Evidence from clinical trials was inconclusive for clinical outcomes, such as mortality. Therefore, the review focused on intermediate outcomes. Premixed insulin analogues were similar to premixed human insulin in decreasing fasting glucose levels, hemoglobin A1c levels, and the incidence of hypoglycemia but were more effective in decreasing postprandial glucose levels (mean difference, –1.1 mmol/L; 95% CI, –1.4 to –0.7 mmol/L [–19.2 mg/dL; 95% CI, –25.9 to –12.5 mg/dL]). Compared with long-acting insulin analogues, premixed insulin analogues were superior in decreasing postprandial glucose levels (mean difference, –1.5 mmol/L; CI, –1.9 to –1.2 mmol/L [–27.9 mg/dL; CI, –34.3 to –21.5 mg/dL]) and hemoglobin A1c levels (mean difference, –0.39% [CI, –0.50% to –0.28%]) but were inferior in decreasing fasting glucose levels (mean difference, 0.7 mmol/L; CI, 0.3 to 1.0 mmol/L [12.0 mg/dL; CI, 6.0 to 18.1 mg/dL]) and were associated with a higher incidence of hypoglycemia. Compared with noninsulin antidiabetic agents, premixed insulin analogues were more effective in decreasing fasting glucose levels (mean difference, –1.1 mmol/L; CI, –1.7 to –0.6 mmol/L [–20.5 mg/dL; CI, –29.9 to –11.2 mg/dL]), postprandial glucose levels (mean difference, –2.1 mmol/L; CI, –3.4 to –0.8 mmol/L [–37.4 mg/dL; CI, –61.0 to –13.7 mg/dL]), and hemoglobin A1c levels (mean difference, –0.49% [CI, –0.86% to –0.12%]) but were associated with a higher incidence of hypoglycemia.” (R. Qayyum, rqayyum@jhmi.edu)
Ipratropium & Mortality in COPD: Risks of all-cause and cardiovascular were higher among 32,130 patients using ipratropium for chronic obstructive pulmonary disease in a nested case–control study that included 320,501 control participants (pp. 380-90). Among 11,897 patients with cause-of-death data, 2,405 case patients had respiratory deaths and 3,159 case patients had cardiovascular deaths, the researcher report, adding these findings from a conditional logistic regression analysis: “Adjusted odds ratios (ORs) for all-cause mortality were 0.80 (95% CI, 0.78 to 0.83) for inhaled corticosteroids, 1.11 (CI, 1.08 to 1.15) for ipratropium, 0.92 (CI, 0.88 to 0.96) for long-acting beta-agonists, and 1.05 (CI, 0.99 to 1.10) for theophylline. Ipratropium was associated with increased cardiovascular deaths (OR, 1.34 [CI, 1.22 to 1.47]), whereas inhaled corticosteroids were associated with reduced risk for cardiovascular death (OR, 0.80 [CI, 0.72 to 0.88]). Results were consistent across sensitivity analyses.” (T. A. Lee, todd.lee@va.gov)
PPIs & CAP: Countering the conclusions of studies reporting an increased risk of community-acquired pneumonia among patients taking proton-pump inhibitors, a nested case–control study concludes that this risk is present only for the first 30 days of treatment and even during this period the association may not be causal (pp. 391-8). Using 1987–2002 data from the U. K. General Practice Research Database, the investigators found these trends among 80,066 cases and nearly 800,000 controls: “Overall, current PPI use was not associated with an increased risk for CAP (adjusted OR, 1.02 [95% CI, 0.97 to 1.08]) or risk for CAP that required hospitalization (adjusted OR, 1.01 [CI, 0.91 to 1.12]). There was a strong increase in risk for CAP associated with current use of PPI therapy that was started within the previous 2 days (adjusted OR, 6.53 [CI, 3.95 to 10.80]), 7 days (adjusted OR, 3.79 [CI, 2.66 to 5.42]), and 14 days (adjusted OR, 3.21 [CI, 2.46 to 4.18]), but there was no statistically significant association for longer-term current PPI therapy. A separate matched case–control analysis, which included the 3 strongest confounders as additional matching factors, yielded similar results as the primary analysis (adjusted OR, 0.96 [CI, 0.91 to 1.02]).” (Y-X Yang, yangy@mail.med.upenn.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
Sept. 17, 2008 * Vol. 15, No. 181
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Sept. 17 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2008; 300).
Metabolic Disorders with Bisphenol A: Patients with high urinary levels of bisphenol A are more likely to have diagnoses of cardiovascular diseases or diabetes as well as elevated hepatic enzymes, according to an analysis of data from the National Health and Nutrition Examination Survey 2003–04 (pp. 1303-10). BPA, used extensively in epoxy resins in consumer products such as food and beverage containers, is one of the world’s most commonly produced chemicals, the authors note, adding these details from their regression analysis of metabolic problems and urinary BPA levels: “Higher urinary BPA concentrations were associated with cardiovascular diagnoses in age-, sex-, and fully adjusted models (OR per 1-SD increase in BPA concentration, 1.39; 95% confidence interval [CI], 1.18–1.63; P = .001 with full adjustment). Higher BPA concentrations were also associated with diabetes (OR per 1-SD increase in BPA concentration, 1.39; 95% confidence interval [CI], 1.21–1.60; P < .001) but not with other studied common diseases. In addition, higher BPA concentrations were associated with clinically abnormal concentrations of the liver enzymes gamma-glutamyltransferase (OR per 1-SD increase in BPA concentration, 1.29; 95% CI, 1.14–1.46; P < .001) and alkaline phosphatase (OR per 1-SD increase in BPA concentration, 1.48; 95% CI, 1.18–1.85; P = .002).” (D. Melzer, david.melzer@pms.ac.uk)
Sequential Therapy for H. pylori: Increased resistance is limiting the effectiveness of standard regimens for eradicating Helicobacter pylori, authors of a commentary explain, and the time has come to switch to the more effective sequential regimens that are now emerging (pp. 1346-7). “Sequential therapy … consists of 10 days of treatment with a PPI, plus amoxicillin for the first 5 days and a combination of clarithromycin and tinidazole for the second 5 days,” the writers note. “Sequential therapy is based on observations made when 2-drug therapies (PPI plus amoxicillin) were the standard of care for treating H pylori. The combination of PPI and amoxicillin led to many treatment failures and the eradication rate achieved with a therapeutic strategy of initially administering 14-day dual therapy (PPI plus amoxicillin) followed by 7-day triple therapy in individuals in whom the original therapy failed was significantly greater than the reverse sequence (7-day triple therapy as an initial strategy with 14-day dual therapy for failures). In a study involving 300 patients with H pylori infection who were randomized to sequential therapy or triple therapy, the eradication rate with the sequential regimen was statistically significantly greater than with the standard treatment regimen for the intention-to-treat analysis: 89% (95% CI, 83.6%–93.7%) vs 77% (95% CI, 70.6%–84.0%; P = .01). A series of randomized controlled trials from Italy have shown that eradication rates are high with this approach. A recent meta-analysis of 10 trials found an eradication rate of 93.4% (95% CI, 91.3%–95.5%) with sequential therapy compared with an eradication rate of 76.9% (95% CI, 71%–82.8%) with PPI triple therapy, despite publication bias.” (N. Vakil, nvakil@wisc.edu)

>>>PNN NewsWatch
* An FDA import alert issued yesterday warns of potential problems with the quality of more than 30 generic products manufactured by Ranbaxy Laboratories at its Indian plants located in Dewas and Paonta Sahib. The action follows an FDA inspection of the plants that uncovered “significant deviations” from Current Good Manufacturing Practices. Because Ranbaxy’s ganciclovir oral capsules are the sole source of this product in the U.S., FDA is not detaining shipments of that agent at U.S. borders, but other products on the list may be blocked from entry. FDA recommended that consumers continue to take products already dispensed; it made no specific recommendations to pharmacies that have the products in stock.
* FDA last week approved an orphan immune globulin product,
Gamunex, for treatment of chronic inflammatory demyelinating polyneuropathy (CIDP), a rare autoimmune disorder characterized by progressive weakness and impaired sensory function in the legs and arms. In clinical trials, Gamunex improved certain motor functions for up to 48 weeks after the initial treatment.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
Sept. 18, 2008 * Vol. 15, No. 182
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Sept. 18 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2008; 359).
Telmisartan, Aspirin, & Dipyridamole for Secondary Cardiovascular Protection: Two research reports and an editorial explore the efficacy of agents for preventing secondary cardiovascular events and stroke.
Long-term therapy with telmisartan (given to patients with the drugs mentioned in the second report) failed to lower the incidence of recurrent stroke, major cardiovascular events, or diabetes among 20,332 patients with recent ischemic stroke who participated in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) study (pp. 1225-37). Compared with placebo, telmisartan 80 mg daily produced these outcomes: “The median interval from stroke to randomization was 15 days. During a mean follow-up of 2.5 years, the mean blood pressure was 3.8/2.0 mm Hg lower in the telmisartan group than in the placebo group. A total of 880 patients (8.7%) in the telmisartan group and 934 patients (9.2%) in the placebo group had a subsequent stroke (hazard ratio in the telmisartan group, 0.95; 95% confidence interval [CI], 0.86 to 1.04; P = 0.23). Major cardiovascular events occurred in 1,367 patients (13.5%) in the telmisartan group and 1,463 patients (14.4%) in the placebo group (hazard ratio, 0.94; 95% CI, 0.87 to 1.01; P = 0.11). New-onset diabetes occurred in 1.7% of the telmisartan group and 2.1% of the placebo group (hazard ratio, 0.82; 95% CI, 0.65 to 1.04; P = 0.10).” (S. Yusuf,
yusufs@mcmaster.ca)
In the same population, PRoFESS study investigators randomized patients to receive aspirin 25 mg plus extended-release dipyridamole 200 mg twice daily or clopidogrel 75 mg daily (pp. 1238-51). Rates of recurrent stroke were similar between the groups (some of whom also received telmisartan, as detailed above), the investigators report, adding these details: “Recurrent stroke occurred in 916 patients (9.0%) receiving ASA–ERDP and in 898 patients (8.8%) receiving clopidogrel (hazard ratio, 1.01; 95% confidence interval [CI], 0.92 to 1.11). The secondary outcome occurred in 1,333 patients (13.1%) in each group (hazard ratio for ASA–ERDP, 0.99; 95% CI, 0.92 to 1.07). There were more major hemorrhagic events among ASA–ERDP recipients (419 [4.1%]) than among clopidogrel recipients (365 [3.6%]) (hazard ratio, 1.15; 95% CI, 1.00 to 1.32), including intracranial hemorrhage (hazard ratio, 1.42; 95% CI, 1.11 to 1.83). The net risk of recurrent stroke or major hemorrhagic event was similar in the two groups (1,194 ASA–ERDP recipients [11.7%], vs. 1,156 clopidogrel recipients [11.4%]; hazard ratio, 1.03; 95% CI, 0.95 to 1.11).” (R. L. Sacco,
rsacco@med.miami.edu)
Commenting on these reports, editorialists identify these “insights from incoherence” (pp. 1287-9): “Interpreting the results of the PRoFESS trial is not easy. First, the failure to demonstrate noninferiority despite essentially identical rates of the primary outcome between the treatment groups is attributable to the extremely stringent noninferiority margin, itself attributable to the fact that the trial was designed under the (apparently mistaken) assumption that low-dose aspirin plus extended-release dipyridamole was in truth superior to clopidogrel. More at issue, how do we interpret the null results of the PRoFESS trial in light of the previous evidence showing clear superiority for low-dose aspirin plus extended-release dipyridamole as compared with aspirin, but not for clopidogrel as compared with aspirin, for secondary prevention of stroke? Logic suggests three non–mutually exclusive solutions: the results of the PRoFESS trial are a statistical fluke, clopidogrel is somewhat better than previous evidence suggests, or low-dose aspirin plus extended-release dipyridamole is somewhat worse than previous evidence suggests. If the third solution is correct, one might wonder whether the winner in this latest battle of the ‘superaspirins’ was aspirin itself.” (D. M. Kent, Tufts U., Boston)
Medical Neighborhoods: “To deliver on its promise, the medical home needs a hospitable and high-performing medical neighborhood,” writes the author of a Perspective article (pp. 1202-5). Provision of primary care through the medical-home model is advantageous, he maintains, but more effective alignment of the interests of all physicians and hospitals is needed. (E. S. Fisher, Dartmouth Inst. for Health Policy and Clinical Practice, Lebanon, NH)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
Sept. 19, 2008 * Vol. 15, No. 183
Providing news and information about medications and their proper use

>>>Allergy/Immunology Report
Source:
Sept. issue of the Journal of Allergy and Clinical Immunology (www.jacionline.org/current; 2008; 122).
Climate change and allergic disease: An increasing burden from allergic diseases can be expected as the average temperature of the earth increases during this century, conclude authors of a review article (pp. 443-53). “Climate change is potentially the largest global threat to human health ever encountered,” the group maintains. “The earth is warming, the warming is accelerating, and human actions are largely responsible. If current emissions and land use trends continue unchecked, the next generations will face more injury, disease, and death related to natural disasters and heat waves, higher rates of climate-related infections, and widespread malnutrition, as well as more allergic and air pollution–related morbidity and mortality. This review highlights links between global climate change and anticipated increases in prevalence and severity of asthma and related allergic disease mediated through worsening ambient air pollution and altered local and regional pollen production. The pattern of change will vary regionally depending on latitude, altitude, rainfall and storms, land-use patterns, urbanization, transportation, and energy production. The magnitude of climate change and related increases in allergic disease will be affected by how aggressively greenhouse gas mitigation strategies are pursued, but at best an average warming of 1 to 2°C is certain this century. Thus, anticipation of a higher allergic disease burden will affect clinical practice as well as public health planning. A number of practical primary and secondary prevention strategies are suggested at the end of the review to assist in meeting this unprecedented public health challenge.” (K. M. Shea, kshea@email.unc.edu)
Children’s Affect & Asthma Medication Adherence: The complicated relationships among parent or child negative affect, adherence to antiasthmatic medications, and control of asthmatic symptoms are explored in a study of 104 children aged 8–18 years (pp. 490-5). Based on questionnaire results and electronic monitoring of metered-dose inhaler devices, the investigators report: “Both child and parent negative affect scores predicted symptom scores, whether reported by child or parent, and child negative affect scores predicted school absence because of asthma. In a lagged analysis taking into account time sequence, medication adherence predicted prednisone bursts but not subjective symptom scores. Nonadherence did not explain the relationship between negative affect and symptom scores, but parent negative affect predicted prednisone bursts even when controlling for level of adherence.” (B. Bender, benderb@njc.org)
Asthma-Related ED Visits After Smoking Ban: Fewer asthma-related visits to the emergency departments among adults and children with the disease followed implementation of a smoke-free law in the Lexington, KY, area (pp. 537-41). Comparing ED visits at four hospitals in Fayette County over the 2001–06 time period, the investigators found these trends: “Adjusting for seasonality, secular trends, and demographic characteristics, ED visits for asthma declined 22% from prelaw to postlaw (P < .0001; 95% CI, 14% to 29%). The rate of decline was 24% in adults age 20 years and older (P < .0001), whereas the decrease among children 19 years or younger was 18% (P = .01).” (E. J. Hahn, ejhahn00@email.uky.edu)

>>>PNN NewsWatch
* Covidien and Mallinckrodt Inc. informed health professionals of increases in the risk of leukemia following use of Phosphocol P 32, a product approved for the intracavitary instillation for the treatment of peritoneal or pleural effusions caused by metastatic disease. Two children (ages 9 and 14) with hemophilia developed acute lymphocytic leukemia approximately 10 months after intra-articular injections of Phosphocol P 32 (0.6 and 1.5 mCi total dose). This drug is not indicated in the intra-articular treatment of hemarthroses. Additionally, postmarketing experience identified radiation injury (necrosis and fibrosis) to the small bowel, cecum, and bladder following administration of P 32 into the peritoneal cavity. Health professionals should refer to the product’s revised prescribing information for updated information regarding the appropriate use of Phosphocol P 32.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
Sept. 22, 2008 * Vol. 15, No. 184
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Early-release articles from Lancet (www.thelancet.com; 2008; 372).
Antibiotics in Pregnancy: Two reports from the ORACLE studies and a related editorial explore use of antibiotics in pregnant women with premature rupture of membranes or spontaneous preterm labor with intact membranes.
Among children born to 4,148 women with PROM who participated in the ORACLE I trial, prescription of antibiotics for PROM had little effect on children’s health at age 7 years, ORACLE researchers conclude (doi: 10.1016/S0140-6736(08)61202-7). Looking at use of erythromycin and amoxicillin–clavulanate (co-amoxiclav), the researchers found these outcomes among 3,298 eligible children: “There was no difference in the proportion of children with any functional impairment after prescription of erythromycin, with or without co-amoxiclav, compared with those born to mothers who received no erythromycin (594 [38.3%] of 1,551 children vs 655 [40.4%] of 1,620; odds ratio 0.91, 95% CI 0.79–1.05) or after prescription of co-amoxiclav, with or without erythromycin, compared with those born to mothers who received no co-amoxiclav (645 [40.6%] of 1,587 vs 604 [38.1%] of 1,584; 1.11, 0.96–1.28). Neither antibiotic had a significant effect on the overall level of behavioural difficulties experienced, on specific medical conditions, or on the proportions of children achieving each level in reading, writing, or mathematics at key stage one.” (S. Kenyon,
racle@leicester.ac.uk">oracle@leicester.ac.uk)
The risk of cerebral palsy was increased by exposure to antibiotics among 3,196 children born to 4,221 women with spontaneous preterm labor and intact membranes, without overt signs of clinical infection, an ORACLE II article concludes (doi: 10.1016/S0140-6736(08)61203-9): “More children whose mothers had received erythromycin or co-amoxiclav developed cerebral palsy than did those born to mothers who received no erythromycin or no co-amoxiclav, respectively (erythromycin: 53 [3.3%] of 1,611 vs 27 [1.7%] of 1562, 1.93, 1.21–3.09; co-amoxiclav: 50 [3.2%] of 1,587 vs 30 [1.9%] of 1586, 1.69, 1.07–2.67). The number needed to harm with erythromycin was 64 (95% CI 37–209) and with co-amoxiclav 79 (42–591).” (S. Kenyon,
racle@leicester.ac.uk">oracle@leicester.ac.uk)
Editorialists add this advice (doi: 10.1016/S0140-6736(08)61248-9): “The lessons to be learned seem clear: contrary to popular opinion (‘might as well give them, they don’t do any harm&rsquoWinking, antibiotics are not risk free. There are good reasons not to give them in association with threatened preterm labour unless there is clear evidence of infection. It is vital that practice is not extended by stealth beyond that which is justified by the evidence, and interventions in pregnancy should always be evaluated with proper long-term follow-up. Many drugs have different pharmacodynamics during pregnancy, and their effects can vary between mother and fetus. Research in perinatal medicine is poorly funded compared with conditions affecting the end of life. Drug companies are reluctant to research in pregnancy because of the litigation risk. The data from these ORACLE follow-ups emphasise the case for increased governmental funding for such important long-term outcome studies.” (P. J. Steer,
p.steer@imperial.ac.uk)

>>>PNN JournalWatch
* The Risk of Myocardial Infarction and Pharmacologic and Nonpharmacologic Myocardial Infarction Predictors in Rheumatoid Arthritis: A Cohort and Nested Case-Control Analysis, in Arthritis & Rheumatism, 2008; 58: 261221–. Reprints: F. Wolfe, fwolfe@arthritis-research.org
* Prevention of Atrial Fibrillation With 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors, in
Circulation, 2008; 118: 1285–93. Reprints: O. Adam.
* Beyond the Randomized Clinical Trial: The Role of Effectiveness Studies in Evaluating Cardiovascular Therapies, in
Circulation, 2008; 118: 1294–303. Reprints: B. K. Nallamothu.
* Novel Insights in Chronic Lymphocytic Leukemia: Are We Getting Closer to Understanding the Pathogenesis of the Disease?, in
Journal of Clinical Oncology, 2008; 26: 4497–503. Reprints: F. Caligaris-Cappio, caligaris.federico@hsr.it
* Blogging During Terminal Care: Communication, Color Schemes, and Creating a Community, in
Journal of Clinical Oncology, 2008; 26: 4504–6. Reprints: L. A. Bach, leon.bach@med.monash.edu.au
* Healthcare Professional Training: A Comparison of Geriatric Competencies, in
Journal of the American Geriatrics Society, 2008; 56: 1724–9. Reprints: M. Mezey, mathy.mezey@nyu.edu
* A Case of Cocaine-Induced Acute Interstitial Nephritis, in
American Journal of Kidney Diseases, 2008; 52: 792–5. Reprints: D. Wojciechowski.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
Sept. 23, 2008 * Vol. 15, No. 185
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Sept. 22 issue of the Archives of Internal Medicine (http://archinte.ama-assn.org/current.dtl; 2008; 168).
Insulin, Hyperglycemia, & Hypertension: Among patients with type 1 diabetes, hyperglycemia is a risk factor for new-onset hypertension, one that can be minimized through intensive insulin therapy, according to the Diabetes Control and Complications Trial (DCCT) and its observational follow-up, the Epidemiology of Diabetes Intervention and Complications (EDIC) study (pp. 1867-73). Defining incident hypertension as two consecutive study visits with a systolic blood pressure of 140 mm Hg or higher, a diastolic blood pressure of 90 mm Hg or higher, or use of antihypertensive medications to treat high blood pressure, the investigators found: “Participants were enrolled from August 23, 1983, through June 30, 1989. During a 15.8-year median follow-up, 630 of 1,441 participants developed hypertension. During the DCCT, the incidence of hypertension was similar comparing participants assigned to intensive vs conventional therapy. However, intensive therapy during the DCCT reduced the risk of incident hypertension by 24% during EDIC study follow-up (hazard ratio, 0.76; 95% confidence interval [CI], 0.64–0.92). A higher hemoglobin A1c level, measured at baseline or throughout follow-up, was associated with increased risk for incident hypertension (adjusted hazard ratios, 1.11 [95% CI, 1.06–1.17] and 1.25 [95% CI, 1.14–1.37], respectively, for each 1% higher hemoglobin A1c level), and glycemic control appeared to mediate the antihypertensive benefit of intensive therapy. Older age, male sex, family history of hypertension, greater baseline body mass index, weight gain, and greater albumin excretion rate were independently associated with increased risk of hypertension.” (I. H. de Boer, deboer@u.washington.edu)
Preventable Medication-Related Hospital Admissions: In a 40-day study of medication-related admissions at 21 Dutch hospitals, adverse drug events were an important cause of hospitalizations, and about one-half of these were preventable, researchers report (pp. 1890-6). Compared with control patients who were admitted for elective surgery, the study shows: “Almost 13,000 unplanned admissions were screened, of which 714 (5.6%) were medication related. Almost half (46.5%) of these admissions were potentially preventable, resulting in 332 case patients matched with 332 controls. Outcomes were favorable in most patients. The main determinants of preventable medication-related hospital admissions were impaired cognition (odds ratio, 11.9; 95% confidence interval, 3.9–36.3), 4 or more comorbidities (8.1; 3.1–21.7), dependent living situation (3.0; 1.4–6.5), impaired renal function (2.6; 1.6–4.2), nonadherence to medication regimen (2.3; 1.4–3.8), and polypharmacy (2.7; 1.6–4.4).” (P. M. L. A. van den Bemt, P.vandenBemt@uu.nl)
Resistance Among Community-Acquired E. coli: A study of 11 Spanish hospitals in 2002–03 shows that extended-spectrum beta-lactamase–producing Escherichia coli are a “notable cause of community-acquired infection,” especially urinary tract infections (pp. 1897-902). The case–control analysis concludes that fosfomycin and amoxicillin–clavulanate are likely effective for cystitis, adding these study details: “A total of 122 cases were included. Risk factors selected by multivariate analysis included the following: age older than 60 years; female sex; diabetes mellitus; recurrent urinary tract infections (UTIs); previous invasive procedures of the urinary tract; follow-up in outpatient clinic; and previous receipt of aminopenicillins, cephalosporins, and fluoroquinolones. Urinary tract infections accounted for 93% of the cases; 6% of the patients were bacteremic and 10% needed hospitalization. The cure rate of patients with cystitis was 93% with fosfomycin therapy (all isolates were susceptible); among patients treated with amoxicillin–clavulanate, cure rates were 93% for those with susceptible isolates (minimum inhibitory concentration 8 µg/mL) and 56% for those with intermediate or resistant isolates (minimum inhibitory concentration 16 µg/mL) (P = .02).” (J. Rodríguez-Baño, jrb@nacom.es)

>>>PNN NewsWatch
* A survey shows that 94% of Ontarians trust their pharmacists more than the government as a source of drug information.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
Sept. 24, 2008 * Vol. 15, No. 186
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Sept. 24 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2008; 300).
Morbidity, Mortality with Inhaled Anticholinergics for COPD: Used for treating patients with chronic obstructive pulmonary disorder, the inhaled anticholinergics ipratropium bromide or tiotropium bromide are associated with a significantly increased risk of cardiovascular death, myocardial infarction, or stroke, according to a systematic review and meta-analysis (pp. 1439-50). “After a detailed screening of 103 articles, 17 trials enrolling 14,783 patients were analyzed,” report the researchers. “Follow-up duration ranged from 6 weeks to 5 years. Cardiovascular death, MI, or stroke occurred in 135 of 7,472 patients (1.8%) receiving inhaled anticholinergics and 86 of 7,311 patients (1.2%) receiving control therapy (RR, 1.58 [95% confidence interval {CI}, 1.21–2.06]; P < .001, I2 = 0%). Among individual components of the primary end point, inhaled anticholinergics significantly increased the risk of MI (RR, 1.53 [95% CI 1.05–2.23]; P = .03, I2 = 0%) and cardiovascular death (RR, 1.80 [95% CI, 1.17–2.77]; P = .008, I2 = 0%) without a statistically significant increase in the risk of stroke (RR, 1.46 [95% CI, 0.81–2.62]; P = .20, I2 = 0%). All-cause mortality was reported in 149 of the patients treated with inhaled anticholinergics (2.0%) and 115 of the control patients (1.6%)(RR, 1.26 [95% CI, 0.99–1.61]; P = .06, I2 = 2%). A sensitivity analysis restricted to 5 long-term trials (>6 months) confirmed the significantly increased risk of cardiovascular death, MI, or stroke (2.9% of patients treated with anticholinergics vs 1.8% of the control patients; RR, 1.73 [95%CI, 1.27–2.36]; P < .001, I2 = 0%).” (S. Singh, sosingh@wfubmc.edu)
Banning Tobacco Sales in Pharmacies: Calling a San Francisco ban on tobacco sales in pharmacies “the right prescription,” a Commentary author offers this analysis of the situation (pp. 1451-3): “Why should pharmacies, but not all retail stores, be prohibited from selling cigarettes and other tobacco products? The answer lies in the ways pharmacies are different from other retailers, including the health focus of pharmacies, the greater vulnerability of some individuals who enter pharmacies, and the conflict of interest in selling both tobacco and pharmaceuticals. The perception of pharmacies, reinforced by their marketing, is that they are associated with good health. Allowing tobacco sales in pharmacies implicitly sends a message that it is not so dangerous to smoke.…
“With a ban in place, pharmacy staff can offer the right response when customers ask for a pack of cigarettes: ‘I’m sorry this is a health-promoting business; we don’t sell tobacco. May I offer you advice on how to quit?’” (M. H. Katz,
mitch.katz@sfdph.org)
Importation of Prescription Medications: Arguing that “the quality and price of prescription medications should ultimately serve as the main signals that determine which producers win the competition for sales to American patients,” authors of a Commentary provide this analysis on the importation of prescription medications from lower-income countries (pp. 1453-5): “The annual expenditure on statins alone for outpatients in the United States is approximately $20 billion, so a 50% reduction in prices resulting from increased trade in this class of medications alone would produce savings of $10 billion, or more than 4 times the FDA’s annual budget. Focusing on safety is necessary to avoid the importation of contaminated medications, but a solution that limits imported medications to protect the interests of the domestic pharmaceutical industry would be anticompetitive and not in the best interest of American patients.” (A. S. Detsky, adetsky@mtsinai.on.ca)

>>>PNN NewsWatch
* Hepatic failure and hepatorenal syndrome, including fatalities, have been reported with erlotinib (Tarceva), OSI and Genentech report, particularly in those with baseline hepatic impairment. Therapy should be closely monitored and the product used with extra caution in patients with total bilirubin >3x ULN.
*
Ucyclyd Pharma is warning of particulate matter in its Ammonul Injection 10% (sodium phenylacetate and sodium benzoate) product. The company suggests that use of a MilIex Durapore GV 33 mm Sterile Syringe Filter (0.22 µm) during the admixture process when injecting Ammonul into the 10% Dextrose IV bag to remove particulate matter.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
Sept. 25, 2008 * Vol. 15, No. 187
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Early-release articles and the Sept. 25 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2008; 359).
Alteplase After Ischemic Stroke: Intravenous alteplase administered 3–4.5 hours after the onset of symptoms of acute ischemic stroke significantly improved clinical outcomes, compared with placebo, but the drug was more frequently associated with symptomatic intracranial hemorrhage, a research study concludes (pp. 1317-29). Assessing the effects of 0.9 mg/kg doses of intravenous alteplase on a primary end point of disability at 90 days, dichotomized as a favorable outcome (0–1 on the modified Rankin scale) or an unfavorable outcome (2–6 on the scale), European Cooperative Acute Stroke Study (ECASS) III investigators found: “We enrolled a total of 821 patients in the study and randomly assigned 418 to the alteplase group and 403 to the placebo group. The median time for the administration of alteplase was 3 hours 59 minutes. More patients had a favorable outcome with alteplase than with placebo (52.4% vs. 45.2%; odds ratio, 1.34; 95% confidence interval [CI], 1.02 to 1.76; P = 0.04). In the global analysis, the outcome was also improved with alteplase as compared with placebo (odds ratio, 1.28; 95% CI, 1.00 to 1.65; P < 0.05). The incidence of intracranial hemorrhage was higher with alteplase than with placebo (for any intracranial hemorrhage, 27.0% vs. 17.6%; P = 0.001; for symptomatic intracranial hemorrhage, 2.4% vs. 0.2%; P = 0.008). Mortality did not differ significantly between the alteplase and placebo groups (7.7% and 8.4%, respectively; P = 0.68). There was no significant difference in the rate of other serious adverse events.” (W. Hacke, werner.hacke@med.uni-heidelberg.de)
Writing that there’s “not a moment to lose” in starting thrombolytic therapy for acute stroke, an editorialist delivers an ultimatum to neurologists (pp. 1393-5): “The frequently quoted statistic that only 4% of all patients with stroke receive rt-PA must be viewed as an important indictment of our health care system and of the field of neurology in particular. The patients are coming in, but we are not. The real lesson of ECASS III is not that we can wait longer before treating; the lesson is that systems such as the Joint Commission criteria for accreditation of a hospital as a Primary Stroke Center must be widely adopted. Policies and procedures must be instituted to ensure that patients are promptly identified and treated, quality outcome data must be used to select and designate treatment centers of excellence for patients with acute stroke, and patients should be diverted to these centers. The public expects no less, and given the past decade of distortion of the NINDS study findings and delay in implementing thrombolytic therapy for acute stroke, we have not a minute to lose.” (P. Lyden, VA Med. Ctr., San Diego)
Health Care in the Next Administration: While the presidential candidates debate whether to debate tomorrow, their health care platforms are assessed by two senior health policy advisors, David Cutler of Harvard University for Democrat Barack Obama and Gail Wilensky of Project HOPE for Republican John McCain, in a video posted on the journal website. In accompanying early-release Perspectives articles, the candidates provide comments on their positions.
“I do not believe that reforming our health care system should mean issuing burdensome mandates that push American families away from private coverage and creating new government bureaucracies that will translate into higher taxes, reduced provider payments, and long waiting lines,” concludes Sen. McCain. “The key to real reform is to strengthen the doctor–patient relationship and provide American families with more choices for high-quality and affordable care.”
Sen. Obama counters with a discussion of medical malpractice and prevention, concluding: “This election will have enormous consequences for health care in our country. As president, I will modernize our health care delivery system and ensure that all Americans have access to high-quality, affordable medical care. I believe that with help and collaboration, especially from those who work so hard to keep us healthy, we can make health care reform a reality.”

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
Sept. 26, 2008 * Vol. 15, No. 188
Providing news and information about medications and their proper use

>>>Gastroenterology Report
Source:
Sept. issue of Gastroenterology (www.gastrojournal.org/current; 2008; 135).
Folate, Vitamin B6, p53 Expression, & Risk of Colon Cancer: In a prospective cohort study of women with 22 years of follow-up, low folate and vitamin B6 intake was linked to an increased risk of p53-overexpressing colon cancers but not wild-type tumors (pp. 770-80). Previous research in laboratory animals had indicated that folate deficiency can induce p53 mutation. In the current analysis, researchers found: “A total of 399 incident colon cancers accessible for p53 expression were available. The effect of folate differed significantly according to p53 expression (Pheterogeneity = .01). Compared with women reporting folate intake <200 µg/day, the multivariate relative risks (RRs) for p53-overexpressing (mutated) cancers were 0.54 (95% confidence interval [CI], 0.36–0.81) for women who consumed 200–299 µg/day, 0.42 (95% CI, 0.24–0.76) for women who consumed 300–399 µg/day, and 0.54 (95% CI, 0.35–0.83) for women who consumed 400 µg/day. In contrast, total folate intake had no influence on wild-type tumors (RR, 1.05; 95% CI, 0.73–1.51; comparing 400 with <200 µg/day). Similarly, high vitamin B6 intake conferred a protective effect on p53-overexpressing cancers (top versus bottom quintile: RR, 0.57; 95% CI, 0.35–0.94; Pheterogeneity = .01) but had no effect on p53 wild-type tumors.” (E. S. Schernhammer, eva.schernhammer@channing.harvard.edu)
H. pylori Vaccine: Further clinical study is warranted of a Helicobacter pylori vaccine, researchers conclude based on positive results from a Phase I study (pp. 787-95). These results were recorded among 57 H. pylori–negative volunteers who received alum controls or vaccines with various antigens, doses, and administration schedules: “Local and systemic adverse reactions were mild and similar in placebo and vaccine recipients on the monthly schedules. All subjects responded to 1 or 2 of the antigens and 86% of all vaccines mounted immunoglobulin G antibody responses to all 3 antigens. Vaccinees exhibited an antigen-specific cellular response. Vaccination 18–24 months later elicited anamnestic antibody and cellular responses. “(G. Del Giudice, giuseppe.del_giudice@novartis.com)

>>>Chest Highlights
Source:
Sept. issue of Chest (www.chestjournal.org/current.shtml; 2008; 134).
Cardiovascular, All-Cause Mortality & ICS Use: Supporting results of previous research, an analysis of data from the Nurses’ Health Study shows that both cardiovascular and all-cause mortality are reduced among patients using inhaled corticosteroids for treatment of asthma (pp. 546-51). The results support the possibility that the anti-inflammatory benefits of ICSs extend beyond the airways. Among the 121,700 registered nurses who began the study in 1976, the investigators found these patterns based on 1998 ICS use data and 2003 mortality assessments: “Among 2,671 eligible women (ie, those who responded to the 1998 supplement [85%], met criteria for persistent asthma, and had not received a prior diagnosis of COPD), 54% reported ICS use. Over the next 5 years, 87 women (3.3%) died (cardiovascular deaths, 22; cancer deaths, 31; other, 34 [including 4 from asthma]). Compared to asthmatic women who did not use ICSs, those receiving therapy with ICSs had lower all-cause mortality (OR, 0.58; 95% confidence interval [CI], 0.36 to 0.92). ICS users were at significantly lower risk of cardiovascular death (OR, 0.35; 95% CI, 0.13 to 0.93), but not of death from cancer (OR, 0.66; 95% CI, 0.32 to 1.38) or other causes (OR, 0.62; 95% CI, 0.30 to 1.27).” (C. A. Camargo, ccamargo@partners.org)
Triple Thrombolytic Therapy in AF: Triple antithrombotic therapy consisting of aspirin, clopidogrel, and warfarin produced a high rate of major bleeding among 104 patients with atrial fibrillation who were undergoing percutaneous coronary intervention with stent implantation, researchers report (pp. 559-67). Use of glycoprotein IIb/IIIa inhibitors and multivessel/left main artery disease during the PCI procedure were independent predictors for early major bleeding, the group notes, while triple thrombolytic therapy, occurrence of early major bleeding, and baseline anemia were independent predictors for late major bleeding. (G. Y. H. Lip, g.y.h.lip@bham.ac.uk)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
Sept. 29, 2008 * Vol. 15, No. 189
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Sept. 27 issue of Lancet (www.thelancet.com; 2008; 372).
ARBs in ACE Inhibitor–Intolerant Patients: Among a group of 5,926 patients intolerant to ACE inhibitors and with established coronary artery, peripheral vascular, or cerebrovascular disease, or diabetes with end-organ damage, telmisartan was well tolerated and efficacious, report investigators from the Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) (pp. 1174-83). Compared with placebo, 80-mg doses of the angiotensin II receptor blocker produced these outcomes: “The median duration of follow-up was 56 (IQR 51–64) months. All randomised patients were included in the efficacy analyses. Mean blood pressure was lower in the telmisartan group than in the placebo group throughout the study (weighted mean difference between groups 4.0/2.2 [SD 19.6/12.0] mmHg). 465 (15.7%) patients experienced the primary outcome in the telmisartan group compared with 504 (17.0%) in the placebo group (hazard ratio 0.92, 95% CI 0.81–1.05, p = 0.216). One of the secondary outcomes—a composite of cardiovascular death, myocardial infarction, or stroke—occurred in 384 (13.0%) patients on telmisartan compared with 440 (14.8%) on placebo (0.87, 0.76–1.00, p = 0.048 unadjusted; p=0.068 after adjustment for multiplicity of comparisons and overlap with primary outcome). 894 (30.3%) patients receiving telmisartan were hospitalised for a cardiovascular reason, compared with 980 (33.0%) on placebo (relative risk 0.92, 95% CI 0.85–0.99; p = 0.025). Fewer patients permanently discontinued study medication in the telmisartan group than in the placebo group (639 [21.6%] vs 705 [23.8%]; p = 0.055); the most common reason for permanent discontinuation was hypotensive symptoms (29 [0.98%] in the telmisartan group vs 16 [0.54%] in the placebo group).” (S. Yusuf, yusufs@mcmaster.ca)

>>>BMJ Highlights
Source:
Early-release article from BMJ (www.bmj.org; 2008; 337).
Continuous Glucose Monitoring During Pregnancy: Improved glycemic control in the third trimester, lower birth weight, and reduced risk of macrosomia were recorded among women who used continuous glucose monitoring during pregnancy (a1680). Included in the 96-patient, open-label, randomized trial were 71 women with type 1 diabetes and 25 with type 2 conditions. Compared with standard antenatal care, continuous glucose monitoring produced these results: “Women randomised to continuous glucose monitoring had lower mean HbA1c levels from 32 to 36 weeks’ gestation compared with women randomised to standard antenatal care: 5.8% (SD 0.6) v 6.4% (SD 0.7). Compared with infants of mothers in the control arm those of mothers in the intervention arm had decreased mean birthweight standard deviation scores (0.9 v 1.6; effect size 0.7 SD, 95% confidence interval 0.0 to 1.3), decreased median customised birthweight centiles (69% v 93%), and a reduced risk of macrosomia (odds ratio 0.36, 95% confidence interval 0.13 to 0.98).” (H. R. Murphy, Helen.Murphy@ipswichhospital.nhs.uk)

>>>PNN NewsWatch
* In a German clinical trial conducted investigating the use of high-dose epoetin alfa to treat acute ischemic stroke, more patients who received epoetin alfa had died by 90 days compared with patients who received the placebo (16% versus 9%), FDA announced last week. Roughly one-half of all deaths in both groups occurred within the first 7 days after starting the drug, with death from intracranial hemorrhage occurring among approximately 4% of patients who received epoetin alfa and 1% of patients in the placebo group. While awaiting more information about this study, FDA said that the increased mortality in patients receiving epoetin alfa in the German trial suggests the need to closely monitor patients enrolled in other ongoing trials for adverse outcomes and to evaluate whether the potential benefits for enrolled patients outweigh the risks in these trials.

>>>PNN JournalWatch
* American College of Endocrinology Pre-Diabetes Consensus Conference: Part One, in Diabetes Care, 2008; 31: 2062–9. Reprints: Z. T. Bloomgarden, Mount Sinai Sch. of Med., New York.
* Retail Clinics, Primary Care Physicians, and Emergency Departments: A Comparison of Patients’ Visits, in
Health Affairs, 2008; 27: 1272–82. Reprints: A. Mehrotra.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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
Sept. 30, 2008 * Vol. 15, No. 190
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Oct. issue of Diabetes Care (http://care.diabetesjournals.org/current.shtml; 2008; 31).
Benefits of Initial Short-Term Intensive Insulin Therapy: Better glycemic control and significant improvement of beta-cell function in new-onset type 2 diabetic patients with severe hyperglycemia were achieved with a 6-month course of intensive insulin therapy, compared with oral antidiabetic drugs (OADs) (pp. 1927-32). Upon diagnosis, all patients were hospitalized, treated with intensive insulin injections for 10–14 days, and then randomized to insulin or OADs. Oral glucose tolerance tests (OGTTs) at this point and after 6 months of treatment showed the following: “At the 6th month of the study, the A1C level was significantly lower in the insulin group than in the OAD group (6.33 ± 0.70% vs. 7.50 ± 1.50%; P = 0.002). During the follow-up visit, the A1C level was still better in the insulin group (6.78 ± 1.21% vs. 7.84 ± 1.74%; P = 0.009). All parameters regarding beta-cell function measured in the OGTT were improved significantly in both groups after 6 months of treatment. Compared with the OAD group, the homeostasis model assessment of beta-cell function index, insulin area under the curve, and insulinogenic index were better in the insulin group.” (H-D Lin, chenhs@vghtpe.gov.tw)
Pharmacogenetics of Gliclazide in Asian Patients: Among 1,268 patients with untreated type 2 diabetes that had been diagnosed within the prior 5 years, researchers found that the Ser1369Ala variant in the ABCC8 gene influenced the antidiabetic efficacy of gliclazide (pp. 1939-44). At 23 Chinese hospitals, tests of 25 single nuclear polymorphisms in 11 candidate genes showed these results in patients treated with this sulfonylurea: “After 8 weeks of gliclazide therapy, mean fasting plasma glucose (FPG) was reduced from 11.1 mmol/l at baseline to 7.7 mmol/l. In cohort 1, we genotyped all 25 SNPs (n = 661) and found that Ser1369Ala of the ABCC8 gene and rs5210 of the KCNJ11 gene were significantly associated with decreases in FPG (P = 0.002). We further genotyped Ser1369Ala in cohort 2 (n = 607) and confirmed the association identified in cohort 1. In the pooled analysis, compared with subjects with the Ser/Ser genotype, subjects with the Ala/Ala genotype had a 7.7% greater decrease in FPG (P < 0.001), an 11.9% greater decrease in 2-h plasma glucose (P = 0.003), and a 3.5% greater decrease in A1C (P = 0.06) after 8 weeks of treatment with gliclazide.” (X. Xu, xipingxu18@gmail.com)
Weight Change & Glycemic/Blood Pressure Control: A period of weight loss immediately after diagnosis of type 2 diabetes “may be a critical time to apply weight-loss treatments to improve risk factor control,” based on a study of 2,574 patients (pp. 1960-5). Looking at weight-loss patterns over the first 3 years after diagnosis, the researchers found improved glycemic and blood pressure control when patients initially lost weight, even if they later regained it: “The weight-trajectory groups were defined as higher stable weight (n = 418; 16.2%), lower stable weight (n = 1,542; 59.9%), weight gain (n = 300; 11.7%), and weight loss (n = 314; 12.2%). The latter had a mean weight loss of 10.7 kg (–9.8%; P < 0.001) by 18 months, with near-complete regain by 36 months. After adjusting for age, sex, baseline control, and related medication use, those with higher stable weight, lower stable weight, or weight-gain patterns were more likely than those who lost weight to have above-goal A1C (odds ratio [OR] 1.66 [95% CI 1.12–2.47], 1.52 [1.08–2.14], and 1.77 [1.15–2.72], respectively). Those with higher stable weight or weight-gain patterns were more likely than those who lost weight to have above-goal blood pressure (1.83 [1.31–2.57] and 1.47 [1.03–2.10], respectively).” (A. C. Feldstein, adrianne.c.feldstein@kpchr.org)

>>>PNN NewsWatch
* Statins do not increase the risk of developing amyotrophic lateral sclerosis (ALS), according to an FDA analysis published in the current issue of Pharmacoepidemiology and Drug Safety. During long-term placebo-controlled clinical trials, FDA found that 9 of about 64,000 patients treated with a statin and 10 of about 56,000 patients treated with placebo were diagnosed with Lou Gehrig’s disease, yielding an incidence of ALS in patients treated with statins of 4.2 cases per 100,000 patient–years and with placebo, 5.0 cases per 100,000 patient–years.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, 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.