Sep 2007

PNN Quarterly File—Third Quarter 2007

PNN Pharmacotherapy Line
July 2, 2007 * Vol. 14, No. 127
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
June 30 issue of Lancet (www.thelancet.com; 2007; 369).
Cervical Cancer Vaccine: In an 18,644-patient, Phase III study, a new human papillomavirus vaccine active against viral types 16 and 18 reduced the occurrence of cervical intraepithelial neoplasia (CIN) 2+ associated with HPV16 or HPV18, indicating that the product could be useful for preventing cervical cancer (pp. 2161-70). The vaccine, an AS04-adjuvanted, L1 virus-like-particle prophylactic candidate vaccine, was tested against hepatitis A vaccine in girls and women aged 15–25 years, with these results: “Mean length of follow-up for women in the primary analysis for efficacy at the time of the interim analysis was 14.8 (SD 4.9) months. Two cases of CIN2+ associated with HPV16 or HPV18 DNA were seen in the HPV16/18 vaccine group; 21 were recorded in the control group. Of the 23 cases, 14 (two in the HPV16/18 vaccine group, 12 in the control group) contained several oncogenic HPV types. Vaccine efficacy against CIN2+ containing HPV16/18 DNA was 90.4% (97.9% CI 53.4–99.3; p <0.0001). No clinically meaningful differences were noted in safety outcomes between the study groups.” (J. Paavonen, U. Helsinki, Helsinki; Jorma.Paavonen@hus.fi)
Autologous Cell Injections for Stress Incontinence: In 63 women with urinary stress incontinence, injections of autologous myoblasts and fibroblasts into the rhabdosphincter and the urethra were effective in reducing symptoms and improving anatomical and physiologic parameters (pp. 2179-86). Concluding that long-term data from larger trials are needed to determine if this approach should be a standard treatment for urinary incontinence, the authors provide these findings: “At 12-months’ follow-up, 38 of the 42 women injected with autologous cells were completely continent, compared with two of the 21 patients given conventional treatment with collagen. The median incontinence score decreased from a baseline of 6.0 ([interquartile range] 6.0–6.0; where 6 represents complete incontinence), to 0 (0–0) for patients treated with autologous cells, and 6.0 (3.5–6.0) for patients treated with collagen (p <0.0001). Ultrasonographic measurements showed that the mean thickness of the rhabdosphincter increased from a baseline of 2.13 mm (SD 0.39) for all patients to 3.38 mm (0.26) for patients treated with autologous cells and 2.32 mm (0.44) for patients treated with collagen (p <0.0001). Contractility of the rhabdosphincter increased from a baseline of 0.58 mm (SD 0.32) to 1.56 mm (0.28) for patients treated with autologous cells and 0.67 mm (0.51) for controls (p <0.0001). The change in the thickness of the urethra after treatment was not significantly different between treatment groups. No adverse effects were recorded in any of the 63 patients.” (H. Strasser, Med. U., Innsbruck, Austria; hannes.strasser@uibk.ac.at)
>>>PNN NewsWatch
* The Institute of Medicine’s Committee on the Future Health Care Workforce for Older Americans held its second meeting last Thursday at the U. Calif., San Francisco. Members heard speakers address these topics: the PACE (Programs of All-inclusive Care for the Elderly) model; innovative models of care for the future, in dentistry, and for minority populations; facilitators and barriers to dissemination of new models of care; future technologies; and recruitment and retention of physicians, nurses, and paraprofessionals and in rural areas. Miriam Mobley Smith, PharmD, of Chicago State U. represents pharmacy on the committee.

>>>PNN JournalWatch
* Impact of Financial Incentives on Clinical Autonomy and Internal Motivation in Primary Care: Ethnographic Study, in BMJ, 2007; 334: 1357 ff. Reprints: R. McDonald, U. Manchester, Manchester, U.K.; ruth.mcdonald@manchester.ac.uk
* Implementing the NHS Information Technology Programme: Qualitative Study of Progress in Acute Trusts, in
BMJ, 2007; 334: 1360 ff. Reprints: J. Hendy, Imperial College, London; j.hendy@imperial.ac.uk
* The Role of Iron in Diabetes and Its Complications, in
Diabetes Care, 2007; 30: 1926–33. Reprints: S. Swaminathan, U. Ark. for Med. Sci., Little Rock; sswaminathan@uams.edu
* Gut Hormones, Obesity, Polycystic Ovarian Syndrome, Malignancy, and Lipodystrophy Syndromes, in
Diabetes Care, 2007; 30: 1934–9. Reprints: Z. T. Bloomgarden, Mount Sinai Sch. of Med., New York.

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

PNN Pharmacotherapy Line
July 3, 2007 * Vol. 14, No. 128
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
July 3 issue of the Annals of Internal Medicine (www.annals.org/current.shtml; 2007; 147).
Aggressive Statin Therapy in Older Patients: Additional clinical benefits were achieved by higher statin doses in 3,809 patients older than 65 who had coronary heart disease and LDL cholesterol levels less than 3.4 mmol/L (130 mg/dL) (pp. 1-9). Comparing 10 versus 80 mg/day doses of atorvastatin in the Treating to New Targets study, researchers found: “Absolute risk was reduced by 2.3% and relative risk by 19% for major cardiovascular events in favor of the high-dose atorvastatin group (hazard ratio, 0.81 [95% CI, 0.67 to 0.98]; P = 0.032). Among the components of the composite outcome, the mortality rates from CHD, nonfatal non–procedure-related myocardial infarction, and fatal or nonfatal stroke (ischemic, embolic, hemorrhagic, or unknown origin) were all lower in older patients who received high-dose atorvastatin, although the difference was not statistically significant for each individual component. The improved clinical outcome in patients 65 years of age or older was not associated with persistent elevations in creatine kinase levels.” (N. K. Wenger, nwenger@emory.edu)
Beta-Blockers & Atherosclerotic Progression: Beta-blocker therapy can slow the progression of coronary atherosclerosis, according to a post-hoc, pooled analysis of patient data from four intravascular ultrasonography (IVUS) trials of 1,515 patients with coronary artery disease (pp. 10-8). “Patients who received beta-blockers (n = 1,154) were more likely to have histories of myocardial infarction, angina, and hypertension than were patients who did not receive beta-blockers (n = 361),” the investigators write. “The estimated annual change in atheroma volume was statistically significantly less in patients who received beta-blockers. This was true for univariate and multivariable analyses that controlled for history of myocardial infarction, angina, and hypertension (mean [±SE] atheroma volume, –2.4 ± 0.5 mm3/y in treated patients vs. –0.4 ± 0.8 mm3/y in untreated patients; P = 0.034). Accordingly, atheroma volume statistically significantly decreased at follow-up IVUS in patients who received beta-blockers (P <0.001) and did not change in patients who did not receive beta-blockers (P = 0.86). Additional adjustments for low-density lipoprotein cholesterol level, concomitant medications, and clinical trial did not change the results.” (S. E. Nissen, Cleveland Clinic Foundation, Cleveland; nissens@ccf.org)
Dietary Counseling & Weight Loss: A meta-analysis of 46 trials of dietary counseling shows that the intervention produces modest weight losses that diminish over time (pp. 41-50). Concluding that future studies should focus on ways to minimize loss to follow-up and factors that results in more effective weight loss, the authors note: “Random-effects model meta-analyses of 46 trials of dietary counseling revealed a maximum net treatment effect of –1.9 (95% CI, –2.3 to –1.5) BMI units (approximately –6%) at 12 months. Meta-analysis of changes in weight over time (slopes) and meta-regression suggest a change of approximately –0.1 BMI unit per month from 3 to 12 months of active programs and a regain of approximately 0.02 to 0.03 BMI unit per month during subsequent maintenance phases. Different analyses suggested that calorie recommendations, frequency of support meetings, inclusion of exercise, and diabetes may be independent predictors of weight change.” (M. L. Dansinger, mdansinger@tufts-nemc.org)

>>>PNN NewsWatch
* A new boxed warning has been added to the labeling of omalizumab (Xolair, Genentech), and a new MedGuide should be distributed with the product, FDA announced yesterday. Revisions address the risk of anaphylaxis following any doses of omalizumab, even when no reaction occurred with earlier doses. The drug is approved to treat adults and adolescents (12 years of age and above) with moderate to severe persistent asthma who have a positive skin test or in vitro reactivity to a perennial aeroallergen and whose symptoms are inadequately controlled with inhaled corticosteroids.
*
PNN will not be published on Wed., July 4, 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 © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 5, 2007 * Vol. 14, No. 129
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
July 5 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2007; 357).
Use of Trastuzumab in Clinical Practice: A review article presents background information on trastuzumab along with information on clinical trials, toxicity, clinical relevance of HER2 testing, and use of the agent for adjuvant therapy in HER2-dependent breast cancer, metastatic breast cancer, and early-stage breast cancer (pp. 39-51). The author concludes: “The convergence of biotechnology (the development of humanized antibodies), preclinical science (the identification of the biologic role of HER2), and translational studies (the clinical trials showing activity and identifying new lines of research) led to the approval and availability of trastuzumab, the first monoclonal antibody that has been shown to prolong life in patients with a human epithelial malignant condition. Its development highlights the need to continue to categorize breast cancer and other cancers into biologically meaningful subtypes as well as the critical importance of well-conceived clinical studies. The experience with trastuzumab also shows the continuing need for clinical judgment and rational extrapolation of data, since not every clinical situation can be anticipated or addressed by clinical trials.” (C. A. Hudis, Memorial Sloan-Kettering Cancer Ctr., New York; hudisc@mskcc.org)
Rosiglitazone Interim Analysis: Results of the unplanned interim analysis of data from the RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes) trial, released earlier by the Journal (see PNN, June 7), are published in this issue along with accompanying editorials (pp. 28-38, 63-4, 64-6, 67-9).

JAMA Highlights
Source:
July 4 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2007; 298).
Pharmacy Benefit Design as Public Health Tool: Increased prescription-drug cost sharing between payers and patients is highly correlated with reductions in pharmacy use, but the long-term consequences of benefit changes on health are still uncertain, warn authors of a review article (pp. 61-9). Focusing on the utility of pharmacy benefit design on achieving public health goals, the writers report: “Increased cost sharing is associated with lower rates of drug treatment, worse adherence among existing users, and more frequent discontinuation of therapy. For each 10% increase in cost sharing, prescription drug spending decreases by 2% to 6%, depending on class of drug and condition of the patient. The reduction in use associated with a benefit cap, which limits either the coverage amount or the number of covered prescriptions, is consistent with other cost-sharing features. For some chronic conditions, higher cost sharing is associated with increased use of medical services, at least for patients with congestive heart failure, lipid disorders, diabetes, and schizophrenia. While low-income groups may be more sensitive to increased cost sharing, there is little evidence to support this contention.” (D. P. Goldman, RAND Corp., Santa Monica, Calif.; dgoldman@rand.org)
Cocoa Intake & Blood Pressure: Among 44 otherwise healthy adults with untreated blood pressures in the prehypertension or stage I hypertension ranges, ingestion of small amounts of polyphenol-rich dark chocolate as part of a usual diet efficiently reduced BP and improved formation of vasodilative nitric oxide (pp. 49-60). Compared with polyphenol-free white chocolate, dark chocolate 6.3 grams/daily produced these results: “From baseline to 18 weeks, dark chocolate intake reduced mean (SD) systolic BP by –2.9 (1.6) mm Hg (P <0.001) and diastolic BP by –1.9 (1.0) mm Hg (P <0.001) without changes in body weight, plasma levels of lipids, glucose, and 8-isoprostane. Hypertension prevalence declined from 86% to 68%. The BP decrease was accompanied by a sustained increase of S-nitrosoglutathione by 0.23 (0.12) nmol/L (P <0.001), and a dark chocolate dose resulted in the appearance of cocoa phenols in plasma. White chocolate intake caused no changes in BP or plasma biomarkers.” (D. Taubert, U. Hosp., Cologne, Germany; dirk.taubert@medizin.uni-koeln.de)

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

PNN Pharmacotherapy Line
July 6, 2007 * Vol. 14, No. 130
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
July issue of Pharmacotherapy (www.atypon-link.com/PPI/toc/phco/27/7; 2007; 27).
Blunted Influenza Vaccine Response with Anti-infective Drugs: Zidovudine plus trimethoprim–sulfamethoxazole causes a clinically significant suppression of humoral immune responses to influenza vaccination in HIV-infected patients, report authors of a 23-patient study (pp. 937-47). All patients were receiving antiretroviral therapy and had CD4+ counts greater than 350 cells/mm3. Depending on whether they were already taking zidovudine and their own preferences, patients were placed in one of four parallel groups: zidovudine only; TMP–SMX only; both drugs; or neither drug. Results showed: “Mean influenza B-specific serum immunoglobulin (Ig)G titers were significantly lower in patients receiving TMP–SMX alone (0.98 ± 0.60 reference value, p = 0.010) or the combination of zidovudine plus TMP–SMX (0.73 ± 0.29 reference value, p = 0.003) compared with those receiving neither drug (1.95 ± 0.38 reference value). This corresponded to a significantly lower percentage of patients in the combination group that achieved immunoprotective titers to influenza B compared with the group who received neither drug (control group; 20% vs 100%, p = 0.048).” (D. J. Feola, djfeol2@email.uky.edu)
Aprotinin in Cardiac Surgery: The safety, efficacy, and pharmacoeconomic benefit of aprotinin in cardiac surgery require “more robust evidence,” conclude investigators who conducted a retrospective review of 335 inpatients at a community nonteaching hospital (pp. 988-94). Comparing experiences of those receiving aminocaproic acid versus aprotinin, the authors found “... no difference in total donor exposures to blood products (1.86 vs 1.16 units/patient, p = 0.07), total packed red blood cells (PRBCs) received (1.25 vs 0.86 units/patient, p = 0.09), postoperative donor exposures to blood products (0.91 vs 0.48 unit/patient, p = 0.13), or postoperative PRBCs received (0.61 vs 0.40 unit/patient, p = 0.23). No difference was noted in any other clinical outcome in the aprotinin group versus the aminocaproic acid group, including postoperative azotemia (13.0% vs 10.4%, p = 0.46), new onset of atrial fibrillation (14.8% vs 15.0%, p = 0.95), myocardial infarction, stroke, or death. Mean ± SD total hospital length of stay was similar in the aprotinin group versus the aminocaproic acid group (8.1 ± 3.8 vs 7.4 ± 2.8 days, p = 0.08), but length of stay from surgery to discharge was longer in the aprotinin group than in the aminocaproic acid group (5.9 ± 0.17 vs 5.4 ± 0.12 days, p = 0.032).” (J. L. Kristeller, Wilkes U., Wilkes-Barre, Pa.)
Topical Calcineurin Inhibitors in Atopic Dermatitis: Despite a black-box warning added to the prescribing information for topical calcineurin inhibitors, these drugs remain important treatment options for patients with atopic dermatitis, concludes a review article (pp. 1020-8). Noting that a causal link between TCI use and lymphomas is unproven, the authors write: “[FDA] recommendations were based on a theoretical risk of malignancy derived from safety profiles, animal data, and reported cases of malignancy from clinical trials and postmarketing safety surveillance of oral calcineurin inhibitors. We know of no data that suggest that TCI use increases the risk of malignancy. Several dermatologic associations have issued statements supporting the safety of TCIs, and independent oncology experts have concluded that reported lymphomas were not related to TCI use.” (P. J. Munzenberger, pmunzen@wayne.edu)

>>>PNN NewsWatch
* The first generic versions of terbinafine hydrochloride tablets have been approved by FDA. Bioequivalent to Lamisil, the tablets are indicated for onychomycosis, or nail fungal infections. Applications from numerous companies were approved. FDA also approved a generic 1% terbinafine hydrochloride cream formulation made by Taro Pharmaceuticals for use in treating athlete’s feet.
* Cases of fatal calcium–
ceftriaxone precipitates in the lungs and kidneys have occurred in term and premature neonates, FDA and Roche are warning. Hyperbilirubinemic neonates, especially prematures, should not be treated with ceftriaxone, and calcium-containing solutions or products must not be mixed or administered simultaneously (even via separate lines) with ceftriaxone or administered within 48 hours of ceftriaxone.

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

PNN Pharmacotherapy Line
July 9, 2007 * Vol. 14, No. 131
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
July 7 issue of Lancet, a special theme issue on HIV/AIDS (www.thelancet.com; 2007; 370).
Darunavir–Ritonavir for HIV Infection: Darunavir–ritonavir proved to be noninferior to lopinavir–ritonavir treatment in a study of 595 patients with HIV infection (pp. 49-58). Concluding that the darunavir combination should be considered as a treatment option, the investigators report these details: “187 (31%) were protease inhibitor naive; 476 of 582 (82%) were susceptible to four or more protease inhibitors. At week 48, significantly more darunavir–ritonavir than lopinavir–ritonavir patients had HIV RNA of less than 400 copies per mL (77% [220 of 286] vs 68% [199 of 293]; estimated difference 9%, 95% CI 2–16). Fewer virological failures treated with darunavir–ritonavir than with lopinavir–ritonavir developed primary protease inhibitor mutations (21% [n = 6] vs 36% [n = 20]) and nucleoside analogue-associated mutations (14% [n = 4] vs 27% [n = 15]). Safety data were generally similar between the groups; grade 3 or 4 adverse events occurred in 80 (27%) darunavir–ritonavir and 89 (30%) lopinavir–ritonavir patients.” (J. Valdez Madruga, Centro de Referência e Treinamento DST/AIDS, São Paulo, Brazil; valdezmr@uol.com.br)
Cancers in Patients with HIV Infection: Increased risk of cancers in patients with HIV infection is likely cause by immune deficiency rather than lifestyle or other factors, according to a meta-analysis that compared data from HIV studies with those conducted in recipients of solid organ grafts (pp. 59-67). “Seven studies of people with HIV/AIDS (n = 444,172) and five of transplant recipients (n = 31,977) were included. For 20 of the 28 types of cancer examined, there was a significantly increased incidence in both populations. Most of these were cancers with a known infectious cause, including all three types of AIDS-defining cancer, all HPV-related cancers, as well as Hodgkin’s lymphoma (HIV/AIDS meta-analysis SIR 11.03, 95% CI 8.43–14.4; transplant 3.89, 2.42–6.26), liver cancer (HIV/AIDS 5.22, 3.32–8.20; transplant 2.13, 1.16–3.91), and stomach cancer (HIV/AIDS 1.90, 1.53–2.36; transplant 2.04, 1.49–2.79). Most common epithelial cancers did not occur at increased rates.” (A. Grulich, U. New South Wales, Darlinghurst, Australia; agrulich@nchecr.unsw.edu.au)
Etravirine for HIV Infection: At week 24, better virologic suppression was recorded with an investigational nonnucleoside reverse-transcriptase inhibitor, etravirine (TMC125), than with placebo (pp. 39-48). In a Phase III trial, treatment-experienced patients who were on stable but failing antiretroviral therapy received either TMC125 in doses of 200 mg twice daily or placebo, with these results: “591 patients were randomised and treated (295 patients in the TMC125 group and 296 in the placebo group). By week 24, 51 (17%) patients in the TMC125 group and 73 (25%) in the placebo group had discontinued, mainly because of virological failure. 183 (62%) patients in the TMC125 group and 129 (44%) in the placebo group achieved confirmed viral load below 50 copies per mL at week 24 (difference 18%, 95% CI 11–26; p = 0.0003). The type and frequency of adverse events were much the same in the two groups.” (A. Lazzarin, San Raffaele U., Milan, Italy; lazzarin.adriano@hsr.it)

>>>PNN JournalWatch
* Managing Smoking Cessation, in BMJ, 2007; 335: 37–41. Reprints: P. Aveyard, U. Birmingham, Birmingham, U.K.; p.n.aveyard@bham.ac.uk
* Randomized Trial to Improve Prescribing Safety in Ambulatory Elderly Patients, in
Journal of the American Geriatrics Society, 2007; 55: 977–85. Reprints: M. A. Raebel, Kaiser Permanente Colorado, Denver; Marsha.A.Raebel@kp.org
* Medicare Part D and Nursing Home Residents, in
Journal of the American Geriatrics Society, 2007; 55: 1115–25. Reprints: D. G. Stevenson, stevenson@hcp.med.harvard.edu
* Is Cocaine Desire Reduced by
N-Acetylcysteine?, in American Journal of Psychiatry, 2007; 164: 1115–7. Reprints: S. D. LaRowe.
* Hepatitis A Vaccine Recommendations, in
Pediatrics, 2007; 120: 189–99. Reprints: American Academy of Pediatrics Committee on Infectious Diseases.
* Prevention of Varicella: Recommendations for Use of Varicella Vaccines in Children, Including a Recommendation for a Routine 2-Dose Varicella Immunization Schedule, in
Pediatrics, 2007; 120: 221–31. Reprints: American Academy of Pediatrics Committee on Infectious Diseases.
* Research Criteria for the Diagnosis of Alzheimer’s Disease: Revising the NINCDS–ADRDA Criteria, in
Lancet Neurology, doi: 10.1016/S1474-4422(07)70178-3. Reprints: B. Dubois, Salpêtrière Hosp., Paris; bruno.dubois@psl.aphp.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 © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 10, 2007 * Vol. 14, No. 132
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
July 9 issue of the Archives of Internal Medicine (http://archinte.ama-assn.org/current.dtl; 2007; 167).
Primary PCI vs. Fibrinolysis for MI in Patients with DM: An analysis of participants in 19 trials shows that patients with diabetes who have ST-segment elevation myocardial infarction benefit more from primary percutaneous coronary intervention than from fibrinolysis, but they still have greater mortality than do patients without diabetes (pp. 1353-9). The pooled analysis assessed the clinical endpoints of total deaths, recurrent MI, death or nonfatal recurrent infarction, and stroke at 30 days, with these results: “Of 6,315 patients, 877 (14%) had diabetes. Thirty-day mortality (9.4% vs 5.9%; P <0.001) was higher in patients with diabetes. Mortality was lower after primary PCI compared with fibrinolysis in both patients with diabetes (unadjusted odds ratio, 0.49; 95% confidence interval, 0.31–0.79; P = 0.004) and without diabetes (unadjusted odds ratio, 0.69; 95% confidence interval, 0.54–0.86, P = 0.001), with no evidence of heterogeneity of treatment effect (P = 0.24 for interaction). Recurrent infarction and stroke were also reduced after primary PCI in both patient groups. After multivariable analysis, primary PCI was associated with decreased 30-day mortality in patients with and without diabetes, with a point estimate of greater benefit in diabetic patients.” (J. P. Ottervanger, Isala Klinieken, Zwolle, the Netherlands; v.r.c.derks@isala.nl)
Bleeding with Warfarin: Bleeding from warfarin use is a prevalent reaction and an important cause of mortality, justifying the black box warning added to the product labeling in 2006, write FDA authors (pp. 1414-9). Based on warfarin prescriptions reported in the National Prescription Audit Plus database of IMS Health, adverse event reports submitted to FDA, deaths caused by therapeutic use of anticoagulants from vital statistics data, and warfarin bleeding complications from national hospital emergency department data, the authors found: “The number of dispensed outpatient prescriptions for warfarin increased 45%, from 21 million in 1998 to nearly 31 million in 2004. The FDA’s Adverse Event Reporting System indicated that warfarin is among the top 10 drugs with the largest number of serious adverse event reports submitted during the 1990 and 2000 decades. From US death certificates, anticoagulants ranked first in 2003 and 2004 in the number of total mentions of deaths for drugs causing ‘adverse effects in therapeutic use.’ Data from hospital emergency departments for 1999 through 2003 indicated that warfarin was associated with about 29,000 visits for bleeding complications per year, and it was among the drugs with the most visits. These data are consistent with literature reports of major bleeding frequencies for warfarin as high as 10% to 16%.” (D. K. Wysowski, diane.wysowski@fda.hhs.gov)

>>>PNN NewsWatch
* Rivastigmine transdermal system (Exelon, Novartis) has been approved by FDA for once-daily treatment of mild to moderate Alzheimer’s disease. Gastrointestinal adverse effects occur much less frequently with the patch, with one-third the number of episodes of nausea and vomiting produced by capsules. The patch is preferred over oral capsules by 70% of Alzheimer’s disease caregivers, who cite better adherence to treatment schedule, less interference with daily lives, and ease of use.
* Three lots of
ertapenem sodium injection (Invanz)—numbers 0803930, 0803940, and 0803950—are being recalled because they may contain broken glass, FDA and Merck report. Broken glass pieces have been found on two occasions in the reconstituted solution for injection of this anti-infective agent. Health care professionals are advised to immediately stop dispensing all products from these three lots.
* At its Pharmacy Strategies Conference yesterday in Boston,
McKesson Corp. announced enhancements to its Health Mart franchise, including a medication adherence network, medication therapy management platform and services, front-end program, and reimbursement optimization services. The MTM program will be piloted in a multiorganizational initiative with the Wisconsin Pharmacy Quality Collaborative, and results will be analyzed by researchers at UCSF.

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

PNN Pharmacotherapy Line
July 11, 2007 * Vol. 14, No. 133
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
July 11 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2007; 298).
Prophylactic Antibiotics & Recurrent UTIs in Children: In a study conducted in 27 primary care pediatric practices, antimicrobial prophylaxis was not associated with decreased risk of recurrent urinary tract infection but was linked to an increased risk of resistant infections (pp. 179-86). Using a time-to-event analysis nested case–control study to analyze data from 2001 to 2006, the investigators found: “Among 74,974 children in the network, 611 (0.007 per person–year) had a first UTI and 83 (0.12 per person–year after first UTI) had a recurrent UTI. In multivariable Cox time-to-event models, factors associated with increased risk of recurrent UTI included white race (0.17 per person–year; hazard ratio [HR], 1.97; 95% confidence interval [CI], 1.22–3.16), age 3 to 4 years (0.22 per person–year; HR, 2.75; 95% CI, 1.37–5.51), age 4 to 5 years (0.19 per person–year; HR, 2.47; 95% CI, 1.19–5.12), and grade 4 to 5 vesicoureteral reflux (0.60 per person–year; HR, 4.38; 95% CI, 1.26–15.29). Sex and grade 1 to 3 vesicoureteral reflux were not associated with risk of recurrence. Antimicrobial prophylaxis was not associated with decreased risk of recurrent UTI (HR, 1.01; 95% CI, 0.50–2.02), even after adjusting for propensity to receive prophylaxis, but was a risk factor for antibimicrobial resistance among children with recurrent UTI (HR, 7.50; 95% CI, 1.60–35.17).” (P. H. Conway, pconway2@mail.med.upenn.edu)
Reduced Risk of Diabetes with Hydroxychloroquine: Patients with rheumatoid arthritis have a lower risk of diabetes when treated with hydroxychloroquine, according to a prospective observational study of 4,905 adults with 21.5 years of follow-up (pp. 187-93). The investigators compared 1,808 patients who used hydroxychloroquine with 3,097 never-users, with these results: “During the observation period, incident diabetes was reported by 54 patients who had taken hydroxychloroquine and by 171 patients who had never taken hydroxychloroquine, with incidence rates of 5.2 per 1,000 patient–years of observation compared with 8.9 per 1,000 patient–years of observation, respectively (P <0.001). In time-varying multivariable analysis with adjustments for possible confounding factors, the hazard ratio for incident diabetes among patients who had taken hydroxychloroquine was 0.62 (95% confidence interval, 0.42-0.92) compared with those who had not taken hydroxychloroquine. In Poisson regression, the risk of incident diabetes was significantly reduced with increased duration of hydroxychloroquine use (P <0.001 for trend); among those taking hydroxychloroquine for more than 4 years (n = 384), the adjusted relative risk of developing diabetes was 0.23 (95% confidence interval, 0.11-0.50; P <0.001), compared with those who had not taken hydroxychloroquine.” (M. C. M. Wasko, wasko@pitt.edu)
Incretin Therapy in Type 2 Diabetes: For nonpregnant adults with type 2 diabetes, incretin therapy offers “an alternative option” to hypoglycemic agents, concludes a systematic review and meta-analysis (pp. 194-206). But “careful postmarketing surveillance” is needed for these agents, especially the dipeptidyl peptidase 4 inhibitors, the authors add, noting: “Of 355 potentially relevant articles identified, 51 were retrieved for detailed evaluation and 29 met the inclusion criteria. Incretins lowered hemoglobin A1c compared with placebo (weighted mean difference, –0.97% [95% confidence interval {CI}, –1.13% to –0.81%] for [glucagonlike peptide]-1 analogues and –0.74% [95% CI, –0.85% to –0.62%] for DPP4 inhibitors) and were noninferior to other hypoglycemic agents. Glucagonlike peptide 1 analogues resulted in weight loss (1.4 kg and 4.8 kg vs placebo and insulin, respectively) while DPP4 inhibitors were weight neutral. Glucagonlike peptide 1 analogues had more gastrointestinal side effects (risk ratio, 2.9 [95% CI, 2.0–4.2] for nausea and 3.2 [95% CI, 2.5–4.4] for vomiting). Dipeptidyl peptidase 4 inhibitors had an increased risk of infection (risk ratio, 1.2 [95% CI, 1.0–1.4] for nasopharyngitis and 1.5 [95% CI, 1.0–2.2] for urinary tract infection) and headache (risk ratio, 1.4 [95% CI, 1.1–1.7]). All but 3 trials had a 30-week or shorter duration; thus, long-term efficacy and safety could not be evaluated.” (A. G. Pittas, apittas@tufts-nemc.org)

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

PNN Pharmacotherapy Line
July 12, 2007 * Vol. 14, No. 134
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
July 12 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2007; 357).
Treatment of Hepatitis C Virus Infection: The standard 24-week regimen of peginterferon alfa-2a/ribavirin produced better sustained virologic responses among 1,469 patients with hepatitis C virus genotype 2 or 3 infection than did a shorter 16-week regimen of the same drugs (pp. 124-34). Defining sustained virologic response as an undetectable serum HCV RNA level (<50 IU/mL) at 24 weeks after the end of treatment, the researchers found: “The study failed to demonstrate that the 16-week regimen was noninferior to the 24-week regimen. The sustained virologic response rate was significantly lower in patients treated for 16 weeks than in patients treated for 24 weeks (62% vs. 70%; odds ratio for 16 weeks vs. 24 weeks, 0.67; 95% confidence interval, 0.54 to 0.84; P <0.001). In addition, the rate of relapse (a detectable HCV RNA level during follow-up in patients who had undetectable HCV RNA at the end of treatment) was significantly greater in the 16-week group (31%, vs. 18% in the 24-week group; P <0.001). The sustained virologic response rates in patients with a pretreatment serum HCV RNA level of 400,000 IU per milliliter or less was 82% with the 16-week regimen and 81% with the 24-week regimen. Among patients with a rapid virologic response (an undetectable HCV RNA level by week 4), sustained virologic response rates were 79% in the 16-week group and 85% in the 24-week group (P = 0.02).” (M. L. Shiffman, mshiffma@vcu.edu)
Individualized approaches are increasingly needed for managing HCV, an editorialist writes (pp. 176-8): “How can we harness these advances for the clinical management of infection with HCV? Such management, like that for other complex chronic diseases, may be morphing into a personalized approach that could gradually supplant ‘one-size-fits-all’ medicine. This paradigm shift signifies an emerging trend in the future of medicine, as we translate basic science into clinical medicine. This translation has already occurred in cancer chemotherapy and other therapeutics, with the use of the genetic blueprints of individual patients. As more markers associated with responses to treatment for HCV infection are identified, a mathematical model based on all such markers could be developed to predict the ultimate treatment response in a given patient. Instead of shortened therapy for patients with HCV genotype 2 or 3, a customized management and therapeutic regimen would be designed for each patient. In the context of the study by Schiffman et al., patients with HCV genotype 3, high viral load, advanced fibrosis, and obesity who are black, older, and male should be treated for 24 weeks, and whites with HCV genotype 2 and with the opposite characteristics could be treated for a shorter duration.” (T. J. Liang, NIH, Bethesda, Md.)

>>>Circulation Report
Source:
Early-release article from and the July 10 issue of Circulation (http://circ.ahajournals.org/current.shtml).
SALT for Low-Renin Hypertension: In the Spironolactone, Amiloride, Losartan, and Thiazide (SALT) trial, bendroflumethiazide 5 mg was as effective as spironolactone in hypertensive patients with a low plasma renin but normal potassium levels (doi: 10.1161/CIRCULATIONAHA.107.690396). After reporting similar hypotensive effects with the above drugs at those doses, the researchers conclude: “Because this result differs from that expected in primary hyperaldosteronism, our finding argues against low-renin hypertension including a large, undiagnosed pool of primary hyperaldosteronism. However, spironolactone was the more effective natriuretic agent, suggesting that inappropriate aldosterone release or response may still contribute to the Na+ retention of low-renin hypertension.” (M. J. Brown, U. Cambridge, Cambridge, U.K.; m.j.brown@cai.cam.ac.uk)
Arginine Supplementation in PAD: In contrast to benefits observed with short-term administration of l-arginine, long-term use failed to increase nitric oxide synthesis or improve vascular reactivity in a 6-month study of 133 patients with intermittent claudication caused by peripheral arterial disease (pp. 188-95). The authors add, “The expected placebo effect observed in studies of functional capacity was attenuated in the l-arginine-treated group.” (J. P. Cooke, john.cooke@stanford.edu)

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

PNN Pharmacotherapy Line
July 13, 2007 * Vol. 14, No. 135
Providing news and information about medications and their proper use

>>>JAPhA Highlights
Source:
Jul/Aug issue of the Journal of the American Pharmacists Assoc. (www.japha.org; 2007; 47)
Pharmacist Supply: The number of pharmacists practicing in the U.S. has ballooned since 2000, report researchers who reanalyzed the pharmacist workforce projections for 2020 (pp. 463-70). The increase has been driven primarily by pharmacists working longer and the growing number of schools and campuses of pharmacy, the authors note, adding these details: “Increased U.S. pharmacist supply estimates (236,227 in 2007 to 304,986 in 2020) indicate that pharmacists will remain the third largest professional health group behind nurses and physicians. Increases were driven by longer persistence in the workforce (59%), increased numbers of U.S. graduates (35%), and increases from international pharmacy graduates (IPGs) achieving U.S. licensure (6%). Since more pharmacists are expected to be working part time the full-time equivalent (FTE) supply will be reduced by about 15%. The mean age of pharmacists was projected to decline from 47 to 43 by 2020. Because of unequal distribution across age groups, large pharmacist cohorts approaching retirement age will result in fewer pharmacists available to replace them. The ratio of pharmacists to the over-65 population is expected to decrease after 2011 and continue to fall beyond 2020; this is likely a reflection of baby boomers passing through older age cohorts.” (K. K. Knapp, kknapp@touro.edu)
MTM Pilot Project in N.C.: Pharmacist-delivered medication therapy management at community pharmacies and an ambulatory clinic in North Carolina “did not necessarily result in reductions in prescription drug use or cost,” concludes a study conducted from 2004 to 2006 (pp. 471-83). Comparing 67 patients who used a large number of prescription medications with some 600 participants in two control groups, the researchers found this impact of the efforts of 10 community/ambulatory pharmacists: “Pharmacists identified an average of 3.6 potential drug therapy problems (PDTPs) per patient at the first visit. The most common PDTP categories were ‘potential underuse’ and ‘more cost-effective drug available.’ Pharmacist actions were divided nearly equally between activities that would result in increased and decreased drug use. Pharmacists recommended a drug therapy change in about 50% of patients and contacted the prescriber more than 85% of the time. About 50% of patients with PDTPs had a change in drug therapy. Prescription use during the post-intervention period decreased in both the study and control groups but was statistically significant only among the control groups. No significant differences were observed in patient co-payment or insurer prescription costs. Pharmacists provided the following educational services: medication use (90%), disease management (88%), adherence, and self-care (60%). Survey results indicated that patients highly valued the service.” (D. B. Christensen, U. North Carolina, Chapel Hill; dalechristensen@whidbey.com)
CPT Code-Change Proposal: Over a 2-year period, nearly 2.8 million medication therapy management encounters occurred at 240 practice sites in the U.S. and in the VA system, according to data submitted to the CPT Editorial Panel by the Pharmacist Services Technical Advisory Coalition (pp. 491-5). Using a purposive sampling technique to provide support for a petition to change the CPT codes used in billing for pharmacists’ MTM services to Category 1 (permanent), the Coalition identified 858,405 face-to-face MTM encounters at 240 practice sites in all 50 states, the District of Columbia, and Puerto Rico. Nearly 1 million face-to-face patient encounters were reported each year in the VA system, with care provided to 327,817 unique patients, usually in primary care and medicine clinics. “Migration of MTM CPT codes to Category I status should help patients gain increased access to these services,” the authors conclude, adding that a decision of the CPT panel will be disclosed when CPT 2008 is released in Oct. 2007. “As more pharmacists provide MTM services and bill for them using CPT codes, more payers can be expected to provide compensation. The next steps in the evolution of MTM CPT codes are to gather data in support of tiered intensity or resource-based relative value scale codes and establish the relative value of MTM services.” (B. J. Isetts, isett001@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 © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 16, 2007 * Vol. 14, No. 136
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
July 14 issue of Lancet (www.thelancet.com; 2007; 370).
Appropriate Prescribing in the Elderly: Use of geriatric medicine service approaches, pharmacist involvement in patient care, and computerized decision support are three approaches shown to improve appropriateness of prescribing for older patients in a variety of settings, according to a review article that is the first in a series on Prescribing in Elderly People (pp. 173-84). “Prescribing is no longer viewed as a solitary activity undertaken by physicians,” the authors conclude. “Prescribing authority in the UK has been extended to other health professions, notably nursing and pharmacy. Continual assessment of pharmacist prescribing suggests that it has been positively received by the medical profession. There has been very little objective robust data for the effect of prescribing by pharmacists on patient outcome, so further assessment will be needed.” (A. Spinewine, Ctr. for Clinical Pharmacy, Université catholique de Louvain, Brussels, Belgium; anne.spinewine@facm.ucl.ac.be)
Staged-Approach Chemotherapy for Advanced Colorectal Cancer: A comparison of sequential versus combination chemotherapy in 2,135 patients challenges the assumption that maximum tolerated treatment must be used first in advanced or metastatic colorectal cancer (pp. 143-52). Study participants were previously untreated and were being managed with noncurative intent. Comparing single-agent fluorouracil until failure followed by single-agent irinotecan (strategy A; control group); fluorouracil until failure (B), then combination chemotherapy with either fluorouracil plus irinotecan (B-ir) or fluorouracil plus oxaliplatin (B-ox); and combination chemotherapy (C-ir or C-ox), the authors found: “Median survival of patients allocated to control strategy A was 13.9 months. Median survival of each of the other groups was longer (B-ir 15.0, B-ox 15.2, C-ir 16.7, and C-ox 15.4 months). However, log-rank comparison of each group against control showed that only C-ir—the first-line combination strategy including irinotecan—satisfied the statistical test for superiority (p = 0.01). Overall comparison of strategy B with strategy C was within the predetermined non-inferiority boundary of HR = 1.18 or less (HR = 1.06, 90% CI 0.97–1.17).” (M. Seymour, Cookridge Hosp., Leeds, U.K.; matt.seymour@leedsth.nhs.uk)

>>>BMJ Highlights
Source:
July 14 issue of BMJ (www.bmj.org; 2007; 335).
Probiotics in Hospitalized Adults: The incidence of antibiotic-associated diarrhea and Clostridium difficile–associated diarrhea was reduced among 135 patients aged 50 and older who consumed a probiotic preparation during courses of antibiotics during hospitalization (pp. 80 ff). During courses of antibiotics and for 1 week afterwards, study participants drank either a probiotic drink containing Lactobacillus casei, L. bulgaricus, and Streptococcus thermophilus or a control milkshake, with these results: “7/57 (12%) of the probiotic group developed diarrhoea associated with antibiotic use compared with 19/56 (34%) in the placebo group (P = 0.007). Logistic regression to control for other factors gave an odds ratio 0.25 (95% confidence interval 0.07 to 0.85) for use of the probiotic, with low albumin and sodium also increasing the risk of diarrhoea. The absolute risk reduction was 21.6% (6.6% to 36.6%), and the number needed to treat was 5 (3 to 15). No one in the probiotic group and 9/53 (17%) in the placebo group had diarrhoea caused by C difficile (P = 0.001). The absolute risk reduction was 17% (7% to 27%), and the number needed to treat was 6 (4 to 14).” (M Hickson, Imperial Coll., London; mhickson@hhnt.nhs.uk)

>>>PNN JournalWatch
* Immunology of Helicobacter pylori: Insights into the Failure of the Immune Response and Perspectives on Vaccine Studies, in Gastroenterology, 2007; 133: 288–308. Reprints: K. T. Wilson, keith.wilson@vanderbilt.edu
* Mumps Outbreaks in Canada and the United States: Time for New Thinking on Mumps Vaccines, in
Clinical Infectious Diseases, 2007; 45: CID50311ABS. Reprints: H. Peltola.

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

PNN Pharmacotherapy Line
July 17, 2007 * Vol. 14, No. 137
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release articles from and July 17 issue of Annals of Internal Medicine (www.annals.org; 2007; 147).
Oral Medications for DM: Older oral antidiabetic agents (second-generation sulfonylureas and metformin) are as good as or better than newer, more expensive agents (thiazolidinediones, alpha-glucosidase inhibitors, and meglitinides), concludes a systematic review (early release). Based on data included in 216 controlled trials published by Jan. 2006 and 2 systematic reviews published by Nov. 2005, the authors note: “Evidence from clinical trials was inconclusive on major clinical end points, such as cardiovascular mortality. Therefore, the review was limited mainly to studies of intermediate end points. Most oral agents (thiazolidinediones, metformin, and repaglinide) improved glycemic control to the same degree as sulfonylureas (absolute decrease in hemoglobin A1c level of about 1 percentage point). Nateglinide and alpha-glucosidase inhibitors may have slightly weaker effects, on the basis of indirect comparisons of placebo-controlled trials. Thiazolidinediones were the only class that had a beneficial effect on high-density lipoprotein cholesterol levels (mean relative increase, 0.08 to 0.13 mmol/L [3 to 5 mg/dL]) but a harmful effect on low-density lipoprotein (LDL) cholesterol levels (mean relative increase, 0.26 mmol/L [10 mg/dL]) compared with other oral agents. Metformin decreased LDL cholesterol levels by about 0.26 mmol/L (10 mg/dL), whereas other oral agents had no obvious effects on LDL cholesterol levels. Most agents other than metformin increased body weight by 1 to 5 kg. Sulfonylureas and repaglinide were associated with greater risk for hypoglycemia, thiazolidinediones with greater risk for heart failure, and metformin with greater risk for gastrointestinal problems compared with other oral agents. Lactic acidosis was no more common in metformin recipients without comorbid conditions than in recipients of other oral diabetes agents.” (S. Bolen, Johns Hopkins U., Baltimore; sgolden4@jhmi.edu)
Gonorrheal Resistance to Fluoroquinolones: Ongoing national and local antimicrobial susceptibility monitoring of Neisseria gonorrhoeae isolates is needed for appropriate treatment of gonorrhea, concludes an analysis of U.S. trends (pp. 81-8). Noting that penicillin resistance has waned in the years since its use was discontinued but resistance to fluoroquinolones is climbing, the investigators report these findings for 82,064 episodes of urethral gonorrhea in 1988 through 2003: “The median age of patients was 26 years, and 74.1% of patients were African American. The proportion of men treated with penicillins for gonorrhea declined from 39.5% in 1988 to 0% in 1994, while the proportion of those receiving fluoroquinolone treatment increased from 0% in 1988 to 42.0% in 2003. Penicillin resistance peaked at 19.6% in 1991, then declined to 6.5% in 2003. Tetracycline resistance peaked at 25.8% in 1997 and declined to 14.4% in 2003. The first fluoroquinolone-resistant isolate was found in 1991. Nationally, 0.4% of isolates were fluoroquinolone-resistant in 1999 and were identified in 39% of [Gonococcal Isolate Surveillance Project] cities. By 2003, 4.1% of isolates were fluoroquinolone-resistant and were identified in 70% of GISP cities. Isolates with decreased susceptibility to ceftriaxone, cefixime, azithromycin, and spectinomycin remained rare. In 2001, 3 multidrug-resistant isolates with decreased susceptibility to cefixime were identified.” (S. A. Wang, sjw8@cdc.gov)
Refining Evidence-Based Recommendation Development: The U.S. Preventive Services Task Force reports refinements in the way it develops evidence-based guidelines, including new methods for evidence reviews and recommendation development (pp. 117-22; www.preventiveservices.ahrq.gov; 800/358-9295; AHRQPubs@ahrq.hhs.gov)

>>>PNN NewsWatch
* FDA yesterday approved the GeneSearch BLN Assay (Veridex), the first molecular-based laboratory test for detecting breast cancer in sentinel lymph nodes. In a clinical trial, the assay showed strong agreement with results from extensive microscopic examination of the lymph nodes of 416 patients. The test accurately predicted that breast cancer had spread nearly 88% of the time in women with metastasis. Patients without metastasis were identified accurately 94% of the time.

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

PNN Pharmacotherapy Line
July 18, 2007 * Vol. 14, No. 138
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
July 18 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2007; 298).
Detecting Adverse Drug Effects: The possibility of implementing computer-based pharmacoepidemiology in the U.S. is explored in a Commentary (pp. 333-4). The authors acknowledge that the U.S. has a health care system based in autonomous private practices and that the profit motive in the pharmaceutical industry complicates aggressive recognition of adverse drug effects. Nevertheless, they note, the availability of “large managed care organizations, the federally supported and regulated medical systems, such as the Veterans Affairs systems, the armed forces, and the Medicare clinical database, which is potentially linked to medication exposure through the Medicare Part D program” could lead to quick establishment of a computerized system for assuring drug safety. They conclude: “There is a fortunate confluence of interests since cross-linked computerized medical records would not only help to improve communication within the health system thus likely reducing medical errors, but also would help to facilitate detection of rare adverse events. Another benefit of such linked databases is suggested by the unexpected finding of apparent beneficial effects of selective serotonin reuptake inhibitors on nonpsychiatric illness. The mining of such data may result in unexpected applications of already marketed safe drugs for new important purposes, a form of computerized serendipity. These findings would require adequate clinical trials for proof. However, the level of profitability may be small and patent rights on the new indication would be complex. Therefore, actually conducting clinical trials based on unanticipated survey findings presents problems for a profit-driven industry. An alternative funding and selection mechanism is needed, which would require appropriate discussion and legislation ensuring swift objective analyses and actions.” (C. P. O’Brien, brien@mail.trc.upenn.edu">obrien@mail.trc.upenn.edu)
Healthy Eating for Treating Breast Cancer: In the Women’s Healthy Eating and Living (WHEL) trial, survivors of early breast cancer had no reduction in additional breast cancer events or mortality when they consumed a diet very high in vegetables, fruit, and fiber and low in fat during a 7.3-year follow-up period (pp. 289-98). The 3,088 women participants in the trial received either telephone counseling supplemented with cooking classes and newsletters promoting the healthy diet or print materials promoting the “5-A-Day” dietary guidelines, with these results: “From comparable dietary patterns at baseline, a conservative imputation analysis showed that the intervention group achieved and maintained the following statistically significant differences vs the comparison group through 4 years: servings of vegetables, +65%; fruit, +25%; fiber, +30%, and energy intake from fat, –13%. Plasma carotenoid concentrations validated changes in fruit and vegetable intake. Throughout the study, women in both groups received similar clinical care. Over the mean 7.3-year follow-up, 256 women in the intervention group (16.7%) vs 262 in the comparison group (16.9%) experienced an invasive breast cancer event (adjusted hazard ratio, 0.96; 95% confidence interval, 0.80–1.14; P = .63), and 155 intervention group women (10.1%) vs 160 comparison group women (10.3%) died (adjusted hazard ratio, 0.91; 95% confidence interval, 0.72–1.15; P = .43). No significant interactions were observed between diet group and baseline demographics, characteristics of the original tumor, baseline dietary pattern, or breast cancer treatment.” (J. P. Pierce, jppierce@ucsd.edu)
Triglycerides & Cardiovascular Health: Two articles and an editorial explore the relationship between nonfasting triglyceride levels and various cardiovascular indices (pp. 299-308; 309-16; 336-8). The editorialist provides this advice to clinicians: “It is important to recognize that when triglyceride levels are between 150 and 1,000 mg/dL, the risk for atherosclerosis-related events is significantly increased. Therefore, it is important to aggressively and comprehensively treat patients with dyslipidemias that include high levels of triglycerides, low levels of HDL-C, and the presence of small LDL-C particles, using both lifestyle change and medications if necessary.” (P. E. McBride, pem@medicine.wisc.edu)

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

PNN Pharmacotherapy Line
July 19, 2007 * Vol. 14, No. 139
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Early-release article from and July 19 issue of the New England Journal of Medicine (http://content.nejm.org/; 2007; 357).
FDA Reform: Seeking to influence a House–Senate committee that is resolving differences between the two chambers’ FDA reauthorization legislation, Journal editors call for these components in the final version (doi: 10.1056/NEJMe078154; G. D. Curfman):
* Authority for FDA to mandate adequately powered postmarketing clinical trials of the safety of approved drugs and to require specific timetables for their completion and reporting of results
* Authority to conduct an annual review of drug safety for the first 3 years after a drug’s approval and again at 7 years
* Inclusion in drug advertising to patients of a toll-free telephone number and a Web address for adverse drug reaction reporting
* Substantial penalties for drug advertising that overstates efficacy or understates adverse effects
* Ability for FDA to mandate changes to drug labels as new information about safety and efficacy becomes available
* A pharmacovigilance plan at the time of approval of every drug
* Registration of clinical trials in a public database
Prophylaxis in Peripheral Arterial Disease: In the Warfarin Antiplatelet Vascular Evaluation (WAVE) trial, combination oral anticoagulant and antiplatelet therapy was no more effective than antiplatelet therapy alone in preventing major cardiovascular complications but was associated with an increase in life-threatening bleeding (pp. 217-27). Targeting combination therapy to an INR of 2.0 to 3.0, the WAVE investigators determined: “A total of 2161 patients were randomly assigned to therapy. The mean follow-up time was 35 months. Myocardial infarction, stroke, or death from cardiovascular causes occurred in 132 of 1080 patients receiving combination therapy (12.2%) and in 144 of 1081 patients receiving antiplatelet therapy alone (13.3%) (relative risk, 0.92; 95% confidence interval [CI], 0.73 to 1.16; P = 0.48). Myocardial infarction, stroke, severe ischemia, or death from cardiovascular causes occurred in 172 patients receiving combination therapy (15.9%) as compared with 188 patients receiving antiplatelet therapy alone (17.4%) (relative risk, 0.91; 95% CI, 0.74 to 1.12; P = 0.37). Life-threatening bleeding occurred in 43 patients receiving combination therapy (4.0%) as compared with 13 patients receiving antiplatelet therapy alone (1.2%) (relative risk, 3.41; 95% CI, 1.84 to 6.35; P <0.001).” (S. Anand, anands@mcmaster.ca)
An editorialist concurs with use of antiplatelet therapy alone in these patients (pp. 293-6): “At this time, the data indicate that antiplatelet treatment alone affords a better outcome than does combined therapy with an anticoagulant in the long-term management of peripheral arterial disease. Further information on the pathobiologic basis for bleeding in patients with peripheral arterial disease is needed to develop successful clinical strategies to prevent bleeding and to devise safer antiplatelet and anticoagulant drugs.” (E. R. Mohler III, U. Pennsylvania, Philadelphia)
Certolizumab Pegol for Crohn’s Disease: Two research studies report modest benefits associated with use of an investigational pegylated Fab fragment that binds tumor necrosis factor alpha in patients with moderate to severe Crohn's disease (pp. 228-38; 239-50). Commenting on certolizumab pegol, an editorialist makes these comparisons with adalimumab (pp. 296-8): “Certolizumab and adalimumab are designed to be self-administered. As such, monitoring adherence to therapy may be difficult. On the other hand, self-administration saves indirect costs, such as time lost from work, and as such may be more appealing to some patients than administration of the drug by a practitioner; it may even increase adherence to therapy. What effect self-administration may have on safety is unknown, although the adverse-event profiles in the PRECISE trials were similar to those expected on the basis of other trials of anti–TNF-alpha drugs. The authors of the PRECISE trials appropriately caution against trying to directly compare the different anti–TNF-alpha antibodies on the basis of published reports on clinical trials. However, in the absence of head-to-head clinical trials, or even studies of comparative effectiveness, such comparisons will probably be common.” (J. D. Lewis, U. Pennsylvania, Philadelphia)

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

PNN Pharmacotherapy Line
July 20, 2007 * Vol. 14, No. 140
Providing news and information about medications and their proper use

>>>Cardiology Report
Source:
July 17 and 24 issues of the Journal of the American College of Cardiology (http://content.onlinejacc.org/current.dtl; 2007; 50).
No Interaction Between Clopidogrel, Statin: In the CHARISMA trial, no evidence was uncovered that supports theoretical concerns and ex vivo results indicating a potential detrimental interaction between clopidogrel and statins metabolized by the CYP 3A4 isoenzyme (pp. 291-5). Comparing data on statins predominantly metabolized by 3A4 (atorvastatin, lovastatin, simvastatin; CYP3A4-MET) with other statins (pravastatin, fluvastatin; non–CYP3A4-MET), the authors identified these outcomes in patients also receiving long-term clopidogrel 75 mg/day: “Of 15,603 patients enrolled, 10,078 received a statin at baseline (8,245 CYP3A4-MET, 1,748 non–CYP3A4-MET) and 5,496 did not. For the overall population, the primary end point [composite of myocardial infarction, stroke, or cardiovascular death at median follow-up of 28 months] was 6.8% with clopidogrel and 7.3% with placebo (hazard ratio [HR] 0.93; p = 0.22). This was similar among patients on CYP3A4-MET (5.9% clopidogrel, 6.6% placebo, HR 0.89; p = 0.18) or non–CYP3A4-MET statin (5.7% clopidogrel, 7.2% placebo, HR 0.78; p = 0.19). There was no interaction between statin types and randomized treatment (p = 0.69). Patients on atorvastatin (n = 4,127) (5.7% clopidogrel, 7.1% placebo, HR 0.80; p = 0.06) or pravastatin (n = 1,440) (5.1% clopidogrel, 7.0% placebo, HR 0.72; p = 0.13) had similar event rates.” (E. J. Topol, etopol@scripps.edu)
Racial Differences with Warfarin Bleeding in AF: Warfarin-related intracranial hemorrhage occurred more frequently in nonwhites than whites in an analysis of racial-ethnic differences in crude ICH event rates combined with data from pharmacy and laboratory records (pp. 309-15). Concluding that blacks, Hispanics, and Asians were at successively greater ICH risk than whites, the investigators report these details: “Between 1995 and 2000, we identified 18,867 qualifying AF hospitalizations (78.5% white, 8% black, 9.5% Hispanic, and 3.9% Asian) and 173 qualifying ICH events over 3.3 years follow-up. Achieved anticoagulation intensity was lower among blacks but not different between the other groups. Warfarin was associated with increased ICH risk in all races, but the magnitude of risk was greater among nonwhites. There were no gender differences. The hazard ratio for ICH with whites as referent was 4.06 for Asians (95% confidence interval [CI] 2.47 to 6.65), 2.06 for Hispanics (95% CI 1.31 to 3.24), and 2.04 (95% CI 1.25 to 3.35) for blacks.” (A. Yuh-Jer Shen, Kaiser Foundation Hosp., Los Angeles; albert.y-j.shen@kp.org)
Framingham Predictions in Kidney Disease: The Framingham instrument poorly predicts cardiac events in individuals with chronic kidney disease, but discrimination can be improved through use of refit models, concludes an analysis of pooled data from the ARIC (Atherosclerosis Risk In Communities) and CHS (Cardiovascular Health Study) trials (pp. 217-24): “There were 577 women and 357 men with CKD. Thirty-five men (9.8%) and 30 women (5.2%) and 74 men (20.7%) and 56 women (9.7%) had cardiac events within 5 and 10 years, respectively; 5-year events were predicted in 6.0% and 1.9% and 10-year events in 13.9% and 4.8% of men and women, respectively. For 5-year events, C-statistics assessing discrimination were 0.62 and 0.77, while 10-year C-statistics were 0.60 and 0.73 for men and women, respectively. Calibration was also poor, with Framingham scores generally underpredicting events in individuals with CKD at 5 and 10 years. Discrimination was significantly improved by refitting models with population-specific coefficients, while recalibration improved prediction in women.” (D. E. Weiner, dweiner@tufts-nemc.org)

>>>PNN NewsWatch
* Rosiglitazone provides no better A1C levels than do other antidiabetic therapies, according to a systematic review just released by the Cochrane Library. Most of the 18 trials of 8,432 people failed to address mortality, diabetes-related morbidity, or quality of life. Adverse effects confirmed in the analysis were edema and weight gain of 5 kg. New studies are needed to assess trade-offs, the review states.

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

PNN Pharmacotherapy Line
July 23, 2007 * Vol. 14, No. 141
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
July 21 issue of BMJ (www.bmj.org; 2007; 335).
Outcomes with Self-Monitoring of Blood Glucose: Among reasonably well controlled noninsulin-treated patients with type 2 diabetes, use of self-monitoring of blood glucose is of questionable effectiveness in improving glycemic control, according to a study of 453 patients in 46 general practices in the U.K. (pp. 132 ff). Three groups were compared—a control group that received usual care and glycosylated hemoglobin measurements every 3 months, a group that used self-monitoring and was advised to contact their physicians for interpretation of results, and a self-monitoring group that received additional training in interpretation and application of results. The investigators report: “At 12 months the differences in HbA1c level between the three groups (adjusted for baseline HbA1c level) were not statistically significant (P = 0.12). The difference in unadjusted mean change in HbA1c level from baseline to 12 months between the control and less intensive self monitoring groups was –0.14% (95% confidence interval –0.35% to 0.07%) and between the control and more intensive self monitoring groups was –0.17% (–0.37% to 0.03%).” (A. Farmer, U. Oxford, Oxford, U.K.; andrew.farmer@dphpc.ox.ac.uk)

>>>Lancet Highlights
Source:
Early-release articles from Lancet (www.thelancet.com; 2007; 370).
Normalizing CD4 Counts in Patients with HIV: If combination antiretroviral therapy can be maintained for a sufficiently long time period, CD4 counts normalize in patients with HIV, report researchers who studied 1,835 antiretroviral-naive patients who started cART in EuroSIDA, a pan–European observational cohort study (DOI: 10.1016/S0140-6736(07)60948-9). Rates of increase in CD4 counts per year were assessed between pairs of consecutive viral load assays that were below 50 copies/mL, with these results: “The median CD4 count at starting cART was 204 cells per µL ([interquartile range] 85–330). The greatest mean yearly increase in CD4 count of 100 cells per µL was seen in the year after starting cART. Significant, but lower, yearly increases in CD4 count, around 50 cells per µL, were seen even at 5 years after starting cART in patients whose current CD4 count was less than 500 cells per µL. The only groups without significant increases in CD4 count were those where cART had been taken for more than 5 years with a current CD4 count of more than 500 cells per µL, (current mean CD4 count 774 cells per µL; 95% CI 764–783). Patients starting cART with low CD4 counts (<200 cells per µL) had significant rises in CD4 counts even after 5 years of cART.” (A. Mocroft, Royal Free and U. Coll. London Med. Sch., London; a.mocroft@pcps.ucl.ac.uk)
Commenting on this study, editorialists note (doi: 10.1016/S0140-6736(07)60949-0): “A potential weakness is that [these authors] included patients with intermittent periods of virological suppression, analysing only those periods when suppression was present, although censoring the analysis at time of first viral rebound or adjusting for the time each patient spent with unsuppressed viraemia did not affect the findings. Loss of virological suppression followed by re-suppression could result in different CD4 responses. Nevertheless, the researchers have shown that at least for patients with ideal responses to combination ART, normalisation of CD4 counts is likely to be achievable across a range of baseline counts.” (G. Maartens, U. Cape Town, Cape Town, South Africa;
gary.maartens@uct.ac.za

>>>PNN JournalWatch
* Are Citizens Of The World Satisfied With Their Health?, in Health Affairs, doi: 10.1377/hlthaff.26.5.w545. Reprints: J. Clifton, Gallup Organization, Washington, D.C.
* Internet-Based Self-Management Offers an Opportunity To Achieve Better Asthma Control in Adolescents, in
Chest, 2007; 132: 112–9. Reprints: V. van der Meer, Leiden U. Med. Ctr., Leiden, the Netherlands; V.van_der_Meer@lumc.nl
* Understanding How Leading Bacterial Pathogens Subvert Innate Immunity to Reveal Novel Therapeutic Targets, in
Journal of Allergy and Clinical Immunology, 2007; 120: 13–22. Reprints: V. Nizet, vnizet@ucsd.edu
* Traditional Chinese Herbal Remedies for Asthma and Food Allergy, in
Journal of Allergy and Clinical Immunology, 2007; 120: 25–31. Reprints: X-M Li, Mount Sinai Sch. of Med., New York; xiu-min.li@mssm.edu

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

PNN Pharmacotherapy Line
July 24, 2007 * Vol. 14, No. 142
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
July 23 issue of the Archives of Internal Medicine (http://archinte.ama-assn.org/current.dtl; 2007; 167).
Preventing Outpatient Venous Thromboembolism: Responding to a research study in this issue of Archives (pp. 1471-5; F. A. Spencer, fspence@mcmaster.ca) that shows that outpatient venous thromboembolism is threefold more common than inpatient VTE, almost one-half of the outpatients with VTE had been recently hospitalized, and fewer than one-half of the recently hospitalized patients had received VTE prophylaxis during their hospitalization, an editorialist calls for action in the inpatient setting (pp. 1451-2): “The culture surrounding inpatient VTE prophylaxis is undergoing a transition from optional to mandatory. For example, in 2003, Medicare and the Centers for Disease Control and Prevention initiated the Surgical Care Improvement Project. The aim is to reduce the rate of surgical complications such as infection, myocardial infarction, and VTE. Medicare has recently launched 2 official quality VTE prophylaxis process (not outcome) measures under this initiative: (1) surgical patients will be expected to have recommended VTE prophylaxis ordered, and (2) surgical patients will be expected to receive appropriate VTE prophylaxis within 24 hours before surgery to 24 hours after surgery. While these measures may seem modest, they constitute an important first official step in the eventual mandating of VTE prophylaxis.” (Samuel Z. Goldhaber, sgoldhaber@partners.org)
Drug Prophylaxis of Venous Thromboembolism: In direct comparisons, low molecular weight heparins are more effective for preventing deep venous thrombosis than is unfractionated heparin, conclude authors of a meta-analysis of 36 randomized controlled trials (pp. 1476-86). Noting that both treatments reduce venous thromboembolic risk but neither alters mortality in hospitalized medical patients, the researchers add: “Compared with the control, UFH was associated with a reduced risk of ... DVT (risk ratio [RR], 0.33; 95% confidence interval [CI], 0.26–0.42) and pulmonary embolism (RR, 0.64; 95% CI, 0.50–0.82), as was LMWH (RR, 0.56; 95% CI, 0.45–0.70; and RR, 0.37; 95% CI, 0.21–0.64, respectively). A UFH dosage of 5,000 U 3 times daily was more effective in preventing DVT than a UFH dosage of 5,000 U twice daily when compared with the control (RR, 0.27; 95% CI, 0.20–0.36; vs RR, 0.52; 95% CI, 0.28–0.96). Neither UFH nor LMWH reduced mortality. When directly compared with UFH, LMWH was associated with a lower risk of DVT (RR, 0.68; 95% CI, 0.52–0.88) and injection site hematoma (RR, 0.47; 95% CI, 0.36–0.62), but no difference was seen between the 2 agents in the risk of bleeding or thrombocytopenia.” (H. Krum, Monash U., Melbourne, Victoria, Australia; henry.krum@med.monash.edu.au)
Dosing & Safety of Enoxaparin: In an analysis of data from the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines) National Quality Improvement Initiative, investigators determined that almost one-half of patients given enoxaparin received a dose that was not recommended and had worse outcomes (pp. 1539-44). Concluding that better adherence to recommendations could improve the safety profile of this agent, the authors report these findings: “Of 10,687 patients, 2002 (18.7%) received an excess dose and 3,116 (29.2%) received a lower-than-recommended dose of enoxaparin. Patients receiving excess doses were older (median age, 78 vs 66 years), smaller (median body mass index [calculated as weight in kilograms divided by height in meters squared], 26.2 vs 27.8), and more likely to be female (59.5% vs 38.2%) than patients receiving recommended doses (P < .001 for all). After adjustment for baseline characteristics, an excess dose was significantly associated with major bleeding (odds ratio, 1.43; 95% confidence interval [CI], 1.18–1.75) and death (odds ratio, 1.35; 95% CI, 1.03–1.77) compared with a recommended dose. A lower-than-recommended dose was not associated with major bleeding (odds ratio, 1.01; 95% CI, 0.84–1.21), but there was a trend toward higher mortality (odds ratio, 1.25; 95% CI, 0.93–1.68).” (N. M. Allen LaPointe, allen003@mc.duke.edu)

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

PNN Pharmacotherapy Line
July 25, 2007 * Vol. 14, No. 143
Providing news and information about medications and their proper use

>>>Psychiatry Highlights
Source:
July issue of the American Journal of Psychiatry (http://ajp.psychiatryonline.org/current.dtl; 2007; 164).
Suicidality with Treatments for Depression: Two research studies and an editorial explore the complicated connections among antidepressants, nondrug depression therapies, and suicidality among patients with depression. An editorialist provides this bottom-line summary of the findings: “It is much more likely that suicidal behavior leads to treatment than that treatment leads to suicidal behavior.”
Suicide attempts before and after the start of antidepressant treatments are not specific to medications and probably reflect referral of patients with more serious conditions to specialists, researchers note (pp. 1029-34). Using outpatient claims from a prepaid health plan, investigators looked at initial antidepressant prescriptions from primary care practitioners (n = 70,368) or psychiatrists (n = 7,297) and at initial psychotherapy visits (n = 54,123), and then searched the records for suicide attempts during the 90 days before and 180 days after these events. Results showed the following: “Overall incidence of suicide attempt was highest among patients receiving antidepressant prescriptions from psychiatrists (1,124 per 100,000), lower among those starting psychotherapy (778 per 100,000), and lowest among those receiving antidepressant prescriptions in primary care (301 per 100,000). The pattern of attempts over time was the same in all three groups: highest in the month before starting treatment, next highest in the month after starting treatment, and declining thereafter. Results were unchanged after eliminating patients receiving overlapping treatment with medication and psychotherapy. Overall incidence of suicide attempt was higher in adolescents and young adults, but the time pattern was the same across all three treatments.” (G. E. Simon)
SSRIs do not place patients at greater risk of suicide, concludes a study of 226,866 veterans with new diagnoses of depression in 2003 or 2004 and at least 6 months of follow-up (pp. 1044-9). Comparing SSRIs with new-generation nonserotonergic-specific (non-SSRI) antidepressants (bupropion, mirtazapine, nefazodone, venlafaxine), tricyclic antidepressants, or no antidepressant therapy, the researchers found: “Suicide attempt rates were lower among patients who were treated with antidepressants than among those who were not, with a statistically significant odds ratio for SSRIs and tricyclics. For SSRIs versus no antidepressant, this effect was significant in all adult age groups. Suicide attempt rates were also higher prior to treatment than after the start of treatment, with a significant relative risk for SSRIs and for non-SSRIs. For SSRIs, this effect was seen in all adult age groups and was significant in all but the 18–25 group.” (R. D. Gibbons)
Invoking the mandate to “first do no harm,” an editorialist comments on these studies (pp. 989-91): “As both articles by Simon and Savarino and Gibbons et al. demonstrate, the rate of suicidal behavior in depressed patients initiating treatment is quite high before
any exposure to antidepressant or psychotherapeutic treatment. In order to advance our treatment of real patients in real world settings, we need to conduct clinical trials that include, rather than exclude, these high-risk patients. Only by empanelling depressed patients at significant suicide risk into randomized trials and then systematically assessing the impact of treatment on suicidality and depression will we be able to delineate the effects of antidepressants and psychotherapy on depression and suicide risk. In the meantime, the disturbing increase in the suicide rate in adolescents at a time when antidepressant treatment is becoming less frequent in this population should serve as a warning that the consequences of not receiving treatment for depression may be fatal.” (D. Brent, U. Pittsburgh School of Medicine, Pittsburgh; brentda@upmc.edu)

>>>PNN NewsWatch
* In today’s JAMA (www.jama.com), researchers question results from meta-analyses that are based on standardized mean differences, finding that this method makes data extraction “particularly liable to errors that can negate or even reverse the findings of the study” (pp. 430-7; P. C. Gøtzsche, Nordic Cochrane Centre, Copenhagen, Denmark; pcg@cochrane.dk).

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

PNN Pharmacotherapy Line
July 26, 2007 * Vol. 14, No. 144
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
July 26 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2007; 357).
Dexamethasone for Bronchiolitis: A single dose of oral dexamethasone 1 mg/kg, delivered to infants in 20 emergency departments for moderate or severe bronchiolitis, failed to significantly affect hospital admissions, respiratory status at 4 hours, or later outcomes (pp. 331-9). Comparing the drug with placebo in 600 patients, the investigators report these results: “The admission rate was 39.7% for children assigned to dexamethasone, as compared with 41.0% for those assigned to placebo (absolute difference, –1.3%; 95% confidence interval [CI], –9.2 to 6.5). Both groups had respiratory improvement during observation; the mean 4-hour RACS was –5.3 for dexamethasone, as compared with –4.8 for placebo (absolute difference, –0.5; 95% CI, –1.3 to 0.3). Multivariate adjustment did not significantly alter the results, nor were differences detected in later outcomes.” (H. M. Corneli, U. Utah, Salt Lake City)
An editorialist predicts little change in clinical practice based on these findings (pp. 402-4): “Despite the value of this study, the long history of therapies and recommendations attending bronchiolitis suggest that the study’s results will not appreciably change the nature of the care provided by the primary physician faced with a young, distressed infant and anxious parents. Withholding therapy is much more difficult than giving it.” (C. B. Hall, U. Rochester, Rochester, N.Y.)
Treatment of Refractory Testicular Cancer: High-dose chemotherapy plus hematopoietic stem-cell rescue, even when used as third-line or later therapy or in patients with platinum-refractory disease, can be curative for testicular tumors, according to a retrospective review (pp. 340-8): “Of the 184 patients, 116 had complete remission of disease without relapse during a median follow-up of 48 months (range, 14 to 118). Of the 135 patients who received the treatment as second-line therapy, 94 were disease-free during follow-up; 22 of 49 patients who received treatment as third-line or later therapy were disease-free. Of 40 patients with cancer that was refractory to standard-dose platinum, 18 were disease-free. A total of 98 of 144 patients who had platinum-sensitive disease were disease-free, and 26 of 35 patients with seminoma and 90 of 149 patients with nonseminomatous germ-cell tumors were disease-free. Among the 184 patients, there were three drug-related deaths during therapy. Acute leukemia developed in three additional patients after therapy.” (L. H. Einhorn, Indiana U. Cancer Ctr., Indianapolis; leinhorn@iupui.edu)
Rofecoxib & Cardiovascular Events: In the Vioxx in Colorectal Cancer Therapy: Definition of Optimal Regime (VICTOR) trial, an increased frequency of adverse cardiovascular events was identified among 2,434 patients following a median of 7.4 months of colorectal cancer prophylaxis with rofecoxib 25 mg/day (pp. 360-9). During a median of about 33 months of follow-up after termination of the trial when rofecoxib was pulled from the market worldwide in Sept. 2004, the researchers found these trends: “Of the 23 confirmed cardiovascular thrombotic events, 16 occurred in the rofecoxib group during or within 14 days after the treatment period, with an estimated relative risk of 2.66 (from the Cox proportional-hazards model; 95% confidence interval [CI], 1.03 to 6.86; P = 0.04). Analysis of the Antiplatelet Trialists’ Collaboration end point (the combined incidence of death from cardiovascular, hemorrhagic, and unknown causes; of nonfatal myocardial infarction; and of nonfatal ischemic and hemorrhagic stroke) gave an unadjusted relative risk of 1.60 (95% CI, 0.57 to 4.51; P = 0.37). Fourteen more cardiovascular thrombotic events, six in the rofecoxib group, were reported within the 2 years after trial closure, with an overall unadjusted relative risk of 1.50 (95% CI, 0.76 to 2.94; P = 0.24). Four patients in the rofecoxib group and two in the placebo group died from thrombotic causes during or within 14 days after the treatment period, and during the follow-up period, one patient in the rofecoxib group and five patients in the placebo group died from cardiovascular causes.” (D. J. Kerr, University of Oxford, Radcliffe Infirmary, Oxford, U.K.; david.kerr@clinpharm.ox.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 © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
July 27, 2007 * Vol. 14, No. 145
Providing news and information about medications and their proper use

>>>Geriatrics Highlights
Source:
August issue of the Journal of the American Geriatrics Society (http://www.blackwell-synergy.com/toc/jgs/55/8; 2007; 55).
Costs of Postherpetic Neuralgia: Health care costs associated with postherpetic neuralgia—which goes undiagnosed in as many as 80% of patients with the condition—are substantially greater than costs of herpes zoster pain that resolves in 30 days, according to a retrospective cohort analysis of a claims database (pp. 1168-75). One-year excess health care expenditures attributable to herpes zoster pain or PHN showed these trends: “For the Medicare cohort, the average excess cost per patient was $1,300 in the year after a diagnosis of herpes zoster with 30 days or fewer of analgesic use and ranged from $2,200 to $2,300 per patient with PHN or possible PHN. Patients with possible PHN were 53% more prevalent than patients with PHN in the Medicare cohort and accounted for half of all excess expenditures. Findings were similar in the younger cohorts with commercial insurance and Medicaid except that costs attributable to PHN and possible PHN were higher, and patients with possible PHN were three to five times as prevalent as patients with PHN.” (R. H. Dworkin, robert_dworkin@urmc.rochester.edu)
Treating Postherpetic Neuralgia: For treating older patients with postherpetic neuralgia in whom the drug is not contraindicated, desipramine “appears to be more effective and less expensive than gabapentin or pregabalin,” concludes a cost-utility analysis of a hypothetical cohort of patients with PHN (pp. 1176-84). Comparing daily doses of desipramine 100 mg, gabapentin 1,800 mg, and pregabalin 450 mg, the authors calculate these costs per quality-adjusted life-year: “Desipramine was more effective and less expensive than gabapentin or pregabalin (dominant) under all conditions tested. Gabapentin was more effective than pregabalin but at an incremental cost of $216,000/QALY. Below $140/month, gabapentin became more cost-effective than pregabalin at a threshold of $50,000/QALY, and below $115/month gabapentin dominated pregabalin.” (A. B. O’Connor, alec_oconnor@urmc.rochester.edu)
Cognition & H2 Antagonist Use in Blacks: In 1,558 community-dwelling blacks aged 65 and older with no baseline risk cognitive impairment, use of histamine-2 receptor antagonists was associated with increased risk for cognitive impairment (pp. 1248-53). The 5-year longitudinal observational study revealed these relationships: “Incident cognitive impairment occurred in 275 (17.7%) participants. After controlling for age, education, baseline cognitive score, the use of anticholinergics, and history of diabetes mellitus and depression, continuous use of H2As was associated with greater risk of incident cognitive impairment than for nonusers (odds ratio = 2.42; 95% confidence interval = 1.17–5.04).” (M. Boustani, mboustani@regenstrief.org)
Hypertension & Dementia in the Young–Old: Better control of elevated systolic blood pressure before age 75 could reduce patients’ risk of dementia, according to a prospective cohort study conducted in a Seattle health-maintenance organization (pp. 1161-7). Among a cohort of 2,356 HMO members aged 65 or older who were initially without dementia, investigators found these trends in systolic and diastolic blood pressures: “Within the youngest age group (65–74 at enrollment) a greater risk for dementia was found in participants with high SBP (≥160 mm Hg) (hazard ratio (HR) = 1.60, 95% confidence interval (CI) = 1.01–2.55) or borderline-high DBP (80–89 mm Hg) (HR = 1.59, 95% CI = 1.07–2.35) than for those with normal BP (SBP <140 mm Hg and DBP <80 mm Hg). The dementia risk associated with SBP declined with increasing age (SBP-by-age interaction, P = .01). SBP declined similarly with aging in subjects who developed dementia and those who did not. Thus, in this sample, the association between SBP and dementia risk was not dependent on when BP was measured in relation to onset of dementia.” (G. Li, gli@u.washington.edu)

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

PNN Pharmacotherapy Line
July 30, 2007 * Vol. 14, No. 146
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
July 28 issue of Lancet (www.thelancet.com; 2007; 370).
Psychosis & Cannabis Use: Use of cannabis increases the risk of psychosis later in life by 41%, according to a systematic review 35 longitudinal and population-based studies (pp. 319-28). Noting that the risk of affective disorders with marijuana use is less clear, the authors provide these details: “There was an increased risk of any psychotic outcome in individuals who had ever used cannabis (pooled adjusted odds ratio = 1.41, 95% CI 1.20–1.65). Findings were consistent with a dose–response effect, with greater risk in people who used cannabis most frequently (2.09, 1.54–2.84). Results of analyses restricted to studies of more clinically relevant psychotic disorders were similar. Depression, suicidal thoughts, and anxiety outcomes were examined separately. Findings for these outcomes were less consistent, and fewer attempts were made to address non-causal explanations, than for psychosis. A substantial confounding effect was present for both psychotic and affective outcomes.” (S. Zammit, Cardiff U., Cardiff, U.K.; zammits@cardiff.ac.uk)
Risks of Assisted Reproduction: While in vitro fertilization has been performed for three decades and 1% or more of live births in developed countries are the product of assisted reproductive technologies, little is known about the health of these infants, concludes a review article (pp. 351-9). The authors explain: “Some of the morbidity associated with ART does not result from the techniques but from the underlying health risks of being subfertile. Much of the amplified risk associated with ART is related to high birth order. However, risk of intrauterine and subsequent perinatal complications is enhanced after ART, and urogenital malformations can be present in boys, even in singleton infants. No increase in discord or other difficulties within families has been recorded. Long-term follow-up of children born after ART to reproductive age and beyond is necessary.” (A. G. Sutcliffe, U. College, London; a.sutcliffe@medsch.ucl.ac.uk)

>>>PNN NewsWatch
* FDA documents provided to advisory panels that meet today show a 38% increase in risk of ischemic events associated with rosiglitazone therapy, the Wall Street Journal reports this morning. Complicating the deliberations of the Endocrine and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Committee. will be “somewhat inconsistent findings” among clinical trials of the thiazolidinedione, but FDA staff wrote that they view its risk of myocardial infarction with “considerable concern.”
* On Friday,
FDA announced that it is permitting restricted use of tegaserod maleate (Zelnorm) under a treatment investigational new drug protocol to treat irritable bowel syndrome with constipation and chronic idiopathic constipation in women younger than 55 who meet specific guidelines.

>>>PNN JournalWatch
* Psychosocial Interventions and Opioid Detoxification for Drug Misuse: Summary of NICE Guidance, in BMJ, 2007; 335: 203–5. Reprints: S. Pilling, U. Coll., London; s.pilling@ucl.ac.uk
* Exposure to Substances in the Workplace and New-Onset Asthma: An International Prospective Population-Based Study (ECRHS-II), in
Lancet, 2007; 370: 336–41. Reprints: M. Kogevinas, Municipal Inst. of Med. Res., Barcelona, Spain; kogevinas@imim.es
* Effects of the Long-Acting Human Glucagon-Like Peptide-1 Analog Liraglutide on Beta-Cell Function in Normal Living Conditions, in
Diabetes Care, 2007; 30: 2032–3. Reprints: A. Mari, Inst. of Biomedical Engineering-CNR, Padova, Italy; andrea.mari@isib.cnr.it
* Thiazolidinediones and Heart Failure: A Teleo-Analysis, in
Diabetes Care, 2007; 30: 2148–53. Reprints: S. Singh, Wake Forest U., Winston-Salem, N.C.; sosingh@wfubmc.edu
* Effect of Chromium Supplementation on Glucose Metabolism and Lipids: A Systematic Review of Randomized Controlled Trials, in
Diabetes Care, 2007; 30: 2154–63. Reprints: E. Balk, ebalk@tufts-nemc.org
* Interleukin-17 in Fashion, at Last: Ten Years After Its Description, Its Cellular Source Has Been Identified, in
Arthritis & Rheumatism, 2007; 56: 2111–5. Reprints: P. Miossec, Hôpital Edouard Herriot, Lyon, France; miossec@univ-lyon1.fr
* Progressive Multifocal Leukoencephalopathy in Rheumatic Diseases: Evolving Clinical and Pathologic Patterns of Disease, in
Arthritis & Rheumatism, 2007; 56: 2116–28. Reprints: L. H. Calabrese, Cleveland Clinic Found., Cleveland; calabrl@ccf.org

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

PNN Pharmacotherapy Line
July 31, 2007 * Vol. 14, No. 147
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
August issue of Diabetes Care (http://care.diabetesjournals.org/current.shtml; 2007; 30).
Fenofibrate Therapy in Metabolic Syndrome: A variety of beneficial effects of fenofibrate were evident in a study of 59 patients with fasting hypertriglyceridemia and two or more ATP III criteria for metabolic syndrome (pp. 1945-51). Noting that reduced fasting and postprandial free fatty acid oxidation and inflammatory responses were most highly correlated with reductions in large VLDL particles, the authors report: “Fenofibrate treatment lowered fasting triglycerides (–46.1%, P < 0.0001) and postprandial (area under the curve) triglycerides (–45.4%, P < 0.0001) due to significant reductions in postprandial levels of large (–40.8%, P < 0.0001) and medium (–49.5%, P < 0.0001) VLDL particles. The number of fasting total LDL particles was reduced in fenofibrate-treated subjects (–19.0%, P = 0.0033) primarily due to reductions in small LDL particles (–40.3%, P < 0.0001); these treatment differences persisted postprandially. Fasting and postprandial oxidized fatty acids were reduced in fenofibrate-treated subjects compared with placebo-administered subjects (–15.3%, P = 0.0013, and 31.0%, P < 0.0001, respectively), and fenofibrate therapy lowered fasting and postprandial soluble vascular cell adhesion molecule-1 (VCAM-1) (–10.9%, P = 0.0005, and –12.0%, P = 0.0001, respectively) as well as fasting and postprandial soluble intercellular adhesion molecule-1 (ICAM-1) (–14.8%, P < 0.0001, and –15.3%, P < 0.0001, respectively). Reductions in VCAM-1 and ICAM-1 were correlated with reductions in fasting and postprandial large VLDL particles (P < 0.0001) as well as postprandial oxidized fatty acids (P < 0.0005).” (R. S. Rosenson, rrosenso@umich.edu)
Testosterone Supplementation in Elderly Men: In a 2-year trial, transdermal testosterone 5 mg/day failed to improve carbohydrate tolerance or alter insulin secretion or action in a group of 55 elderly men with testosterone deficiency (pp. 1972-8). Concluding that testosterone deficiency is not the likely cause of age-associated deterioration in glucose tolerance, the investigators add these details: “Despite restoring bioavailable testosterone to values observed in young men, the change (24 months minus baseline values) in fasting and postprandial glucose, insulin, and C-peptide concentrations and meal appearance, glucose disposal, and endogenous glucose production were virtually identical to those observed after 2 years of placebo. The change over time in insulin and C-peptide concentrations post–intravenous glucose injection also did not differ. Furthermore, the change over time in insulin action and glucose effectiveness (measured with the unlabeled and labeled ‘oral’ and ‘intravenous’ minimal models), as well as insulin secretion and hepatic insulin clearance (measured with the C-peptide model), did not differ in the testosterone and placebo groups.” (R. A. Rizza, rizza.robert@mayo.edu)
First-Line Sitagliptin–Metformin in DM: An initial combination of sitagliptin and metformin was effective and generally well tolerated among 1,091 patients with type 2 diabetes mellitus in a 24-week trial (pp. 1979-87). Comparing sitagliptin 100 and 200 mg and/or metformin 1,000 and 2,000 mg, the researchers report: “The mean baseline A1C was 8.8% in the randomized patients. The placebo-subtracted A1C change from baseline was –2.07% (S100/M2000), –1.57% (S100/M1000), –1.30% (M2000), –0.99% (M1000), and –0.83% (S100) (P < 0.001 for comparisons versus placebo and for coadministration versus respective monotherapies). The proportion of patients achieving an A1C <7% and <6.5% was 66 and 44%, respectively, in the S100/M2000 group (P < 0.001 vs. S100 or M2000). For the open-label cohort (n = 117; baseline A1C 11.2%) treated with S100/M2000, the within-group mean A1C change from baseline was –2.9%. The incidence of hypoglycemia was low (0.5–2.2%) across active treatment groups and not significantly different from that in the placebo group (0.6%). The incidence of gastrointestinal adverse experiences was similar for coadministration therapies compared with their respective metformin monotherapy.” (D. Williams-Herman, debora_williamsherman@merck.com)

>>>PNN NewsWatch
* The vote of FDA panels yesterday was 22–1 that rosiglitazone should remain on the U.S. market. But panelists also supported new warnings for the drug’s labeling, by a margin of 20–3.

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

PNN Pharmacotherapy Line
Aug. 1, 2007 * Vol. 14, No. 148
Providing news and information about medications and their proper use

>>>Circulation Highlights
Source:
Early-release articles from Circulation (http://circ.ahajournals.org/rapidaccess.shtml; 2007).
Statin Use in Low LDL: Patients with coronary heart disease and LDL cholesterol levels less than 60 mg/dL benefited from statin therapy, concludes a study of 6,107 consecutive patients at a tertiary center or affiliated community clinic (doi: 10.1161/CIRCULATIONAHA.107.694117). The researchers report: “A total of 4,295 patients (70%) had at least 1 prescription for any medication during the 150-day observation period after the low LDL value. Their mean age was 65 years, 43% had prior ischemic heart disease, and 47% had diabetes mellitus. Statins were prescribed in 2,564 patients (60%) after the low LDL value was observed. During a mean follow-up of 2.0 ± 1.4 years after the observation period, there were 510 deaths. After controlling for the propensity to receive a statin, statin therapy was associated with improved survival (hazard ratio [HR], 0.65; 95% CI, 0.53 to 0.80). This lower mortality was also observed for subgroups of patients already taking statins at baseline (HR, 0.58; 95% CI, 0.38 to 0.88), those with extremely low LDL levels (<40 mg/dL, n = 623; HR, 0.51; 95% CI, 0.33 to 0.79), and those without a history of ischemic heart disease (n = 2,438; HR, 0.58; 95% CI, 0.42 to 0.80). Statin use was not associated with an increase in malignancy, transaminase elevation, or rhabdomyolysis.” (N. J. Leeper, nleeper@cvmed.stanford.edu)
Statin Use in Children: In 214 children with familial hypercholesterolemia, early initiation of statin therapy can help prevent atherosclerosis during adolescence, according to a 2-year study of pravastatin in 8–18 year olds (doi: 10.1161/CIRCULATIONAHA.106.671016). Assessing the relationship between age at onset of statin initiation and long-term carotid intima-media thickness, the investigators found: “Blood samples were taken on a regular basis for lipids and safety parameters, and a carotid IMT measurement was performed after an average treatment period of 4.5 years. Follow-up data for 186 children were available for the statistical analyses. Multivariate analyses revealed that age at statin initiation was an independent predictor for carotid IMT after follow-up with adjustment for carotid IMT at initiation of statin treatment, sex, and duration of treatment. Early initiation of statin treatment was associated with a subsequently smaller IMT. Furthermore, no serious laboratory adverse events were reported during follow-up, and statin treatment had no untoward effects on sexual maturation.” (B. A. Hutten, U. Amsterdam, Amsterdam; b.a.hutten@amc.uva.nl)
Evidence-Based Pharmacotherapy for HF: In patients with heart failure, a focused effort on early treatment initiation, appropriate dosages, and persistence with the regimen using evidence-based pharmacotherapy would provide long-term benefits, concludes a Danish study (doi: 10.1161/CIRCULATIONAHA.106.669101). The authors studied 107,092 patients discharged following a first hospitalization for HF: “Prescriptions of dispensed medication and mortality were identified by an individual-level linkage of nationwide registers. Inclusion was irrespective of left ventricular function. Treatment with renin–angiotensin inhibitors (eg, angiotensin-converting enzyme inhibitors and angiotensin-2 receptor blockers), beta-blockers, spironolactone, and statins was initiated in 43%, 27%, 19%, and 19% of patients, respectively. Patients who did not initiate treatment within 90 days of discharge had a low probability of later treatment initiation. Treatment dosages were in general only 50% of target dosages and were not increased during long-term treatment. Short breaks in therapy were common, but most patients reinitiated treatment. Five years after initiation of treatment, 79% patients were still on renin–angiotensin inhibitors, 65% on beta-blockers, 56% on spironolactone, and 83% on statins. Notably, multiple drug treatment and increased severity of heart failure was associated with persistence of treatment. Nonpersistence with renin–angiotensin inhibitors, beta-blockers, and statins was associated with increased mortality with hazard ratios for death of 1.37 (95% CI, 1.31 to 1.42), 1.25 (95% CI, 1.19 to 1.32), 1.88 (95% CI, 1.67 to 2.12), respectively.” (G. H. Gislason, Gentofte U. Hosp., Hellerup, Denmark; gg@heart.dk)

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

PNN Pharmacotherapy Line
Aug. 2, 2007 * Vol. 14, No. 149
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Aug. 2 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2007; 357).
Progesterone for Prevention of Prematurity: Two studies, a review article, and an editorial explore pharmacologic options for prevention of premature labor and birth.
In 661 women with twin gestations, weekly intramuscular injections of 17-alpha-hydroxyprogesterone starting at 16–20 weeks failed to reduce the rate of preterm birth (pp. 454-61): “Baseline demographic data were similar in the two study groups. Six women were lost to follow-up; data from 655 were analyzed (325 in the 17P group and 330 in the placebo group). Delivery or fetal death before 35 weeks occurred in 41.5% of pregnancies in the 17P group and 37.3% of those in the placebo group (relative risk, 1.1; 95% confidence interval [CI], 0.9 to 1.3). The rate of the prespecified composite outcome of serious adverse fetal or neonatal events was 20.2% in the 17P group and 18.0% in the placebo group (relative risk, 1.1; 95% CI, 0.9 to 1.5). Side effects of the injections were frequent in both groups, occurring in 65.9% and 64.4% of subjects, respectively (P = 0.69), but were generally mild and limited to the injection site.” (D. J. Rouse,
drouse@uab.edu)
Among 250 women with short cervix, vaginal progesterone from 24 to 34 weeks’ gestation significantly reduced the rate of spontaneous early preterm delivery, compared with placebo (pp. 462-9): “Spontaneous delivery before 34 weeks of gestation was less frequent in the progesterone group than in the placebo group (19.2% vs. 34.4%; relative risk, 0.56; 95% confidence interval [CI], 0.36 to 0.86). Progesterone was associated with a nonsignificant reduction in neonatal morbidity (8.1% vs. 13.8%; relative risk, 0.59; 95% CI, 0.26 to 1.25; P = 0.17). There were no serious adverse events associated with the use of progesterone.” (K. H. Nicolaides, King’s College Hosp. Med. Sch., London;
kypros@fetalmedicine.com)
An editorialist writes that, despite the current confusion, a definitive answer is in sight (pp. 499-501): “Fortunately, the arguments need not go on indefinitely. There are at least 14 ongoing trials involving women with high-risk pregnancies (both singleton and twin) that aim to recruit a total of more than 5,000 women ..., and I am aware of at least 2 more currently awaiting funding decisions. These should have ample power to test the effect of progesterone on important fetal outcomes as well as any differential effect in twin gestations, and long-term follow-up of the surviving children will provide important additional information. In the meantime, the remaining uncertainties about both efficacy and fetal safety mean that even women at high risk for preterm delivery should join one of the ongoing randomized trials, rather than take a treatment for which the efficacy and safety have not been proved. The hormone named [in 1930] by Allen and Corner [progestin] is not yet ready to enter the therapeutic armamentarium as a pregnancy-prolonging agent.” (J. G. Thornton, U. Nottingham, Nottingham, U.K.)
Review article authors make these recommendations for prevention of preterm delivery (pp. 477-87): “In sum, as compared with beta-adrenergic–receptor agonists, nifedipine would seem to be a reasonable choice for initial tocolysis, given the oral route of administration, low frequency of side effects, and efficacy in reducing neonatal complications. Nifedipine can be used at any gestational age when labor-inhibition therapy is being considered.
“For pregnancies of less than 32 weeks’ gestation, a reasonable alternative to nifedipine is indomethacin or other COX inhibitors. These agents have been shown to be more effective than the beta-adrenergic–receptor agonists in comparative studies. Indomethacin should be avoided in women with a platelet dysfunction or bleeding disorder, hepatic or renal dysfunction, gastrointestinal ulcerative disease, or asthma (in women with hypersensitivity to aspirin). We generally avoid the use of these agents in gestations of more than 32 weeks to avoid in utero closure or narrowing or neonatal patency of the ductus arteriosus.
“The use of beta-adrenergic–receptor agonists is an alternative to therapy with nifedipine and indomethacin. The side-effect profile of this class of drugs is less favorable than that of nifedipine, but their effectiveness in stopping contractions appears to be similar.” (H. N. Simhan, U. Pittsburgh, Pittsburgh;
hsimhan@mail.magee.edu)

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

PNN Pharmacotherapy Line
Aug. 3, 2007 * Vol. 14, No. 150
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Aug. issue of Pharmacotherapy (www.pharmacotherapy.org; 2007; 27).
Antimicrobial Dosing in Obesity: Factors to be considered and actions to take when determining antimicrobial agent doses in patients with obesity are reviewed in an article from the Society of Infectious Diseases Pharmacists (pp. 1081-91): “Physiologic changes in obesity can alter both the volume of distribution and clearance of many commonly used antimicrobials. These changes often present challenges such as estimation of creatinine clearance to predict drug clearance. Although these physiologic changes are increasingly being characterized, few studies assessing alterations in tissue drug distribution and the effects of obesity on antimicrobial pharmacokinetics have been published. The available data are most plentiful for antibiotics that historically have included clinical therapeutic drug monitoring. These data suggest that dosing of vancomycin and aminoglycosides be based on total body weight and adjusted body weight, respectively. Obese patients may require larger doses of beta-lactams to achieve similar concentrations as those of patients who are not obese. Fluoroquinolone pharmacokinetics are variably altered by obesity, which prevents a uniform approach. Data on the pharmacokinetics of drugs that have activity against gram-positive organisms— quinupristin–dalfopristin, linezolid, and daptomycin—reveal that they are altered in the presence of obesity, but more data are needed to solidify dosing recommendations. Limited data are available on nonantibacterials. An understanding of the physiologic changes in obesity and the available literature on specific antibiotics is valuable in providing a framework for rational selection of dosages in this increasingly common population of obese patients.” (D. T. Bearden, Oregon St. U., Portland; beardend@ohsu.edu)
Economic Analysis of Triptans for Acute Migraine: In an analysis of costs and therapeutic success with triptan therapy for acute migraine, eletriptan 20 and 40 mg doses provided the most favorable results in both baseline and sensitivity calculations (pp. 1092-101). Taking the perspective of the Medicaid program, the researchers found these results for 100 migraine attacks: “The two treatments associated with the lowest cost to treat 100 migraine attacks were eletriptan 20 mg (range $1,549–$1,658) and eletriptan 40 mg ($1,578–$1,661). Naratriptan 2.5 mg (range $1,734–$2,018), sumatriptan 25 mg ($1,853–$1,954), and zolmitriptan 5 mg ($1,854–$1,960) were associated with the highest cost to treat 100 migraine attacks. Eletriptan 40 mg was associated with the lowest cost/success (range $57.03–$60.05); naratriptan 2.5 mg ($99.39–$1,15.65), sumatriptan 25 mg ($107.11–$112.93), and rizatriptan 5 mg ($99.41–$111.25) were associated with the highest cost/success values. Changes in dosing assumptions did not significantly change the rank ordering of triptans across either economic end point.” (C. D. Mullins, dmullins@rx.umaryland.edu)
Loss of Glycemic Control in DM: In a 4-year retrospective analysis of an administrative database from a large health plan, one-third of patients with type 2 diabetes mellitus experienced loss of glycemic control (pp. 1102-10). For patients initially begun on metformin, sulfonylurea, or thiazolidinedione monotherapy, the Novartis-funded study reports: “Mean age was 50.7 years; 5027 (53.4%) were men. Mean baseline A1C value was 8.4%, and about 70% of patients had an AIC value of 7% or greater before starting therapy. Mean follow-up was 1.9 years, and mean decrease in A1C values was 1.47% (to 6.91%). The probabilities of attaining A1C goals were similar for patients receiving metformin, sulfonylurea, or thiazolidinedione therapy. The rate of therapy intensification among patients taking metformin (24.7%) was lower than that of patients taking a sulfonylurea (30.1%, p <0.001) but similar to that of those taking a thiazolidinedione (24.6%). Secondary failure occurred in 36.3% of patients; mean time from the start of therapy to its failure was about 1.51 years. Patients receiving a sulfonylurea were 1.25 (95% confidence interval [CI] 1.05–1.50) times more likely than patients receiving metformin to experience secondary failure, whereas failure rates were similar for thiazolidinediones and metformin (odds ratio 0.78, 95% CI 0.62–0.99).” (J. Wogen, MedMentis Consulting LLC, Towaco, N.J.; jen@medmentis.com)

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

PNN Pharmacotherapy Line
Aug. 6, 2007 * Vol. 14, No. 151
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Aug. 4 issue of Lancet (www.thelancet.com; 2007; 370).
Early Interferon in MS: Early use of interferon beta-1b prevents the development of confirmed disability in patients with multiple sclerosis, concludes the placebo-controlled Betaferon/Betaseron in Newly Emerging multiple sclerosis For Initial Treatment (BENEFIT) study (pp. 389-97). Adding that these results support use of this agent after the first manifestation of relapsing–remitting MS, the authors provide these details about interferon beta-1b 250 mcg subcutaneously administered every other day: “Of the 468 patients originally randomised, 418 (89%) entered the follow-up phase; 392 (84%) completed 3 years’ post-randomisation follow-up. After 3 years, 99 (37%) patients in the early group developed [clinically definite MS (CDMS)] compared with 85 (51%) patients in the delayed treatment group. Early treatment reduced the risk of CDMS by 41% (hazard ratio 0.59, 95% CI 0.44–0.80; p = 0.0011; absolute risk reduction 14%) compared with delayed treatment. Over 3 years, 42 (16%) patients in the early group and 40 (24%) in the delayed group had confirmed EDSS progression; early treatment reduced the risk for progression of disability by 40% compared with delayed treatment (0.60, 0.39–0.92; p = 0.022; absolute risk reduction 8%). The FAMS-TOI score was high and stable in both groups over the 3-year period (p = 0.31).” (L. Kappos, U. Hosp., Basel, Switzerland; lkappos@uhbs.ch)

>>>BMJ Highlights
Source:
Aug. 4 issue of BMJ (www.bmj.org; 2007; 335).
HRT in Postmenopausal Women: Consistent with the results of the Women’s Health Initiative and secondary preventive studies, the Women’s International Study of Long Duration Oestrogen after Menopause (WISDOM) demonstrates that hormone-replacement therapy increases cardiovascular and thromboembolic risk when started many years after menopause (pp. 239 ff). In a trial planned for 10 years’ duration, estrogen-only therapy (conjugated equine estrogens 0.625 mg orally daily) was compared with combined hormone therapy (conjugated equine estrogens plus medroxyprogesterone acetate 2.5/5.0 mg orally daily), with these results: “The trial was prematurely closed during recruitment, after a median follow-up of 11.9 months (interquartile range 7.1–19.6, total 6,498 women–years) in those enrolled, after the publication of early results from the women’s health initiative study. The mean age of randomised women was 62.8 (SD 4.8) years. When combined hormone therapy (n = 2,196) was compared with placebo (n = 2,189), there was a significant increase in the number of major cardiovascular events (7 v 0, P = 0.016) and venous thromboembolisms (22 v 3, hazard ratio 7.36 (95% CI 2.20 to 24.60)). There were no statistically significant differences in numbers of breast or other cancers (22 v 25, hazard ratio 0.88 (0.49 to 1.56)), cerebrovascular events (14 v 19, 0.73 (0.37 to 1.46)), fractures (40 v 58, 0.69 (0.46 to 1.03)), and overall deaths (8 v 5, 1.60 (0.52 to 4.89)). Comparison of combined hormone therapy (n = 815) versus oestrogen therapy (n = 826) outcomes revealed no significant differences.” (A. H. MacLennan, U. Adelaide, Adelaide, Australia; alastair.maclennan@adelaide.edu.au)

>>>PNN JournalWatch
* Adolescents’ Access and Consent to the Human Papillomavirus Vaccine: A Critical Aspect for Immunization Success, in Pediatrics, 2007; 120: 434–7. Reprints: E. S. Rome, Cleveland Clinic, Cleveland, Ohio; romee@ccf.org
* Restless Legs Syndrome: What Is a Pediatrician to Do?, in
Pediatrics, 2007; 120: 438–9. Reprints: N. J. Blum, Children’s Hosp., Philadelphia; blum@email.chop.edu
* Beyond Unfractionated Heparin and Warfarin: Current and Future Advances, in
Circulation, 2007; 116: 552–60. Reprints: J. W. Eikelboom, eikelbj@mcmaster.ca
* Stress, Dysregulation of Drug Reward Pathways, and the Transition to Drug Dependence, in
American Journal of Psychiatry, 2007; 164: 1149–59. Reprints: G. Koob.
* Antenatal Depression: Navigating the Treatment Dilemmas, in
American Journal of Psychiatry, 2007; 164: 1162–5. Reprints: M. P. Freeman, marlene.freeman@utsouthwestern.edu
* Molecularly Targeted Oncology Therapeutics and Prolongation of the QT Interval, in
Journal of Clinical Oncology, 2007; 25: 3362–71. Reprints: L. L. Siu, Princess Margaret Hosp., Toronto; lillian.siu@uhn.on.ca

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

PNN Pharmacotherapy Line
Aug. 7, 2007 * Vol. 14, No. 152
Providing news and information about medications and their proper use

>>>Maraviroc Approved for HIV
FDA yesterday approved the first in a new class of antiretroviral agents, maraviroc (Selzentry, Pfizer). The CCR5 blocker is approved for treatment of adults with CCR5-tropic HIV-1 who have been treated with other HIV medications and who have evidence of elevated serum levels of HIV. The product will be available in mid-September.
Rather than fighting HIV inside white blood cells, maraviroc prevents the virus from entering uninfected cells by blocking the predominant route of entry, the CCR5 co-receptor. CCR5 is a protein on the surface of some types of immune cells. Among patients who have previously received HIV medications, 50% to 60% have circulating CCR5-tropic HIV-1.
FDA’s accelerated approval of maraviroc is based on safety and effectiveness data from two double-blind, placebo-controlled studies of 24 weeks’ duration. The 1,076 clinical trial participants were selected because they still showed evidence of HIV-1 in their blood, despite treatment with other HIV medications. A blood test for CCR5 tropic HIV-1 was used during clinical trials to identify patients appropriate for treatment with maraviroc. Approximately twice as many patients receiving maraviroc combined with an optimized background therapy achieved undetectable viral load at 24 weeks compared with those receiving optimized background therapy alone.
A boxed notice in the maraviroc product labeling warns of hepatoxicity with the drug, and a statement in the Warnings/Precautions section details the possibility of myocardial infarctions. The most common adverse events reported with maraviroc were cough, fever, upper respiratory tract infections, rash, musculoskeletal symptoms, abdominal pain, and dizziness.
The safety and effectiveness of maraviroc have not been established in adult and pediatric patients who have never been treated with any other HIV drug. Additionally, the drug has not been tested or studied in pregnant women. The FDA recommends that HIV-positive women should not breast feed, whether or not they are on antiretroviral medications.

>>>Internal Medicine Report
Source:
Early-release article from the Annals of Internal Medicine (www.annals.org/current.shtml; 2007; 147).
Safety of Rosiglitazone: A new meta-analysis of rosiglitazone clinical trial data—one that includes studies with zero values for treatment and control groups—shows neither increased nor decreased risk of myocardial infarction and cardiac-related deaths associated with use of the thiazolidinedione (early release). “A recent, widely publicized meta-analysis of 42 clinical trials concluded that rosiglitazone was associated with an approximately 43% increased risk for myocardial infarction and an approximately 64% increased risk for cardiovascular death,” the authors write. “The sensitivity of these conclusions to several methodological choices was not assessed. The meta-analysis was not based on a comprehensive search for all studies that might yield evidence about rosiglitazone’s cardiovascular effects. Studies were combined on the basis of a lack of statistical heterogeneity, despite substantial variability in study design and outcome assessment. The meta-analytic approach that was used required the exclusion of studies with zero events in the treatment and control groups. Alternative meta-analytic approaches that use continuity corrections show lower odds ratios that are not statistically significant. We conclude that the risk for myocardial infarction and death from cardiovascular disease for diabetic patients taking rosiglitazone is uncertain: Neither increased nor decreased risk is established.” (S. Kaul, Cedars-Sinai Med. Ctr., Los Angeles; kaul@cshs.org)

>>>PNN NewsWatch
* Seeking to go one better than Wal-Mart and Target, Publix Super Markets yesterday began offering free antibiotics at its 684 pharmacies in Florida and other southeastern states. With a prescription, 14-day supplies will be provided of amoxicillin, cephalexin, cotrimoxazole, ciprofloxacin, penicillin VK, ampicillin, and erythromycin.

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

PNN Pharmacotherapy Line
Aug. 8, 2007 * Vol. 14, No. 153
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Aug. 8 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2007; 298).
Gaps in Vaccine Financing: The current vaccine financing system has resulted in gaps for underinsured children in the United States, concludes a study of state immunization programs (pp. 638-43). Percentages of states in which underinsured children were unable to receive publicly purchased vaccines were determined using a two-phase method consisting of a 1-hour interview of nine program managers and a national survey in 2006. Results showed the following: “Immunization program managers from 48 states (96%) participated in the study. Underinsured children were not eligible to receive publicly purchased meningococcal conjugate or pneumococcal conjugate vaccines in the private sector in 70% and 50% of states, respectively, or in the public sector in 40% and 17% of states, respectively. Due to limited financing for new vaccines, 10 states changed their policies for provision of publicly purchased vaccines between 2004 and early 2006 to restrict access to selected new vaccines for underinsured children. The most commonly cited barriers to implementation in underinsured children were lack of sufficient federal and state funding to purchase vaccines.” (G. M. Lee, Harvard Med. Sch. and Harvard Pilgrim Health Care, Boston; grace_lee@hphc.org)
An editorialist provides these “reasons and remedies” for addressing this problem (pp. 680-2): “The growing problem of underinsurance for vaccines is not just about a lack of sufficient public financing to do the job. Rather, widely varying state-level approaches to underinsurance for childhood and adolescent vaccines likely reflect varying levels of agreement among the general public that the increasing number of recommended vaccines are all equally deserving of programmatic prioritization and public financing.
“Consequently, today’s problem of underinsurance is principally a result of implicit prioritization of recommended vaccines. Administrators in private health insurance plans and public officials prioritize certain recommended vaccines over others, likely using different rationales (eg, cost, cost-effectiveness, clinical burden of preventable disease) across plans and state programs to do so.” (M. M. Davis,
mattdav@med.umich.edu)
Cost-effectiveness of Bone Densitometry in Older Men: In a Markov microsimulation model that used a societal perspective, bone densitometry followed by bisphosphonate therapy as appropriate was cost-effective for men aged 65 years or older with a self-reported prior clinical fracture and men aged 80 to 85 years with no prior fracture (pp. 629-37). Assuming hypothetical cohorts of older white men with or without prior clinical fracture, the researchers determined these costs per quality-adjusted life-year: “Lifetime costs per QALY gained for the densitometry and follow-up treatment strategy were less than $50,000 for men aged 65 years or older with a prior clinical fracture and for men aged 80 years or older without a prior fracture. These results were most sensitive to oral bisphosphonate cost and fracture reduction efficacy, the strength of association between bone mineral density and fractures, fracture rates and disutility, and medication adherence.” (J. T. Schousboe, Park Nicollet Health Svc., Minneapolis; john.schousboe@parknicollet.com)
Nonpharmaceutical Interventions During Influenza Pandemic: Based on experiences gained during the 1918–19 influenza pandemic, nonpharmaceutical interventions can be effective companion measures to developing effective vaccines and medications for prophylaxis and treatment, authors write (pp. 644-54). Historical archival research shows the following: “School closure and public gathering bans activated concurrently represented the most common combination implemented in 34 cities (79%); this combination had a median duration of 4 weeks (range, 1–10 weeks) and was significantly associated with reductions in weekly [excess death rate]. The cities that implemented nonpharmaceutical interventions earlier had greater delays in reaching peak mortality (Spearman r = –0.74, P < .001), lower peak mortality rates (Spearman r = 0.31, P = .02), and lower total mortality (Spearman r = 0.37, P = .008). There was a statistically significant association between increased duration of nonpharmaceutical interventions and a reduced total mortality burden (Spearman r = –0.39, P = .005).” (M. S. Cetron, mcetron@cdc.gov)

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

PNN Pharmacotherapy Line
Aug. 9, 2007 * Vol. 14, No. 154
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Early-release article from and Aug. 9 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2007; 357).
FDA Hearing on Rosiglitazone: “Lessons for scientists, practitioners, and regulators alike” were provided via the July 30 hearing of FDA advisory panels considering the future of rosiglitazone, writes an author of a Commentary article (doi: 10.1056/NEJMp078167). He notes: “Drugs are approved or removed from the market on the basis of evidence from randomized, controlled trials. In the FDA hearing on rosiglitazone, several meta-analyses ... revealed a significant increase in the risk of myocardial ischemic events among patients taking rosiglitazone. However, an interim analysis of the ongoing Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) trial, which was designed specifically to assess cardiovascular risk among patients receiving rosiglitazone, failed to demonstrate a similar risk. In addition, two large observational studies, one conducted by Tricare for the Department of Defense and one conducted by WellPoint (the largest health insurer in the United States), noted no appreciable signal of increased cardiovascular risk with either of the available thiazolidinediones.... The contrasts among the levels of evidence and the results regarding the safety of rosiglitazone raised new questions about relative and absolute risks but also highlighted the weaknesses of observational studies examining events that are common and whose rates are likely to be increased only slightly by a given drug, even in a large cohort (such as that used by WellPoint, which comprised 160,000 patient records).” (C. J. Rosen, Maine Ctr. for Osteoporosis, St. Joseph Hosp., Bangor)
Preventing Joint Disease Through Prophylaxis in Hemophilia: In young boys with severe hemophilia A, regular prophylactic infusions of recombinant factor VIII prevented joint damage and decreased the frequency of joint and other hemorrhages more than did an enhanced episodic infusion schedule of the agent (pp. 535-44). Researchers report these results: “Sixty-five boys younger than 30 months of age were randomly assigned to prophylaxis (32 boys) or enhanced episodic therapy (33 boys). When the boys reached 6 years of age, 93% of those in the prophylaxis group and 55% of those in the episodic-therapy group were considered to have normal index-joint structure on MRI (P = 0.006). The relative risk of MRI-detected joint damage with episodic therapy as compared with prophylaxis was 6.1 (95% confidence interval, 1.5 to 24.4). The mean annual numbers of joint and total hemorrhages were higher at study exit in the episodic-therapy group than in the prophylaxis group (P <0.001 for both comparisons). High titers of inhibitors of factor VIII developed in two boys who received prophylaxis; three boys in the episodic-therapy group had a life-threatening hemorrhage. Hospitalizations and infections associated with central-catheter placement did not differ significantly between the two groups.” (M. J. Manco–Johnson, Mountain States Regional Hemophilia and Thrombosis Ctr., Aurora, Colo.; marilyn.manco-johnson@uchsc.edu)
Rituximab for Severe Pemphigus: While adverse effects limit its use to more severe types of pemphigus, rituximab administered in a single cycle is an effective treatment for this condition, concludes a study of 21 patients who had not responded to 8 weeks of prednisone therapy (pp. 545-52). Four weekly infusions of rituximab 375 mg/sq m produced these outcomes: “Eighteen of 21 patients (86%; 95% confidence interval, 64 to 97%) had a complete remission at 3 months. The disease relapsed in nine patients after a mean of 18.9 ± 7.9 months. After a median follow-up of 34 months, 18 patients (86%) were free of disease, including 8 who were not receiving corticosteroids; the mean prednisone dose decreased from 94.0 ± 10.2 to 12.0 ± 7.5 mg per day (P = 0.04) in patients with corticosteroid-refractory disease and from 29.1 ± 12.4 to 10.9 ± 16.5 mg per day (P = 0.007) in patients with corticosteroid-dependent disease. Pyelonephritis developed in one patient 12 months after rituximab treatment, and one patient died of septicemia 18 months after rituximab treatment. These patients had a profound decrease in the number of circulating B lymphocytes but normal serum levels of IgG.” (P. Joly, Hôpital Charles Nicolle, Rouen, France; Pascal.Joly@chu-rouen.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 © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Aug. 10, 2007 * Vol. 14, No. 155
Providing news and information about medications and their proper use

>>>Allergy/Immunology Report
Source:
Aug. issue of the Journal of Allergy and Clinical Immunology (www.jacionline.org/current; 2007; 120).
Probiotics for Allergic Disease: The complex effects of probiotics in patients with allergic disease are explored in a review article (pp. 255-62): “Although there is a sound theoretical basis for anticipating benefits, there are currently insufficient data to recommend probiotics as a part of standard therapy in any allergic conditions. Furthermore, although there have been several studies to show a benefit in prevention of atopic eczema, other studies have failed to support this. None of the studies has shown any clear preventive effect on sensitization, nor any allergic disease other than eczema. The term ‘probiotic’ is often used loosely to include bacterial strains with little documented immunomodulatory capacity or controlled studies to support the claims. It is not known whether effects in experimental systems have any clinical relevance. Finally, very little is known about this large, complex internal ecosystem. Explanations for the varied results between studies include host factors (including genetic differences in microbial responses and allergic predisposition) and other environmental factors, such as general microbial burden, individual microbiota, diet (including consumption of prebiotic substances), and treatment with antibiotics. As more studies are completed, these factors are likely to make robust meta-analyses problematic to perform.” (S. L. Prescott, U. Western Australia, Perth, Western Australia, Australia; sprescott@meddent.uwa.edu.au)
Aspirin & Asthma: Data from an oral aspirin challenge (OAC) study provide reassurance for the safety of outpatient aspirin desensitization (pp. 273-7). In 210 consecutive patients referred with suspected aspirin-exacerbated respiratory disease, the researchers noted these relationships: “Of 147 patients who reported seeking acute medical care for their historical aspirin/NSAID-induced asthma attacks, 101 (69%) were treated in an emergency department and released, and 46 (31%) required hospitalization. During OAC in these 147 subjects, 23 (16%) had a 20% to 29% decrease and 14 (10%) had a 30% or greater decrease in FEV1 values from baseline. Of the 46 patients previously hospitalized for aspirin/NSAID-induced asthma attacks, 9 (20%) had a 20% to 29% decrease and 6 (13%) had a 30% or greater decrease in FEV1 during OAC. By contrast, of the 63 patients who treated their prior aspirin/NSAID-induced reactions at home, 5 (8%) had a 20% to 29% decrease and 5 (8%) had a 30% or greater decrease in FEV1 during OAC (P = not significant for both).” (A. N. Williams, Scripps Clinic, San Diego; a.williams33@yahoo.com)

>>>PNN NewsWatch
* Following analysis of data provided by AstraZeneca, FDA has preliminarily concluded that use of omeprazole and esomeprazole is not associated with an increased risk of myocardial infarction and other cardiac problems. AstraZeneca in May had sent FDA preliminary data from two small long-term clinical studies in patients with severe gastroesophageal reflux disease who randomly received either omeprazole or esomeprazole or surgery to control their GERD. The results from the study of omeprazole and analyses from an ongoing study of esomeprazole raised concerns that long-term use of these drugs may have increased the risk of myocardial infarction, heart failure, and sudden death in those patients, compared with patients who received surgery. The company then provided additional data from pooled analyses of other controlled studies, and considering all the data, FDA staff concluded that no “change [in] prescribing patterns or ... use of these products” is indicated at this time.
*
FDA is also warning consumers not to buy or eat three red yeast rice products promoted and sold on Web sites because they may contain lovastatin. The products are: Red Yeast Rice and Red Yeast Rice/Policosonal Complex, sold by Swanson Healthcare Products, Inc. and manufactured by Nature’s Value Inc. and Kabco Inc., respectively; and Cholestrix, sold by Sunburst Biorganics. FDA has issued warning letters advising Swanson and Sunburst Biorganics to stop promoting and selling the products. Companies that do not resolve violations in FDA warning letters risk enforcement actions, such as an injunction against continuing violations and a seizure of illegal products.

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

PNN Pharmacotherapy Line
Aug. 13, 2007 * Vol. 14, No. 156
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Aug. 11 issue of Lancet (www.thelancet.com; 2007; 370).
Warfarin v. Aspirin in AF: Anticoagulation therapy is an effective means of preventing stroke in patients older than 75 who have atrial fibrillation, according to results from BAFTA, the Birmingham Atrial Fibrillation Treatment of the Aged Study (pp. 493-503). Warfarin dosed to an INR of 2 to 3 provided greater protection than did aspirin 75 mg/day, the researchers report, adding these details: “There were 24 primary events (21 strokes, two other intracranial haemorrhages, and one systemic embolus) in people assigned to warfarin and 48 primary events (44 strokes, one other intracranial haemorrhage, and three systemic emboli) in people assigned to aspirin (yearly risk 1.8% vs 3.8%, relative risk 0.48, 95% CI 0.28–0.80, p = 0.003; absolute yearly risk reduction 2%, 95% CI 0.7–3.2). Yearly risk of extracranial haemorrhage was 1.4% (warfarin) versus 1.6% (aspirin) (relative risk 0.87, 0.43–1.73; absolute risk reduction 0.2%, −0.7 to 1.2).” (J. Mant, U. Birmingham, Birmingham, U.K.; j.w.mant@bham.ac.uk)
Sapropterin in Phenylketonuria: Sapropterin, a synthetic form of tetrahydrobiopterin (BH4), reduced blood phenylalanine among patients with phenylketonuria, indicating that it might be useful as an adjunct to a restrictive low-phenylalanine diet (pp. 504-10). “88 of 89 enrolled patients received at least one dose of study drug, and 87 attended the week 6 visit,” write the authors. “Mean age was 20 (SD 9.7) years. At baseline, mean concentration of phenylalanine in blood was 843 (300) µmol/L in patients assigned to receive sapropterin, and 888 (323) µmol/L in controls. After 6 weeks of treatment, patients given sapropterin had a decrease in mean blood phenylalanine of 236 (257) µmol/L, compared with a 3 (240) µmol/L increase in the placebo group (p <0.0001). After 6 weeks, 18/41 (44%) patients (95% CI 28–60) in the sapropterin group and 4/47 (9%) controls (95% CI 2–20) had a reduction in blood phenylalanine concentration of 30% or greater from baseline. Blood phenylalanine concentrations fell by about 200 µmol/L after 1 week in the sapropterin group and this reduction persisted for the remaining 5 weeks of the study (p <0.0001). 11/47 (23%) patients in the sapropterin group and 8/41 (20%) in the placebo group experienced adverse events that might have been drug-related (p = 0.80). Upper respiratory tract infections were the most common disorder.” (H. L. Levy; harvey.levy@childrens.harvard.edu)

>>>BMJ Highlights
Source:
Early-release article from BMJ (www.bmj.org; 2007; 335).
Probiotics in Childhood Diarrhea: In a 12-month comparison of five probiotic preparations, not all were effective for treatment of acute episodes of diarrhea in children (doi: 10.1136/bmj.39272.581736.55). Patients were infants and children aged 3 to 36 months who were visiting family pediatricians. The randomized controlled trial compared an oral rehydration solution with probiotic formulations, with these results: “571 children were allocated to intervention. Median duration of diarrhoea was significantly shorter (P <0.001) in children who received [Lactobacillus] rhamnosus strain GG (78.5 hours) and [a] mix of four bacterial strains (70.0 hours) than in children who received oral rehydration solution alone (115.0 hours). One day after the first probiotic administration, the daily number of stools was significantly lower (P <0.001) in children who received L rhamnosus strain GG and in those who received the probiotic mix than in the other groups. The remaining preparations did not affect primary outcomes. Secondary outcomes were similar in all groups.” (A. Guarino, U. Naples Federico II, Naples, Italy; alfguari@unina.it)

>>>PNN JournalWatch
* Photoprotection, in Lancet, 2007; 370: 528–37. Reprints: S. Lautenschlager, Triemli Hosp., Zurich, Switzerland; stephan.lautenschlager@triemli.stzh.ch
* Cardiovascular Protection Using Beta-Blockers: A Critical Review of the Evidence, in
Journal of the American College of Cardiology, 2007; 50: 563–72. Reprints: F. H. Messerli, Columbia U. Coll. of Physicians and Surgeons, New York; fmesserl@chpnet.org
* Back to the Future: Using Aminoglycosides Again and How to Dose Them Optimally, in
Clinical Infectious Diseases, 2007; 45 (early release). Reprints: G. L. Drusano, Ordway Res. Inst., Albany, N.Y.
* Tipranavir: A New Option for the Treatment of Drug-Resistant HIV Infection, in
Clinical Infectious Diseases, 2007; 45 (early release). Reprints: Z. Temesgen, Mayo Clinic, Rochester, Minn.

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

PNN Pharmacotherapy Line
Aug. 14, 2007 * Vol. 14, No. 157
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Aug. 13/27 issue of the Archives of Internal Medicine (http://archinte.ama-assn.org/current.dtl; 2007; 167).
Antioxidants for Cardiovascular-Event Prevention in Women: Supplementation with ascorbic acid, vitamin E, or beta carotene had no significant effect on cardiovascular events among women at high risk for cardiovascular disease (pp. 1610-8). In the Women’s Antioxidant Cardiovascular Study, 8,171 women health professionals aged 40 years or older with histories of CVD or 3 or more CVD risk factors received either ascorbic acid 500 mg/day, vitamin E 600 IU every other day, and/or beta-carotene 50 mg every other day, with these results over a median of 9.4 years of follow-up: “A total of 1,450 women experienced 1 or more CVD outcomes. There was no overall effect of ascorbic acid (relative risk [RR], 1.02; 95% CI, 0.92–1.13 [P = .71]), vitamin E (RR, 0.94; 95% CI, 0.85–1.04 [P = .23]), or beta carotene (RR, 1.02; 95% CI, 0.92–1.13 [P = .71]) on the primary combined end point or on the individual secondary outcomes of myocardial infarction, stroke, coronary revascularization, or CVD death. A marginally significant reduction in the primary outcome with active vitamin E was observed among the prespecified subgroup of women with prior CVD (RR, 0.89; 95% CI, 0.79–1.00 [P = .04]; P value for interaction, .07). There were no significant interactions between agents for the primary end point, but those randomized to both active ascorbic acid and vitamin E experienced fewer strokes (P value for interaction, .03).” (N. R. Cook, ncook@rics.bwh.harvard.edu)
Gender, Pacemaker Placement, & Amiodarone Use: Regardless of weight or BMI, women more frequently require permanent pacemakers during amiodarone treatment of atrial fibrillation than do men, according to data from the Fibrillation Registry Assessing Costs, Therapies, Adverse events, and Lifestyle (FRACTAL) (pp. 1648-53). Among 1,005 patients with new-onset AF, researchers noted: “Amiodarone use was associated with an increased risk of pacemaker insertion (hazard ratio [HR], 2.01; 95% confidence interval [CI], 1.08–3.76) after adjustment for age, sex, atrial flutter, coronary artery disease, heart failure, and hypertension. The effect of amiodarone use was modified by sex, with a significant risk in women but not in men (HR, 4.69; 95% CI, 1.99–11.05 vs HR, 1.05; 95% CI, 0.42–2.58 [P = .02]). This interaction remained significant after adjustment for weight, body mass index, weight-adjusted amiodarone dose, and use of other antiarrhythmic or rate control drugs.” (P. Zimetbaum, pzimetba@bidmc.harvard.edu)
Standardized Orders & Intensive in CAP: Among patients with community-acquired pneumonia, length of hospital stay was reduced significantly by use of standardized order sets combined with intensive clinical case management, primarily because of a reduction in the time from clinical stability to discharge (pp. 1664-9). The study comprised three sequential blocks, one in which 110 patients received conventional treatment, a second in which 119 patients received care guided by SOSs and supported by ICCM, and a third in which 115 patients were treated using the SOSs but without ICCM. The investigators report: “The mean ± SD time to clinical stability was not significantly different between the groups (block 1, 3.3 ± 1.4 days; block 2, 3.2 ± 1.2 days; and block 3, 3.4 ± 1.3 days). The mean LOS was significantly lower in block 2 (5.3 ± 3.5 days) than in blocks 1 (8.8 ± 4.4 days) (P <.001) and 3 (7.3 ± 3.9 days) (P <.01) and significantly lower in block 3 than in block 1 (P = .05). Time to change to oral antibiotics was earlier in block 2 (3.7 ± 0.9 days) than in blocks 1 and 3 (5.7 ± 2.4 and 5.0 ± 1.9 days, respectively) (P <.001). The mean time from clinical stability to hospital discharge was significantly shorter for block 2 (2.1 ± 2.2 days) than for blocks 1 (5.3 ± 4.4 days) (P <.001) and 3 (4.9 ± 4.2 days) (P <.001). Patients in block 2 had a greater proportion with progressive ambulation (P <.001), pneumococcal (P <.001) or influenza vaccination (P <.01), deep-venous thrombosis prophylaxis (P = .01), and smoking cessation counseling (P = .01). There was no significant difference between the blocks in mortality or hospital readmission rate.” (S. Fishbane, Winthrop U. Hosp., Mineola, N.Y.; sfishbane@winthrop.org)

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

PNN Pharmacotherapy Line
Aug. 15, 2007 * Vol. 14, No. 158
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Aug. 15 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2007; 298).
Papillomavirus in Preexisting Infection: Among women who were already positive for human papillomavirus, vaccination against HPV types 16 and 18 did not increase clearance of the virus (pp. 743-53). Concluding that the vaccine should not be used to treat prevalent infections, the researchers note these results from a Phase III trial of 2,189 women aged 18–25 years: “There was no evidence of increased viral clearance at 6 or 12 months in the group who received HPV vaccine compared with the control group. Clearance rates for HPV-16/18 infections at 6 months were 33.4% (82/248) in the HPV vaccine group and 31.6% (95/298) in the control group (vaccine efficacy for viral clearance, 2.5%; 95% confidence interval, –9.8% to 13.5%). Human papillomavirus 16/18 clearance rates at 12 months were 48.8% (86/177) in the HPV vaccine group and 49.8% (110/220) in the control group (vaccine efficacy for viral clearance, –2.0%; 95% confidence interval, –24.3% to 16.3%). There was no evidence of a therapeutic effect for other oncogenic or nononcogenic HPV categories, among women receiving all vaccine doses, among women with single infections, or among women stratified by the following entry variables: HPV-16/18 serology, cytologic results, HPV DNA viral load, time since sexual debut, Chlamydia trachomatis or Neisseria gonorrhoeae infection, hormonal contraceptive use, or smoking.” (A. Hildesheim, Hildesha@exchange.nih.gov)
Lipid Measures in CHD: Apo B:apo A-I ratios added little new predictive capability to traditional lipid measures such as total cholesterol:HDL-C ratios, according to an analysis of data from the Framingham cohort (pp. 776-85). “After a median follow-up of 15.0 years, 291 participants, 198 of whom were men, developed CHD,” the authors write. “In multivariate models adjusting for nonlipid risk factors, the apo B:apo A-I ratio predicted CHD (hazard ratio [HR] per SD increment, 1.39; 95% confidence interval [CI], 1.23–1.58 in men and HR, 1.40; 95% CI, 1.16–1.67 in women), but risk ratios were similar for total cholesterol:HDL-C (HR, 1.39; 95% CI, 1.22–1.58 in men and HR, 1.39; 95% CI, 1.17–1.66 in women) and for LDL-C:HDL-C (HR, 1.35; 95% CI, 1.18–1.54 in men and HR, 1.36; 95% CI 1.14–1.63 in women). In both sexes, models using the apo B:apo A-I ratio demonstrated performance characteristics comparable with but not better than that for other lipid ratios. The apo B:apo A-I ratio did not predict CHD risk in a model containing all components of the Framingham risk score including total cholesterol:HDL-C (P = .12 in men; P = .58 in women).” (R. S. Vasan, Framingham Heart Study, Framingham, Mass.; vasan@bu.edu)
Targeting HDL-C: Aggressive interventions to raise HDL cholesterol levels do not add much benefit to what can be achieved with lifestyle interventions alone, according to a review article (pp. 786-98). Looking at evidence in 31 randomized controlled trials, the authors observe: “Currently available therapeutic and lifestyle strategies, when optimized, increase HDL-C levels by 20% to 30%. While basic and small pilot studies have shown promise, proof that increasing HDL-C levels confers a reduction in major cardiovascular outcomes independent of changes in levels of low-density lipoprotein cholesterol or triglycerides has been more elusive. Some novel therapeutic agents in human studies appear to effectively increase HDL-C levels, whereas other novel strategies that target HDL metabolism or function may have minimal effect on HDL-C levels.” (M. H. Shishehbor, Cleveland Clinic, Cleveland; shishem@gmail.com)

>>>PNN NewsWatch
* Black-box warnings concerning heart failure are being added to the product labeling of the two marketed thiazolidinediones, FDA announced yesterday. Significant weight gain and edema can occur with rosiglitazone and pioglitazone, FDA concluded, placing patients at increased risk for heart failure and related deaths. The new warning advises health professionals to observe patients carefully for the signs and symptoms of heart failure and to take appropriate actions when needed. These drugs should not be used by people with serious or severe heart failure who have marked limits on their activity and who are comfortable only at rest or who are confined to bed or a chair.

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

PNN Pharmacotherapy Line
Aug. 16, 2007 * Vol. 14, No. 159
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Aug. 16 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2007; 357).
Safety of Medical Abortion Following Prior Abortion: In a study of medical abortions from Denmark, researchers found “no evidence that a previous medical abortion, as compared with a previous surgical abortion, increases the risk of spontaneous abortion, ectopic pregnancy, preterm birth, or low birth weight” (pp. 648-53). All women living in Denmark who had undergone surgical or drug-induced abortion for nonmedical reasons between 1999 and 2004 were included in the analysis, which relied on data on subsequent pregnancies as recorded in national registries. The authors report these results: “Among 11,814 pregnancies in women who had had a previous first-trimester medical abortion (2,710 women) or surgical abortion (9,104 women), there were 274 ectopic pregnancies (respective incidence rates, 2.4% and 2.3%), 1,426 spontaneous abortions (12.2% and 12.7%), 552 preterm births (5.4% and 6.7%), and 478 births with low birth weight (4.0% and 5.1%). After adjustment for maternal age, interval between pregnancies, gestational age at abortion, parity, cohabitation status, and urban or nonurban residence, medical abortion was not associated with a significantly increased risk of ectopic pregnancy (relative risk, 1.04; 95% confidence interval [CI], 0.76 to 1.41), spontaneous abortion (relative risk, 0.87; 95% CI, 0.72 to 1.05), preterm birth (relative risk, 0.88; 95% CI, 0.66 to 1.18), or low birth weight (relative risk, 0.82; 95% CI, 0.61 to 1.11). Gestational age at medical abortion was not significantly associated with any of these adverse outcomes.” (J. Zhang, zhangj@mail.nih.gov)
Prescription Drug Advertising to Consumers: Despite criticisms of direct-to-consumer advertising of prescription drugs, spending for these promotions have increased in recent years (pp. 673-81). Concluding that their findings “suggest that calls for a moratorium on such advertising for new drugs would represent a dramatic departure from current practices,” the investigators note these trends in the decade since television spots became permissible in the U.S.: “Total spending on pharmaceutical promotion grew from $11.4 billion in 1996 to $29.9 billion in 2005. Although during that time spending on direct-to-consumer advertising increased by 330%, it made up only 14% of total promotional expenditures in 2005. Direct-to-consumer campaigns generally begin within a year after the approval of a product by the FDA. In the context of regulatory changes requiring legal review before issuing letters, the number of letters sent by the FDA to pharmaceutical manufacturers regarding violations of drug-advertising regulations fell from 142 in 1997 to only 21 in 2006.” (J. M. Donohue, jdonohue@pitt.edu)
Science & Drug Evaluation: In the many areas of life where the federal government seeks to protect citizens, only in the realm of pharmaceuticals is science formally integrated into decision processes, writes the author of a Perspectives article. (pp. 633-5). Suggesting ways in which science can be kept “on top in drug evaluation,” the author concludes: “The approval, prescribing, and safety surveillance of prescription drugs involve a complicated mix of science, regulatory law, clinical judgment, business, and politics. It is not easy to ensure that science dominates in such a heady brew, but despite missteps such as the latest move with respect to rosiglitazone, an open model holds more promise for data-driven public decision making than those followed in the energy, finance, and defense sectors, among others. As Congress persists in allowing industry funding to dominate the FDA budget (and, many fear, its perspective as well), it will be especially important for the scientific community to remain independent, conduct rigorous analyses, and make its voice heard clearly to ensure that drug-review decisions are driven solely by the data.” (J. Avorn, Harvard Med. Sch., Boston)

>>>PNN NewsWatch
* FDA yesterday announced hearings, slated for Oct. 18–19, on safety of OTC cold and cough products when used in young children.

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

PNN Pharmacotherapy Line
Aug. 17, 2007 * Vol. 14, No. 160
Providing news and information about medications and their proper use

>>>Gastroenterology Report
Source:
Aug. issue of Gastroenterology (www.gastrojournal.org; 2007; 133).
Statins & Colorectal Cancer: Prolonged statin use does not protect patients against colorectal cancer, according to a large population-based case–control study conducted at 454 general practices in the U.K. (pp. 393-402). Comparing frequencies of colorectal cancer among those taking NSAIDs, COX-2 inhibitors, and statins, the investigators found: “We analyzed 5,686 cases and 24,982 matched controls with ≥4 years of records. The adjusted odds ratio for colorectal cancer associated with any statin prescription was 0.93 (95% confidence interval: 0.83–1.04), with no trend in duration of use or number of prescriptions. For any nonsteroidal anti-inflammatory drug prescription the adjusted odds ratio was 0.94 (95% confidence interval: 0.88–1.00), with a significant decrease in risk with increasing number of prescriptions and an adjusted odds ratio of 0.76 (0.60–0.95) for ≥25 prescriptions. Prolonged use of cyclooxygenase-2 inhibitors was minimal, but for those receiving ≥25 prescriptions the adjusted odds ratio was 0.34 (0.14–0.85). Results were similar in the subset of participants with ≥8 years of records; the adjusted odds ratio for ≥61 months of statin prescriptions was 1.00 (0.67–1.48).” (Y. Vinogradova, U. Nottingham, Nottingham, U.K.; yana.vinogradova@nottingham.ac.uk)
Enzyme Therapy for Celiac Sprue: Use of a combination enzyme product can raise the tolerable gluten threshold in patients with celiac sprue, avoiding the need for highly restricted diets, conclude authors of an in vitro/in vivo study (pp. 472-80). Testing glutamine-specific endoprotease (EP-B2 from barley) and a prolyl endopeptidase (SC PEP from Sphingomonas capsulata), for digestion of gluten under gastric conditions, the investigator note: “The analysis revealed that EP-B2 extensively proteolyzes complex gluten proteins in bread, whereas SC PEP rapidly detoxifies the residual oligopeptide products of EP-B2 digestion. In vitro dose variation data suggests that an approximate 1:1 weight ratio of the 2 enzymes should maximize their synergistic potential. The efficacy of this 2-enzyme glutenase was verified in a rat model of gastric gluten digestion.” (C. Khosla, khosla@stanford.edu)

>>>PNN NewsWatch
* A recommendation to include initial genetic testing of patients beginning warfarin therapy is now a part of product labeling for this anticoagulant, FDA announced yesterday. Specifically, people with variations in two genes, CYP2C9 and VKORC1, may need lower warfarin doses than other patients, the new information notes. The usual genetic form of CYP2C9 with normal enzyme activity is CYP2C9*1. Studies indicate that the CYP2C9*2 and CYP2C9*3 genetic variations are important because patients with these variations metabolize warfarin more slowly than do patients with CYP2C9*1. In a study among whites, approximately 11% of the patients carried the CYP2C9*2 and 7% carried the CYP2C9*3 variation. Limited clinical data suggest CYP2C9 genetic variations occur less frequently in nonwhites. Patients with CYP2C9 and VKORC1 genetic variations require lower warfarin initial and maintenance dose to stay within the target INR. Future clinical studies are expected to identify which initial warfarin doses are most appropriate for people with different CYP2C9 and VKORC1 gene variants.
* An accidental overdose of the highly concentrated
Kaletra Oral Solution in a pediatric patient is the subject of a Dear Healthcare Provider Letter from Abbott Laboratories. A 44-day-old infant received a significantly large dose of Kaletra (6.5 mL) and died 9 days later of cardiogenic shock. Health professionals should pay special attention to accurate calculation of the dose of lopinavir/ritonavir, transcription of the medication order, dispensing information, and dosing instructions to minimize the risk for medication errors.
*
Entecavir (Baraclude) is not recommended for HIV/hepatitis B virus co-infected patients who are not also receiving highly active antiretroviral therapy due to the potential for the development of HIV resistance, warns a notice from FDA and Bristol-Myers Squibb.

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

PNN Pharmacotherapy Line
Aug. 20, 2007 * Vol. 14, No. 161
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Aug. 18 issue of Lancet (www.thelancet.com; 2007; 370).
Celecoxib After Stent Implantation: Adjunctive use of celecoxib for 6 months after stent implantation in patients with coronary artery disease was safe and reduced the need for revascularization of the target lesion, concludes a randomized trial of 274 patients (pp. 567-74). All patients received aspirin 100 mg and clopidogrel 75 mg daily, and the intervention group also received celecoxib 400 mg before the stent procedure and 200 mg twice daily for 6 months. Results showed the following: “At 6 months, mean in-stent late luminal loss was lower in the celecoxib group (0.49 mm, SD 0.47) than in the control group (0.75 mm, 0.60) (absolute difference 0.26 mm; 95% CI 0.12–0.40). Frequency of secondary outcomes at 6 months was also lower in the celecoxib group, mainly because of a reduced need for revascularisation of the target lesion.” (H-S Kim, Seoul Natl. U. Hosp., Seoul, South Korea; hyosoo@snu.ac.kr)
Antigen Sparing for Avian Influenza Vaccine Production: A recombinant H5N1 split-virion vaccine provided greater immunogenicity when administered with a proprietary adjuvant, indicating that the strategy might be a means of increasing production capacity in the event of an avian influenza pandemic (pp. 580-9). Comparing four antigen doses (3.8, 7.5, 15, and 30 mcg hemagglutinin given with or without adjuvant, the investigators report: “All eight vaccine formulations had a good safety profile. No serious adverse events were reported. The adjuvanted vaccines induced more injection-site symptoms and general symptoms than did the non-adjuvanted vaccines, but most were mild to moderate in intensity and transient in nature. The adjuvanted formulations were significantly more immunogenic than the non-adjuvanted formulations at all antigen doses. At the lowest antigenic dose (3.8 mcg), immune responses for the adjuvanted vaccine against the recombinant homologous vaccine strain (A/Vietnam/1194/2004 NIBRG-14, clade 1) met or exceeded all US Food and Drug Administration and European Union licensure criteria. Furthermore, 37 of 48 (77%) participants receiving 3.8 mcg of the adjuvanted vaccine seroconverted for neutralising antibodies against a strain derived by reverse genetics from a drifted H5N1 isolate (A/Indonesia/5/2005, clade 2).” (G. Leroux-Roels, Ghent U. and Hosp., Ghent, Belgium; Geert.LerouxRoels@UGent.be)

>>>BMJ Highlights
Source:
Early-release article from BMJ (www.bmj.org; 2007; 335).
Acupuncture for Osteoarthritis: No further improvement in pain scores was noted when acupuncture was added to a course of advice and exercise in 352 adults with knee osteoarthritis, according to a randomized controlled trial (doi: 10.1136/bmj.39280.509803.BE). “Follow-up rate at six months was 94%,” report the investigators. “The mean (SD) baseline pain score was 9.2 (3.8). At six months mean reductions in pain were 2.28 (3.8) for advice and exercise, 2.32 (3.6) for advice and exercise plus true acupuncture, and 2.53 (4.2) for advice and exercise plus non-penetrating acupuncture. Mean differences in change scores between advice and exercise alone and each acupuncture group were 0.08 (95% confidence interval –1.0 to 0.9) for advice and exercise plus true acupuncture and 0.25 (–0.8 to 1.3) for advice and exercise plus non-penetrating acupuncture. Similar non-significant differences were seen at other follow-up points. Compared with advice and exercise alone there were small, statistically significant improvements in pain intensity and unpleasantness at two and six weeks for true acupuncture and at all follow-up points for non-penetrating acupuncture.” (N. E. Foster, n.foster@keele.ac.uk)

>>>PNN NewsWatch
* FDA on Friday warned that nursing infants are at risk of morphine overdose if their mothers take codeine and are ultrarapid metabolizers of the drug.

>>>PNN JournalWatch
* Management of Acute Organophosphorus Pesticide Poisoning, in Lancet, 2007; doi: 10.1016/S0140-6736(07)61202-1. Reprints: M. Eddleston, Scottish Poisons Information Bureau, Edinburgh, U.K.; eddlestonm@yahoo.com

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

PNN Pharmacotherapy Line
Aug. 21, 2007 * Vol. 14, No. 162
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Aug. 21 issue of the Annals of Internal Medicine (www.annals.org/current.shtml; 2007; 147).
Selenium for DM Prevention: In a secondary analysis of a 1,202-patient study conducted in dermatology clinics, long-term selenium supplementation failed to reduce the incidence of type 2 diabetes mellitus and in fact may have increased onset of the disease (pp. 217-23). Participants—living in an area of the eastern U.S. with low selenium intake and free of DM at baseline—received oral selenium 200 mcg/day or placebo, with these results: “During an average follow-up of 7.7 years (SD, 2.7), type 2 diabetes developed in 58 selenium recipients and 39 placebo recipients (incidence, 12.6 cases per 1,000 person–years vs. 8.4 cases per 1,000 person–years, respectively; hazard ratio, 1.55 [95% CI, 1.03 to 2.33]). The lack of benefit of selenium supplementation on the incidence of type 2 diabetes persisted in analyses stratified by age, sex, body mass index, and smoking status. An exposure–response gradient was found across tertiles of baseline plasma selenium level, with a statistically significantly increased risk for type 2 diabetes in the highest tertile of baseline plasma selenium level (hazard ratio, 2.70 [CI, 1.30 to 5.61]).” (S. Stranges, Warwick Med. Sch., Coventry, U.K.; s.stranges@warwick.ac.uk)
Describing this study as “more bad news for supplements,” editorialists write (pp. 271-2): “In the past decade, randomized, controlled clinical trials have shown that beta-carotene and vitamin E supplements, which were widely believed to be safe, increase mortality and morbidity. No dietary supplement, including selenium, has proven useful so far for the prevention of cardiovascular disease or cancer in the general U.S. population. The balance of the potential benefits and harms of selenium supplementation depends on the dietary selenium intake in different countries. However, the U.S. public needs to know that most people in this country receive adequate selenium from their diet. By taking selenium supplements on top of an adequate dietary intake, people may increase their risk for diabetes.” (E. Guallar, Johns Hopkins U., Baltimore;
eguallar@jhsph.edu)
Cysteamine for Nephropathic Cystinosis: Long-term oral cysteamine therapy reduced morbidity and death associated with nephropathic cystinosis, concludes a retrospective, nonrandomized case series of 58 men and 42 women seen at the NIH Clinical Ctr. over a 21-year period (pp. 242-50). “Of 100 adults with nephropathic cystinosis, 92 had received a renal allograft and 33 had died,” the investigators report. “At least half of the patients had hypothyroidism, hypergonadotropic hypogonadism (in men), pulmonary insufficiency, swallowing abnormalities, or myopathy. One third of the patients had retinopathy or vascular calcifications, and 24% had diabetes. Homozygosity for the 57-kb CTNS deletion was associated with an increased risk for death and morbidity. The 39 patients who received long-term (8 years or more) oral cysteamine therapy were taller and heavier, had a renal allograft later in life, had lower cholesterol levels, and experienced fewer complications and deaths than patients who received cysteamine for fewer than 8 years. The frequency of diabetes mellitus, myopathy, pulmonary dysfunction, hypothyroidism, and death increased as time off cysteamine treatment increased, and it decreased as time on cysteamine therapy increased.” (W. A. Gahl, bgahl@helix.nih.gov)
Half-lives of Systematic Reviews: Within 2 years of publication, one-fourth of high-quality systematic reviews required updating, write authors of a survival analysis (pp. 224-33): “The cohort of 100 systematic reviews included a median of 13 studies and 2,663 participants per review. A qualitative or quantitative signal for updating occurred for 57% of reviews (95% CI, 47% to 67%). Median duration of survival free of a signal for updating was 5.5 years (CI, 4.6 to 7.6 years). However, a signal occurred within 2 years for 23% of reviews and within 1 year for 15%. In 7%, a signal had already occurred at the time of publication. Only 4% of reviews had a signal within 1 year of the end of the reported search period; 11% had a signal within 2 years of the search. Shorter survival was associated with cardiovascular topics (hazard ratio, 2.70 [CI, 1.36 to 5.34]) and heterogeneity in the original review (hazard ratio, 2.15 [CI, 1.12 to 4.11]).” (K. G. Shojania, Ottawa Hosp., Ottawa; kshojania@ohri.ca)

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

PNN Pharmacotherapy Line
Aug. 22, 2007 * Vol. 14, No. 163
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Aug. 22/29 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2007; 298).
Pediatric Hypertension: Hypertension and prehypertension were frequently undiagnosed in a group of 14,187 children and adolescents seen at least three times for well-child care in 1999–2006 (pp. 874-9). The researchers found: “Of 507 children and adolescents (3.6%) who had hypertension, 131 (26%) had a diagnosis of hypertension or elevated blood pressure documented in the electronic medical record. Patient factors that increased the adjusted odds of a correct diagnosis were a 1-year increase in age over age 3 (odds ratio [OR], 1.09; 95% confidence interval [CI], 1.03–1.16), number of elevated blood pressure readings beyond 3 (OR, 1.77; 95% CI, 1.21–2.57), increase of 1% in height-for-age percentile (OR, 1.02; 95% CI, 1.01–1.03), having an obesity-related diagnosis (OR, 2.61; 95% CI, 1.49–4.55), and number of blood pressure readings in the stage 2 hypertension range (OR, 1.68; 95% CI, 1.29–2.19). Of 485 children and adolescents (3.4%) who had prehypertension, 55 (11%) had an appropriate diagnosis documented in the electronic medical record. Patient factors that increased the adjusted odds of being diagnosed with prehypertension included a 1-year increase in age over age 3 (OR, 1.21; 95% CI, 1.09–1.34) and number of elevated blood pressure readings beyond 3 (OR, 3.07; 95% CI, 2.20–4.28).” (D. C. Kaelber, dkaelber@partners.org)
Pediatric Obesity: In addressing the epidemic of obesity among American children, clinicians need to take a broader perspective, writes the author of a commentary article (pp. 920-2): “The Institute of Medicine has appropriately called for a national campaign to abate the spreading epidemic of childhood obesity. Although actions by local nonprofit organizations, select states, and influential public leaders are encouraging, current efforts are isolated, fragmented, and uncoordinated. A more efficient and unified effort is required, with coordinated individual and population interventions, strong research and measurement, and development of replicable models. Sustainable professional, public, corporate, nonprofit, and philanthropic resources are needed on a large scale to match the scope of the problem. Moreover, individual physicians, county and state medical societies, and national medical specialty associations now have the opportunity, the means, and the rationale to champion the environmental and social changes that are necessary to alter the daily eating, exercise, and lifestyle choices made by children and adults across the United States. This requires greater awareness by physicians that the community itself is as much a patient in need as the individuals and families in the examination room.” (R. Lavizzo–Mourey, Robert Wood Johnson Foundation, Princeton, N.J.; ped@rwjf.org">oped@rwjf.org)

>>>PNN NewsWatch
* The share of seniors without drug coverage dropped significantly under Medicare’s new drug benefit, according to a Health Affairs article based on a survey of more than 16,000 seniors. Seniors with drug coverage from any source were less likely to face high monthly drug costs or skip prescribed medications because of cost than were seniors who remained without drug coverage, the article notes. However, seniors who enrolled in a Medicare Part D plan did not fare as well as those who relied on other sources of drug coverage, such as employer-sponsored coverage or benefits from the Department of Veterans Affairs.
* To help prepare for and respond to
medical emergencies among school children, the American College of Emergency Physicians is partnering with Safety4Kids, producers of public television’s SeeMore’s Playhouse, to launch a campaign aimed at improving children’s health and safety at school and home. As part of this effort, ACEP is sending educational materials to elementary schools for distribution to teachers and parents.
* Prescription pick-up kiosks would be useful additions to
pharmacy services, according to 70% of respondents to the latest WilsonRx Survey Report. Waits of more than 5 minutes were commonly reported and were an important factor in dissatisfaction with the pharmacy.

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

PNN Pharmacotherapy Line
Aug. 23, 2007 * Vol. 14, No. 164
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Aug. 23 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2007; 357).
Sexuality in Older Americans: Older adults in the U.S. are often sexually active, have sexual difficulties, but rarely discuss these problems with physicians, according to a survey of 3,005 adults aged 57 to 85 years (pp. 762-74). The investigators report: “The prevalence of sexual activity declined with age (73% among respondents who were 57 to 64 years of age, 53% among respondents who were 65 to 74 years of age, and 26% among respondents who were 75 to 85 years of age); women were significantly less likely than men at all ages to report sexual activity. Among respondents who were sexually active, about half of both men and women reported at least one bothersome sexual problem. The most prevalent sexual problems among women were low desire (43%), difficulty with vaginal lubrication (39%), and inability to climax (34%). Among men, the most prevalent sexual problems were erectile difficulties (37%). Fourteen percent of all men reported using medication or supplements to improve sexual function. Men and women who rated their health as being poor were less likely to be sexually active and, among respondents who were sexually active, were more likely to report sexual problems. A total of 38% of men and 22% of women reported having discussed sex with a physician since the age of 50 years.” (S. T. Lindau, slindau@uchicago.edu)
Different motivations for sexual activity among men and women are emphasized in an accompanying editorial (pp. 820-2): “As compared with studies in men, studies in women have emphasized the effect of relationship factors and mental health, which increasingly are proving to be more important predictors of sexual well-being than the physiological factors of sexual arousal and response. Relationship factors and mental health are likely to be as important as or more important than physiological factors as women age. Whereas many women report a decrease in their sexual interest and responsiveness as they progress through midlife, they are less likely to become distressed or worried about such changes as they get older. For many women, being in a relationship, the quality of that relationship, and a partner’s sexual problems are more important than their sexual responsiveness. Women also differ with regard to what they find rewarding about sex. Some are motivated principally by the desire for intimacy, whereas for others the desire for sexual pleasure and orgasm is equally important or even more important. These different motivational patterns may be affected in different ways by aging, although this remains to be shown.” (J. H. J. Bancroft, Kinsey Inst. for Research in Sex, Gender, and Reproduction, Indiana U., Bloomington)
‘Sicko’ Health System: Solutions to flaws in the American health care system, as documented in Michael Moore’s movie Sicko, are proposed in a Commentary (pp. 733-5): “For now, the best step may be to require employers either to provide their workers with good private coverage or to enroll them, at a modest cost, in a new public program modeled after Medicare. Workers enrolled in this new public framework could be asked to pay a modest premium on top of employers’ contributions, based on their income, and they could be allowed to enroll in qualified private plans—as people with Medicare coverage can today. No doubt many employers would seize the opportunity to obtain inexpensive coverage for their workers, which would give the new public insurance plan a large, diverse enrollment and a great deal of leverage to contain costs and improve care. But employers could also implement their own cost-control and quality-enhancement strategies, without having to bear the burden of uncompensated charity care for the uninsured and underinsured.” (J. S. Hacker, Yale U., New Haven, Ct.)

>>>PNN NewsWatch
* Risperidone (Risperdal, Janssen) has been approved by FDA for two pediatric indications: schizophrenia in adolescents aged 13–17 and short term treatment of manic or mixed episodes of bipolar I disorder in those aged 10–17 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 © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Aug. 24, 2007 * Vol. 14, No. 165
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
Aug. 28 issue of the Journal of the American College of Cardiology (http://content.onlinejacc.org/current.dtl; 2007; 50).
Valsartan for Slowing Early Cardiovascular Disease: Valsartan slowed progression and/or reversed early cardiovascular disease in a study of 76 asymptomatic high-risk patients with prehypertension or controlled hypertension (pp. 835-9). Comparing double-blind placebo or valsartan 160 mg once daily for 6 months followed by single-blind valsartan for an additional 6 months in both groups, the researchers found: “Valsartan significantly reduced the [Rasmussen Disease Score] after 6 months versus Plac (p < 0.03) and at 12 months (either 12 or 6 months of Val, p < 0.0001). The major contribution in risk score reduction was due to an increase in small artery elasticity and a decrease in BP, and after 12 months there was a reduction in left ventricular mass index (p < 0.03).” (D. A. Duprez, dupre007@umn.edu)
Antilipid Agents for Rheumatoid Arthritis: Cholesterol lowering has anti-inflammatory effects and improves vascular function in patients with rheumatoid arthritis, according to a study of simvastatin 20 mg and ezetimibe 10 mg daily for 6 weeks in 20 participants (pp. 852-8). Disease activity and inflammatory markers were reduced by both drugs, the investigators note, adding these details: “Both ezetimibe and simvastatin significantly reduced total cholesterol (–0.62 ± 0.55 mmol/l and –1.28 ± 0.49 mmol/l, respectively; p < 0.001), low-density lipoprotein cholesterol (–0.55 ± 0.55 mmol/l and –1.28 ± 0.49 mmol/l; p < 0.0001), and C-reactive protein (–5.35 ± 9.25 mg/l and –5.05 ± 6.30 mg/l; p < 0.001). Concomitantly, Disease Activity Score (–0.55 ± 1.01 and –0.67 ± 0.91; p = 0.002), aortic [pulse wave velocity] (–0.69 ± 1.15 m/s and –0.71 ± 0.71 m/s; p = 0.001), and [brachial artery flow-mediated dilation] (1.37 ± 1.17% and 2.51 ± 2.13%; p = 0.001) were significantly improved by both drugs.” (K. Mäki-Petäjä, U. Cambridge, Cambridge, U. K.; km391@cam.ac.uk)
Resting Heart Rate in Cardiovascular Disease: In a state-of-the-art paper, authors argue that “the potential role of [heart rate] and its modulation should be considered in future cardiovascular guidance documents” (pp. 823-30): “The importance of resting HR as a prognostic factor and potential therapeutic target is not yet generally accepted. Recent large epidemiologic studies have confirmed earlier studies that showed resting HR to be an independent predictor of cardiovascular and all-cause mortality in men and women with and without diagnosed cardiovascular disease. Clinical trial data suggest that HR reduction itself is an important mechanism of benefit of beta-blockers and other heart-rate lowering drugs used after acute myocardial infarction, in chronic heart failure, and in stable angina pectoris. Pathophysiological studies indicate that a relatively high HR has direct detrimental effects on the progression of coronary atherosclerosis, on the occurrence of myocardial ischemia and ventricular arrhythmias, and on left ventricular function. Studies have found a continuous increase in risk with HR above 60 beats/min. Although it may be difficult to define an optimal HR for a given individual, it seems desirable to maintain resting HR substantially below the traditionally defined tachycardia threshold of 90 or 100 beats/min.” (K. Fox, Royal Brompton Hosp., London; k.fox@rbh.nthames.nhs.uk)

>>>PNN NewsWatch
* FDA yesterday proposed creation of a consumer-friendly rating system for sunscreen products designed to help consumers identify the level of ultraviolet A protection offered by a product. Under the system, one star would represent low UVA protection, two stars would represent medium protection, three stars would represent high protection, and four stars would represent the highest UVA protection available in an OTC sunscreen product. If a sunscreen product does not provide at least a low level (one star) of protection, FDA is proposing to require that the product bear a “no UVA protection” marking on the front label near the SPF value. In addition, this Warnings statement in the Drug Facts box will be required: “UV exposure from the sun increases the risk of skin cancer, premature skin aging, and other skin damage. It is important to decrease UV exposure by limiting time in the sun, wearing protective clothing, and using a sunscreen.”

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

PNN Pharmacotherapy Line
Aug. 27, 2007 * Vol. 14, No. 166
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Aug. 25 issue of Lancet (www.thelancet.com; 2007; 370).
Calcium, Vitamin D, & Bone Loss: Daily doses of at least 1,200 mg of calcium and, when combined treatment is needed, 800 IU of vitamin D are recommended for use in patients at risk for osteoporotic fractures based on a meta-analysis of 29 randomized trials of 63,897 participants (pp. 657-66). The authors report: “In trials that reported fracture as an outcome (17 trials, n = 52,625), treatment was associated with a 12% risk reduction in fractures of all types (risk ratio 0.88, 95% CI 0.83–0.95; p = 0.0004). In trials that reported bone-mineral density as an outcome (23 trials, n = 41,419), the treatment was associated with a reduced rate of bone loss of 0.54% (0.35–0.73; p < 0.0001) at the hip and 1.19% (0.76–1.61%; p < 0.0001) in the spine. The fracture risk reduction was significantly greater (24%) in trials in which the compliance rate was high (p < 0.0001). The treatment effect was better with calcium doses of 1,200 mg or more than with doses less than 1,200 mg (0.80 vs 0.94; p = 0.006), and with vitamin D doses of 800 IU or more than with doses less than 800 IU (0.84 vs 0.87; p = 0.03).” (B. M. P. Tang, U. Sydney, Penrith, Australia; benjamin@clubsalsa.com.au)
Managing Septic Shock: Epinephrine alone is just as effective for management of septic shock as norepinephrine plus dobutamine, according to a randomized double-blind study of 330 patients at 19 intensive care units in France (pp. 676-84). Comparing doses of the drugs titrated to maintain a mean blood pressure of 70 mm Hg, the investigators found: “At day 28, there were 64 (40%) deaths in the epinephrine group and 58 (34%) deaths in the norepinephrine plus dobutamine group (p = 0.31; relative risk 0.86, 95% CI 0.65–1.14). There was no significant difference between the two groups in mortality rates at discharge from intensive care (75 [47%] deaths vs 75 [44%] deaths, p = 0.69), at hospital discharge (84 [52%] vs 82 [49%], p = 0.51), and by day 90 (84 [52%] vs 85 [50%], p = 0.73), time to haemodynamic success (log-rank p = 0.67), time to vasopressor withdrawal (log-rank p = 0.09), and time course of SOFA score. Rates of serious adverse events were also similar.” (D. Annane, U. Versailles Saint Quentin, Paris; djillali.annane@rpc.aphp.fr)
MI as Prediabetes Equivalent: Among 8,291 Italian patients with a myocardial infarction within the previous 3 months and free of diabetes at that point, the annual incidences of impaired fasting glucose and diabetes were significantly higher than in population-based cohorts (pp. 667-75). The researchers conclude that their data “indicate that myocardial infarction could be a prediabetes risk equivalent”: “During 26,795 person-years (mean follow-up 3.2 years [SD 0.9]), 998 individuals (12%) developed new-onset diabetes (incidence 37 cases per 1,000 person–years). Of the 7,533 without impaired fasting glucose at baseline, 2,514 (33%) developed new-onset impaired fasting glucose or diabetes (incidence 123 cases per 1000 person–years), rising to 3,859 (62%) of 6,229 with the lower cutoff for impaired fasting glucose of 5.6 mmol/L (incidence 321 cases per 1,000 person–years).” (D. Mozaffarian, dmozaffa@hsph.harvard.edu)

>>>BMJ Highlights
Source:
Aug. 25 issue of BMJ (www.bmj.org; 2007; 335).
Treating Pediatric Pyelonephritis: For first-line treatment of initial episodes of pyelonephritis in children, oral antibiotics are as effective as parenteral agents, concludes a 502-patient study (pp. 386 ff). Statistically similar results with regard to scarring scintigraphy at 12 months, time to defervescence, white cell count, and percentage of patients with sterile urine were observed with oral amoxicillin–clavulanic acid 50 mg/kg/day in three doses for 10 days and parenteral ceftriaxone 50 mg/kg/day in a single dose for 3 days followed by the oral agents for 7 days. (G. Montini, U. Padua, Padua, Italy; montini@pediatria.unipd.it)

>>>PNN JournalWatch
* Pandemic Influenza Planning in Nursing Homes: Are We Prepared?, in Journal of the American Geriatrics Society, 2007; 55: 1431–7. Reprints: L. Mody, lonamody@umich.edu

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

PNN Pharmacotherapy Line
Aug. 28, 2007 * Vol. 14, No. 167
Providing news and information about medications and their proper use

>>>Geriatrics Highlights
Source:
Sept. issue of the Journal of the American Geriatrics Society (www.blackwell-synergy.com/toc/jgs/55/9; 2007; 55).
Drugs v. Psychotherapy for Late-Life Depression: Compared with interpersonal psychotherapy, maintenance antidepressant pharmacotherapy provided superior and sustained improvements in overall well-being among 116 patients aged 70 or older with major depression (pp. 1325-32). The study tested paroxetine and monthly manual-based psychotherapy, and these changes were noted in the Quality of Well-Being Scale (QWB) and six specific health-related quality of life domains derived from the Medical Outcomes Study 36-item Short-Form Health Survey subscales: “All domains of HR-QOL except physical functioning improved with successful acute and continuation treatment. After controlling for any effects of psychotherapy, pharmacotherapy was superior to placebo in preserving overall well-being (P = .04, effect size (r) = 0.23), social functioning (P = .02, r = 0.27), and role limitations due to emotional problems (P = .007, r = 0.30). Interpersonal psychotherapy (controlling for the effects of pharmacotherapy) did not preserve HR-QOL better than supportive clinical management.” (C. F. Reynolds III, U. Pittsburgh, Pittsburgh; reynoldscf@upmc.edu)
Quality of Pharmacotherapy for Older Veterans: A retrospective analysis of veterans being discharged from the emergency department or urgent care clinic at a VA medical center shows that substantial numbers are at risk for adverse events as a result of suboptimal prescribing and inadequate mediation monitoring (pp. 1339-48). The study included 421 veterans aged 65 or older who received 757 new medications at the time of discharge, and results showed the following: “The most frequently prescribed medications were nonsteroidal antiinflammatory drugs (n = 59), opioid analgesics (n = 47), and fluoroquinolone antibiotics (n = 46). Overall, 134 (31.8%) subjects were found to have suboptimal pharmacotherapy with regard to their discharge medications; 49 (11.6%) were prescribed a drug to avoid, 53 (12.6%) received a drug that introduced a new drug–drug interaction, 24 (5.7%) were given a drug that introduced a drug–disease interaction, and 74 (17.6%) did not have a quality indicator satisfied (61% of these evaluated prescribing and 39% evaluated medication monitoring). No consistent associations between patient or visit characteristics and suboptimal pharmacotherapy were identified in multivariable models.” (S. N. Hastings, hasti003@mc.duke.edu)
HIV Infections Among Older Adults: An increasing number of adults aged 50 and older are living with HIV/AIDS or are newly diagnosed with the infection, according to an analysis of 1992–2004 data from New Jersey (pp. 1393-7). Trends in the 11th most populous state in the U.S. show: “The proportion of all persons aged 50 and older living with HIV/AIDS in 2004 was significantly greater than the comparable proportion of persons in 1992. Proportionally, more persons were newly diagnosed with HIV who were aged 50 and older according to sex and for each of the three major race or ethnicity groups (white non-Hispanic, black non-Hispanic, and Hispanic) than were persons younger than 50. Each of these increases was statistically significant.” (S. M. Paul, N.J. Dept. of Health and Senior Svc., Trenton, N.J.; Sindy.Paul@doh.state.nj.us)

>>>PNN NewsWatch
* The National Association of Boards of Pharmacy has suspended indefinitely administration of its North American Pharmacist Licensure Examination (NAPLEX) and the Georgia Multistate Pharmacy Law Examination following allegations of breaches in the integrity of the examination. According news stories and blogs posted on the Web, federal marshals earlier this month seized computers at the U. Georgia College of Pharmacy and the home of a faculty member as part of an investigation. In a memo to state boards of pharmacy posted on the NABP Web site, Executive Director/Secretary Carmen A. Catizone wrote that “the examinations will be reactivated as soon as possible when NABP is confident that both examinations are able to validly assess the entry-level competence of pharmacists to safely practice pharmacy.”

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

PNN Pharmacotherapy Line
Aug. 29, 2007 * Vol. 14, No. 168
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Sept. issue of Diabetes Care (http://care.diabetesjournals.org/current.shtml; 2007; 30).
Basal–Bolus Insulin in Hospitalized Patients: In 130 patients with type 2 diabetes who were insulin-naive upon admission to non-ICU areas of hospitals, treatment with insulin glargine and glulisine improved glycemic control significantly more than was achieved with sliding-scale insulin (SSI) (pp. 2181-6). In the Randomized Study of Basal–Bolus Insulin Therapy in the Inpatient Management of Patients with Type 2 Diabetes (RABBIT 2) trial, investigators administered insulin glargine once daily and glulisine before meals with adjustments for glucose levels of 201–400 mg/dL. Compared with SSI four times daily for blood glucose levels above 140 mg/dL, the basal–bolus approach provided these results: “The mean admission blood glucose was 229 ± 6 mg/dl and A1C 8.8 ± 2%. A blood glucose target of <140 mg/dl was achieved in 66% of patients in the glargine and glulisine group and in 38% of those in the SSI group. The mean daily blood glucose between groups ranged from 23 to 58 mg/dl, with an overall blood glucose difference of 27 mg/dl (P < 0.01). Despite increasing insulin doses, 14% of patients treated with SSI remained with blood glucose >240 mg/dl. There were no differences in the rate of hypoglycemia or length of hospital stay.” (G. E. Umpierrez, geumpie@emory.edu)
Assessing Barriers to Insulin Treatment: A short questionnaire provided reliable and valid measures of psychological resistance to insulin treatment in a validation study involving 448 patients and a cross-validation effort in 449 additional patients (pp. 2199-204). The Barriers to Insulin Treatment Questionnaire provided these results: “Analyses in the first sample yielded five components that accounted for 74.5% of the variance based on 14 items and led to the following subscales: fear of injection and self-testing, expectations regarding positive insulin-related outcomes, expected hardship from insulin treatment, stigmatization by insulin injections, and fear of hypoglycemia. In addition, an overall sum score of all values was calculated. The structure of the questionnaire was cross-validated in the second sample, with almost identical component loadings and an explained variance of 69.4%. An additional confirmatory factor analysis also indicated an acceptable to good model fit with root mean square error of approximation equal to 0.04 and comparative fit index equal to 0.97. Coefficients of reliability (Cronbach’s alpha 0.62–0.85 and 0.78 for overall sum score) were acceptable, considering the very small number of items for each scale.” (F. Petrak, LWL-Klinik Dortmund/Ruhr-Universität Bochum, Wiesbaden, Germany; mail@dr-frank-petrak.de)
Effects of Depression on Self-care: Even low levels of depressive symptoms are associated with “nonadherence to important aspects of diabetes self-care,” including taking medications, according to a survey of 879 patients with type 2 diabetes (pp. 2222-7). Using the Harvard Department of Psychiatry/National Depression Screening Day Scale (HANDS), the Summary of Diabetes Self-Care Activities, and self-reported medication adherence, the researchers found these results: “Of the patients, 19% met the criteria for probable major depression (HANDS score 9), and an additional 66.5% reported at least some depressive symptoms. After controlling for covariates, patients with probable major depression reported significantly fewer days’ adherent to diet, exercise, and glucose self-monitoring regimens (P < 0.01) and 2.3-fold increased odds of missing medication doses in the previous week (95% CI 1.5–3.6, P < 0.001) compared with all other respondents. Continuous depressive symptom severity scores were better predictors of nonadherence to diet, exercise, and medications than categorically defined probable major depression. Major depression was a better predictor of glucose monitoring. Among the two-thirds of patients not meeting the criteria for major depression (HANDS score <9, n = 709), increasing HANDS scores were incrementally associated with poorer self-care behaviors (P < 0.01).” (J. S. Gonzalez, jsgonzalez@partners.org)

>>>PNN NewsWatch
* Medco’s $1.29 billion purchase of PolyMedica Corp. is “a big step” into the “fast-growing business of managing the care of chronic diseases,” the Wall Street Journal writes today.

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

PNN Pharmacotherapy Line
Aug. 30, 2007 * Vol. 14, No. 169
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Aug. 30 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2007; 357).
Reversal of Idiopathic Hypogonadotropic Hypogonadism: “Brief discontinuation of hormonal therapy to assess reversibility of hypogonadotropic hypogonadism is reasonable,” based on a study showing that about 10% of men with absent or partial puberty have sustained reversal of hypogonadism upon interruption of treatments such as pulsatile gonadotropin-releasing hormone, transdermal testosterone, and testosterone or human chorionic gonadotropin injections (pp. 863-73). “Ten sustained reversals were identified retrospectively,” the authors report. “Five sustained reversals were identified prospectively among 50 men with idiopathic hypogonadotropic hypogonadism after a mean (± SD) duration of treatment interruption of 6 ± 3 weeks. Of the 15 men who had a sustained reversal, 4 had anosmia. At initial evaluation, 6 men had absent puberty, 9 had partial puberty, and all had abnormal secretion of GnRH-induced luteinizing hormone. All 15 men had received previous hormonal therapy to induce virilization, fertility, or both. Among those whose hypogonadism was reversed, the mean serum level of endogenous testosterone increased from 55 ± 29 ng per deciliter (1.9 ± 1.0 nmol per liter) to 386 ± 91 ng per deciliter (13.4 ± 3.2 nmol per liter, P <0.001), the luteinizing hormone level increased from 2.7 ± 2.0 to 8.5 ± 4.6 IU per liter (P <0.001), the level of follicle-stimulating hormone increased from 2.5 ± 1.7 to 9.5 ± 12.2 IU per liter (P <0.01), and testicular volume increased from 8 ± 5 to 16 ± 7 ml (P <0.001). Pulsatile luteinizing hormone secretion and spermatogenesis were documented.” (N. Pitteloud, npitteloud@partners.org)
Saline v. Albumin for Traumatic Brain Injury: Among critically ill patients with traumatic brain injury, higher mortality rates were observed when albumin was used for fluid resuscitation, compared with saline (pp. 874-84). In the Saline versus Albumin Fluid Evaluation (SAFE) study, patients with traumatic brain injury were randomized to albumin or saline and assessed for up to 24 months, with these results: “We followed 460 patients, of whom 231 (50.2%) received albumin and 229 (49.8%) received saline. The subgroup of patients with GCS scores of 3 to 8 were classified as having severe brain injury (160 [69.3%] in the albumin group and 158 [69.0%] in the saline group). Demographic characteristics and indexes of severity of brain injury were similar at baseline. At 24 months, 71 of 214 patients in the albumin group (33.2%) had died, as compared with 42 of 206 in the saline group (20.4%) (relative risk, 1.63; 95% confidence interval [CI], 1.17 to 2.26; P = 0.003). Among patients with severe brain injury, 61 of 146 patients in the albumin group (41.8%) died, as compared with 32 of 144 in the saline group (22.2%) (relative risk, 1.88; 95% CI, 1.31 to 2.70; P <0.001); among patients with GCS scores of 9 to 12, death occurred in 8 of 50 patients in the albumin group (16.0%) and 8 of 37 in the saline group (21.6%) (relative risk, 0.74; 95% CI, 0.31 to 1.79; P = 0.50).” (J. Myburgh, ANZICS Clinical Trials Group, Carlton, Victoria, Australia; j.myburgh@unsw.edu.au)
Anabolic Therapies for Osteoporosis: Use of parathyroid hormone and investigational anabolic agents has the potential to improve treatment of osteoporosis, according to a review article (pp. 905-16). The authors explain: “We are now on the verge of seeing a new class of agents, the so-called anabolics. Anabolic agents have the potential to rebuild skeletal losses by stimulating the processes and mechanisms associated with bone formation. PTH is the only prototypical anabolic agent available at this time. However, other agents may be developed, based on a new understanding of anabolic pathways and intermediate molecules such as bone morphogenetic proteins, Wnt, and [insulin-like growth factor I] and their regulatory molecules. Although the systemic administration of anabolic agents constitutes a promising therapeutic approach, the modification of anabolic signals specifically within bone may become another new avenue for the treatment of osteoporosis.” (E. Canalis, Saint Francis Hosp. and Med. Ctr., Hartford, Conn.; ecanalis@stfranciscare.org)

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

PNN Pharmacotherapy Line
Aug. 31, 2007 * Vol. 14, No. 170
Providing news and information about medications and their proper use

>>>Rheumatology Highlights
Source:
Sept. issue of Arthritis & Rheumatism (www3.interscience.wiley.com/cgi-bin/jhome; 2007; 56).
Cancer Risk & Biologic Agents for RA: Among 13,001 patients followed for about 49,000 patient–years, risk of skin cancer was increased in those receiving biologic therapies for rheumatoid arthritis (pp. 2886-95). Comparing the frequency of incident cancers among the study participants with those in the general population as reported in the U.S. Natl. Cancer Inst. SEER (Surveillance, Epidemiology, and End-Results) database, the researchers determined: “Biologic exposure was 49%. There were 623 incident cases of nonmelanotic skin cancer and 537 other cancers. The standardized incidence ratios and 95% confidence intervals (95% CIs) compared with SEER data were as follows: all cancers 1.0 (1.0–1.1), breast 0.8 (0.6–0.9), colon 0.5 (0.4–0.6), lung 1.2 (1.0–1.4), lymphoma 1.7 (1.3–2.2). Biologics were associated with an increased risk of nonmelanotic skin cancer (OR 1.5, 95% CI 1.2–1.8) and melanoma (OR 2.3, 95% CI 0.9–5.4). No other malignancy was associated with biologic use; the OR (overall risk) of any cancer was 1.0 (95% CI 0.8–1.2).” (F. Wolfe, Natl. Data Bank for Rheumatic Diseases, Wichita, Kans; fwolfe@arthritis-research.org)
Serious Infections with Anti-TNF-alpha Therapy of RA: Especially early in treatment of rheumatoid arthritis with anti-tumor necrosis factor–alpha therapies, the risk of serious infections is increased significantly, according to a study of 8,659 patients on these agents and 2,170 patients on traditional disease-modifying antirheumatic drugs (pp. 2896-904). Contradicting previous studies showing no increase in risk, the authors report: “When the at-risk period was defined as ‘receiving treatment,’ the adjusted incidence rate ratio comparing patients receiving anti-TNF-alpha therapy with patients receiving DMARD therapy was 1.22 (95% confidence interval [95% CI] 0.88–1.69). Limiting follow-up to the first 90 days, however, revealed an adjusted incidence rate ratio of 4.6 (95% CI 1.8–11.9). Rates of infection were increased in the 90 days immediately following drug discontinuation and beyond, explained by selection factors for drug discontinuation.” (D. P. M. Symmons, U. Manchester, Manchester, U.K.; eborah.symmons@manchester.ac.uk">Deborah.symmons@manchester.ac.uk)

>>>PNN NewsWatch
* FDA yesterday approved lanreotide acetate injection (Somatuline Depot, Beaufour Ipsen and Tercica) for long-term treatment of patients with acromegaly who have had inadequate response to or cannot be treated with surgery and/or radiation therapy. This new treatment lowers levels of growth hormone and insulin-like growth factor in the body. Excessive growth hormone secretion, working through insulin-like growth factor, can cause enlargement of the hands, feet, facial bones, and enlargement of internal organs such as the heart and liver. If untreated, patients with acromegaly often have a shortened life span because of heart and respiratory diseases, diabetes mellitus, and colon cancer. The safety and effectiveness of this orphan drug was determined in two pivotal clinical trials involving a total of 400 patients. Common adverse effects included diarrhea, gallstones, skin reactions such as itching, slow heart rate, and change in blood glucose levels (sometimes necessitating adjustment of medications in patients with diabetes).
* The nation has squandered the opportunity to learn important disaster-planning lessons from
Hurricane Katrina and its aftermath, says Joe Dawsey, executive director of the Coastal Family Health Center, in a conversation published on the Health Affairs Web site. Marking the second anniversary of Katrina, the article recounts how Katrina virtually destroyed Coastal’s network of nine community health clinics in the Biloxi, Miss., area. “If Katrina happened tomorrow, I honestly don’t believe we’d be better off,” Dawsey says. He explains that early-stage recovery efforts “were all very chaotic.” The Federal Emergency Management Agency “had a good response plan. They just didn’t follow through with it. . . . They had Disaster Response Teams come in, and we’d spend hours making detailed plans, and then that team would rotate out and a whole new group would show up. And we’d have to start from the beginning with the new group.”
*
PNN will not be published on Mon., Sept. 3, 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 © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Sept. 4, 2007 * Vol. 14, No. 171
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Early-release article from and Sept. 1 issue of Lancet (www.thelancet.com; 2007; 370).
COPD as Worldwide, Pervasive Problem: Three articles explore the extensive and unrecognized international impact of chronic obstructive pulmonary disease.
A worldwide study shows “higher levels and more advanced staging of spirometrically confirmed COPD than have typically been reported” and notes that the levels are higher than can be explained through age and smoking alone (pp. 741-50). Among 9,425 participants at 12 sites, the researchers found these results of postbronchodilator spirometry testing plus questionnaires: “The prevalence of stage II or higher COPD was 10.1% (SE 4.8) overall, 11.8% (7.9) for men, and 8.5% (5.8) for women. The ORs for 10-year age increments were much the same across sites and for women and men. The overall pooled estimate was 1.94 (95% CI 1.80–2.10) per 10-year increment. Site-specific pack–year ORs varied significantly in women (pooled OR = 1.28, 95% CI 1.15–1.42, p = 0.012), but not in men (1.16, 1.12–1.21, p = 0.743).” (A. S. Buist, Oregon Health and Science U., Portland;
BOLD@kpchr.org)
Based on data from the Guangzhou Biobank Cohort Study, 1.9 million current residents of China can be expected to die from COPD caused by second-hand smoke exposure (pp. 751-7). The risk of COPD was increased by 48% (95% CI, 1.18–1.85) among those with high-level exposure (40 hours per week for 5 years) to passive smoking at home and work, and respiratory symptoms were significantly elevated, by 16%, among those with increasing passive smoking exposure (95% CI, 1.07–1.25). (K. K. Cheng, U. Birmingham, Edgbaston, Birmingham, U.K.;
k.k.cheng@bham.ac.uk)
Concluding that prevention of COPD may need to start in fetal life, researchers found that poor airway function at birth is a significant risk factor for airflow obstruction in young adulthood (pp. 758-64). Among 123 participants enrolled at birth in the Tucson Children’s Respiratory Study in 1980–94, later measures of pulmonary function showed that infants in the lowest quartile also had significantly lower values on these tests up to age 22. (F. D. Martinez,
fernando@arc.arizona.edu)
ACE Inhibition, Diuretics in Diabetes: In the Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE) trial, routine administration of a fixed combination of perindopril and indapamide to patients with type 2 diabetes was well tolerated and reduced the risks of major vascular events, including death, researchers conclude (doi: 10.1016/S0140-6736(07)61303-8). Calculating a number needed to treat of 79, the group notes: “Compared with patients assigned placebo, those assigned active therapy had a mean reduction in systolic blood pressure of 5.6 mm Hg and diastolic blood pressure of 2.2 mm Hg. The relative risk of a major macrovascular or microvascular event was reduced by 9% (861 [15.5%] active vs 938 [16.8%] placebo; hazard ratio 0.91, 95% CI 0.83–1.00, p = 0.04). The separate reductions in macrovascular and microvascular events were similar but were not independently significant (macrovascular 0.92; 0.81–1.04, p = 0.16; microvascular 0.91; 0.80–1.04, p = 0.16). The relative risk of death from cardiovascular disease was reduced by 18% (211 [3.8%] active vs 257 [4.6%] placebo; 0.82, 0.68–0.98, p = 0.03) and death from any cause was reduced by 14% (408 [7.3%] active vs 471 [8.5%] placebo; 0.86, 0.75–0.98, p = 0.03).” (A. Patel, U. Sydney, Sydney; apatel@george.org.au)

>>>PNN JournalWatch
* Effect of Antibiotic Prescribing on Antibiotic Resistance in Individual Children in Primary Care: Prospective Cohort Study, in BMJ, 2007; 335: 429 ff. Reprints: D. Mant, U. Oxford, Oxford, U.K.; david.mant@dphpc.ox.ac.uk
* Antidepressant Use in the Postpartum Period: Practical Considerations, in
American Journal of Psychiatry, 2007; 164: 1329–32. Reprints: J. L. Payne.
* Delayed-Onset Posttraumatic Stress Disorder: A Systematic Review of the Evidence, in
American Journal of Psychiatry, 2007; 146: 1319–26. Reprints: B. Andrews.
* Prevention of Human Papillomavirus Infection: Provisional Recommendations for Immunization of Girls and Women with Quadrivalent Human Papillomavirus Vaccine, in
Pediatrics, 2007; 120: 666–8. Reprints: American Academy of Pediatrics Committee on Inf. Diseases.
* Suicide and Suicide Attempts in Adolescents, in
Pediatrics, 2007; 120: 669–76. Reprints: B. N. Shain, and the AAP Committee on Adolescence.

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

PNN Pharmacotherapy Line
Sept. 5, 2007 * Vol. 14, No. 172
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Sept. 4 issue of the Annals of Internal Medicine (www.annals.org/current.shtml; 2007; 147).
Outcomes & Adherence to Depression Guidelines: While only one-third of 1,131 primary care patients received care for depression in close alignment with guideline recommendations, their outcomes were better than when prescribers veered from the advice (pp. 320-9). These results were noted at 45 primary care practices in 13 states in 1996–98: “Quality of care was high (clinician adherence 79%) for 6 indicators, including primary care clinician detection of depression. Quality of care was low (adherence, 20% to 38%) for 8 indicators, including management of suicide risk (3 indicators), alcohol abuse (2 indicators), and elderly patients; assessment of symptoms and history of depression; and treatment adjustment for patients who did not respond to initial treatment. Greater adherence to practice guidelines significantly predicted fewer depressive symptoms on continuous measures (P <0.001 for 12 months, P <0.01 for 18 months, and P < 0.001 for 24 months) and dichotomous measures (P <0.05 for 18 and 24 months).” (K. A. Hepner, hepner@rand.org)
Nitrofurazone Urinary Catheters in Trauma Patients: Nitrofurazone-impregnated urinary catheters appear to reduce the need to change or prescribe new antimicrobial therapy in patients with indwelling catheters by reducing the incidence of bacteriuria and funguria, according to a study of 212 consecutive adult trauma patients in 2003–05 (pp. 285-93). Defining catheter-associated bacteriuria and funguria as at least 1,000 colony-forming units per milliliter, the authors report: “1,190 urine cultures were obtained over 1,001 catheter-days. Catheter-associated bacteriuria and funguria occurred less frequently in the nitrofurazone catheter group than in the silicone catheter group (7 of 77 [9.1%] vs. 19 of 77 [24.7%]; incidence per 1,000 catheter-days, 13.8 vs. 38.6; adjusted risk, 0.31 [95% CI, 0.14 to 0.70]; P = 0.005). Onset of [catheter-associated bacteriuria and funguria] was delayed in the nitrofurazone group (P = 0.01), and nitrofurazone catheters led to fewer instances of new or changed antimicrobial therapy (adjusted risk, 0.27 [CI, 0.10 to 0.69]; P = 0.006).” (J. Stensballe, Copenhagen U. Hosp., Copenhagen; jakob.stensballe@rh.regionh.dk)
Renal Function & Fondaparinux, Enoxaparin Comparison: Analyzing data from the Fifth Organization to Assess Strategies in Acute Ischemic Syndromes (OASIS 5) trial, researchers report that the safety of fondaparinux over enoxaparin is most marked among patients with reduced renal function and derives primarily from lower rates of major bleeding with this drug (pp. 304-10): “The rates of the composite end point [death, myocardial infarction, refractory ischemia, and major bleeding] were lower with fondaparinux than with enoxaparin in all quartiles of GFR, but the differences were statistically significant only among patients with a GFR less than 58 mL/min per 1.73 m2.” (K. A.. A. Fox, U. Edinburgh, Edinburgh, U.K.; k.a.a.fox@ed.ac.uk)

>>>PNN NewsWatch
* FDA has licensed a new, second-generation vaccine to protect against smallpox. ACAM2000 (Acambis) is intended for the inoculation of people at high risk of exposure to smallpox and could be used to protect individuals and populations during a bioterrorist attack. It will be included in the CDC’s Strategic National Stockpile of medical supplies. The vaccine contains live vaccinia virus and works by causing a mild infection that stimulates an immune response that effectively protects against smallpox without actually causing the disease. Care must be taken to prevent the live virus from spreading from the inoculation site to other parts of the body and to other individuals. ACAM2000 was effective in those who had never been vaccinated for smallpox and those who had received smallpox vaccination many years earlier. ACAM2000 also was found to be acceptable as a booster in those previously vaccinated for smallpox. About 1 in 175 healthy adults who received smallpox vaccine for the first time developed inflammation and myocarditis and/or pericarditis. Of the 10 affected adults, 4 had no symptoms and at the end of the study, all but 1 had their symptoms resolve.
* Today’s
JAMA is a special theme issue on medical education.

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

PNN Pharmacotherapy Line
Sept. 6, 2007 * Vol. 14, No. 173
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Sept. 6 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2007; 357).
Epoetin Alfa in Critically Ill Patients: Among 1,460 medical, surgical, or trauma patients, use of epoetin alfa reduced mortality but not the need for red-cell transfusions (pp. 965-76). The intervention also increased the incidence of thrombotic events, the EPO Critical Care Trials Group notes, adding these details for once-weekly treatment with epoetin alfa 40,000 IU: “As compared with the use of placebo, epoetin alfa therapy did not result in a decrease in either the number of patients who received a red-cell transfusion (relative risk for the epoetin alfa group vs. the placebo group, 0.95; 95% confidence interval [CI], 0.85 to 1.06) or the mean (±S D) number of red-cell units transfused (4.5 ± 4.6 units in the epoetin alfa group and 4.3 ± 4.8 units in the placebo group, P = 0.42). However, the hemoglobin concentration at day 29 increased more in the epoetin alfa group than in the placebo group (1.6 ± 2.0 g per deciliter vs. 1.2 ± 1.8 g per deciliter, P <0.001). Mortality tended to be lower at day 29 among patients receiving epoetin alfa (adjusted hazard ratio, 0.79; 95% CI, 0.56 to 1.10); this effect was also seen in prespecified analyses in those with a diagnosis of trauma (adjusted hazard ratio, 0.37; 95% CI, 0.19 to 0.72). A similar pattern was seen at day 140 (adjusted hazard ratio, 0.86; 95% CI, 0.65 to 1.13), particularly in those with trauma (adjusted hazard ratio, 0.40; 95% CI, 0.23 to 0.69). As compared with placebo, epoetin alfa was associated with a significant increase in the incidence of thrombotic events (hazard ratio, 1.41; 95% CI, 1.06 to 1.86).” (H. L. Corwin, Dartmouth–Hitchcock Med. Ctr., Lebanon, N.H.; howard.l.corwin@hitchcock.org)
Editorialists describe future research possibilities (pp. 1037-9): “This intriguing trial should incite some investigators in bedside-to-bench research to explain the potential survival benefits of erythropoietin in trauma patients; others may seek understanding of unanticipated adverse events. Clinical investigators may reexamine the risk–benefit ratio for administering erythropoietin to patients with chronic renal failure in the ICU, given their high prevalence of vascular disease. Large observational studies are needed of anemia, erythropoietin, transfusions, and myocardial ischemia in patients in the ICU, in whom the biomarker troponin is commonly elevated, conferring an increased risk of death. Health services research on behavioral approaches to blood conservation and restrictive transfusion strategies will also advance this field.” (D. Cook, McMaster U., Hamilton, Ont., Canada)
Dronedarone in Atrial Fibrillation, Flutter: Compared with placebo, dronedarone proved significantly more effective for maintaining sinus rhythm and reducing the ventricular rate during recurrence of arrhythmia, according to data from the European Trial in Atrial Fibrillation or Flutter Patients Receiving Dronedarone for the Maintenance of Sinus Rhythm (EURIDIS) and the American–Australian–African Trial with Dronedarone in Atrial Fibrillation or Flutter Patients for the Maintenance of Sinus Rhythm (ADONIS; pp. 987-9). In 828 patients receiving 400 mg of this antiarrhythmic agent—similar to amiodarone but developed to have fewer adverse effects—twice daily and 409 patients receiving placebo, these results were recorded: “In the European trial, the median times to the recurrence of arrhythmia were 41 days in the placebo group and 96 days in the dronedarone group (P = 0.01). The corresponding durations in the non–European trial were 59 and 158 days (P = 0.002). At the recurrence of arrhythmia in the European trial, the mean (± SD) ventricular rate was 117.5 ± 29.1 beats per minute in the placebo group and 102.3 ± 24.7 beats per minute in the dronedarone group (P <0.001); the corresponding rates in the non–European trial were 116.6 ± 31.9 and 104.6 ± 27.1 beats per minute (P <0.001). Rates of pulmonary toxic effects and of thyroid and liver dysfunction were not significantly increased in the dronedarone group.” (B. N. Singh, bsingh@ucla.edu)
Calling for “treatment that is better than the disease,” editorialists note that both multimechanism and single-mechanism approaches for maintaining sinus rhythm “presume a clearer understanding of the actual electrophysiological mechanism of atrial fibrillation than is currently available” (pp. 1039-41; M. D. Ezekowitz, Lankenau Inst. for Med. Res., Wynnewood, Pa.).


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

PNN Pharmacotherapy Line
Sept. 7, 2007 * Vol. 14, No. 174
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Sept. issue of Pharmacotherapy (www.atypon-link.com/PPI/toc/phco/27/9; 2007; 27).
Therapeutic Use of Acetaminophen & Acute Liver Failure: Reports of acute liver failure with “therapeutic” acetaminophen use are possibly inaccurate, representing inadvertent overdosages, based on a comparison of retrospective and prospective published studies (pp. 1219-30). Researchers examined 791 reports of adults who received repeated dosages of acetaminophen 4 grams/day or lower for at least 24 hours, with these results: “The prospective studies reported no cases of fulminant hepatic injury, liver transplantation, or death due to acetaminophen. Of the 30,865 subjects in these studies, 129 (0.4%) were identified who had a serum aminotransferase level that exceeded the upper limit of normal, including 61 subjects in randomized trials in which the proportion of serum aminotransferase level increase was the same as or less than that in the placebo group and 68 subjects in trials without a placebo group. In addition, 4,263 (13.8%) received the maximum recommended therapeutic dosage (3.9–4 g/day). In the retrospective reports, 96 patients (1.0%) had a serum alanine aminotransferase level that exceeded the upper limit of normal, one (0.01%) underwent liver transplantation, and six (0.06%) died. Causality relationship of acetaminophen for each retrospective case was assessed with the Naranjo adverse drug reaction probability scale. The mean ± SD Naranjo score for all 103 retrospective cases was 3.2 ± 1.9, indicating a possible relationship between the increased aminotransferase levels and acetaminophen use. Some retrospective reports contained information suggesting that the patient had ingested an overdose despite a history of therapeutic use.” (R. C. Dart, Rocky Mountain Poison and Drug Ctr., Denver; rdart@rmpdc.org)
Dietary Supplements & Warfarin Use: Patients using coenzyme Q10 or ginger supplements have a greater risk of bleeding while taking warfarin, according to a prospective longitudinal study of 171 adults (pp. 1237-47). Using patient notes recorded in a 16-week diary, the investigators determined: “87 (51%) [patients] reported at least one bleeding event and 36 (21%) had a supratherapeutic INR. Seventy-three patients (43%) indicated they had used at least one [complementary and alternative medicine] product previously reported to interact with warfarin. Warfarin use of less than 3 months’ duration was the only statistically significant risk factor identified for supratherapeutic INR. The CAM therapies associated with an increased risk of self-reported bleeding included cayenne, ginger, willow bark, St. John’s wort, and coenzyme Q10. Use of more than one CAM while receiving warfarin was also a significant risk factor. Two CAMs were independently associated with an increased risk of self-reported bleeding: coenzyme Q10 (odds ratio [OR] 3.69, 95% confidence interval [CI] 1.88–7.24) and ginger (OR 3.20, 95% CI 2.42–4.24). Other risk factors significantly associated with increased bleeding included high target INR (2.5–3.5), diarrhea, acetaminophen use, increased alcohol consumption, and increased age.” (S. Shalansky, Lions Gate Hosp., North Vancouver, B.C., Canada)
Enoxaparin in Neonates: For treating neonatal thrombosis, enoxaparin “may be effective,” authors write, based on a retrospective chart review (pp. 1263-71). But initial doses of 1.5 mg/kg every 12 hours are likely inadequate, and kinetics of the drug require further evaluation in this age group. (D. C. Knoppert, St. Joseph’s Hosp., London, Ont., Canada)

>>>PNN NewsWatch
* Payments to pharmacies for prescription drug claims under Medicare Part D were not made for more than 30 days for 44.1% of claims filed during 2006, according to a study released yesterday in advance of publication in the Journal of the American Pharmacists Assoc. Marvin D. Shepherd and colleagues at the U. Texas–Austin analyzed nearly 3 million claims adjudicated during 2006 and paid electronically by June 2007. Payments to pharmacies were delayed throughout the year, but especially in the first 6 months of the program and particularly to independent pharmacies. The Fair and Speedy Treatment (FAST) of Medicare Prescription Drug Claims Act of 2007 has been introduced into Congress; if passed, it would require correctly submitted electronic Part D claims to be paid within 14 days and paper claims within 30 days.

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

PNN Pharmacotherapy Line
Sept. 10, 2007 * Vol. 14, No. 175
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Sept. 8 issue of BMJ (www.bmj.org; 2007; 335).
Antidiabetic Agents in Patients with Diabetes and Heart Failure: All antidiabetic agents except metformin are associated with increased harm in patients with concomitant diabetes and heart failure, according to a systematic review, and that drug was linked to increased all-cause mortality in two studies (pp. 497 ff). The authors write: “Eight studies were included. Three of four studies found that insulin use was associated with increased risk for all cause mortality (odds ratio 1.25, 95% confidence interval 1.03 to 1.51; 3.42, 1.40 to 8.37 in studies that did not adjust for diet and antidiabetic drugs; hazard ratio 1.66, 1.20 to 2.31; 0.96, 0.88 to 1.05 in the studies that did). Metformin was associated with significantly reduced all cause mortality in two studies (hazard ratio 0.86, 0.78 to 0.97) compared with other antidiabetic drugs and insulin; 0.70, 0.54 to 0.91 compared with sulfonylureas); a similar trend was seen in a third. Metformin was not associated with increased hospital admission for any cause or for heart failure specifically. In four studies, use of thiazolidinediones was associated with reduced all cause mortality (pooled odds ratio 0.83, 0.71 to 0.97, I2 = 52%, P = 0.02). Thiazolidinediones were associated with increased risk of hospital admission for heart failure (pooled odds ratio 1.13 (1.04 to 1.22), I2 = 0%, P = 0.004). The two studies of sulfonylureas had conflicting results, probably because of differences in comparator treatments. Important limitations were noted in all studies.” (J. A. Johnson, jeff.johnson@ualberta.ca)

>>>Lancet Highlights
Source:
Early-release article from and Sept. 8 issue of Lancet (www.thelancet.com; 2007; 370).
Cardiovascular Toll of Stress: The detrimental effects on the cardiovascular system of changes in sympathetic–parasympathetic balance and the tone of the hypothalamic–pituitary–adrenal axis are reviewed (doi: 10.1016/S0140-6736(07)61305-1). “Ample evidence exists for a strong and consistent association of acute and chronic psychological stress with cardiovascular risk factors, such as hypertension and insulin resistance, and with outcomes such as ischaemia, arrhythmia, and pump failure,” the authors note. “Therefore, physicians should remain cognisant of the cardiovascular risk associated with chronic mental illness and psychological stressors, should take seriously patient symptoms (such as chest pain) that arise in conjunction with negative emotions, and should help their patients to alleviate unnecessary psychosocial strain, by advising that a healthy lifestyle should include stress reduction, anger management, and treatment of mental illness.” (D. J. Brotman, Johns Hopkins Hosp., Baltimore; brotman@jhmi.edu)
Depression & Changes in Health: Depression produces a large decrease in health—greater than that of angina, arthritis, asthma, or diabetes—leading researchers to conclude that the disease should be a public-health priority (pp. 851-8). The WHO World Health Survey studied health, health-related outcomes, and their determinants among adults, finding: “Observations were available for 245,404 participants from 60 countries in all regions of the world. Overall, 1-year prevalence for ICD-10 depressive episode alone was 3.2% (95% CI 3.0–3.5); for angina 4.5% (4.3–4.8); for arthritis 4.1% (3.8–4.3); for asthma 3.3% (2.9–3.6); and for diabetes 2.0% (1.8–2.2). An average of between 9.3% and 23.0% of participants with one or more chronic physical disease had comorbid depression. This result was significantly higher than the likelihood of having depression in the absence of a chronic physical disease (p <0.0001). After adjustment for socioeconomic factors and health conditions, depression had the largest effect on worsening mean health scores compared with the other chronic conditions. Consistently across countries and different demographic characteristics, respondents with depression comorbid with one or more chronic diseases had the worst health scores of all the disease states.” (S. Chatterji, chatterjis@who.int)

>>>PNN JournalWatch
* Food Additives and Hyperactive Behaviour in 3-Year-Old and 8/9-Year-Old Children in the Community: A Randomised, Double-Blinded, Placebo-Controlled Trial, in Lancet, 2007; doi: 10.1016/S0140-6736(07)61306-3. Reprints: J. Stevenson, U. Southampton, Southampton , U.K.; jsteven@soton.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 © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Sept. 11, 2007 * Vol. 14, No. 176
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Sept. 10 issue of the Archives of Internal Medicine (http://archinte.ama-assn.org/current.dtl; 2007; 167).
Mortality Effects of Vitamin D: More analysis is needed to determine why, but intake of vitamin D supplements in daily doses of 300–2,000 IU appears to reduce mortality, according to a meta-analysis (pp. 1730-7). Based on 18 randomized controlled trials with 57,311 participants and 4,777 all-cause deaths over a mean of 5.7 years, the authors report: “In 9 trials, there was a 1.4- to 5.2-fold difference in serum 25-hydroxyvitamin D between the intervention and control groups. The summary relative risk for mortality from any cause was 0.93 (95% confidence interval, 0.87–0.99). There was neither indication for heterogeneity nor indication for publication biases. The summary relative risk did not change according to the addition of calcium supplements in the intervention.” (P. Autier, Intl. Agency for Research on Cancer, Lyon, France; autierp@iacr.fr)
An editorialist ponders questions raised by these data (pp. 1709-10): “Would even a greater reduction in mortality accrue than that suggested in this meta-analysis if intakes of vitamin D were higher, if compliance was improved, if higher levels of 25-hydroxyvitamin D were attained, and if the duration of supplementation was longer? Which causes of death mostly accounted for the reduced mortality? Was the reduced mortality primarily in the winter months when vitamin D levels typically plummet and when excess mortality occurs? Research on vitamin D should be continued to clearly elucidate the specific benefits and optimal intakes and levels of vitamin D. Nonetheless, based on the total body of evidence of health conditions associated with vitamin D deficiency, abetted with the results from this meta-analysis, a more proactive attitude to identify, prevent, and treat vitamin D deficiency should be part of standard medical care. From a broader public health perspective, the roles of moderate sun exposure, food fortification with vitamin D, and higher-dose vitamin D supplements for adults need to be debated.” (E. Giovannucci,
egiovann@hsph.harvard.edu)
ADRs Reported to FDA: From 1998 to 2005, adverse drug reactions reported to FDA grew more serious and were increasingly fatal, according an analysis conducted by the Institute for Safe Medication Practices (pp. 1752-9). “From 1998 through 2005, reported serious adverse drug events increased 2.6-fold from 34,966 to 89,842, and fatal adverse drug events increased 2.7-fold from 5,519 to 15,107,” the authors write. “Reported serious events increased 4 times faster than the total number of outpatient prescriptions during the period. In a subset of drugs with 500 or more cases reported in any year, drugs related to safety withdrawals accounted for 26% of reported events in that group in 1999, declining to less than 1% in 2005. For 13 new biotechnology products, reported serious events grew 15.8-fold, from 580 reported in 1998 to 9,181 in 2005. The increase was influenced by relatively few drugs: 298 of the 1,489 drugs identified (20%) accounted for 407,394 of the 467,809 events (87%).” (T. J. Moore, tmoore@ismp.org)

>>>PNN NewsWatch
* Viracept (nelfinavir) contains the process-related impurity ethyl methanesulfonate (EMS), Pfizer is warning health professionals. EMS is a potential human carcinogen, and animal studies indicate that the chemical is also teratogenic and mutagenic. FDA has asked Pfizer to implement new specifications to limit the presence of EMS in Pfizer-manufactured Viracept products. For pediatric patients who are stable on Viracept-containing regimens, FDA and Pfizer agree that the benefit–risk ratio remains favorable and those patients may continue to receive Viracept. Pediatric patients who need to begin HIV treatment should not start regimens containing Viracept until further notice. Pregnant women who need to begin antiretroviral therapy should not be offered regimens containing Viracept until further notice. As a precautionary measure, pregnant women currently receiving Viracept should be switched to an alternative antiretroviral therapy while Pfizer and FDA work to implement the long-term EMS specification for Viracept. For pregnant women with no alternative treatment options, FDA and Pfizer agree that the risk–benefit ratio remains favorable for the continued use of Viracept.

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

PNN Pharmacotherapy Line
Sept. 12, 2007 * Vol. 14, No. 177
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Sept. 12 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2007; 298).
Safety of Thiazolidinediones: Rosiglitazone is associated with significantly increased risk of myocardial infarction but not cardiovascular morbidity, according to a meta-analysis of four studies of at least 12 months’ duration (pp. 1189-95; S. Singh, Wake Forest U., Winston-Salem, N.C.; sosingh@wfubmc.edu). A second meta-analysis assessed pioglitazone data from 19 trials, and while the risks of nonfatal heart failure were increased, this thiazolidinedione was “associated with a significantly lower risk of death, myocardial infarction, or stroke among a diverse population of patients with diabetes” (pp. 1180-8; A. M. Lincoff, Cleveland Clinic, Cleveland; lincofa@ccf.org).
Recalling the COX-2 safety debates, editorialists describe current concerns about the glitazones as “déjà vu all over again” (pp. 1216-8): “The recent FDA committee meeting on rosiglitazone considered efficacy and safety data and determined that the drug’s benefits outweighed potential risks. However, it is not clear how the committee ‘calculated’ the benefit–risk ratio. While there are rigorous methods for weighing benefits and risk, these analyses are not often considered in FDA advisory committee meetings. The FDA could develop or codify methods for such calculations and require them as part of New Drug Applications or for continued marketing of drugs. The lessons regarding drug safety based on the events from recent years are numerous. Fixing the current system will be difficult, but the cost of not fixing the system and further diminishing the public’s trust is too high a price to pay.” (D. H. Solomon,
dhsolomon@partners.org)
Vitamin Supplements in CKD: In 2,056 adult patients with advanced chronic kidney disease or end-stage renal disease followed for a median of 3.2 years, high doses of folic acid and B vitamins failed to improve survival or reduce the incidence of vascular disease (pp. 1163-70). Study participants received either placebo or a daily capsule containing folic acid 40 mg, pyridoxine hydrochloride 100 mg, and cyanocobalamin 2 mg. While homocysteine levels were significantly reduced with the vitamin supplement, other outcome measures were unaffected, including all-cause mortality, strokes, amputations, and a composite of those three events. (R. L. Jamison, rjamison@stanford.edu)
Carvedilol in Pediatric Heart Failure: Preliminary results from a study of 161 children and adolescents with heart failure indicate that carvedilol may be an ineffective treatment in this patient population (pp. 1171-9). The researchers report no significant difference in a composite measure of heart failure outcomes among patients treated with low- or high-dose carvedilol or placebo. “The odds ratio for worsened outcome for patients in the combined carvedilol group vs the placebo group was 0.79 (95% CI, 0.36–1.59; P = .47),” the investigators note. “A prespecified subgroup analysis noted significant interaction between treatment and ventricular morphology (P = .02), indicating a possible differential effect of treatment between patients with a systemic left ventricle (beneficial trend) and those whose systemic ventricle was not a left ventricle (nonbeneficial trend).” (R. E. Shaddy, Children’s Hosp., Philadelphia; shaddyr@email.chop.edu)

>>>PNN NewsWatch
* By a vote of 14–5, an FDA advisory committee yesterday recommended against a staff-generated proposal to reduce the recommended doses of erythropoiesis-stimulating agents. According to this morning’s Wall Street Journal, some panel members supported an Amgen-recommended range that “would leave the doses generally unchanged.” Others were in favor of “small trims or adjustments” in the hemoglobin target that guides dosing.
*
FDA has added information to the ceftriaxone (Rocephin, Roche) labeling warning of an incompatibility with calcium-containing products. Because of this incompatibility, ceftriaxone should not be mixed with calcium-containing products and not administered in the same or different infusion lines or sites in any patient within 48 hours of each other, FDA recommends. Fatalities have been reported with simultaneous administration of ceftriaxone and calcium-containing products. All have involved neonates, but FDA cautioned that patients of any age could be affected when ceftriaxone and calcium form insoluble precipitates.

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

PNN Pharmacotherapy Line
Sept. 13, 2007 * Vol. 14, No. 178
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Sept. 13 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2007; 357).
Treatment of AL Amyloidosis: In 100 patients with newly diagnosed immunoglobulin-light-chain (AL) amyloidosis, high-dose melphalan plus autologous stem-cell rescue was not superior to standard-dose melphalan plus dexamethasone (pp. 1083-93). Analyzing results on an intention-to-treat basis with overall survival as the primary endpoint, the Intergroupe Francophone du Myélome investigators found these results after a median follow-up of 3 years: “The estimated median overall survival was 22.2 months in the group assigned to receive high-dose melphalan and 56.9 months in the group assigned to receive melphalan plus high-dose dexamethasone (P = 0.04). Among patients with high-risk disease, overall survival was similar in the two groups. Among patients with low-risk disease, there was a nonsignificant difference between the two groups in overall survival at 3 years (58% in the group assigned to receive high-dose melphalan vs. 80% in the group assigned to receive melphalan plus high-dose dexamethasone; P = 0.13).” (A. Jaccard, Centre Hospitalier Universitaire, Limoges, France; arnaud.jaccard@chu-limoges.fr)
Idraparinux for Venous Thromboembolic Disease: Compared with standard therapy, an investigational long-acting inhibitor of activated factor X, idraparinux, proved less effective in patients with pulmonary embolism and equivalent but safer in patients with other types of venous thromboembolism (pp. 1094-104). Analyzing data from two randomized, open-label, noninferiority trials involving 2,904 patients with deep-vein thrombosis and 2,215 patients with pulmonary embolism, the van Gogh Investigators report these results with idraparinux 2.5 mg once weekly versus heparin followed by an adjusted-dose vitamin K antagonist: “In the study of patients with deep venous thrombosis, the incidence of recurrence at day 92 was 2.9% in the idraparinux group as compared with 3.0% in the standard-therapy group (odds ratio, 0.98; 95% confidence interval [CI], 0.63 to 1.50), a result that satisfied the prespecified noninferiority requirement. At 6 months, the hazard ratio for idraparinux was 1.01. The rates of clinically relevant bleeding at day 92 were 4.5% in the idraparinux group and 7.0% in the standard-therapy group (P = 0.004). At 6 months, bleeding rates were similar. In the study of patients with pulmonary embolism, the incidence of recurrence at day 92 was 3.4% in the idraparinux group and 1.6% in the standard-therapy group (odds ratio, 2.14; 95% CI, 1.21 to 3.78), a finding that did not meet the noninferiority requirement.” (H. R. Buller, Academic Med. Ctr., Amsterdam; h.r.buller@amc.uva.nl)
Typhoid Vaccination & Public Health: The international health community needs to “increase the priority and sense of urgency” concerning control of typhoid fever to achieve global control, conclude authors of a Perspectives article (pp. 1069-71). Two newer-generation vaccines have been available for two decades and have proven “extremely safe,” the writers note, adding: “Vi polysaccharide is a subunit vaccine administered parenterally in a single dose; it was found in studies to confer about 70% protection, lasting at least 3 years, and is licensed for use in persons 2 years of age or older. The orally administered, live attenuated Ty21a vaccine, licensed for use in persons 2 years of age or older, is given in three or four doses and confers 53 to 96% protection, depending on the vaccine formulation and the context of the evaluation. Protection for 7 years after administration has been shown. The continued high incidence of typhoid fever in many regions, along with the rise and spread of drug-resistant strains, led the WHO in 2000 to recommend immunizing school-aged children with these newer vaccines in areas where typhoid fever is a substantial public health problem and particularly where antibiotic-resistant S. typhi strains are prevalent. But so far, only two countries — China and Vietnam — have incorporated typhoid vaccination into their routine immunization programs, and only in a limited fashion.” (D. DeRoeck)

>>>PNN NewsWatch
* Aprotinin (Trasylol, Bayer) should remain on the U.S. market, an FDA advisory committee recommended yesterday in a 15–1 vote.

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

PNN Pharmacotherapy Line
Sept. 14, 2007 * Vol. 14, No. 179
Providing news and information about medications and their proper use

>>>Infectious Disease Report
Source:
Oct. 1 issue of Clinical Infectious Diseases (www.journals.uchicago.edu/CID/journal/contents/v45n7.html; 2007; 45).
Histoplasmosis Guidelines: New antifungal agents are incorporated into updated evidence-based guidelines for management of histoplasmosis (pp. 807-25). Prepared by an expert panel of the Infectious Diseases Society of America, the document updates guidelines published in 2000 with this advice (L. J. Wheat, MiraVista Diagnostics/MiraBella Technologies, Indianapolis; jwheat@miravistalabs.com):
* Itraconazole is the preferred azole for initial therapy for patients with mild-to-moderate histoplasmosis and as step-down therapy after receipt of amphotericin B.
* Patients with severe or moderately severe histoplasmosis should be treated with an amphotericin B formulation initially.
* Itraconazole drug levels should be measured during the first month in patients with disseminated or chronic pulmonary histoplasmosis, and these levels should be documented in the medical record, as well as the physician’s response to levels that are too low.
* Itraconazole should not be given to patients receiving contraindicated medications (i.e., pimozide, quinidine, dofetilide, lovastatin, simvastatin, midazolam, and triazolam).
Treatment of Candidemia: For treatment of 595 patients with candidemia or other forms of invasive candidiasis, micafungin 100 and 150 mg daily was noninferior to standard dosages of caspofungin (70 mg followed by 50 mg daily), investigators report (pp. 883-93): “At the end of blinded intravenous therapy, treatment was considered successful for 76.4% of patients in the micafungin 100 mg group, 71.4% in the micafungin 150 mg group, and 72.3% in the caspofungin group. The median time to culture negativity was 2 days in the micafungin 100 mg group and the caspofungin group, compared with 3 days in the micafungin 150 mg groups. There were no significant differences in mortality, relapsing and emergent infections, or adverse events between the study arms.” (P. G. Pappas, U. Ala., Birmingham)
Pillbox Organizers in HIV Therapy: By improving adherence to antiretroviral therapy and virologic suppression, pillbox organizers are cost-effective at about $19,000 per quality-adjusted life–year (pp. 908-15). Concluding that these adherence devices “should be a standard intervention to improve adherence to antiretroviral therapy,” the researchers report these results for 245 patients with HIV in 1996–2000: “Pillbox organizer use was estimated to improve adherence by 4.1%–4.5% and was associated with a decrease in viral load of 0.34–0.37 log10 copies/mL and a 14.2%–15.7% higher probability of achieving a viral load [of 400 copies/mL or less] (odds ratio, 1.8–1.9). All effect estimates were statistically significant.” (M. L. Peterson, U. Calif., Berkeley)
Polysaccharide Pneumococcal Vaccine in HIV: All patients with HIV infection should be vaccinated with polysaccharide pneumococcal vaccine, conclude authors who performed a retrospective case–control study at four Spanish hospitals (e82-e87). Odds ratios for pneumococcal disease were reduced by receipt of antiretroviral therapy (0.23, 95% CI, 0.14–0.36) and receipt of PPV (0.44, 95% CI, 0.22–0.88). (M. Peñaranda, Hosp. Son Dureta, Barcelona)

>>>PNN NewsWatch
* Serious adverse events, including deaths, have occurred in patients treated with the Fentora formulation of fentanyl, Cephalon and FDA are warning. In a letter to health professionals, the company notes that deaths have occurred as a result of improper patient selection (e.g., use in opioid-nontolerant patients), improper dosing, and/or improper product substitution. To reduce the risk of respiratory depression with Fentora, Cephalon suggests that the drug not be used in opioid-nontolerant patients and should not be prescribed for acute pain, postoperative pain, headache or migraine, or sports injuries, sticking instead to labeled indications. In addition, Fentora is not a generic version of Actiq and should not be used as a substitute for this or other fentanyl products. Patients with unrelieved breakthrough pain should use no more than 2 tablets per episode and must wait at least 4 hours before treating another breakthrough episode with Fentora.

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

PNN Pharmacotherapy Line
Sept. 17, 2007 * Vol. 14, No. 180
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Sept. 15 issue of Lancet (www.thelancet.com; 2007; 370).
Drug-Eluting v. Bare-Metal Stents: Sirolimus-eluting stents performed better than bare-metal or paclitaxel-eluting stents for achieving key clinical outcomes, conclude authors who performed a meta-analysis using data from 38 clinical trials of 18,023 patients (pp. 937-48). “Mortality was similar in the three groups: hazard ratios (HR) were 1.00 (95% credibility interval 0.82–1.25) for sirolimus-eluting versus bare-metal stents, 1.03 (0.84–1.22) for paclitaxel-eluting versus bare-metal stents, and 0.96 (0.83–1.24) for sirolimus-eluting versus paclitaxel-eluting stents,” write the researchers. “Sirolimus-eluting stents were associated with the lowest risk of myocardial infarction (HR 0.81, 95% credibility interval 0.66–0.97, p = 0.030 vs bare-metal stents; 0.83, 0.71–1.00, p = 0.045 vs paclitaxel-eluting stents). There were no significant differences in the risk of definite stent thrombosis (0 days to 4 years). However, the risk of late definite stent thrombosis (>30 days) was increased with paclitaxel-eluting stents (HR 2.11, 95% credibility interval 1.19–4.23, p = 0.017 vs bare-metal stents; 1.85, 1.02–3.85, p = 0.041 vs sirolimus-eluting stents). The reduction in target lesion revascularisation seen with drug-eluting stents compared with bare-metal stents was more pronounced with sirolimus-eluting stents than with paclitaxel-eluting stents (0.70, 0.56–0.84; p = 0.0021).” (P. Jüni, U. Bern, Bern, Switzerland; juni@ispm.unibe.ch)
Dabigatran v. Enoxaparin for VTE: In 3,494 patients who had undergone hip-replacement therapy, oral dabigatran etexilate was similar to enoxaparin in reduction of risk of venous thromboembolism and safety (pp. 949-56). Using a median treatment duration of 33 days, the investigators found these results with oral dabigatran etexilate 220 mg or 150 mg once daily, starting with a half-dose 1–4 hours after surgery, or subcutaneous enoxaparin 40 mg once daily starting the evening before surgery: “The primary efficacy outcome [composite of total venous thromboembolism and death from all causes] occurred in 60 (6.7%) of 897 individuals in the enoxaparin group versus 53 (6.0%) of 880 patients in the dabigatran etexilate 220 mg group (absolute difference −0.7%, 95% CI −2.9 to 1.6%) and 75 (8.6%) of 874 people in the 150 mg group (1.9%, −0.6 to 4.4%). Both doses were thus non-inferior to enoxaparin. There was no significant difference in major bleeding rates with either dose of dabigatran etexilate compared with enoxaparin (p = 0.44 for 220 mg, p = 0.60 for 150 mg). The frequency of increases in liver enzyme concentrations and of acute coronary events during the study did not differ significantly between the groups.” (B. I. Eriksson, Sahlgrenska U. Hosp./Östra, Göteborg, Sweden; b.eriksson@orthop.gu.se)

>>>BMJ Highlights
Source:
Early-release article from BMJ (www.bmj.org; 2007; 335).
Cancer Risk with OCs: In a cohort study from the U.K., oral contraception was not associated with an increased incidence of cancer and may “produce a net public health gain,” researchers conclude (doi: 10.1136/bmj.39289.649410.55). The study included approximately 339,000 woman–years for those who had never used OCs and 744,000 woman–years for ever-users. The latter group had significantly lower rates of cancers of the colon/rectum, uterus, and ovaries, and they less frequently had tumors of unknown sites, other malignancies, and main gynecologic cancers. With increased duration of OC use, significantly increased trends were found with cervical and CNS/pituitary cancer, but rates of uterine body and ovarian cancer declined. (P. C. Hannaford, U. Aberdeen, Aberdeen, U.K.; p.hannaford@abdn.ac.uk)

>>>PNN JournalWatch
* Diagnosis and Management of Lung Cancer: ACCP Guidelines (2nd Edition), in Chest, 2007; 132 (suppl 3). Reprints: American College of Chest Physicians.
* To Drink or Not to Drink? That Is the Question, in
Circulation, 2007; 116: 1306–17. Reprints: R. A. Kloner, Good Samaritan Hosp., Los Angeles; rkloner@goodsam.org
* Chronic Proton Pump Inhibitor Therapy and the Risk of Colorectal Cancer, in
Gastroenterology, 2007; 133: 748–54. Reprints: Y-X Yang, yangy@mail.med.upenn.edu
* Eradication Therapy for
Helicobacter pylori, in Gastroenterology, 2007; 133: 985–1001. Reprints: N. Vakil, Aurora-Sinai Med. Ctr., Milwaukee; nvakil@wisc.edu

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

PNN Pharmacotherapy Line
Sept. 19, 2007 * Vol. 14, No. 182
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Sept. 19 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2007; 298)
Indications for Amiodarone: Patients most likely to benefit from amiodarone therapy are those with atrial fibrillation and left ventricular dysfunction, acute sustained ventricular arrhythmias, and implantable cardioverter-defibrillators and symptomatic shocks, and those about to undergo cardiac surgery, according to a Clinician’s Corner review article (pp. 1312-22). Reviewing evidence-based clinical indications for the drug, the authors write: “Amiodarone may have clinical value in patients with left ventricular dysfunction and heart failure as first-line treatment for atrial fibrillation, though other agents are available. Amiodarone is useful in acute management of sustained ventricular tachyarrhythmias, regardless of hemodynamic stability. The only role for prophylactic amiodarone is in the perioperative period of cardiac surgery. Amiodarone may be effective as an adjunct to implantable cardioverter-defibrillator therapy to reduce number of shocks. However, amiodarone has a number of serious adverse effects, including corneal microdeposits (>90%), optic neuropathy/neuritis (1%-2%), blue-gray skin discoloration (4%-9%), photosensitivity (25%-75%), hypothyroidism (6%), hyperthyroidism (0.9%-2%), pulmonary toxicity (1%-17%), peripheral neuropathy (0.3% annually), and hepatotoxicity (elevated enzyme levels, 15%-30%; hepatitis and cirrhosis, <3% [0.6% annually]).” (R. G. Trohman, rtrohman@rush.edu)
Assessing Technology in Health Care: Only 0.05% of health care spending in the U.S. goes for technology assessment, authors explain, but interest in this area has been renewed by the Medicare Modernization Act and other developments (pp. 1323-5). Several elements are needed for an effective process, the group notes: “A new technology assessment initiative built on administrative independence, dedicated funding, reliable research, trustworthy methods, wide dissemination, and legitimacy will offer a solid foundation for efforts to balance the benefits of medical technologies and the costs that result from their adoption. But information alone will not be sufficient. Information must be tied to appropriate infrastructure and financial incentives to affect medical practice. Health plans need appropriate incentives to use the information in their coverage decisions. Hospitals and physicians will need incentives to use the information in their treatment decisions. Simultaneously, evaluative research can guide incentives, insurance benefits, and the organization of care, ensuring that efforts to control costs and improve care are firmly grounded in the best evidence. In an era of increasing costs and growing complexity of care, few health initiatives are as important as a substantial program in the evaluation of medical technology and outcomes.” (E. J. Emanuel, eemanuel@cc.nih.gov)

>>>PNN NewsWatch
* FDA yesterday approved for marketing the Nanosphere Verigene Warfarin Metabolism Nucleic Acid Test (Verigene System; Nanosphere Inc.) for use in identifying patients with variants of CYP2C9 and VKORC1. The Nanosphere test is not intended to be a stand-alone tool to determine optimum drug dosage, but should be used along with clinical evaluation and other tools, including INR, to determine the best treatment for patients. FDA cleared the test based on results of a study conducted by the manufacturer of hundreds of DNA samples as well as on a broad range of published literature. In a three-site study, the test was accurate in all cases where the test yielded a result; 8% of the tests could not identify which genetic variants were present.
*
Procter & Gamble has received a warning letter from FDA about allegedly unlawful marketing claims for the Vicks Early Defense Foaming Hand Sanitizer, specifically that the product will prevent colds and provide antimicrobial activity for up to 3 hours.
* The
Drug Safety Newsletter is a new FDA publication that provides information on postmarketing drug safety reviews, other emerging drug safety issues, and recently approved new molecular entities.

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

PNN Pharmacotherapy Line
Sept. 20, 2007 * Vol. 14, No. 183
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Sept. 20 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2007; 357)
Antenatal Corticosteroids: Two research studies and an editorial present new information on long-term neonatal outcomes following corticosteroid use in mothers at risk for preterm delivery.
Antenatal corticosteroids for preterm labor reduced neonatal morbidity without changing major neurosurgery disability or body size at age 2, concludes the first study (pp. 1179-89). Mothers whose children were included in the analysis had received an initial 7-day course of corticosteroids followed by intramuscular betamethasone 11.4 mg or saline placebo weekly while at risk for preterm delivery before 32 weeks’ gestation. Results showed: “Of the 1,085 children who were alive at 2 years of age, 1,047 (96.5%) were seen for assessment (521 exposed to repeat-corticosteroid treatment and 526 exposed to placebo). The rate of survival free of major disability was similar in the repeat-corticosteroid and placebo groups (84.4% and 81.0%, respectively; adjusted relative risk, 1.04, 95% confidence interval, 0.98 to 1.10; adjusted P = 0.20). There were no significant differences between the groups in body size, blood pressure, use of health services, respiratory morbidity, or child behavior scores, although children exposed to repeat doses of corticosteroids were more likely than those exposed to placebo to warrant assessment for attention problems (P = 0.04).” (C. A. Crowther, U. Adelaide, North Adelaide, Australia;
caroline.crowther@adelaide.edu.au)
Physical and neurocognitive measures were similar among infants whose mothers received corticosteroid injections or placebo, the second study reports, but cerebral palsy was more common with steroid use (pp. 1190-8). Using a method similar to that in the first study, the researchers found these results on the Bayley Scales of Infant Development and other tests: “A total of 556 infants were available for follow-up; 486 children (87.4%) underwent physical examination and 465 (83.6%) underwent Bayley testing at a mean (± SD) corrected age of 29.3 ± 4.6 months. There were no significant differences in Bayley results or anthropometric measurements. Six children (2.9% of pregnancies) in the repeat-corticosteroid group had cerebral palsy as compared with one child (0.5% of pregnancies) in the placebo group (relative risk, 5.7; 95% confidence interval, 0.7 to 46.7; P = 0.12).” (R. J. Wapner, Columbia U., New York)
Assessing the early gains and long-term questions flowing from corticosteroid use during late pregnancy, an editorialist writes (pp. 1248-50): “Both of the studies reported in this issue of the Journal offer reassurance that weekly courses of prenatal corticosteroid therapy, now commonly used in practice, do not significantly increase risks for major adverse neurodevelopmental outcomes or sustained somatic growth delays. Yet the two sets of investigators offer different recommendations: Crowther et al. favor the use of repeat courses in women who remain at risk for preterm delivery, whereas Wapner et al. recommend caution in such practice, because of the higher rate of cerebral palsy observed in their repeat-course group than in their single-course group (although the difference was not significant). More information is needed before it will be clear which strategy is optimal. Further study of neurodevelopmental performance in school-age children is warranted, including the possible increased risk of cerebral palsy among these children, as well as among offspring of women in other trials of weekly corticosteroid therapy, with attention to the doses and regimens used. Pending the availability of such data, if a decision is made to give repeat courses of corticosteroids, it may be prudent to consider the use of lower doses (such as in the ACTORDS study); in all cases, we should inform parents of the limited data on long-term outcomes and should follow survivors for long-term neurodevelopmental outcomes.” (A. D. Stiles, U. North Carolina, Chapel Hill)

>>>PNN NewsWatch
* Children aged 2 to 5 years can now receive MedImmune’s FluMist intranasal vaccine, FDA announced yesterday. The influenza vaccine remains contraindicated in those with asthma and children under 5 with recurrent wheezing.

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

PNN Pharmacotherapy Line
Sept. 21, 2007 * Vol. 14, No. 184
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
Sept. 25 Journal of the American College of Cardiology (http://content.onlinejacc.org/current.dtl; 2007; 50)
Improved Survival in Heart Failure: Survival of patients with end-stage heart failure awaiting heart transplantation has improved substantially since 1990, investigators report (pp. 1282-90). Survival of patients with heart failure on the United Network of Organ Sharing waiting list who are status 1 continues to depend on urgent HT, the study found, but these hopeful trends were found in eras I (1990–94), II (1995–99), and III (2000–05): “The 1-year survival on the HT waiting list improved from 49.5% to 69.0% for status 1 and from 81.8% to 89.4% for status 2 candidates between eras I and III. The predictors of death within 2 months from listing of status 1 candidates included UNOS status 1A, mechanical ventilation, inotropic and intra-aortic balloon pump support, pulmonary capillary wedge pressure >20 mm Hg and serum creatinine >1.5 mg/dl, failed HT, valvular cardiomyopathy, age >60 years, Caucasian ethnicity, and weight ≤70 kg, as well as the lack of intracardiac cardioverter-defibrillator on the day of listing.” (K. Lietz, KL2384@columbia.edu)

>>>Allergy/Immunology Report
Source:
Sept. Journal of Allergy and Clinical Immunology (www.jacionline.org/current; 2007; 120)
Sublingual Immunotherapy: Sublingual immunotherapy (SLIT) induces immune mechanisms similar to those of subcutaneously administered allergens, researchers report based on study of nine patients (pp. 707-13). Characterizing allergen-specific T-cell and interleukin-10 responses during successful birch pollen (Bet v 1) SLIT, the investigators found these comparisons with apple allergen (Mal d 1) and tetanus toxoid: “After 4 weeks, higher frequencies of circulating CD4+CD25+ T cells were detected together with increased FoxP3 and IL-10 and reduced IL-4 and IFN-gamma mRNA expression levels compared with those before SLIT. Proliferation to all 3 antigens was markedly reduced but increased significantly after depletion of CD25+ cells or addition of anti–IL-10 antibodies. After 52 weeks, proliferation in response to Mal d 1 or tetanus toxoid returned to pre-SLIT levels, whereas Bet v 1–induced proliferation remained significantly suppressed and was enhanced by neither depletion of CD25+ cells nor addition of anti–IL-10 antibodies. In parallel, increased IFN-gamma and reduced IL-4, IL-10, and FoxP3 mRNA expression was detected. Neither TGF-beta levels nor cell-cell contact–mediated suppression of CD4+CD25+ cells changed during the course of SLIT.” (B. Bohle, Med. U. Vienna, Wien, Austria; barbara.bohle@meduniwien.ac.at)
While noting “there is no fundamental reason why the 2 forms of immunotherapy should work the same way,” an editorialist comments that this study sheds “some light” on the processes involved (pp. 533-6): “[These] data do point toward a phased and progressive response to SLIT and provide a plausible intellectual framework to explain some of the conflicting data that have been reported hitherto. It might also help explain some of the inconsistencies in the literature on the immunologic effects of [subcutaneous immunotherapy], and it will be instructive to see whether applying these techniques and time-course experiments to [subcutaneous immunotherapy] yield consistent or discordant results.” (A. J. Frew, Brighton Genl. Hosp., Brighton, U.K.)

>>>PNN NewsWatch
* The House and Senate this week passed the FDA Amendments Act of 2007, which includes reauthorization of user fees for prescription drugs and medical devices undergoing review at the federal agency. The legislation also includes the reauthorizations of the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act, FDA noted in a statement, describing those as “two statutes that have provided invaluable information to the agency about medical products’ interaction with pediatric populations.” The Wall Street Journal reports that Congress considered restrictions on prescription drug advertising to consumers, but at the end of the day, lobbying by the pharmaceutical, media, and advertising industries swayed solons to make only minor changes in FDA’s authority to regulate this form of marketing.

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

PNN Pharmacotherapy Line
Sept. 24, 2007 * Vol. 14, No. 185
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Sept. 22 issue of Lancet (www.thelancet.com; 2007; 370).
Under-5 Mortality: The 2015 goal of a 67% decrease in mortality among children younger than 5 years will not be met, investigators conclude based on analysis of available datasets from 172 countries (pp. 1040-54). “Global under-5 mortality has fallen from 110 (109–110) per 1000 in 1980 to 72 (70–74) per 1000 in 2005,” note the authors. “Child deaths worldwide have decreased from 13.5 (13.4–13.6) million in 1980 to an estimated 9.7 (9.5–10.0) million in 2005. Global under-5 mortality is expected to decline by 27% from 1990 to 2015, substantially less than the target of Millennium Development Goal 4 (MDG4) of a 67% decrease. Several regions in Latin America, north Africa, the Middle East, Europe, and southeast Asia have had consistent annual rates of decline in excess of 4% over 35 years. Global progress on MDG4 is dominated by slow reductions in sub-Saharan Africa, which also has the slowest rates of decline in fertility.” (C. J. L. Murray, cjlm@u.washington.edu)

>>>BMJ Highlights
Source:
Sept. 22 issue of BMJ(www.bmj.org; 2007; 335).
Child–Parent Screening for Familial Hypercholesterolemia: Simultaneous screening of children and parents for familial hypercholesterolemia is a promising strategy, according to authors who conducted a meta-analysis of 13 studies involving 1,907 cases and 16,221 controls (pp. 599 ff). The researchers write: “Serum cholesterol concentration discriminated best between people with and without familial hypercholesterolaemia at ages 1–9, when the detection rates with total cholesterol were 88%, 94%, and 96% for false positive rates of 0.1%, 0.5%, and 1%. The results were similar with LDL cholesterol. Screening newborns was much less effective. Once an affected child is identified, measurement of cholesterol would detect about 96% of parents with the disorder, using the simple rule that the parent with the higher serum cholesterol concentration is the affected parent.” (D. S. Wald, London Sch. of Med. and Dentistry, London; d.s.wald@qmul.ac.uk)

>>>PNN NewsWatch
* FDA last week proposed elimination of chlorofluorocarbons in epinephrine metered-dose inhalers. The rule would remove the “essential-use” designation that allows the use of CFCs in these medical devices. FDA said in a news release that it has tentatively concluded that there are no substantial technical barriers to formulating epinephrine as a product that does not release CFCs. A 60-day comment period follows. If the rule is finalized as proposed, epinephrine MDIs containing CFCs would be removed from the market by the end of 2010.
* TWC Global LLC, Inc., has issued a nationwide recall of
Axcil and Desirin, both marketed as dietary supplements, because they contain potentially harmful, undeclared ingredients. FDA reported that its laboratory analysis of Axcil and Desirin found that lot 02B07 contained 3 mg/gram of sildenafil. The products also contained sildenafil analogs sulfosildenafil and sulfohomosildenafil. Consumers who have these products should stop using them immediately and consult a health professional if they experience any problems possibly related to use of these products.

>>>PNN JournalWatch
* Management of Infertility, in BMJ, 2007; 335: 608–11. Reprints: A. H. Balen, Leeds Genl. Infirmary, Leeds, U.K.; adam.balen@leedsth.nhs.uk
* Peanut Allergy: Emerging Concepts and Approaches for an Apparent Epidemic, in
Journal of Allergy and Clinical Immunology, 2007; 120: 491–503. Reprints: S. H. Sicherer, Mount Sinai Hosp., New York; scott.sicherer@mssm.edu
* Gaps in Public Knowledge of Peripheral Arterial Disease. The First National PAD Public Awareness Survey, in
Circulation, 2007; doi: 10.1161/CIRCULATIONAHA.107.725101. Reprints: Alan T. Hirsch, hirsc005@umn.edu
* Intravenous Alteplase for Stroke: Beyond the Guidelines and in Particular Clinical Situations, in
Stroke, 2007; 38: 2612 ff. Reprints: J. De Keyser, U. Med. Ctr., Groningen, the Netherlands; j.h.a.de.keyser@neuro.umcg.nl
* Pharmacy Benefit Caps and the Chronically Ill, in
Health Affairs, 2007; 26: 1333–44. Reprints: G. F. Joyce.
* Direct-To-Consumer Advertisements for HIV Antiretroviral Medications: A Progress Report, in
Health Affairs, 2007; 26: 1392–8. Reprints: A. Kallen.

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

PNN Pharmacotherapy Line
Sept. 25, 2007 * Vol. 14, No. 186
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Sept. 24 issue of the Archives of Internal Medicine (http://archinte.ama-assn.org/current.dtl; 2007; 167).
HIV–Malaria Coinfection: Overlap in characteristics of malaria and HIV-related syndromes presents special problems in sub-Saharan Africa, conclude authors of a review article (pp. 1827-36). Based on six publications on HIV–malaria coinfection, the authors found “10 clinical or laboratory syndromes that are shared by malaria and AIDS-related conditions and that might provoke diagnostic confusion” and “12 antimalarial medications whose coadministration with antiretrovirals is known or suspected to result in drug–drug interactions or overlapping toxicities.” The group concludes: “Standard clinical guidelines do not reflect the full complexity of the interactions and overlaps between the 2 infections. Clinicians who manage HIV-infected patients in malaria-affected regions should systematically consider malaria when evaluating patients with a broad spectrum of symptoms. Further research is urgently needed to define best practices for prevention, diagnosis, and management of HIV-malaria coinfection in this region.” (P. E. Brentlinger, brentp2@u.washington.edu)
Race & Asthma Outcomes: Genetic differences may explain the worse outcomes among black patients with asthma, researchers conclude after studying 678 patients in a large health system (pp. 1846-52). Based on posthospitalization interviews and a median of 1.9 years of follow-up, the investigators found no other factor that would explain racial differences in outcomes: “Black race was associated with a higher risk of [emergency department] visits (hazard ratio [HR], 1.93; 95% confidence interval [CI], 1.39–2.66) and hospitalizations (HR, 1.89; 95% CI, 1.30–2.76). This finding persisted after adjusting for [socioeconomic status] and differences in asthma therapy (adjusted HR for ED visits, 1.73; 95% CI, 1.07–2.81; and adjusted HR for hospitalizations, 2.01; 95% CI, 1.33–3.02).” (S. E. Erickson, sara.erickson@ucsf.edu)
Diastolic BP During Treatment of Systolic Hypertension: During treatment for systolic hypertension, diastolic blood pressure can be lowered to 55 mm Hg in most older patients or to 70 mm Hg among those with concomitant coronary heart disease, concludes the prospective placebo-controlled Systolic Hypertension in Europe Trial (pp. 1884-91). “Rates of noncardiovascular mortality, cardiovascular mortality, and cardiovascular events were 11.1, 12.0, and 29.4, respectively, per 1,000 patient–years with active treatment (n = 2,358) and 11.9, 12.6, and 39.0, respectively, with placebo (n = 2,225),” write the authors. “Noncardiovascular mortality, but not cardiovascular mortality, increased with low diastolic BP with active treatment (P <.005) and with placebo (P <.05); for example, hazard ratios for lower diastolic BP, that is, 65 to 60 mm Hg, were, respectively, 1.15 (95% confidence interval, 1.00–1.31) and 1.28 (95% confidence interval, 1.03–1.59). Low diastolic BP with active treatment was associated with increased risk of cardiovascular events, but only in patients with coronary heart disease at baseline (P < .02; hazard ratio for BP 65–60 mm Hg, 1.17; 95% confidence interval, 0.98–1.38).” (R. H. Fagard, U Z Gasthuisberg-Hypertensie, Leuven, Belgium; robert.fagard@uz.kuleuven.ac.be)
Acupuncture for Low Back Pain: Among 1,162 patients with chronic low back pain, both verum and sham acupuncture produced responses in more patients as a combination of drugs, physical therapy, and exercise (pp. 1892-8). In the German Acupuncture Trials (GERAC) , patients received 10 sessions, usually twice per week, of either acupuncture based on Chinese medicine or superficial needling at nonacupuncture points, or conventional therapy, with these results: “At 6 months, response rate was 47.6% in the verum acupuncture group, 44.2% in the sham acupuncture group, and 27.4% in the conventional therapy group. Differences among groups were as follows: verum vs sham, 3.4% (95% confidence interval, –3.7% to 10.3%; P = .39); verum vs conventional therapy, 20.2% (95% confidence interval, 13.4% to 26.7%; P <.001); and sham vs conventional therapy, 16.8% (95% confidence interval, 10.1% to 23.4%; P <.001.” (H. G. Endres, Ruhr-Universität Bochum, Bochum, Germany; heinz.endres@ruhr-uni-bochum.de)

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

PNN Pharmacotherapy Line
Sept. 26, 2007 * Vol. 14, No. 187
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Sept. 26 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2007; 298).
Care Management of Workers with Depression: For 604 employees covered by a managed behavioral health plan with “significant depression,” a systematic program that identified depression and promoted effective treatment significantly improved both clinical and workplace outcomes (pp. 1401-11). The program included telephonic outreach and care management that encouraged workers to enter outpatient treatment (psychotherapy and/or antidepressant medication), monitored treatment quality continuity, and attempted to improve treatment by giving recommendations to providers. Results showed the following: “Combining data across 6- and 12-month assessments, the intervention group had significantly lower [Quick Inventory of Depressive Symptomatology] self-report scores (relative odds of recovery, 1.4; 95% confidence interval, 1.1–2.0; P = .009), significantly higher job retention (relative odds, 1.7; 95% confidence interval, 1.1–3.3; P = .02), and significantly more hours worked among the intervention (beta =2.0; P=.02; equivalent to an annualized effect of 2 weeks of work) than the usual care groups that were employed.” (P. Wang, wangphi@mail.nih.gov)
To reduce the “burden of depression,” editorialists call for “building villages of coordinated care” (pp. 1451-2): “Exactly how programs to improve depression care are implemented may affect the distribution of benefits—an important issue given evidence of disparities in quality of depression care and the potential for practice-based programs to overcome disparities in depression outcomes. Developers of interventions and policies should consider implications of their design for inclusion of underserved groups who may not seek behavioral health care. Despite the extensive efforts by Wang et al. to reach general employees, the majority of persons had already inquired about outpatient care. Learning how to optimize personal and societal gains by improving access to quality depression care across diverse communities through employer, practice, and community-based programs and policy changes is a next agenda for evidence-based action. As a community participant in the Witness for Wellness program recently stated: ‘Depression is everybody’s business.’” (K. B. Wells,
kwells@ucla.edu)
Omega-3 Fatty Acids & Autoimmunity: Children with genetic risks of developing type 1 diabetes had reduced risk of islet autoimmunity when they took omega-3 fatty acids, authors of a 1,770-patient study report (pp. 1420-8). During a mean follow-up of 6.2 years, the researchers determined: “Fifty-eight children developed IA. Adjusting for HLA genotype, family history of type 1 diabetes, caloric intake, and omega-6 fatty acid intake, omega-3 fatty acid intake was inversely associated with risk of IA (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.21–0.96; P = .04). The association was strengthened when the definition of the outcome was limited to those positive for 2 or more autoantibodies (HR, 0.23; 95% CI, 0.09–0.58; P = .002). In the case–cohort study, omega-3 fatty acid content of erythrocyte membranes was also inversely associated with IA risk (HR, 0.63; 95% CI, 0.41–0.96; P = .03).” (J. M. Norris, U. Colorado, Denver; jill.norris@uchsc.edu)

>>>PNN NewsWatch
* Sitagliptin, used as initial therapy of type 2 diabetes in conjunction with metformin, provided significant and sustained improvement in blood glucose control compared with metformin alone and was generally well tolerated over a 1-year period, researchers reported at the European Association for the Study of Diabetes meeting in Amsterdam. To match the twice-daily dosing pattern of metformin, sitagliptin was given in this study as 50 mg two times daily; mean A1C was reduced by 1.8 percentage points from baseline during the trial.
*
Steven Galson, MD, director of the FDA Center for Drug Evaluation and Research, becomes the Acting Surgeon General on Oct. 1, the Bush Administration announced late last week. Long-time FDA staff person Janet Woodcock, MD, becomes Acting CDER Director; she retains her position as Deputy Commissioner and permanent Chief Medical Officer.

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

PNN Pharmacotherapy Line
Sept. 27, 2007 * Vol. 14, No. 188
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Sept. 27 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2007; 357).
Thimerosal & Neuropsychological Outcomes: In a study of 1,047 children aged 7–10 years, early exposure to mercury from thimerosal-containing vaccines and immune globulins was associated with no deficits in neuropsychological functioning (pp. 1281-92). Autism-spectrum disorders were not assessed, but 42 other neuropsychological outcomes were measured using standardized tests, with these results: “We detected only a few significant associations with exposure to mercury from thimerosal. The detected associations were small and almost equally divided between positive and negative effects. Higher prenatal mercury exposure was associated with better performance on one measure of language and poorer performance on one measure of attention and executive functioning. Increasing levels of mercury exposure from birth to 7 months were associated with better performance on one measure of fine motor coordination and on one measure of attention and executive functioning. Increasing mercury exposure from birth to 28 days was associated with poorer performance on one measure of speech articulation and better performance on one measure of fine motor coordination.” (W. W. Thompson, wct2@cdc.gov)
In two accompanying Perspective articles, authors explore the implications of this study and thimerosal-related developments in the legal arena. “Despite several years of reassuring studies, the thimerosal controversy continues to be emotionally charged,” one author writes (pp. 1278-9). “Physicians, scientists, government policy advisors, and child advocates who have publicly stated that vaccines don’t cause neurologic problems or autism have been harassed, threatened, and vilified, receiving hate mail and occasionally death threats. The CDC, in response to planned protests at its gates, recently beefed up security and instructed personnel about how to respond if physically attacked.” (P. A. Offit, Children’s Hosp., Philadelphia)
An attorney explains how some parents have sought damages outside the federal Vaccine Injury Compensation Program (pp. 1275-7): “Several families have already tried to bypass the VICP process, going directly to court with creative legal arguments. Some assert that thimerosal is not included in the legal definition of a ‘vaccine’ or that it represents an ‘adulteration’ so their claims should be exempt from the VICP process. The government and vaccine makers argue that such claimants must file first with the VICP, and so far they are generally winning on this issue. Other claimants are having better luck with different end-run approaches—suing companies that make thimerosal, for instance, arguing that the preservative suppliers are not vaccine makers; filing class-action suits on behalf of parents; or demanding medical monitoring for vaccinated children who do not yet show signs of autism. Even in instances in which claimants are making modest procedural headway, such lawsuits seem a long way from resolution.” (S. D. Sugarman, U. Calif., Berkeley)
HDL & Cardiovascular Events: In patients treated with statins to very low LDL cholesterol levels, HDL cholesterol levels were predictive of major cardiovascular events (pp. 1301-10). Emphasizing the importance of increased attention to the HDL subfraction but also noting the benefits of getting LDL cholesterol levels to below 70 mg/dL, Treating to New Targets investigators report: “The HDL cholesterol level in patients receiving statins was predictive of major cardiovascular events across the TNT study cohort, both when HDL cholesterol was considered as a continuous variable and when subjects were stratified according to quintiles of HDL cholesterol level. When the analysis was stratified according to LDL cholesterol level in patients receiving statins, the relationship between HDL cholesterol level and major cardiovascular events was of borderline significance (P = 0.05). Even among study subjects with LDL cholesterol levels below 70 mg per deciliter, those in the highest quintile of HDL cholesterol level were at less risk for major cardiovascular events than those in the lowest quintile (P = 0.03).” (P. Barter, Heart Research Inst., Camperdown, Australia; barterp@hri.org.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 © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Sept. 28, 2007 * Vol. 14, No. 189
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Oct. issue of Diabetes Care (30; 2007; http://care.diabetesjournals.org/content/vol30/issue10/).
Diabetes Self-Management: As part of a three-article “Bench to Clinic” review of diabetes self-management, the importance of medications is discussed and the emerging coaching role of pharmacists briefly mentioned (pp. 2425-32): “Researchers are examining ways to use information in large electronic medication refill databases to support both patients and their clinicians in making decisions about treatment adjustment and adherence support. Because more information alone is unlikely to improve outcomes, researchers are exploring the most effective way to link objective adherence reports from refill data with behavioral counseling by clinical pharmacists and other health professionals. By using already collected refill information to support established clinical relationships, these [Interactive Behavior Change Technology] interventions are designed to improve the quality of diabetes adherence counseling without adding additional clinicians or requiring patients to access health information in new ways.” (J. D. Piette, jpiette@umich.edu)
Effects of Insulin Detemir: Insulin detemir had similar effects as insulin glargine but was less effective 12 to 24 hours after administration in a pharmacokinetic/pharmacodynamic comparison (pp. 2447-52). The two once-daily insulin analogs were assessed in 24 patients with type 1 diabetes using two-week treatment periods with crossover. Patients were withdrawn from the study if their plasma glucose levels were not controlled. Glycemic control was evident in the patients while they were receiving insulin glargine, but only eight participants completed the study with plasma glucose levels lower than 180 mg/dL. Free fatty acids were also lower with insulin glargine than with the detemir analog. (G. B. Bolli, U. Perugia, Perugia, Italy; gbolli@unipg.it)
LDL-C Effects of Glitazones: Compared with rosiglitazone, pioglitazone had more favorable effects on lipoprotein subclasses during treatment of patients with type 2 diabetes and dyslipidemia (pp. 2458-64). During a total of 24 weeks of treatment, similar effects on glycemic control and insulin resistance were noted, but these lipoprotein differences emerged: “PIO treatment increased total VLDL particle concentration less than ROSI treatment and decreased VLDL particle size more than ROSI. PIO treatment reduced total LDL particle concentration, whereas ROSI treatment increased it. Both treatments increased LDL particle size, with PIO treatment having a greater effect. Whereas PIO treatment increased total HDL particle concentration and size, ROSI treatment decreased them; both increased HDL cholesterol levels.” (M. H. Tan, tan_meng@lilly.com)
Weight Change with Inhaled v. Subcutaneous Insulin: Among more than 2,000 patients with types 1 or 2 diabetes over a six-month period, less weight gain was observed with inhaled insulin than with subcutaneously administered product (pp. 2508-10). The researchers write: “In patients with type 1 diabetes, a 0.2-kg increase was noted with Exubera, compared with a 1.1-kg increase with SC insulin. Patients with type 2 diabetes gained only one-half as much weight on a regimen including Exubera than on regimens that only included SC insulin (0.7 vs. 1.6 kg, respectively). The adjusted mean change in weight was statistically different in patients treated with a regimen including Exubera versus an SC insulin–only regimen for both type 1 (–0.87 kg [95% CI –1.24 to –0.50]) and type 2 (–0.93 kg [–1.39 to –0.48]) diabetic subjects.” (P. A. Hollander, priscilh@baylorhealth.edu)

>>>PNN NewsWatch
* President Bush on Thursday signed into law the FDA Amendments Act, reauthorizing user fees, the Best Pharmaceuticals for Children Act, and the Pediatric Research Equity Act. A nonprofit corporation is also established by the legislation; the purpose of the Reagan–Udall Foundation will be to “advance the mission of FDA,” the agency noted in a news release.
* Congress has passed legislation delaying for six months the Oct. 1 implementation of
tamper-resistant prescription pads for Medicaid patients, APhA reported last night. President Bush is expected to sign the bill.

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