Jun 2007

PNN Quarterly File—Second Quarter 2007

PNN Pharmacotherapy Line
Apr. 2, 2007 * Vol. 14, No. 63
Providing news and information about medications and their proper use

>>>Tegaserod Sales, Marketing Suspended in US, Canada
At the request of FDA and Health Canada, Novartis Pharmaceuticals on Friday suspended marketing and sales of tegaserod maleate (Zelnorm) in the U.S. and Canada because of a recently identified increased risk of serious cardiovascular adverse events (angina, myocardial infarctions, and strokes) associated with use of the irritable bowel syndrome drug. Pharmacies and wholesalers should return the product to the company. Novartis will also reimburse patients for out-of-pocket costs of unused and unexpired Zelnorm.
In a news release, FDA said that it would work with Novartis to allow access to Zelnorm as an investigational drug for patients with no other treatment options where the benefits may outweigh the risks. FDA has also indicated to Novartis the possibility of considering limited re-introduction of Zelnorm at a later date if a population of patients can be identified in which the benefits of the drug outweigh the risks. Any such proposal would be the subject of a public advisory committee meeting before an FDA decision.
Tegaserod was first approved in the U.S. in July 2002 for short-term treatment of women with irritable bowel syndrome whose primary symptom is constipation. It was subsequently approved in August 2004 for treatment of chronic constipation for men and women under age 65. The agent has been marketed in 55 countries but was never approved in the European Union.
>>>Protein C Concentrate Licensed for Rare Condition
FDA has licensed Protein C Concentrate (Human), a plasma-derived protein C concentrate for use as replacement therapy in patients with life-threatening blood-clotting complications related to severe congenital protein C deficiency. Approved as an orphan drug, it will marketed by Baxter as Ceprotin.
Severe congenital protein C deficiency is a rare genetic defect found in one to two newborns for every 1 million births. Patients with insufficient levels of protein C experience abnormally high numbers of blood clots. Complete absence of the protein is fatal. Symptoms typically appear soon after birth. Clotting may occur in the blood vessels of the skin, eyes, brain, and kidneys, and throughout the body. Left untreated, clotting may result in blindness, severe brain damage, multi-organ failure, and death for these patients.
Patients with severe inherited protein C deficiency must take oral or injected anticoagulant drugs on a regular basis to avoid blood clots. Ceprotin is intended to treat these patients when they are faced with a life-threatening situation from blood clots in the veins, or the severe skin and systemic blood clotting disorder purpura fulminans.
Baxter enrolled all available patients for the pivotal trial. In 94% of the patients studied for purpura fulminans, Ceprotin was found “effective.” In another 6% of patients, the treatment was found “effective with complications” because they required a dosage adjustment. Overall, 80% of the treatments for blood clots in the veins were determined as “excellent,” while the other 20% were rated as “good.”
None of seven patients who took Ceprotin as a preventive measure before surgery or anticoagulation therapy experienced blood clotting complications. Eight patients who were given Ceprotin as a long-term preventive measure did not experience the severe skin and blood clotting events associated with purpura fulminans.
The most common adverse reactions of the product were rash, itching, and lightheadedness.
Patients, family members, and health professionals can call Baxter at 1-888-CEPROTIN (1-888-237-7684) from 7:00 a.m. to 6:00 p.m., Central Time, Monday through Friday, for more information about this product.

>>>PNN JournalWatch
* Anticoagulation for Three Versus Six Months in Patients with Deep Vein Thrombosis or Pulmonary Embolism, or Both: Randomised Trial, in BMJ, 2007; 334: 674 ff. Reprints: I. A. Campbell. Llandough Hosp., Llandough, Cardiff, U.K.; ian.campbell@cardiffandvale.wales.nhs.uk
* Interventions to Reduce Harm Associated with Adolescent Substance Use, in
Lancet, 2007; doi: 10.1016/S0140-6736(07)60369-9. Reprints: T. Stockwell, U. Victoria, Victoria, B.C., Canada; timstock@uvic.ca
* Intensive Insulin Therapy in Critical Care: A Review of 12 Protocols, in
Diabetes Care, 2007; 30: 1005–11. Reprints: G. W. Soo Hoo, guy.soohoo@med.va.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
Apr. 3, 2007 * Vol. 14, No. 64
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Apr. 3 issue of the Annals of Internal Medicine (www.annals.org; 2007; 146).
Adding Exenatide to TZDs in Type 2 DM: Among 233 patients with type 2 diabetes that was suboptimally controlled with thiazolidinediones, exenatide therapy improved glycemic control, reduced body weight, but caused gastrointestinal symptoms more than did placebo (pp. 477-85). Subcutaneous abdominal injections of exenatide 10 mcg or placebo twice daily were administered with or without metformin for 16 weeks, with these results: “Exenatide treatment reduced hemoglobin A1c level (mean difference, –0.98% [95% CI, –1.21% to –0.74%]), serum fasting glucose level (mean difference, –1.69 mmol/L [–30.5 mg/dL] [CI, –2.22 to –1.17 mmol/L {–40.0 to –21.1 mg/dL}]), and body weight (mean difference, –1.51 kg [CI, –2.15 to –0.88 kg]). Sixteen percent of patients in the exenatide group and 2% of patients in the placebo group discontinued treatment because of adverse events. In the exenatide group, 40% (n = 48) of patients experienced nausea (mostly mild [n = 21] or moderate [n = 19]), 13% experienced vomiting, and 11% experienced hypoglycemia. In the placebo group, 15% of patients experienced nausea, 1% experienced vomiting, and 7% experienced hypoglycemia.” (B. Zinman, Mount Sinai Hosp., Toronto; zinman@mshri.on.ca)
Describing combination exenatide therapy has having many unanswered questions and this “small study” as raising “many questions,” an editorialist draws this conclusion (pp. 527-8): “The study was much too small and much too short. The estimated number of patients with type 2 diabetes worldwide in 2007 is 246 million. Zinman and colleagues’ study exposed only 121 patients from 49 different centers to exenatide and TZDs. Because of its short duration, small size, and lack of power, the study fails to clarify many questions. Among the most important questions are: Will glucose control last more than 16 weeks? Who is at greatest risk for adverse drug reactions? Will dose adjustment improve glucose control and decrease adverse drug reactions? Subgroup analyses would answer some of these important questions. A small study precludes meaningful subgroup analyses. More important, small and short studies provide a false sense of safety, because common severe adverse drug reactions may not occur in the condensed timeline and in the limited number of patients.” (S. Malozowski,
sm87j@nih.gov)

>>>Diabetes Care Highlights
Source:
Apr. issue of Diabetes Care (http://care.diabetesjournals.org; 2007; 30).
Glimepiride v. Metformin Monotherapy: Over 24 weeks in a single-blind study of 285 pediatric patients with type 2 diabetes, glimepiride reduced A1C similarly to metformin and with a similar safety profile, except for greater weight gain (pp. 790-4). Comparing glimepiride 1–8 mg with metformin 500–1000 mg once daily, the researchers found: “Significant reductions from baseline A1C were seen in both the glimepiride (–0.54%, P = 0.001) and metformin (–0.71%, P = 0.0002) groups.... Significant differences were observed in mean changes from baseline in BMI between groups (0.26 kg/m2 for glimepiride and –0.33 kg/m2 for metformin; P = 0.003). The adjusted mean body weight increase was 1.97 kg for glimepiride and 0.55 kg for metformin (P = 0.005). A hypoglycemic episode with blood glucose <50 mg/dl (<2.8 mmol/l) was experienced by 4.9 and 4.2% of glimepiride- and metformin-treated subjects, respectively. A single severe hypoglycemic event occurred in each group.” (M. Gottschalk, mgottsch@ucsd.edu)
QOL with Insulin Glargine v. Rosiglitazone: Greater improvements in health-related quality of life were achieved with addition of insulin glargine, compared with rosiglitazone, in 217 patients with type 2 diabetes uncontrolled by sulfonylureas plus metformin (pp. 795-800). Results showed: “Although subjects treated with insulin glargine experienced significantly greater improvements compared with rosiglitazone in the [Diabetes Symptom Checklist-Revised] total symptom score (P = 0.005), total symptom distress score (P = 0.03), individual domain scores for mood symptoms (P = 0.007), ophthalmologic symptoms (P = 0.007), ophthalmologic distress (P = 0.013), fatigue distress (P = 0.033), and SF-36 perception of general health (P = 0.047).” (A. I. Vinik, Eastern Va. Med. Sch., Norfolk; vinikai@evms.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
Apr. 4, 2007 * Vol. 14, No. 65
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Apr. 4 issue of JAMA (www.jama.com; 2007; 297).
Influenza B Resistance to Neuraminidase Inhibitors: While influenza B viruses with reduced sensitivity to the neuraminidase inhibitors do not appear to arise as frequently as resistant influenza A viruses, a study of 74 children and 348 untreated patients shows that such strains can be transmitted among family members and community contacts (pp.1435-42 ). Concluding that close monitoring of reduced sensitivities is required, researchers report these results from the 2004–05 influenza season in Japan: “In 1 (1.4%) of the 74 children who had received oseltamivir, we identified a variant with reduced drug sensitivity possessing a Gly402Ser neuraminidase substitution. We also identified variants with reduced sensitivity carrying an Asp198Asn, Ile222Thr, or Ser250Gly mutation in 7 (1.7%) of the 422 viruses from untreated patients. Review of the clinical and viral genetic information available on these 7 patients indicated that 4 were likely infected in a community setting, while the remaining 3 were probably infected through contact with siblings shedding the mutant viruses.” (Y. Kawaoka, U. Tokyo, Tokyo; kawaoka@ims.u-tokyo.ac.jp)
Editorialists write that this “news about influenza B drug resistance ... cannot be ignored” (pp. 1492-3): “Influenza B mutants with reduced sensitivity to neuraminidase inhibitors are circulating, and these viruses can cause infections with no difference in duration of symptoms, level of viral shedding, or clinical outcome. Contrary to what had been hoped until now, some resistant variants are vigorous pathogens. Whether these viruses arise by spontaneous mutation or through drug selection, or whether they are transmitted within families or acquired from the community, the resistant variants may be here to stay. In light of the recent observation that oseltamivir may be less effective against influenza B than against influenza A, an important concern is whether suboptimal dosing for these viruses will lead to increased selection of viruses with high-level resistance.” (A. Moscona,
anm2047@med.cornell.edu)
Sumatriptan–Naproxen for Migraine: For acute treatment of migraine, a fixed-dose tablet of sumatriptan 85 mg plus naproxen sodium 500 mg provided more favorable clinical benefits than monotherapy with either agent or placebo in two parallel studies of 2,956 patients (pp. 1443-54). Among the significantly improved clinical measures with combination therapy in both studies were headache relief and absence of photophobia and phonophobia at 2 hours after dosing. “For 2- to 24-hour sustained pain-free response, sumatriptan–naproxen sodium was superior at P <.01 (25% and 23% in studies 1 and 2, respectively) to sumatriptan monotherapy (16% and 14% in studies 1 and 2), naproxen sodium monotherapy (10% and 10% in studies 1 and 2), and placebo (8% and 7% in studies 1 and 2),” the authors note. “The incidence of adverse events was similar between sumatriptan–naproxen sodium and sumatriptan monotherapy.” (J. L. Brandes, Nashville Neuroscience Group, Nashville, Tenn.; jbrandes@nashvilleneuroscience.com)
Statin Use & Sepsis in CKD: The risk of hospitalization for sepsis was reduced significantly among patients with chronic kidney diseases who were taking statins, according to a national prospective cohort study of 1,041 incident dialysis patients in 1995–98 (pp. 1455-64). Based on follow-up in 2005, investigators determined: “With adjustment for demographics and dialysis modality, statin users were substantially less likely to be subsequently hospitalized for sepsis (incidence rate ratio, 0.41; 95% confidence interval [CI], 0.25–0.68). Further adjustment for comorbidities and laboratory values continued to show this protective association (incidence rate ratio, 0.38; 95% CI, 0.21–0.67).” (N. R. Powe, Johns Hopkins Med. Inst., Baltimore; npowe@jhmi.edu)
Postmenopausal Hormone Therapy: In a new secondary analysis of data from the Women’s Health Initiative, those “who initiated hormone therapy closer to menopause tended to have reduced [coronary heart disease] risk compared with the increase in CHD risk among women more distant from menopause,” but the trend did not reach statistical significance (pp. 1465-77). Women taking conjugated equine estrogens had slightly lower CHD risks within the first 10 years after onset of menopausal symptoms. (J. E. Rossouw, rossouwj@nih.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
Apr. 5, 2007 * Vol. 14, No. 66
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Apr. 5 issue of the New England Journal of Medicine (http://content.nejm.org; 2007; 356).
Multivitamins During Pregnancy: In Tanzania, multivitamin supplementation reduced the number of low-birth-weight and small-for-gestational-age births but had no significant effects on prematurity or fetal death among 8,468 HIV-negative pregnant women (pp. 1423-31). In addition to daily supplements of iron and folic acid, study participants took either placebo or daily multivitamins in this double-blind study, beginning at 12–27 weeks of fetal gestational age. Results showed the following: “The incidence of low birth weight was 7.8% among the infants in the multivitamin group and 9.4% among those in the placebo group (relative risk, 0.82; 95% confidence interval [CI], 0.70 to 0.95; P = 0.01). The mean difference in birth weight between the groups was modest (67 g, P <0.001). The rates of prematurity were 16.9% in the multivitamin group and 16.7% in the placebo group (relative risk, 1.01; 95% CI, 0.91 to 1.11; P = 0.87), and the rates of fetal death were 4.3% and 5.0%, respectively (relative risk, 0.87; 95% CI, 0.72 to 1.05; P = 0.15). Supplementation reduced both the risk of a birth size that was small for gestational age (<10th percentile; 10.7% in the multivitamin group vs. 13.6% in the placebo group; relative risk, 0.77; 95% CI, 0.68 to 0.87; P <0.001) and the risk of maternal anemia (hemoglobin level, <11 g per deciliter; relative risk, 0.88; 95% CI, 0.80 to 0.97; P = 0.01), although the difference in the mean hemoglobin levels between the groups was small (0.2 g per deciliter, P <0.001).” (W. W. Fawzi, mina@hsph.harvard.edu)
VT in Hospitalized Patients: In a Clinical Practice article, the case of a 62-year-old man who was hospitalized for fever, cough, and dyspnea provides the basis for a discussion of the need for prophylaxis against venous thromboembolism in hospitalized medical patients (pp. 1438-44). The author provides this bottom line: “Venous thromboembolism is a common but preventable serious complication in hospitalized patients. The patient described in the vignette has several risk factors, including his age and the presence of acute infectious disease, and prophylaxis is warranted. In the absence of a contraindication, I would recommend prophylaxis with unfractionated heparin, a low-molecular-weight heparin, or fondaparinux.... Unfractionated heparin is less expensive but must be given three times daily, whereas low-molecular-weight heparins and fondaparinux are more expensive but can be given once daily. All three agents have been shown to be effective in reducing the risk of venous thromboembolism in randomized trials. For patients who have active gastrointestinal or intracranial bleeding or who are at high risk for bleeding, the use of graduated compression stockings or the intermittent use of pneumatic compression devices is a reasonable alternative.” (C. W. Francis, U. Rochester Med. Ctr., Rochester, N.Y.; charles_francis@urmc.rochester.edu)
Hepatitis/HIV Coinfection: Approaches to treatment of hepatitis B or C infections in patients with HIV are reviewed (pp. 1445-54). For those with hepatitis B coinfections, the authors recommend: “Patients who need treatment for HBV infection but not HIV infection should not receive HBV medications that have activity against HIV. Instead, they should receive agents with HBV activity alone; these agents include entecavir, interferon, and adefovir at a dose of 10 mg per day.... Some experts caution against the use of adefovir alone at a dose of 10 mg, since there is a theoretical risk of HIV resistance, but resistance has not been shown in vivo. Entecavir has not been evaluated in patients with HIV and HBV coinfection who are not receiving effective treatment for HIV at the same time. There is one reported case of resistance to HIV in a patient who was receiving entecavir without antiretroviral therapy. Lamivudine-resistant HBV infection may progress more slowly than untreated HBV infection, and continued therapy with the addition of another nucleotide is prudent in patients who already have lamivudine resistance. When changing or initiating antiretroviral regimens, it is important to continue administering agents with anti-HBV activity, since there is a risk of the immune reconstitution syndrome during recovery of CD4 cell counts; this syndrome may be difficult to distinguish from hepatotoxicity.” (M. J. Koziel, mkoziel@bidmc.harvard.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 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
Apr. 6, 2007 * Vol. 14, No. 67
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Apr. issue of Pharmacotherapy (www.pharmacotherapy.org; 2007; 27).
Clinical Pharmacy Services & Hospital Mortality: Reduction in hospital mortality rates associated with clinical pharmacy services “mandates consideration of a core set of clinical pharmacy services to be offered in United States hospitals,” according to authors who analyzed 1998 MedPAR, hospital survey, and National Clinical Pharmacy Services databases (pp. 481-93). Continuing an earlier research thread, the investigators show that “the number of clinical pharmacy services and staffing variables associated with reduced mortality rates increased from two in 1989 to nine in 1998”: “Seven clinical pharmacy services were associated with reduced mortality rates: pharmacist-provided drug use evaluation (4,491 reduced deaths, p = 0.016), pharmacist-provided in-service education (10,660 reduced deaths, p = 0.037), pharmacist-provided adverse drug reaction management (14,518 reduced deaths, p = 0.012), pharmacist-provided drug protocol management (18,401 reduced deaths, p = 0.017), pharmacist participation on the cardiopulmonary resuscitation team (12,880 reduced deaths, p = 0.009), pharmacist participation on medical rounds (11,093 reduced deaths, p = 0.021), and pharmacist-provided admission drug histories (3,988 reduced deaths, p = 0.001). Two staffing variables, number of pharmacy administrators/100 occupied beds (p = 0.037) and number of clinical pharmacists/100 occupied beds (p = 0.023), were also associated with reduced mortality rates.” (C. A. Bond, cab.bond@ttuhsc.edu)
Adverse Effects of High-Dose Ribavirin: High-dose intravenous ribavirin, used in early phases of the 2003 severe acute respiratory syndrome outbreak, was associated with a high rate of adverse events, according to a retrospective cohort study of 306 patients with confirmed or probable SARS (pp. 494-503). Comparing 183 patients who received very high doses of ribavirin with 123 patients who did not, the investigators found: “In the primary logistic regression analysis, ribavirin use was strongly associated with anemia (odds ratio [OR] 3.0, 99% confidence interval [CI] 1.5–6.1, p < 0.0001), hypomagnesemia (OR 21, 99% CI 5.8–73, p < 0.0001), and bradycardia (OR 2.3, 99% CI 1.0–5.1, p = 0.007). Hypocalcemia, transaminitis, and hyperamylasemia were not associated with ribavirin use. The risk of anemia, hypomagnesemia, and bradycardia attributable to ribavirin use was 27%, 45%, and 17%, respectively.” (M. P. Muller, Mount Sinai Hosp., Toronto; mmuller@mtsinai.on.ca)
ARBs & HF: In a retrospective analysis of hospital discharge summaries from three Canadian provinces, elderly patients with heart failure who were treated with losartan had significantly worse survival rates than those receiving other angiotensin II receptor blockers (pp. 526-34). Demonstrating the absence of a class effect with regard to HF treatment, the researchers report these outcomes for 6,876 patients who had at least one prescription filled for an ARB within 90 days of discharge from a HF-related hospitalization between 1998 and 2003: “Losartan was the most frequently prescribed ARB (61%), followed by irbesartan (14%), valsartan (13%), candesartan (10%), and telmisartan (2%). Irbesartan, valsartan, and candesartan were associated with better survival rates than losartan (adjusted hazard ratios [HRs] and 95% confidence intervals [CIs] 0.65 [0.53–0.79], 0.63 [0.51–0.79], and 0.71 [0.57–0.90], respectively). No difference was noted in mortality in patients prescribed telmisartan compared with those receiving losartan (HR 0.92 [95% CI 0.55–1.54]).” (M. Hudson, marie.hudson@mcgill.ca)
Cinnamon & DM: For patients with poorly controlled type 2 diabetes mellitus, cinnamon supplementation “has a possible modest effect in lowering plasma glucose levels,” conclude authors of a review article (pp. 595-9). However, the group adds, “Clinicians are strongly urged to refrain from recommending cinnamon supplementation in place of the proven standard of care, which includes lifestyle modifications, oral antidiabetic agents, and insulin therapy.” Three studies of 164 patients showed cinnamon supplements to be safe. But only modest improvements in glucose levels in “small patients samples” were demonstrated in two trials, and the other study found no significant differences in blood glucose levels in patients receiving placebo or cinnamon. (D. Q. Pham, david.pham@liu.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 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
Apr. 9, 2007 * Vol. 14, No. 68
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from and Apr. 7 issue of BMJ (www.bmj.org; 2007; 334).
Composite Endpoints in Cardiology Trials: Results of cardiovascular trials that use multiple types of events to assess efficacy and safety can be confusing and misleading when these events are not of similar importance to patients, conclude authors of a systematic review of studies published in six prominent journals in 2002–03 (doi: 10.1136/bmj.39136.682083.AE). Concluding that “higher event rates and larger treatment effects associated with less important components may result in misleading impressions of the impact of treatment,” the investigators report: “Of 114 identified randomised controlled trials that included a composite end point of importance to patients, 68% (n = 77) reported complete component data for the primary composite end point; almost all (98%; n = 112) primary composite end points included a fatal end point. Of 84 composite end points for which component data were available, 54% (n = 45) showed large or moderate gradients in both importance to patients and magnitude of effect across components. When analysed by categories of importance to patients, the most important components were associated with lower event rates in the control group (medians of 3.3–3.7% for fatal, critical, and major outcomes; 12.3% for moderate outcomes; and 8.0% for minor outcomes). Components of greater importance to patients were associated with smaller treatment effects than less important ones (relative risk reduction of 8% for death and 33% for components of minor importance to patients).” (J. W. Busse, j.busse@utoronto.ca)
Managing Menopause: Current concepts about use of hormone-replacement therapy in managing symptoms of menopause are reviewed (pp. 736-41). The author makes these key points (H. Roberts, U. Auckland, Auckland, New Zealand; h.roberts@auckland.ac.nz):
* HRT remains an appropriate treatment for women with moderate to severe menopausal symptoms.
* HRT should not be used for the prevention of chronic disease.
* Treatment should be at the lowest dose for the shortest time necessary to control symptoms.
* Women should be advised of the increased risk of stroke, deep-vein thrombosis, and gallbladder disease with both combined and estrogen-only therapy.
* Combined therapy is also associated with increases in risk of breast cancer and dementia (women older than 65 years).

>>>PNN NewsWatch
* Citing lack of evidence of efficacy, FDA announced on Friday that companies must stop manufacturing and distributing all suppository drug products containing the antiemetic agent trimethobenzamide hydrochloride. These products have been marketed under various names, including Tigan, Tebamide, T-Gen, Trimazide, and Trimethobenz. FDA urged consumers who are using such suppositories containing trimethobenzamide, and who have questions or concerns, to contact their health care providers. Several oral capsules and injectable products containing trimethobenzamide have been approved by FDA and are not affected by this action, which resulted from FDA’s Drug Efficacy Study Implementation review of pre-1962 drug products. Shipments must stop by May 9, but supplies remaining in pharmacies can be used until exhausted.

>>>PNN JournalWatch
* Antifungal Therapy in Children With Invasive Fungal Infections: A Systematic Review, in Pediatrics, 2007; 119: 772–84. Reprints: C. C. Blyth, Sydney Children’s Hosp., Randwick, NSW, Australia.
* Evaluation of Insulin Resistance and Sodium Sensitivity in Normotensive Offspring of Hypertensive Individuals, in
American Journal of Kidney Diseases, 2007; 49: 540–6. Reprints: S. Spaia, 2nd Hospital of IKA Thessaloniki, Thessaloniki, Greece; sspaia@otenet.gr
* Interventions to Reduce Fear of Falling in Community-Living Older People: A Systematic Review, in
Journal of the American Geriatrics Society, 2007; 55: 603 ff. Reprints: R. Zijlstra, Maastricht U., Maastricht, the Netherlands; R.Zijlstra@zw.unimaas.nl
* Penicillin Allergy Skin Testing: What Do We Do Now?, in
Pharmacotherapy, 2007; 27: 542–5. Reprints: J. C. Rotschafer, rotsc001@umn.edu
* Safety of Newer Antidepressants in Pregnancy, in
Pharmacotherapy, 2007; 27: 546–52. Reprints: C. M. Way, Ottawa Hosp., Ottawa, Ont., Canada

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Apr. 10, 2007 * Vol. 14, No. 69
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Apr. 9 issue of the Archives of Internal Medicine (http://archinte.ama-assn.org; 2007; 167).
Cocoa, Tea, & BP: Intake of cocoa-rich foods is associated with lowered blood pressures, but drinking teas has no effect on this parameter, according to a meta-analysis of published studies (pp. 626-34). “Five randomized controlled studies of cocoa administration involving a total of 173 subjects with a median duration of 2 weeks were included,” write the authors. “After the cocoa diets, the pooled mean systolic and diastolic blood pressure were –4.7 mm Hg (95% confidence interval [CI], –7.6 to –1.8 mm Hg; P = .002) and –2.8 mm Hg (95% CI, –4.8 to –0.8 mm Hg; P = .006) lower, respectively, compared with the cocoa-free controls. Five studies of tea consumption involving a total of 343 subjects with a median duration of 4 weeks were selected. The tea intake had no significant effects on blood pressure. The estimated pooled changes were 0.4 mm Hg (95% CI, –1.3 to 2.2 mm Hg; P = .63) in systolic and –0.6 mm Hg (95% CI, –1.5 to 0.4 mm Hg; P = .38) in diastolic blood pressure compared with controls.” (D. Taubert, U. Hosp., Cologne, Germany; dirk.taubert@medizin.uni-koeln.de)
Anthrax Attack: A cost-effectiveness analysis of a hypothetical terrorist attack using anthrax distributed via the U.S. Postal Service concludes that postexposure antibiotic therapy and vaccination of exposed personnel are preferred over preexposure vaccination against the organism (pp. 655-62). Taking a societal perspective, assuming a 10-year timeframe, and comparing preattack vaccination of all distribution center postal personnel, postattack antibiotic therapy followed by vaccination of exposed personnel, and postattack antibiotic therapy without vaccination of exposed personnel, the researchers found: “Postattack antibiotic therapy and vaccination of exposed postal workers is the most cost-effective response compared with other strategies. The incremental cost-effectiveness is $59,558 per quality-adjusted life-year compared with postattack antibiotic therapy alone. Preattack vaccination of all distribution center workers is less effective and more costly than the other 2 strategies. Assuming complete adherence to preattack vaccination, the incremental cost-effectiveness compared with postattack antibiotic therapy alone is almost $2.6 million per quality-adjusted life-year.” (B. Schmitt, brian.schmitt2@med.va.gov)
Antipsychotic Use in NHs: Residents in Ontario nursing homes with high rates of antipsychotic prescribing were 3 times more likely to receive these drugs than were those in low-prescribing homes, irrespective of their clinical conditions, concludes a study of 47,322 residents of 485 provincially regulated facilities (pp. 676-83). “A total of 15,317 residents (32.4%) were dispensed an antipsychotic agent” in this point-prevalence, Dec. 2003 study. “The mean rate of antipsychotic prescribing by home ranged from 20.9% in the quintile of facilities with the lowest mean prescribing rates (quintile 1) to 44.3% in facilities with the highest mean prescribing rates (quintile 5). Compared with individuals residing in nursing homes with the lowest mean antipsychotic prescribing rates, those residing in facilities with the highest rates were 3 times more likely to be dispensed an antipsychotic agent (adjusted odds ratio [AOR], 3.0; 95% confidence interval [CI], 2.74–3.19). Similar rates were observed among residents with psychoses with or without dementia (AOR, 2.7; 95% CI, 2.35–3.09) and residents without psychoses or dementia (AOR, 2.9; 95% CI, 2.19–3.81) who had no identifiable indication for an antipsychotic therapy.” (P. A. Rochon, Kunin-Lunenfeld Applied Res. Unit, Toronto; paula.rochon@utoronto.ca)
Age & HAART Tolerability: Those in the growing older adult population with HIV infection have higher rates of adverse drug events associated with highly active antiretroviral therapy, concludes a study of patients in an integrated health care system (pp. 684-91). Despite these challenges, those aged 50 and older “sustained high therapy adherence to maintain improved virological outcomes and to compensate for their early blunted CD4 T-cell count response compared with younger patients,” investigators note of the 5,090-patient study. “Metabolic (glucose and lipids), hematologic (absolute neutrophils and hemoglobin), and renal (creatinine) abnormalities were more likely among older patients.” (M. J. Silverberg, Kaiser Permanente N. Calif., Oakland; Michael.J.Silverberg@kp.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
Apr. 11, 2007 * Vol. 14, No. 70
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Apr. 11 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2007; 297).
Corticosteroids for AF Prevention After Cardiac Surgery: Addressing a proposed exaggerated inflammatory response following cardiac surgery, researchers found that patients treated with intravenous hydrocortisone had fewer postoperative episodes of atrial fibrillation than did those given placebo (pp. 1562-7). At three university medical centers in Finland, 241 consecutive patients without prior AF or atrial flutter who were undergoing coronary artery bypass graft surgery, aortic valve replacement, or combined CABG surgery and aortic valve replacement received metoprolol 50–150 mg orally plus either hydrocortisone 100 mg or placebo as an evening dose following surgery and then 1 dose every 8 hours for 3 days. The authors report these results: “The incidence of postoperative AF was significantly lower in the hydrocortisone group (36/120 [30%]) than in the placebo group (58/121 [48%]; adjusted hazard ratio, 0.54; 95% confidence interval, 0.35–0.83; P = .004; number needed to treat, 5.6). Compared with placebo, patients receiving hydrocortisone did not have higher rates of superficial or deep wound infections, or other major complications.” (J. Halonen, Kuopio U. Hosp., Kuopio, Finland; jari.halonen@kuh.fi)
Stem-Cell Transplantation for Type 1 DM: Beta-cell function was increased in 14 of 15 newly diagnosed patients with type 1 diabetes mellitus following high-dose immunosuppression followed by autologous nonmyeloablative hematopoietic stem cell transplantation (AHST) (pp. 1568-76). The patients, aged 14–31 years, had not had previous episodes of diabetic ketoacidosis, and this intervention provided these outcomes in this Phase I/II study: “During a 7- to 36-month follow-up (mean 18.8), 14 patients became insulin-free (1 for 35 months, 4 for at least 21 months, 7 for at least 6 months; and 2 with late response were insulin-free for 1 and 5 months, respectively). Among those, 1 patient resumed insulin use 1 year after AHST. At 6 months after AHST, mean total area under the C-peptide response curve was significantly greater than the pretreatment values, and at 12 and 24 months it did not change. Anti–glutamic acid decarboxylase antibody levels decreased after 6 months and stabilized at 12 and 24 months. Serum levels of hemoglobin A1c were maintained at less than 7% in 13 of 14 patients. The only acute severe adverse effect was culture-negative bilateral pneumonia in 1 patient and late endocrine dysfunction (hypothyroidism or hypogonadism) in 2 others. There was no mortality.” (J. C. Voltarelli, Regional Blood Ctr. [Hemocentro], Ribeirão Preto, Brazil; jcvoltar@fmrp.usp.br)
Baculovirus-Expressed Hemagglutinin Influenza Vaccine: An experimental trivalent influenza virus hemagglutinin (rHA0) vaccine produced in insect cells using recombinant baculoviruses was safe and immunogenic in a healthy adult population (pp. 1577-82). The technique could be advantageous by avoiding the dependence on the egg-based production of influenza vaccine, which the authors note “can be time consuming, is not always successful, and can select receptor variants that may have suboptimal immunogenicity.” Use of the new vaccine in 460 adults during the 2004–05 season showed these results: “Rates of local and systemic adverse effects were low, and the rates of systemic adverse effects were not different in either vaccine group than in the placebo group. Hemagglutinin inhibition antibody responses to the H1 component were seen in 3% of placebo, 51% of 75-µg vaccine, and 67% of 135-µg vaccine recipients, while responses to B were seen in 4% of placebo, 65% of 75-µg vaccine, and 92% of 135-µg vaccine recipients. Responses to the H3 component occurred in 11% of placebo, 81% of 75-µg vaccine, and 77% of 135-µg vaccine recipients. Influenza infections in the study population were due to influenza B and A(H3N2), and influenza A infections were A/California/7/2004–like viruses, an antigenically drifted strain. Seven cases of culture-confirmed CDC-defined influenza-like illness occurred in 153 placebo recipients (4.6%) compared with 2 cases (1.3%) in 150 recipients of 75 µg of vaccine, and 0 cases in recipients of 135 µg of vaccine.” (J. J. Treanor, John_Treanor@urmc.rochester.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
Apr. 12, 2007 * Vol. 14, No. 71
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Apr. 12 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2007; 356).
PCI v. Optimal Medical Therapy for CAD: Percutaneous coronary intervention provided no additional benefit when added optimal medical therapy in 2,287 patients with objective evidence of myocardial ischemia and significant coronary artery disease (pp. 1503-16). In the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial, these outcomes were noted during a median follow-up period of 4.6 years between 1999 and 2004: “There were 211 primary events in the PCI group and 202 events in the medical-therapy group. The 4.6-year cumulative primary-event rates were 19.0% in the PCI group and 18.5% in the medical-therapy group (hazard ratio for the PCI group, 1.05; 95% confidence interval [CI], 0.87 to 1.27; P = 0.62). There were no significant differences between the PCI group and the medical-therapy group in the composite of death, myocardial infarction, and stroke (20.0% vs. 19.5%; hazard ratio, 1.05; 95% CI, 0.87 to 1.27; P = 0.62); hospitalization for acute coronary syndrome (12.4% vs. 11.8%; hazard ratio, 1.07; 95% CI, 0.84 to 1.37; P = 0.56); or myocardial infarction (13.2% vs. 12.3%; hazard ratio, 1.13; 95% CI, 0.89 to 1.43; P = 0.33).” (W. E. Boden, Buffalo Genl. Hosp., Buffalo, N.Y.; wboden@kaleidahealth.org)
Asking whether preventive PCI works, editorialists provide this answer (pp. 1572-4): “PCI has an established place in treating angina but is not superior to intensive medical therapy to prevent myocardial infarction and death in symptomatic or asymptomatic patients such as those in this study. Secondary prevention has proved its worth, with lipid-modulating therapy, lifestyle modification, and the use of aspirin, beta-blockers, and ACE inhibitors. Patients whose condition is clinically unstable, who have left main coronary artery disease, or in whom medical therapy has failed to control symptoms remain candidates for revascularization, but PCI should not play a major role as part of a secondary prevention strategy.” (J. S. Hochman, New York U. Sch. of Med., New York)
Anakinra for DM: Blockade of interleukin-1 with the antagonist anakinra “improved glycemia and beta-cell secretory function and reduced markers of systemic inflammation” in 70 patients with type 2 diabetes mellitus, researchers report (pp. 1517-26). They note these results with anakinra doses of 100 mg subcutaneously once daily: “At 13 weeks, in the anakinra group, the glycated hemoglobin level was 0.46 percentage point lower than in the placebo group (P = 0.03); C-peptide secretion was enhanced (P = 0.05), and there were reductions in the ratio of proinsulin to insulin (P = 0.005) and in levels of interleukin-6 (P <0.001) and C-reactive protein (P = 0.002). Insulin resistance, insulin-regulated gene expression in skeletal muscle, serum adipokine levels, and the body-mass index were similar in the two study groups. Symptomatic hypoglycemia was not observed, and there were no apparent drug-related serious adverse events.” (M. Y. Donath, U. Hosp., Zurich, Switzerland; marc.donath@usz.ch)
The author of a Perspectives article discusses the divide between research and practice (pp. 1499-501): “None of the currently available medications ... are successful as long-term monotherapy, and none of them have effectively halted the continuous decline in beta-cell mass. Although the findings regarding anakinra break new ground by demonstrating that inhibition of cytokine function can restore insulin secretion, the ultimate goal is the improvement of blood-glucose control without the need for triple- and quadruple-combination therapies, as well as the prevention of beta-cell death.” (K. I. Rother, NIH)

>>>PNN NewsWatch
* Certain lots of Grifulvin V, Ortho-McNeil’s brand of griseofulvin oral suspension, have been recalled nationwide because of two reports of bottles containing glass fragments. Lot numbers are listed at www.aboutgrifulvin.com.
* Pharmacists should check bottles of
Combivir because of an apparent third-party tampering that used counterfeit labels and resulted in the misbranding of Ziagen as Combivir. FDA and GlaxoSmithKline said that two 60-count misbranded bottles of Combivir Tablets at a Calif. pharmacy contained 300 mg tablets of Ziagen. The counterfeit labels had lot no. 6ZP9760 with expiration dates of Apr. 2010 and Apr. 2009.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Apr. 13, 2007 * Vol. 14, No. 72
Providing news and information about medications and their proper use

>>>JAPhA Highlights
Source:
Mar/Apr issue of the Journal of the American Pharmacists Assoc. (www.japha.org; 2007; 47).
Alcohol–Prescription Drug Interactions: Prescribers and dispensers need to “enhance their efforts to advise patients about alcohol–drug interactions,” conclude authors of a study of 897 patients with alcohol-use disorders (pp. 135-9). Based on telephone and mail surveys of patients at 18 primary care practices in southcentral and southeastern Wisconsin, investigators report these results: “Of the 869 patients who provided usable information on prescription medication use, 348 (40.0%) were taking medications with alcohol interactions or proscriptions; the most frequently reported were bupropion, selective serotonin reuptake inhibitors, and various acetaminophen-containing compounds. Slightly more than 20% of patients were taking medications with moderate to severe alcohol interactions; over one-third of these 184 patients did not recall advice to avoid alcohol.” (R. L. Brown, rlbrown@wisc.edu)
Gemfibrozil–Simvastatin Therapy: An increased risk of serious adverse events, including one death, was identified in a retrospective chart review of 80 patients at an Arizona VA facility who were taking gemfibrozil plus simvastatin (pp. 140-6). Noting that use of the combination therapy often did not meet ATP III criteria and concluding that systems for improving guideline adherence are needed, the researchers write: “Of the 80 patients, 45 (56%) met ATP III guidelines for combination therapy. Among the 80 patients started on these drugs at this VA facility, gemfibrozil was added to simvastatin in 61 patients, simvastatin was added to gemfibrozil in 18, and the agents were begun simultaneously for 1 patient. Common errors included combination treatment when LDL cholesterol values could not be calculated (because of serum triglycerides levels exceeding 400 mg/dL); use of gemfibrozil at triglyceride levels lower than the 500 mg/dL with attainment of non–HDL goals; and use of gemfibrozil when triglyceride levels were not measured. One death secondary to rhabdomyolysis occurred in a patient whose care did not meet ATP III guidelines.” (P. O. Curtin, patrick.curtin2@med.va.gov)
Use of Asthma-Specific Questionnaire: At 10 Detroit-area community pharmacies, use of a 17-item, asthma-specific questionnaire aided pharmacists in problem identification (pp. 147-55). The prospective study of 60 adult and pediatric patients with persistent asthma being treated with daily medications showed these findings for 31 intervention (group 1) participants during a 5- to 10-minute interaction, and 29 control (group 2) participants who received standard care only during 2000–03: “Group 1 and group 2 participants were monitored for a mean of 5.4 and 5.2 months, respectively. Overall, 68 problems were identified in group 1 and 4 in group 2. Confidence in preventing asthma episodes improved 29% and confidence in treating symptomatic episodes improved 10% in group 1 participants, whereas there were no improvements in group 2. Symptom frequency, rescue drug use, restricted activity, and patients with more than two nocturnal episodes per month decreased within both groups. There were low incidences of and no statistically significant group differences for frequency of oral steroids, resource use, and missed school or work days. Likewise, group differences in drug use and understanding were not significant.” (P. J. Munzenberger, pmunzen@wayne.edu)

>>>PNN NewsWatch
* Merck’s investigational COX-2 inhibitor, etoricoxib (Arcoxia), should not be marketed, according to an FDA advisory panel. While panel members agreed that this new agent has cardiovascular risks similar to agents currently on the U.S. market, they apparently have adopted FDA’s new view that me-too status is no longer sufficient to obtain approval, voting 20–1 against the new agent. FDA is not bound to follow the committee’s advice, but it usually does so.
* Drug interactions between
tizanidine (Zanaflex, Acorda Therapeutics) and fluvoxamine or ciprofloxacin are detailed in an FDA warning posted this week on the MedWatch site. Based on increased serum tizanidine levels observed during concomitant therapy with these CYP 1A2 inhibitors, other interactions can be expected with other agents that inhibit this isoenzyme.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Apr. 16, 2007 * Vol. 14, No. 73
Providing news and information about medications and their proper use

>>>Retapamulin Approved as Topical Impetigo Therapy
FDA on Friday approved a new prescription antibiotic, retapamulin ointment (Altabax, Glaxo), for topical treatment of impetigo in patients aged 9 months or older. The drug is indicated for use twice daily for a 5-day period. Glaxo noted in a news release that other prescription topical antibacterials are used as much as three times daily for up to 12 days.
Retapamulin is the first in a new class of antibacterials, the pleuromutilins. By binding to a site on the 50S subunit of the bacterial ribosome, retapamulin inhibits protein synthesis through a unique interaction with the ribosome. In vitro, the active ingredient in retapamulin has shown no target-specific cross-resistance to other established classes of antibacterials, likely because currently no other antibacterials use the exact same mode of action.
Retapamulin was approved on the basis of effectiveness data from a placebo-controlled study comparing it with another antibiotic. The safety database contained approximately 2,000 retapamulin-treated adults and children aged 9 months and older, and about 1,000 similar patients who received different antibiotics or placebo. The most common retapamulin-related adverse event was irritation at the site of the application, which occurred in fewer than 2% of the patients.

>>>Lancet Highlights
Source:
Early-release articles from Lancet (www.thelancet.com; 2007; 369).
High-Potency Polio Vaccine: By offering higher potency among populations with high prevalence of diarrhea and other infections, a high-potency monovalent oral type 1 poliovirus vaccine (mOPV1) could “substantially improve the probability of rapidly eliminating transmission of the disease” (doi: 10.1016/S0140-6736(07)60531-5). Achieving high coverage in areas with persistent poliovirus transmission will be required to accomplish this goal, the researchers explain while providing these results from India’s Utter Pradesh: “The protective efficacy of mOPV1 was estimated to be 30% (95% CI 19–41) per dose against type 1 paralytic disease, compared with 11% (7–14) for the trivalent oral vaccine. 76–82% of children aged 0–23 months were estimated to be protected by vaccination against type 1 poliovirus at the end of 2006, compared with 59% at the end of 2004, before the introduction of mOPV1.” (N. C. Grassly, Imperial College, London; n.grassly@imperial.ac.uk)
Polio Eradication v. Control: In pursuing a strategy of control of wild polioviruses rather than eradicating these pathogens, the long-term costs of effective control must be considered carefully, authors write (doi: 10.1016/S0140-6736(07)60532-7). Concluding that the “large costs for poliomyelitis eradication” might “inappropriately affect commitments to [this] goal,” investigators who conducted an economic analysis based on modeling of endemic areas of India provide these insights: “Our results suggest that the intensity of immunisation must be increased to achieve eradication, and that even small decreases in intensity could lead to large outbreaks. This finding implies the need to pay even higher short-run costs than are currently being spent, which will further exacerbate concerns about continued investment in interventions with high perceived cost-effectiveness ratios. We show that a wavering commitment leads to a failure to eradicate, greater cumulative costs, and a much larger number of cases. We further show that as long as it is technically achievable, eradication offers both lower cumulative costs and cases than control, even with the costs of achieving eradication exceeding several billion dollars more. A low-cost control policy that relies only on routine immunisation for 20 years with discounted costs of more than $3,500 million could lead to roughly 200,000 expected paralytic poliomyelitis cases every year in low-income countries, whereas a low-case control policy that keeps the number of cases at about 1,500 per year could cost around $10,000 million discounted over the 20 years.” (K. M. Thompson, kimt@hsph.harvard.edu)

>>>PNN JournalWatch
* Safety and Efficacy of the HIV-1 Integrase Inhibitor Raltegravir (MK-0518) in Treatment-Experienced Patients with Multidrug-Resistant Virus: A Phase II Randomised Controlled Trial, in Lancet, 2007; 369: 1261–9. Reprints: B-Y Nguyen, bachyen_nguyen@merck.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
Apr. 17, 2007 * Vol. 14, No. 74
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Apr. 17 issue of the Annals of Internal Medicine (www.annals.org; 2007; 146).
Tiotropium Added to Fluticasone–Salmeterol in COPD: Lung function, quality of life, and hospitalization rates in patients were improved among 449 patients with moderate to severe chronic obstructive pulmonary disease when tiotropium was added to fluticasone–salmeterol therapy, but the rate of COPD exacerbations were not changed statistically (pp. 545-55). Comparing various treatments with placebo in a 1-year trial, investigators found: “The proportion of patients in the tiotropium plus placebo group who experienced an exacerbation (62.8%) did not differ from that in the tiotropium plus salmeterol group (64.8%; difference, –2.0 percentage points [95% CI, –12.8 to 8.8 percentage points]) or in the tiotropium plus fluticasone–salmeterol group (60.0%; difference, 2.8 percentage points [CI, –8.2 to 13.8 percentage points]). In sensitivity analyses, the point estimates and 95% confidence bounds shifted in the direction favoring tiotropium plus salmeterol and tiotropium plus fluticasone–salmeterol. Tiotropium plus fluticasone–salmeterol improved lung function (P = 0.049) and disease-specific quality of life (P = 0.01) and reduced the number of hospitalizations for COPD exacerbation (incidence rate ratio, 0.53 [CI, 0.33 to 0.86]) and all-cause hospitalizations (incidence rate ratio, 0.67 [CI, 0.45 to 0.99]) compared with tiotropium plus placebo. In contrast, tiotropium plus salmeterol did not statistically improve lung function or hospitalization rates compared with tiotropium plus placebo.” (S. Aaron, Ottawa Hosp., Ottawa, Ont., Canada; saaron@ohri.ca)
The “search for the magic combination of inhaled bronchodilators and corticosteroids” in COPD is making demonstrable progress, an editorialist writes, but more and better studies are needed (pp. 605-8): “Aaron and colleagues’ findings and those of the TORCH [Towards a Revolution in COPD Health] investigators suggest that we may finally be on the threshold of therapies that decrease the morbidity and mortality of COPD. However, to better ascertain why and which patients benefit from treatment, we must define minimally important clinical differences in outcomes, characterize the various clinical phenotypes of COPD, and investigate biomarkers of disease activity or surrogate markers as predictors of outcome. Future studies in COPD should heed the methodological lessons of Aaron and colleagues’ study and TORCH. We need a new standard in COPD clinical trials: even larger studies, preferably international in scope, that use end points that reflect disease modification. Then, and only then, will we overcome the problems associated with studying this common and deadly disease.” (G. J. Criner,
crinerg@tuhs.temple.edu)
Sequential Triple Therapy for H. pylori: Sequential therapy proved significantly better than standard therapy for eradicating Helicobacter pylori infection, particularly in patients with clarithromycin-resistant strains (pp. 556-63). The investigational 10-day sequential regimen included pantoprazole 40 mg and amoxicillin 1 gram twice daily for the first 5 days, followed by pantoprazole 40 mg, clarithromycin 500 mg, and tinidazole 500 mg, each administered twice daily for the remaining 5 days. It was compared with the standard 10-day regimen of pantoprazole 40 mg, clarithromycin 500 mg, and amoxicillin 1 gram twice daily, with these results: “The eradication rate achieved with the sequential regimen was significantly greater than that obtained with the standard treatment in the intention-to-treat analysis (89% vs. 77%; P = 0.0134; difference, 12% [95% CI, 3% to 20%]), the modified intention-to-treat analysis (91% vs. 78%; P = 0.0022; difference, 13% [CI, 5% to 21%]), and the per-protocol analysis (93% vs. 79%; P = 0.0013; difference, 14% [CI, 6% to 21%]). Sequential therapy was significantly more effective in patients with clarithromycin-resistant strains (89% vs. 29%; P = 0.0034). The incidence of major and minor side effects did not differ between therapy groups (17% in both groups). One patient (0.7%) in the standard therapy group discontinued treatment because of side effects.” (D. Vaira, S. Orsola Hosp., Bologna, Italy; vairadin@med.unibo.it)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 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
Apr. 18, 2007 * Vol. 14, No. 75
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Apr. 18 issue of JAMA (www.jama.com; 2007; 297).
NOS Inhibition in Cardiogenic Shock: Tilarginine, an inhibitor of nitric oxide synthase, failed to reduce mortality rates among 398 patients with refractory cardiogenic shock complicating myocardial infarction (pp. 1657-66). Given as a 1 mg/kg bolus followed by a 5-hour infusion of 1 mg/kg/hr, the drug produced these outcomes in the Tilarginine Acetate Injection in a Randomized International Study in Unstable MI Patients With Cardiogenic Shock (TRIUMPH) trial: “There was no difference in 30-day all-cause mortality between patients who received tilarginine (97/201 [48%]) vs placebo (76/180 [42%]) (risk ratio, 1.14; 95% confidence interval, 0.92–1.41; P = .24). Resolution of shock (133/201 [66%] tilarginine vs 110/180 [61%] placebo; P = .31) and duration of shock (median, 156 [interquartile range, 78–759] hours tilarginine vs 190 [100–759] placebo; P = .16) were similar. At 30 days a similar percentage of patients had heart failure (48% tilarginine vs 51% placebo; P = .51) with a similar percentage of those patients in NYHA class I/II (73% tilarginine vs 75% placebo; P = .27). After 6 months mortality rates were similar in the 2 groups (58% tilarginine vs 59% placebo; hazard ratio, 1.04; 95% confidence interval, 0.79–1.36; P = .80).” (J. S. Hochman, judith.hochman@med.nyu.edu)
Editorialists provide these insights while “looking for the reasons” that nitric oxide synthase inhibition failed to produce significant benefits (pp. 1711-3): “An important consideration is whether NOS inhibition should be considered a closed issue in patients with cardiogenic shock. It is possible that the pathophysiology of the nitric oxide pathway in the setting of cardiogenic shock may not have been investigated thoroughly enough to allow a reliable therapeutic intervention directed at its inhibition. Investigators might develop specific inhibitors of inducible NOS that preserve nitric oxide production regulated by constitutive enzymes. Another consideration may involve nonselective NOS inhibition in conjunction with the use of external administration of nitric oxide titrated under hemodynamic guidance. As is clear from the TRIUMPH trial, cardiogenic shock outcomes are poor even with early revascularization. The failure of tilarginine to improve outcomes is a call for renewed basic, translational, and clinical research efforts for this difficult, perplexing, and highly fatal disease.” (A. Kastrati, Deutsches Herzzentrum, Munich, Germany;
kastrati@dhm.mhn.de)
For-Profit Epoetin Dosing: Reimbursement policies and clinical performance measures may provide incentives for dialysis facilities, especially those for-profit units, to more aggressively dose epoetin, concludes an analysis of data from the U.S. Renal Data System for Nov. and Dec. 2004 (pp. 1667-74). “Compared with patients in nonprofit dialysis facilities (n = 28,199), patients in large for-profit dialysis chain facilities (n = 106,116) were consistently administered the highest doses of epoetin regardless of anemia status,” the investigators report. “Compared with nonprofit facilities, for-profit facilities administered, on average, an additional 3,306 U/wk of epoetin. Among the 6 large chain facilities with a similar patient case-mix, the average dose of epoetin ranged from 17,832 U/wk at chain 5 (nonprofit facilities with a mean hematocrit level of 34.6%) to 24,986 U/wk at chain 2 (for-profit facilities with a mean hematocrit level of 36.5%). Dosing adjustments also differed by type of facility. On average, compared with nonprofit facilities, for-profit facilities increased epoetin doses 3-fold for patients with hematocrit levels of less than 33% and also increased the doses among patients with hematocrit levels in the recommended target of 33% to 36%, especially in the largest for-profit chain facilities. The greatest difference in dosing practice patterns between facilities was found among patients with hematocrit levels of less than 33%.” (D. Cotter, Medical Technology and Practice Patterns Inst., Bethesda, Md.; dcott@mtppi.org)

>>>PNN NewsWatch
* FDA has approved a vaccine for humans against the H5N1 influenza virus. This Sanofi Pasteur avian influenza vaccine could be used in the event the current H5N1 avian virus were to develop the capability to efficiently spread from human to human. It was tested at full doses in 103 healthy adults; another 300 healthy adults received lower vaccine doses or placebo.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Apr. 19, 2007 * Vol. 14, No. 76
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Apr. 19 issue of the New England Journal of Medicine (http://content.nejm.org; 2007; 356).
Torcetrapib Plus Atorvastatin in Familial Hypercholesterolemia: Addition of the cholesteryl ester transfer protein inhibitor torcetrapib to atorvastatin therapy failed to provide further decreases in atherosclerotic processes as measured by carotid intima–media thickness in 850 patients with heterozygous familial hypercholesterolemia (pp. 1620-30). Investigators in the Rating Atherosclerotic Disease Change by Imaging with a New CETP Inhibitor (RADIANCE 1) trial report the following results, which are similar to other recently reported data (see PNN, Mar. 29): “After 24 months, in the atorvastatin-only group, the mean (± SD) HDL cholesterol level was 52.4 ± 13.5 mg per deciliter and the mean low-density lipoprotein (LDL) cholesterol level was 143.2 ± 42.2 mg per deciliter, as compared with 81.5 ± 22.6 mg per deciliter and 115.1 ± 48.5 mg per deciliter, respectively, in the torcetrapib–atorvastatin group. During the study, average systolic blood pressure increased by 2.8 mm Hg in the torcetrapib–atorvastatin group, as compared with the atorvastatin-only group. The increase in maximum carotid intima–media thickness, the primary measure of efficacy, was 0.0053 ± 0.0028 mm per year in the atorvastatin-only group and 0.0047 ± 0.0028 mm per year in the torcetrapib–atorvastatin group (P = 0.87). The secondary efficacy measure, annualized change in mean carotid intima–media thickness for the common carotid artery, indicated a decrease of 0.0014 mm per year in the atorvastatin-only group, as compared with an increase of 0.0038 mm per year in the torcetrapib–atorvastatin group (P = 0.005).” (J. J. P. Kastelein, Academic Med. Ctr., Amsterdam, the Netherlands; j.j.kastelein@amc.uva.nl)
Omeprazole Before Endoscopy for GI Bleeding: High-dose omeprazole infusion before endoscopy of consecutive patients admitted with upper gastrointestinal bleeding “accelerated the resolution of signs of bleeding in ulcers and reduced the need for endoscopic therapy,” researchers report (pp. 1631-40). Omeprazole 80 mg by intravenous bolus followed by infusion at 8 mg/hr or placebo before endoscopy the next morning produced these results: “Over a 17-month period, 638 patients were enrolled and randomly assigned to omeprazole or placebo (319 in each group). The need for endoscopic treatment was lower in the omeprazole group than in the placebo group (60 of the 314 patients included in the analysis [19.1%] vs. 90 of 317 patients [28.4%], P = 0.007). There were no significant differences between the omeprazole group and the placebo group in the mean amount of blood transfused (1.54 and 1.88 units, respectively; P = 0.12) or the number of patients who had recurrent bleeding (11 and 8, P=0.49), who underwent emergency surgery (3 and 4, P = 1.00), or who died within 30 days (8 and 7, P = 0.78). The hospital stay was less than 3 days in 60.5% of patients in the omeprazole group, as compared with 49.2% in the placebo group (P = 0.005). On endoscopy, fewer patients in the omeprazole group had actively bleeding ulcers (12 of 187, vs. 28 of 190 in the placebo group; P = 0.01) and more omeprazole-treated patients had ulcers with clean bases (120 vs. 90, P = 0.001).” (J. Y. Lau, Prince of Wales Hosp., Hong Kong, China; laujyw@surgery.cuhk.edu.hk)
FDA & Telithromycin: Lessons can be learned from the case of telithromycin (Ketek, Sanofi Aventis), writes the author of a Perspectives article who concludes, “If the case of Ketek leads to important reforms, then the drug may have done some good after all” (pp. 1601-4). Noting “substantial safety concerns” that emerged in FDA’s first review of this ketolide antibiotic, the former FDA reviewer adds: “By [June 2006], 23 cases of acute severe liver injury and 12 cases of acute liver failure, 4 of them fatal, had been linked to Ketek. By the end of 2006, Ketek had been implicated in 53 cases of hepatotoxic effects. The FDA did not relabel Ketek to indicate its possible severe hepatotoxicity until 16 months after the first liver-failure cases became public. The withdrawal of approval for two indications, acute bacterial sinusitis and acute exacerbation of chronic bronchitis, for which Ketek’s efficacy had never been demonstrated, did not occur until February 12, 2007—only a day before the Congressional hearing on Ketek.” (D. B. Ross, George Washington U., Washington, D.C.)

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Apr. 20, 2007 * Vol. 14, No. 77
Providing news and information about medications and their proper use

>>>Infectious Diseases Report
Source:
May 15 issue of Clinical Infectious Diseases (www.journals.uchicago.edu/CID/journal/contents/v44n10.html; 2007; 44).
Cost-Effectiveness of Zoster Vaccine: Age should be an important factor from a cost standpoint in recommending varicella zoster vaccine, conclude authors of a cost-effectiveness analysis (pp. 1280-8). Noting that vaccine costs often exceed $100,000 per quality-adjusted life-year, the investigators report these findings derived from data in the Shingles Prevention Study: “For the base case analysis, compared with usual care, vaccination increased quality-adjusted life expectancy by 0.0007–0.0024 quality-adjusted life years per person, depending on age at vaccination and sex. These increases came almost exclusively as a result of prevention of acute pain associated with herpes zoster and postherpetic neuralgia. Vaccination also increased costs by $94–$135 per person, compared with no vaccination. The incremental cost-effectiveness ranged from $44,000 per quality-adjusted life year saved for a 70-year-old woman to $191,000 per quality-adjusted life year saved for an 80-year-old man. For the sensitivity analysis, the decision was most sensitive to vaccine cost. At a cost of $46 per dose, vaccination cost <$50,000 per quality-adjusted life year saved for all adults >60 years of age. Other variables related to the vaccine (duration, efficacy, and adverse effects), postherpetic neuralgia (incidence, duration, and utility), herpes zoster (incidence and severity), and the discount rate all affected the cost-effectiveness ratio by >20%.” (M. B. Rothberg, Baystate Med. Ctr., Springfield, Mass.)
Daily TMP–SMX in HIV: Among 534 Zambian children with HIV infection, benefits of daily trimethoprim–sulfamethoxazole therapy were evident during a clinical trial and thereafter (pp. 1361-7). “A total of 546 child-years of follow-up, 40 deaths, and 80 hospital admissions were observed between the time of trial closure and June 2006,” researchers report. “A total of 117 of 283 children who were alive at trial closure received ART in the posttrial period (median child age at first use of ART, 8.8 years). Rates decreased in both groups during the trial period, suggesting a survivorship effect. Mortality and hospital admission rates before trial closure were 14 (95% confidence interval [CI], 9–21) deaths per 100 child-years and 24 (95% CI, 15–39) hospital admissions per 100 child-years, respectively, for children who were receiving cotrimoxazole, and were 23 (95% CI, 16–34) deaths per 100 child-years and 35 (95% CI, 23–53) hospital admissions per 100 child-years, respectively, for children who were receiving the placebo. After trial closure, rates remained stable in the cotrimoxazole group, but decreased to 15 (95% CI, 8–26) deaths per 100 child-years and 19 (95% CI, 10–41) hospital admissions per 100 child-years, respectively, for the group of children who received placebo and then initiated cotrimoxazole prophylaxis. In both groups combined, mortality rates decreased to 6 (95% CI, 3–11) deaths per 100 child-years and then 2 (95% CI, 0.8–6) deaths per 100 child-years during periods of ART availability; hospital admission rates decreased to 17 (95% CI, 11–27) hospital admissions per 100 child-years and 8 (95% CI, 4–15) hospital admissions per 100 child-years, respectively.” (A. S. Walker, MRC Clinical Trials Unit, London)
Hematologic Toxicity of Interferon in HCV/HIV: Among 133 patients coinfected with hepatitis C virus and HIV, dose modifications of interferon-based therapy for HCV can produce hematologic toxicities that may require hematopoietic growth factor support (pp. 1375-83). During a 48-week study of ribavirin plus interferon-alfa-2a or its pegylated analogue, investigators found: “Subjects treated with pegylated IFN-alfa-2a were more likely to have had dose modifications (dose reduction or discontinuation) than were those treated with IFN-alfa-2a. By multivariate analysis, treatment with pegylated IFN-alfa-2a is associated with higher sustained virologic and/or histologic response. Dose modifications for nonhematologic toxicity are independently associated with lower sustained virologic and/or histologic responses. Although hematologic toxicity was not directly associated with clinical outcome in this analysis, use of hematopoietic growth factors was associated with an increased sustained virologic and/or histologic response.” (C. M. Behler, U. Calif., San Francisco)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 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
Apr. 23, 2007 * Vol. 14, No. 78
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Early-release articles from Lancet (www.thelancet.com; 2007; 369).
Deaths from HRT: Among 948,576 postmenopausal women in the UK Million Women Study, approximately 1,300 additional cases of ovarian cancers and 1,000 additional deaths can be attributed to use of hormone-replacement therapy, investigators report (DOI: 10.1016/S0140-6736(07)60534-0). “When they last reported HRT use, 287,143 women (30%) were current users and 186,751 (20%) were past users. During follow-up, 2,273 incident ovarian cancers and 1,591 deaths from the malignancy were recorded. Current users were significantly more likely to develop and die from ovarian cancer than never users (relative risk 1.20 [95% CI 1.09–1.32; p = 0.0002] for incident disease and 1.23 [1.09–1.38; p = 0.0006] for death). For current users of HRT, incidence of ovarian cancer increased with increasing duration of use, but did not differ significantly by type of preparation used, its constituents, or mode of administration. Risks associated with HRT varied significantly according to tumour histology (p < 0.0001), and in women with epithelial tumours the relative risk for current versus never use of HRT was greater for serous than for mucinous, endometroid, or clear cell tumours (1.53 [1.31–1.79], 0.72 [0.52–1.00], 1.05 [0.77–1.43], or 0.77 [0.48–1.23], respectively). Past users of HRT were not at an increased risk of ovarian cancer (0.98 [0.88–1.11] and 0.97 [0.84–1.11], respectively, for incident and fatal disease). Over 5 years, the standardised incidence rates for ovarian cancer in current and never users of HRT were 2.6 (2.4–2.9) and 2.2 (2.1–2.3) per 1,000, respectively—ie, one extra ovarian cancer in roughly 2,500 users; death rates were 1.6 (1.4–1.8) and 1.3 (1.2–1.4) per 1,000, respectively—ie, one extra ovarian cancer death in roughly 3,300 users.” (V. Beral, Million Women Study Coordinating Ctr., Oxford, U.K.; pa.valerie.beral@ceu.ox.ac.uk)

>>>BMJ Highlights
Source:
Early-release articles from BMJ (www.bmj.org; 2007; 334).
Dietary Sodium Restriction & CV Events: Cardiovascular events that go beyond those related to hypertension are reduced in number by long-term dietary sodium restrictions, according to results of the Trials of Hypertension Prevention (TOHP) (doi: 10.1136/bmj.39147.604896.55). These results were noted among adults aged 30–54 years with prehypertension at multiple sites during TOHP I (1987–90) and TOHP II (1990–95): “744 participants in TOHP I and 2,382 in TOHP II were randomised to a sodium reduction intervention or control. Net sodium reductions in the intervention groups were 44 mmol/24 h and 33 mmol/24 h, respectively. Vital status was obtained for all participants and follow-up information on morbidity was obtained from 2,415 (77%), with 200 reporting a cardiovascular event. Risk of a cardiovascular event was 25% lower among those in the intervention group (relative risk 0.75, 95% confidence interval 0.57 to 0.99, P = 0.04), adjusted for trial, clinic, age, race, and sex, and 30% lower after further adjustment for baseline sodium excretion and weight (0.70, 0.53 to 0.94), with similar results in each trial. In secondary analyses, 67 participants died (0.80, 0.51 to 1.26, P = 0.34).” (N. R. Cook, ncook@rics.bwh.harvard.edu)

>>>PNN JournalWatch
* Delirium in Older People, in BMJ, 2007; 334: 842–6. Reprints: J. Young, St. Luke’s Hosp., Bradford, U.K.; John.young@bradfordhospitals.nhs.uk
* Prevention of Infective Endocarditis. Guidelines From the American Heart Association. A Guideline From the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group, in
Circulation, 2007; doi:10.1161/CIRCULATIONAHA.106.183095. Reprints: W. Wilson.
* Tracking the Microbes in Sepsis: Advancements in Treatment Bring Challenges for Microbial Epidemiology, in
Clinical Infectious Diseases, 2007; 44: 1343–8. Reprints: M. J. Llewelyn, Brighton and Sussex Med. Sch., Falmer, Sussex, U.K.
* Interventions to Reduce Fear of Falling in Community-Living Older People: A Systematic Review, in
Journal of the American Geriatrics Society, 2007; 55: 603 ff. Reprints: R. Zijlstra, Maastricht U., Maastricht, the Netherlands; R.Zijlstra@zw.unimaas.nl
* Patient Centered Experiences in Breast Cancer: Predicting Long-Term Adherence to Tamoxifen Use, in
Medical Care, 2007; 45: 431–9. Reprints: K. L. Kahn.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Apr. 24, 2007 * Vol. 14, No. 79
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Apr. 23 issue of the Archives of Internal Medicine (http://archinte.ama-assn.org; 2007; 167).
Drug Burden Index for the Elderly: Testing formulas for a drug burden index, researchers found that exposure of community-dwelling older people to anticholinergic and sedative medications is associated with poorer physical and cognitive function (pp. 781-7). The drug burden index included total number of prescription and nonprescription medications with and without anticholinergic and sedative properties, daily doses relative to daily doses that produce 50% of pharmacologic effects, and minimum daily doses set by FDA. Among 3,075 well-functioning community-dwelling persons aged 70–79 years, “Use of anticholinergic and sedative medications was associated with poorer physical performance score (anticholinergic exposure, 2.08 vs 2.21, P <.001; sedative exposure, 2.09 vs 2.19, P <.001) and cognitive performance on the Digit Symbol Substitution Test (anticholinergic exposure, 34.5 vs 35.5, P = .045; sedative exposure, 34.0 vs 35.5, P = .01). Associations were strengthened when exposure was calculated by principles of dose response. An increase of 1 U in drug burden index was associated with a deficit of 0.15 point (P <.001) on the physical function scale and 1.5 points (P = .01) on the Digit Symbol Substitution Test. These values were more than 3 times those associated with a single comorbid illness.” (D. R. Abernethy, abernethyd@grc.nia.nih.gov)
Describing the drug burden index as “a step forward,” an editorialist wonders whether this measure will have practical applicability in addition to its potential in pharmacoepidemiologic and health services research (pp. 753-4): “Can the drug burden measure reported in this issue of the
Archives one day help physicians and patients in deciding how to optimize their own medication regimens? We can hope this study may stimulate further refinement and testing of the measure. [These authors] have addressed many of the important attributes that an optimal drug burden index should possess. It should be easy to calculate with available technology, demonstrate adequate predictive ability for a range of health outcomes important to older adults, be efficient to integrate into clinical practice, and be amenable to updates with the advent of new pharmacotherapies and methods to quantify drug–drug and drug–disease interactions.” (J. V. Agostini, joseph.agostini@yale.edu)
Hospital Pharmacy Bar Coding:
“Implementation of a bar code–assisted medication-dispensing system in hospital pharmacies can result in a positive financial return on investment for the health care organization” within 5–10 years, conclude authors of a cost–benefit analysis (pp. 788-94). “In inflation- and time value–adjusted 2005 dollars, total costs during 5 years were $2.24 million ($1.31 million in 1-time costs during the initial 3.5 years and $342,000 per year in recurring costs starting in year 3),” explain the investigators. “The primary benefit was a decrease in adverse drug events from dispensing errors (517 events annually), resulting in an annual savings of $2.20 million. The net benefit after 5 years was $3.49 million. The break-even point for the hospital’s investment occurred within 1 year after becoming fully operational. A net benefit was achieved within 10 years under almost all sensitivity scenarios. In the Monte Carlo simulation, the net benefit during 5 years was $3.2 million (95% confidence interval, –$1.2 million to $12.1 million), and the break-even point for return on investment occurred after 51 months (95% confidence interval, 30 to 180 months).” (S. M. Maviglia, smaviglia@partners.org)
Nononcologic Erythropoietin Use: Potential targets for quality improvement in use of erythropoietin among hospitalized patients with and without chronic kidney disease include degree of anemia, completeness of iron measurement, and use of iron supplementation (pp. 840-6). Analyzing data on 1,360 patients who received at least one dose of rHuEOP during 3,094 hospitalizations over a 3-year period, the authors found: “In patients with CKD, only about half (54%) had adequate iron stores at the time of rHuEPO administration; this rate was even lower in patients without CKD (33%; P <.001). Only 66% of patients with documented iron deficiency who were receiving rHuEPO also received concomitant iron supplementation; this rate did not differ between patients with or without CKD.” (M. A. Fischer, mfischer@partners.org)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 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
Apr. 25, 2007 * Vol. 14, No. 80
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Apr. 25 issue of JAMA (http://jama.ama-assn.org; 2007; 297).
Ranolazine for ACS: Among 6,560 patients with recent-onset ischemic symptoms of non–ST-elevation acute coronary syndromes, addition of ranolazine to standard therapy failed to reduce major cardiovascular events (pp. 1775-83). While demonstrating this drug’s efficacy and safety for treatment of angina, findings in the Metabolic Efficiency With Ranolazine for Less Ischemia in Non–ST-Elevation Acute Coronary Syndromes (MERLIN)-TIMI 36 trial show these results with respect to a primary composite efficacy endpoint of cardiovascular death, myocardial infarction, or recurrent ischemia through the end of study: “The primary endpoint occurred in 696 patients (21.8%) in the ranolazine group and 753 patients (23.5%) in the placebo group (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.83–1.02; P = .11). The major secondary endpoint (cardiovascular death, MI, or severe recurrent ischemia) occurred in 602 patients (18.7%) in the ranolazine group and 625 (19.2%) in the placebo group (HR, 0.96; 95% CI, 0.86–1.08; P = .50). Cardiovascular death or MI occurred in 338 patients (10.4%) allocated to ranolazine and 343 patients (10.5%) allocated to placebo (HR, 0.99; 95% CI, 0.85–1.15; P = .87). Recurrent ischemia was reduced in the ranolazine group (430 [13.9%]) compared with the placebo group (494 [16.1%]; HR, 0.87; 95% CI, 0.76–0.99; P = .03). QTc prolongation requiring a reduction in the dose of intravenous drug occurred in 31 patients (0.9%) receiving ranolazine compared with 10 patients (0.3%) receiving placebo. Symptomatic documented arrhythmias did not differ between the ranolazine (99 [3.0%]) and placebo (102 [3.1%]) groups (P = .84). No difference in total mortality was observed with ranolazine compared with placebo (172 vs 175; HR, 0.99; 95% CI, 0.80–1.22; P = .91).” (D. A. Morrow, dmorrow@partners.org)
Editorialists point to these important messages from the MERLIN-TIMI 36 trial (pp. 1823-5): “First, ranolazine does not significantly improve acute or downstream prognosis; therefore, it should not be routinely added to treatment following an acute coronary event. Second, in terms of antianginal agents, beta-blockers and nitrates should still be considered initial therapies. The enhanced safety information and supportive antianginal data suggest that ranolazine may offer a back-up option for intensification of antianginal treatment if these first-line agents fail. And finally, with the modern redefinition of the central role of medical therapy in the management of chronic ischemic heart disease, the MERLIN-TIMI 36 trial presages development of additional novel therapeutic agents in an attempt to optimize both symptom management and clinical outcomes.” (L. K. Newby,
newby001@mc.duke.edu)
Pneumococcal Disease in Alaska: “Replacement invasive pneumococcal disease” with Streptococcus pneumoniae strains not covered by the 7-valent vaccine is emerging as a problem among Alaska Native children (pp. 1784-92): “In the first 3 years after introduction of routine vaccination with heptavalent pneumococcal conjugate vaccine, overall invasive pneumococcal disease decreased 67% in Alaska Native children younger than 2 years (from 403.2 per 100,000 in 1995–2000 to 134.3 per 100,000 per year in 2001–2003, P <.001). However, between 2001–2003 and 2004–2006, there was an 82% increase in invasive disease in Alaska Native children younger than 2 years to 244.6/100,000 (P = .02). Since 2004, the invasive pneumococcal disease rate caused by nonvaccine serotypes has increased 140% compared with the prevaccine period (from 95.1 per 100,000 in 1995–2000 to 228.6 in 2004–2006, P = .001). During the same period, there was a 96% decrease in heptavalent vaccine serotype disease. Serotype 19A accounted for 28.3% of invasive pneumococcal disease among Alaska children younger than 2 years during 2004–2006. There was no significant increase in nonvaccine disease in non–Native Alaska children younger than 2 years.” (R. J. Singleton, ris2@cdc.gov)

>>>PNN NewsWatch
* Tracheoesophageal fistula formation has been observed in patients with limited-stage small cell lung cancer being treated in a clinical trial with bevacizumab (Avastin, Genentech). Other types of gastrointestinal tract fistulas have been reported previously in patients treated with the drug for colorectal and other types of cancer.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Apr. 26, 2007 * Vol. 14, No. 81
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Apr. 26 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2007; 356).
Antidepressants in Bipolar Depression: Addition of antidepressants to mood stabilizers provided no increased efficacy among patients with bipolar depression, according to a double-blind, placebo-controlled study (pp. 1711-22). But neither was treatment-emergent switch to mania or hypomania noted, researchers report, adding these details about the 26-week trial: “Forty-two of the 179 subjects (23.5%) receiving a mood stabilizer plus adjunctive antidepressant therapy had a durable recovery, as did 51 of the 187 subjects (27.3%) receiving a mood stabilizer plus a matching placebo (P = 0.40). Modest nonsignificant trends favoring the group receiving a mood stabilizer plus placebo were observed across the secondary outcomes. Rates of treatment-emergent affective switch were similar in the two groups.” (G. S. Sachs, gsachs@partners.org)
An editorialist advises careful patient selection in applying the results of this study in practice (pp. 1771-3): “Almost 90% of the patients in the study by Sachs et al. were using a mood stabilizer at randomization. Thus, the study does not address the possibility that antidepressants can cause mania in patients with bipolar depression in the absence of a mood stabilizer. Clinicians should continue to be vigilant about checking for a history of mania before initiating antidepressant therapy in patients with depression. If the depression is severe, electroconvulsive therapy is indicated for bipolar depression. In my own practice, patients with bipolar disorder who have a history of mild mania and severe or lengthy depression are treated with antidepressants; patients with histories of life-threatening mania are almost never treated with antidepressants. Given the low response rate of patients with bipolar depression—whether or not they received antidepressants —in the trials by Sachs et al. and others, further study of newly suggested treatments such as inositol and n–3 fatty acids is needed. Definitive answers to many questions will require study designs, and perhaps new ethical consent tools, that can capture data for a larger and more representative sample of the various subgroups of patients with bipolar disorder.” (R. H. Belmaker, Ben Gurion U., Beersheva, Israel)
Antiretroviral Therapy & MI Risk: Risk of myocardial infarction is increased among patients taking protease inhibitors, partly because of dyslipidemia, conclude researchers who conducted a prospective observational study of 23,437 patients with HIV infection (pp. 1723-35). Through Feb. 2005, the Data Collection on Adverse Events of Anti-HIV Drugs (DAD) Study Group found: “Three hundred forty-five patients had a myocardial infarction during 94,469 person–years of observation. The incidence of myocardial infarction increased from 1.53 per 1000 person–years in those not exposed to protease inhibitors to 6.01 per 1000 person–years in those exposed to protease inhibitors for more than 6 years. After adjustment for exposure to the other drug class and established cardiovascular risk factors (excluding lipid levels), the relative rate of myocardial infarction per year of protease-inhibitor exposure was 1.16 (95% confidence interval [CI], 1.10 to 1.23), whereas the relative rate per year of exposure to nonnucleoside reverse-transcriptase inhibitors was 1.05 (95% CI, 0.98 to 1.13). Adjustment for serum lipid levels further reduced the effect of exposure to each drug class to 1.10 (95% CI, 1.04 to 1.18) and 1.00 (95% CI, 0.93 to 1.09), respectively.” (J.D. Lundgren, U. Copenhagen, Copenhagen; jdl@cphiv.dk)
An editorialist adds (pp. 1773-5): “Aggressive treatment of HIV clearly is the main clinical priority, and such therapy appears to reduce cardiovascular risk, at least in the short term. With increased exposure to antiretroviral therapy, there is increased exposure to cardiovascular risk factors. Being treated with a protease inhibitor may increase cardiovascular risk modestly; however, longer-term studies are needed to understand the significance of this observation and to determine which drugs within the classes of protease inhibitors and nonnucleoside reverse-transcriptase inhibitors may contribute to the problem. Patients with HIV infection are living longer—that’s the good news. But the longer you live, the more likely it is that heart disease will develop, so the treatment of modifiable risk factors is prudent.” (J. H. Stein, U. Wisconsin, Madison)

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Apr. 27, 2007 * Vol. 14, No. 82
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
May issue of Pharmacotherapy (www.atypon-link.com; 2007; 27).
Nesiritide in HF: A point–counterpoint debate on the utility of nesiritide in acute decompensated heart failure assesses “controversy and conflict.”
Calling for “evidence-based treatment” of ADHF with nesiritide, authors conclude (pp. 619-25): “The literature supports that no statistically or clinically relevant evidence links nesiritide to increased mortality in patients with ADHF, and extensive clinical data support its use to relieve symptoms and improve hemodynamic status in these patients. The manufacturer of nesiritide has recently announced the start of an international outcomes study in 7,000 patients to evaluate dyspnea, rehospitalization and mortality rates, renal effects, quality of life, and pharmacoeconomic outcomes. Until these trial results are available, clinicians should use this drug appropriately, by following package insert instructions and [Heart Failure Society of America] guidelines for indications, selection of the appropriate patients, and dosage-escalation instructions. It is time for a concerted effort of basic scientists, clinicians, industry, and the funding institutions to concentrate on concretely mapping the pathophysiology and standard measurable outcomes that will enhance further development of approved and novel therapies for ADHF. It is time for nesiritide use to continue judiciously within the indication, dosage, and safety parameters of the product labeling and HFSA guidelines.” (M. A. Munger,
mmunger@hsc.utah.edu)
Describing the role of nesiritide in ACHF as “limited,” the author of a second article writes that readers should conclude “if nesiritide had never been approved, [then] we would [not] have missed it” (pp. 626-32): “Occasionally, the United States approves a drug that other countries either never add or summarily dismiss, as the risk outweighs the benefit. This appears to be the case with nesiritide. The European Medicines Agency, which is the European equivalent of the FDA, has specifically required that additional data on worsening renal function and mortality at 30 days and 6 months be provided before approval of nesiritide. These data will supposedly be coming from a trial of 1,900 patients in which nesiritide is compared with placebo. Unfortunately, no patients have yet been enrolled, and even when concluded, this trial will not provide information on safety and efficacy relative to other drugs in its class (i.e., nitroglycerin, nitroprusside).” (J. A. Novisasky, St. Elizabeth Med. Ctr., Utica, N.Y.;
JNoviask@stemc.org)
Omega-3 Fatty Acids: A research article and a literature review explore the utility of omega-3 fatty acids in reducing elevated triglyceride levels.
Among 30 patients with stable coronary artery disease and 30 healthy volunteers, omega-3 fatty acid treatment reduced arachidonic acid–eicosapentaenoic acid ratios significantly, but the treatment had no effect on C-reactive protein levels in either group, and only in healthy patients were triglyceride levels reduced (pp. 633-8). Administered as fish oil capsules, daily doses of omega-3 fatty acids 1.5–3 grams/day produced these results: “Mean ± SD baseline AA:EPA ratios were 39.6 ± 19.0 in healthy subjects and 23.7 ± 12.5 in patients with CAD. These ratios decreased significantly in both groups after treatment with 1.5 g/day of omega-3 fatty acids: 9.0 ± 4.2 in healthy subjects and 10.3 ± 8.8 in patients with CAD. After treatment with 3 g/day, the ratios were further reduced: 5.1 ± 3.2 in healthy subjects and 4.9 ± 2.6 in patients with CAD. Supplementation with omega-3 fatty acids did not significantly affect hs-CRP, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, or blood glucose levels. Triglyceride levels were not reduced in patients with CAD but were significantly decreased in healthy subjects (by 20% decrease with omega-3 fatty acids 1.5 g/day and by 32% decrease with 3 g/day).” (D. E. Hilleman, Creighton U., Omaha, Neb.)
Focusing on prescription omega-3 fatty acids, authors of a review article write (pp. 745-54): “In controlled trials, prescription omega-3 fatty acids were well tolerated, with a low rate of both adverse events and treatment-associated discontinuations. The availability of prescription omega-3 fatty acids, which ensures consistent quality and purity, should prove to be valuable for the medical management of hypertriglyceridemia.” (J. M. McKenney, Natl. Clinical Research, Inc., Richmond, Va.;
jmckenney@ncrinc.net)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 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
Apr. 30, 2007 * Vol. 14, No. 83
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Early-release articles from and Apr. 28 issue of Lancet (www.thelancet.com; 2007; 369).
Micafungin for Fungal Infections: In a noninferiority study, micafungin 100 mg/day was as effective as and caused fewer adverse effects than liposomal amphotericin B 3 mg/kg/day (doi: 10.1016/S0140-6736(07)60605-9): “264 individuals were randomly assigned to treatment with micafungin; 267 were randomly assigned to receive liposomal amphotericin B. 202 individuals in the micafungin group and 190 in the liposomal amphotericin B group were included in the per-protocol analyses. Treatment success was observed for 181 (89.6%) patients treated with micafungin and 170 (89.5%) patients treated with liposomal amphotericin B. The difference in proportions, after stratification by neutropenic status at baseline, was 0.7% (95% CI −5.3 to 6.7). Efficacy was independent of the Candida spp and primary site of infection, as well as neutropenic status, APACHE II score, and whether a catheter was removed or replaced during the study. There were fewer treatment-related adverse events—including those that were serious or led to treatment discontinuation—with micafungin than there were with liposomal amphotericin B.” (O. Cornely, Universitätsklinik Köln, Köln, Germany; Oliver.Cornely@ctuc.de)
Valsartan & Cardiovascular Disease: Added to conventional treatment, valsartan prevented more cardiovascular events than treatment without angiotensin receptor blockade, and valsartan benefits went beyond those attributable to blood pressure control (pp. 1431-9). In a trial of 3,081 Japanese patients aged 20–79 years being treated for hypertension, coronary heart disease, and/or heart failure, these results were noted regarding a primary endpoint of composite cardiovascular morbidity and mortality: “After a median follow-up of 3.1 years (range 1–3.9) the primary endpoint was recorded in fewer individuals given valsartan than in controls (92 vs 149; absolute risk 21.3 vs 34.5 per 1,000 patient years; hazard ratio 0.61, 95% CI 0.47–0.79, p = 0.0002). This difference was mainly attributable to fewer incidences of stroke and transient ischaemic attack (29 vs 48; 0.60, 0.38–0.95, p = 0.028), angina pectoris (19 vs 53; 0.35, 0.20–0.58, p <0.0001), and heart failure (19 vs 36; 0.53, 0.31–0.94, p = 0.029) in those given valsartan than in the control group. Mortality or tolerability did not differ between groups.” (S. Mochizuki, Jikei U., Tokyo; m_seibu@jikei.ac.jp)

>>>BMJ Highlights
Source:
Early-release articles from BMJ (www.bmj.org; 2007; 334).
Preventing Diabetes with Drugs: Lifestyle changes are just as effective as drugs for prevention of diabetes, and are much safer and cheaper, according to an analysis of available evidence (doi: 10.1136/bmj.39169.447488.94). Clinical use of glitazones for diabetes prevention is not justified, the authors write, providing this support for that position: “Because of the risk of harming people with no or minimal symptoms, the threshold for use of drugs in otherwise healthy people must be set high. To get the required data for rosiglitazone requires large and long randomised controlled trials measuring its effect on outcomes important to patients and use of healthcare resources. Clinical use of glitazones to prevent diabetes is, at present, impossible to justify because of unproved benefit on patient important outcomes or lasting effect on serum glucose, increased burden of disease labelling, serious adverse effects, increased economic burden, and the availability of effective and less costly lifestyle measures.” (V. M. Montori, kerunit@mayo.edu)

>>>PNN JournalWatch
* Acute Lung Injury and the Acute Respiratory Distress Syndrome: A Clinical Review, in Lancet, 2007; doi: 10.1016/S0140-6736(07)60604-7. Reprints: G. R. Bernard, gordon.bernard@vanderbilt.edu
* Oral Decontamination for Prevention of Pneumonia in Mechanically Ventilated Adults: Systematic Review and Meta-analysis, in
BMJ, 2007; 334: 889 ff. Reprints: E. Y. Chan, Tan Tock Seng Hosp., Singapore; ee_yuee_chan@ttsh.com.sg
* Recurrence of Gestational Diabetes Mellitus: A Systematic Review, in
Diabetes Care, 2007; 30: 1314–9. Reprints: C. Kim, cathkim@umich.edu
* Insulin Resistance Concepts, in
Diabetes Care, 2007; 30: 1320–6. Reprints: Z. T. Bloomgarden, Mount Sinai Sch. of Med., New York.
* Iontophoretic Drug Delivery System: Focus on Fentanyl, in
Pharmacotherapy, 2007; 27: 745–54. Reprints: C. M. Herndon, cherndo@siue.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
May 1, 2007 * Vol. 14, No. 84
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
May 1 issue of the Annals of Internal Medicine (www.annals.org; 2007; 146).
Infliximab in Giant Cell Arteritis and Polymyalgia Rheumatica: Two articles and an editorial explore disappointing results for new uses of infliximab.
Infliximab “is of no benefit and may be harmful” for maintenance therapy in glucocorticoid-induced remission of newly diagnosed giant cell arteritis, concludes a small trial (pp. 621-30). Researchers report these results for 44 patients in a trial terminated early: “Infliximab therapy did not increase the proportion of patients without relapse at week 22 compared with placebo (43% vs. 50%, respectively; difference, –7 percentage points [95% CI, –38 to 23 percentage points; P = 0.65), nor did it increase the proportion of patients whose glucocorticosteroid dosages were tapered to 10 mg/d without relapse (61% vs. 75%, respectively; difference, –14 percentage points [CI, –42 to 14 percentage points]; P = 0.31). The incidence of infection was 71% with infliximab and 56% with placebo (difference, 15 percentage points [CI, –14 to 45 percentage points]).” (G. S. Hoffman, Cleveland Clinic Foundation, Cleveland)
Similar conclusions are reached in a 51-patient trial of infliximab in newly diagnosed polymyalgia rheumatica (pp. 631-9). Concluding that “adding infliximab to prednisone for treating newly diagnosed polymyalgia rheumatica is of no benefit and may be harmful,” the investigators explain: “Four patients (3 in the infliximab group and 1 in the placebo group) did not complete the trial. The proportion of patients who were free of relapse and recurrence at 52 weeks did not differ between groups (6 of 20 patients [30%] in the infliximab group vs. 10 of 27 patients [37%] in the placebo group; adjusted risk difference, –3 percentage points [95% CI, –31 to 24 percentage points]; P = 0.80). In a sensitivity analysis that included dropouts, the best-case scenario yielded a difference of 5 percentage points (CI, –21 to 31 percentage points) between the groups. The secondary outcomes at weeks 22 and 52 did not differ between the groups.” (C. Salvarani, Arcispedale S. Maria Nuova, Reggio Emilia, Italy;
salvarani.carlo@asmn.re.it)
Asking whether these studies take us “any further forward,” an editorialist writes (pp. 674-6): “Although [tumor necrosis factor] appears to be a dead end, the concept of searching for cytokines as mediators of disease and targets of treatment seems valid. The role of dendritic cells and of other important cytokines, such as interleukin-6, suggests that the mechanisms underlying active disease are complex. Does the cytokine profile at initial diagnosis predict outcome? Do patients with [giant cell arteritis] and polymyalgia rheumatica in fact represent a heterogeneous aggregation of patients with different cytokine milieus, all of which we currently manage in the same way? Clinical researchers on GCA and polymyalgia rheumatica have their work cut out for them. Meanwhile, GCA and polymyalgia rheumatica remain therapeutic challenges. For physicians who manage these diseases, the message is that steroids are still the cornerstone of treatment.” (R. Luqmani, Nuffield Orthopaedic Ctr., Oxford, U.K;
raashid.luqmani@ndos.ox.ac.uk)
Agranulocytosis Induced by Nonchemotherapy Drugs: Many nonchemotherapy drugs can cause agranulocytosis, concludes a systematic review of 980 reports involving 125 drugs with definite or probable associations (pp. 657-65). “Drugs for which more than 10 reports were available (carbimazole, clozapine, dapsone, dipyrone, methimazole, penicillin G, procainamide, propylthiouracil, rituximab, sulfasalazine, and ticlopidine) accounted for more than 50% of definite or probable reports,” the authors write. “Proportions of fatal cases decreased between 1966 and 2006. More patients with a neutrophil count nadir less than 0.1 x 109 cells/L had fatal complications than did those with a neutrophil count nadir of 0.1 x 109 cells/L or greater (10% vs. 3%; P < 0.001). Patients treated with hematopoietic growth factors had a shorter median duration of neutropenia (8 days vs. 9 days; P = 0.015) and, among asymptomatic patients at diagnosis, had a lower proportion of infectious or fatal complications (14% vs. 29%; P = 0.030) than patients without such treatment.” (F. Andersohn, Charité—Universitaetsmedizin, Berlin, Germany; frank.andersohn@charite.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
May 2, 2007 * Vol. 14, No. 85
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
May 2 issue of JAMA (http://jama.ama-assn.org; 2007; 297).
Levosimendan for HF: In the Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support (SURVIVE) trial, levosimendan failed to significantly reduce all-cause mortality at 180 days or affect any secondary clinical outcomes, compared with dobutamine (pp. 1883-91). Included in the trial were 1,327 patients hospitalized for acute decompensated heart failure who had these outcomes: “All-cause mortality at 180 days occurred in 173 (26%) patients in the levosimendan group and 185 (28%) patients in the dobutamine group (hazard ratio, 0.91; 95% confidence interval, 0.74–1.13; P = .40). The levosimendan group had greater decreases in B-type natriuretic peptide level at 24 hours that persisted through 5 days compared with the dobutamine group (P <.001 for all time points). There were no statistical differences between treatment groups for the other secondary end points (all-cause mortality at 31 days, number of days alive and out of the hospital, patient global assessment, patient assessment of dyspnea at 24 hours, and cardiovascular mortality at 180 days). There was a higher incidence of cardiac failure in the dobutamine group. There were higher incidences of atrial fibrillation, hypokalemia, and headache in the levosimendan group.” (A. Mebazaa, Hosp. Lariboisière, Paris; alexandre.mebazaa@lrb.aphp.fr)
Mandatory HPV Vaccination: Balancing “public health vs. private wealth,” the editor of JAMA and a coauthor oppose mandatory human papillomavirus vaccination (pp. 1921-3): “[Our] concerns about mandatory HPV vaccination are not motivated by morals, as there are no data to suggest that an appropriately conducted public health program encourages sexual activity. Rather, maintaining the public’s trust is vital—both for HPV vaccination in particular and for school-based vaccination programs more generally. Legislation to make HPV vaccine mandatory has undermined public confidence and created a backlash among parents. There is nothing more important to the success of public health policies than to ensure community acceptability. In the absence of an immediate risk of serious harm, it is preferable to adopt voluntary measures, making state compulsion a last resort.” (C. D. DeAngelis, cathy.deangelis@jama-archives.org)
FDA, PDUFA, & Drug Safety: Responses of FDA to the Institute of Medicine recommendations regarding drug safety are colored by the realities of the Prescription Drug User Fee Act, authors write in a Commentary (pp. 1917-20): “Under PDUFA, the United States has increasingly become the country of first launch, the public testing ground for new medicines, but no corresponding effort has been made to strengthen postmarketing risk surveillance, risk assessment, risk management, and risk communication. Indeed, during the first 10 years of its regime, PDUFA prohibited the use of user fees for improvements in drug safety. According to David Kessler, head of the FDA from 1990 to 1997, ‘PDUFA should have had funding on the safety side from the beginning, but the industry refused to accept that. . . . We wanted it. The industry said no.’ Indeed, PDUFA has created at least the appearance that the FDA has industry rather than the public as its primary client. This impression is reinforced by the negotiations that take place between the FDA and industry to develop PDUFA renewal plans that are only later open for public comment.
“The life cycle approach recommended by the IOM, if it is implemented, will permit both rapid drug approvals and ongoing efforts to ensure the safety of the US drug supply. The current round of PDUFA negotiations and the FDA reform bills pending in the US House and Senate offer a fresh opportunity to harmonize these important twin goals. The IOM committee specifically rejected the notion that these goals are trapped in a zero-sum game in which speed is traded against safety. Rather, by enhancing the opportunities for effective postapproval risk monitoring and management, the FDA can more confidently and more quickly release new drugs to the market despite the uncertainties normally associated with the preapproval process. An increase in transparency and regulatory authority after approval allows for bolder action before approval, and in the end, the public is the winner.” (B. M. Psaty,
psaty@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
May 3, 2007 * Vol. 14, No. 86
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Early-release article from and the May 3 issue of the New England Journal of Medicine (http://content.nejm.org; 2007; 356).
Once-Yearly Zoledronate for Osteoporosis: Fractures were significantly reduced among postmenopausal women who received once-yearly intravenous zoledronic acid, compared with placebo, in a 3-year trial (pp. 1809-22). Researchers who conducted the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Pivotal Fracture Trial report these outcomes with zoledronic acid 5 mg as a 15-minute infusion (n = 3,889) or placebo (n = 3,976): “Treatment with zoledronic acid reduced the risk of morphometric vertebral fracture by 70% during a 3-year period, as compared with placebo (3.3% in the zoledronic-acid group vs. 10.9% in the placebo group; relative risk, 0.30; 95% confidence interval [CI], 0.24 to 0.38) and reduced the risk of hip fracture by 41% (1.4% in the zoledronic-acid group vs. 2.5% in the placebo group; hazard ratio, 0.59; 95% CI, 0.42 to 0.83). Nonvertebral fractures, clinical fractures, and clinical vertebral fractures were reduced by 25%, 33%, and 77%, respectively (P <0.001 for all comparisons). Zoledronic acid was also associated with a significant improvement in bone mineral density and bone metabolism markers. Adverse events, including change in renal function, were similar in the two study groups. However, serious atrial fibrillation occurred more frequently in the zoledronic acid group (in 50 vs. 20 patients, P <0.001).” (D. M. Black, dblack@psg.ucsf.edu)
If implemented effectively in practice, once-yearly bisphosphonate infusions solve many adherence problems, an editorialist writes (pp. 1878-80): “Despite the availability of effective treatments for osteoporosis, poor adherence to drug regimens reduces the benefit and presents a major challenge for health professionals. Intravenous administration ensures that treatment is correctly delivered and avoids the stringent administration instructions required for oral bisphosphonates. In the case of zoledronic acid, even a single infusion appears to ensure efficacy for at least 1 year and probably longer. The practicality and acceptability of annual intravenous therapy in large numbers of women remain to be tested. Nevertheless, increased treatment choices for patients are to be welcomed and may provide one means of improving adherence and treatment outcomes in osteoporosis.” (J. Compston, U. Cambridge, Cambridge, U.K.)
DTC Advertising: In a Perspectives article released in advance of publication, a writer asks whether “Congress can ban consumer drug ads” (doi: 10.1056/NEJMp078080). After discussing the Constitutional issues involved in such a restriction on what some view as free speech, the author provides this assessment of the problem facing health professionals and society in general: “In February, Novartis submitted a review to the FDA that pooled data from 29 clinical trials of Zelnorm (tegaserod), its drug for women with irritable bowel syndrome. The company’s analysis showed that among patients treated with the drug, 0.1% had a heart attack, a stroke, or severe chest pain, and one patient died, whereas the rate among patients taking a placebo was 0.01%, and none died. Though the drug has been on the market for more than 4 years, the FDA withdrew it this past March because it didn’t consider the drug’s benefits sufficient to justify exposing patients to even low risks of a cardiac event. By that time, Zelnorm had become a popular treatment for irritable bowel syndrome despite having limited effectiveness. Why? Perhaps its success had something to do with its highly visible television ad campaign: attractive young women pulled up their shirts to reveal their bellies inscribed with the slogan ‘I feel better.’ Although the drug was only 5 to 10% more effective than placebo for women and was not shown to work at all for men, the belly-baring ad seems to have worked wonders: U.S. doctors wrote 2.1 million prescriptions for Zelnorm in 2005.” (M. Shuchman, NEJM)

>>>PNN NewsWatch
* FDA yesterday proposed that manufacturers of all antidepressant medications update the black-box warnings on their products’ labeling to include warnings about increased risks of suicidal thinking and behavior in young adults ages 18–24 during initial treatment (generally the first 1–2 months). If implemented, the suicidality requirements would apply to all antidepressants.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
May 4, 2007 * Vol. 14, No. 87
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
May issue of Diabetes Care (http://care.diabetesjournals.org; 2007; 30).
Effects of High-Viscosity Hydroxypropylmethylcellulose on Insulin and Glucose: High-viscosity hydroxypropylmethylcellulose, a modified cellulose fiber that produces a viscous gel in the gastrointestinal tract and has been previously shown to lower cholesterol levels, also reduces postprandial glucose and insulin excursions, report researchers who studied 31 overweight or obese men and women without diabetes (pp. 1039-43). Following three breakfast meals ingested with HV-HPMC 0, 4, or 8 grams, these changes were noted: “Peak glucose was significantly lower (P <0.001) after both HV-HPMC–containing meals (7.4 mmol/l [4 g] and 7.4 mmol/l [8 g]) compared with the control meal (8.6 mmol/l). Peak insulin concentrations and the incremental areas for glucose and insulin from 0 to 120 min were also significantly reduced after both HV-HPMC doses versus control (all P <0.01).” (K. C. Maki, Provident Clin. Res., Bloomington, Ind.; kmaki@providentcrc.com)
Low Interstitial Glucose Levels with Biphasic Insulins: A continuous glucose monitoring system revealed similar low interstitial glucose readings in patients with type 2 diabetes during therapy with two biphasic insulins, but fewer nocturnal episodes and less self-reported nocturnal hypoglycemia occurred with biphasic insulin aspart 30, compared with biphasic human insulin 30 (pp. 1044-8). In a double-blind, two-period, crossover trial of 160 patients, these results were noted during two 16-week treatment periods: “No differences in overall incidence of low interstitial glucose (IG) were found. Twenty-four–hour plots of CGMS showed low IG was more frequent at night than during the day and was unrecognized by patients. At night, subjects spent significantly less time (percentage of total CGMS recorded) with IG <3.5 and <2.5 mmol/l during BIAsp 30 than during BHI 30 treatment, respectively (<3.5 mmol/l: 6.36 vs. 7.93% [mean], 0.67 vs. 2.43% [median], P = 0.018; <2.5 mmol/l: 2.35 vs. 2.86% [mean], 0 vs. 0% [median], P = 0.0467). No treatment difference in A1C was observed.” (S. Heller, School of Medicine and Biomedical Sci.,, Sheffield, U.K.; s.heller@sheffield.ac.uk)
OC Use & Gestational Diabetes: Women’s risks of developing gestational diabetes mellitus are influenced by the androgenic composition of hormonal contraceptives taken before pregnancy, according to a case–control study of 14,235 women who delivered a single infant in 1996–98 and were members of Kaiser Permanente for 5 years before the pregnancy (pp. 1062-8). Comparing 356 cases with 368 matched controls, the authors observed: “There was a suggestion that compared with no hormonal contraceptive use, use of a low-androgen hormonal contraceptive before pregnancy was associated with a slight reduction in risk of GDM (odds ratio 0.84 [95% CI 0.58–1.22]), whereas use of a high-androgen hormonal contraceptive was associated with a modest increase in GDM risk (1.43 [0.92–2.22]).” (M. Hedderson, Kaiser Permanente Medical Grp., Oakland, Calif.; monique.m.hedderson@kp.org)
Chromium in Diabetes: In a 6-month, double-blind study of Western patients with type 2 diabetes and moderate glycemic control, chromium administered as chromium yeast had no significant effect on change in A1c levels, lipid profile, body mass index, blood pressure, body fat, or insulin resistance (pp. 1092-6). While chromium “has been reported to improve glycemic control in patients with type 2 diabetes,” the authors write that “concern exists about the possible toxic effects of chromium picolinate.” The study added chromium doses of 400 mcg or placebo to ongoing treatment of diabetes with oral hypoglycemic agents, with these results: “No differences were found for the change in A1C between the intervention and placebo groups, nor were any differences found between the groups for the secondary end points... There is no evidence that chromium in the form of chromium yeast is effective in improving glycemic control in Western patients with type 2 diabetes who are taking oral hypoglycemic agents.” (N. Kleefstra, Diabetes Ctr., Isala Clinics, Zwolle, the Netherlands; kleefstra@langerhans.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
May 7, 2007 * Vol. 14, No. 88
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Early-release articles from Lancet Neurology and the May 5 issue of Lancet (www.thelancet.com; 2007; 369).
Rivastigmine in Mild Cognitive Impairment: In a 48-month study, rivastigmine did not significantly alter the rate of progression from mild cognitive impairment to Alzheimer’s disease (doi: 10.1016/S1474-4422(07)70109-6). The researchers report: “Of 1,018 study patients enrolled, 508 were randomly assigned to rivastigmine and 510 to placebo; 17.3% of patients on rivastigmine and 21.4% on placebo progressed to AD (hazard ratio 0.85 [95% CI 0.64–1.12]; p = 0.225). There was no significant difference between the rivastigmine and placebo groups on the standardised Z score for the cognitive test battery measured as mean change from baseline to endpoint (−0.10 [95% CI −0.63 to 0.44], p = 0.726). Serious adverse events were reported by 141 (27.9%) rivastigmine-treated patients and 155 (30.5%) patients on placebo; adverse events of all types were reported by 483 (95.6%) rivastigmine-treated patients and 472 (92.7%) placebo-treated patients. The predominant adverse events were cholinergic: the frequencies of nausea, vomiting, diarrhoea, and dizziness were two to four times higher in the rivastigmine group than in the placebo group.” (H. H. Feldman, U. Br. Columbia Hosp., Vancouver, B.C., Canada; hfeldman@interchange.ubc.ca)
Transdermal Rotigotine for PD: In the Clinical Efficacy of Pramipexole And Transdermal Rotigotine in Advanced Parkinson’s Disease (CLEOPATRA-PD), transdermal rotigotine (up to 16 mg/24 hours) was noninferior to oral pramipexole (up to 4.5 mg/day) (doi: 10.1016/S1474-4422(07)70108-4). “204 patients were randomly assigned to receive rotigotine, 201 to receive pramipexole, and 101 to receive placebo; 427 (84%) completed the trial,” investigators note. “The number of discontinuations in each group was similar; most were for adverse events. The mean dose of rotigotine was 12.95 mg/24 h (SD 3.54), the mean dose of pramipexole was 3.1 mg/day (1.24). Mean absolute change in off time from baseline was −2.5 h (SE 0.20) with rotigotine, −2.8 h (0.20) with pramipexole, and −0.9 h (0.29) with placebo. The absolute change in off time from baseline compared with placebo was −1.58 h (95% CI −2.27 to −0.90; p <0.0001) for rotigotine and −1.94 h (−2.63 to −1.25; p <0.0001) for pramipexole. Responder rates were 67% (134 of 200 patients) for pramipexole, 59.7% (120 of 201 patients) for rotigotine, and 35% (35 of 100 patients) for placebo.” (W. H. Poewe, Med. U., Innsbruck, Austria; werner.poewe@i-med.ac.at)
Micafungin for Candidemia: For first-line treatment of candidemia and invasive candidosis, micafungin was as effective and safer than liposomal amphotericin B, according to results of a Phase III trial (pp. 1519-27). “264 individuals were randomly assigned to treatment with micafungin [100 mg/day]; 267 were randomly assigned to receive liposomal amphotericin B [3 mg/kg/day],” the authors write. “202 individuals in the micafungin group and 190 in the liposomal amphotericin B group were included in the per-protocol analyses. Treatment success was observed for 181 (89.6%) patients treated with micafungin and 170 (89.5%) patients treated with liposomal amphotericin B. The difference in proportions, after stratification by neutropenic status at baseline, was 0.7% (95% CI −5.3 to 6.7). Efficacy was independent of the Candida spp and primary site of infection, as well as neutropenic status, APACHE II score, and whether a catheter was removed or replaced during the study. There were fewer treatment-related adverse events—including those that were serious or led to treatment discontinuation—with micafungin than there were with liposomal amphotericin B.” (Oliver Cornely, Universitätsklinik Köln, Köln, Germany; Oliver.Cornely@ctuc.de)

>>>PNN JournalWatch
* Photoprotection, in Lancet, 2007; doi: 10.1016/S0140-6736(07)60638-2. Reprints: S. Lautenschlager, Triemli Hosp., Zurich, Switzerland; stephan.lautenschlager@triemli.stzh.ch
* Can Psychiatry Cross the Quality Chasm? Improving the Quality of Health Care for Mental and Substance Use Conditions, in
American Journal of Psychiatry, 2007; 164: 712–9. Reprints: H. A. Pincus.
* Therapy for Head Lice Based on Life Cycle, Resistance, and Safety Considerations, in
Pediatrics, 2007; 119: 965–74. Reprints: M. Lebwohl.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
May 8, 2007 * Vol. 14, No. 89
Providing news and information about medications and their proper use

>>>Geriatrics Highlights
Source:
May issue of the Journal of the American Geriatrics Society (www.blackwell-synergy.com/toc/jgs/55/5; 2007; 55).
Home IV Antibiotic Therapy: Home intravenous antimicrobial therapy was “a viable option for older adults” who received support from a hospital-based team in 2000–03 (pp. 645 ff). “A total of 205 patients received 231 courses of home IV antimicrobials, with 107 courses in patients aged 60 and older and 124 courses in patients younger than 60,” the researchers write. “For both groups, the most common indication for therapy was osteoarticular infections, and the predominant pathogens were Staphylococcus aureus and coagulase-negative Staphylococcus. Older patients were significantly more likely than younger patients to require the assistance of family members to help with the infusion and were more likely to be seen in urgent care or to call the infectious diseases pharmacist or physicians with questions. Overall, clinical outcomes and numbers of adverse events were similar in both groups, with the exception of nephrotoxicity, which was greater in the older group (P = .02).” (P. N. Malani, pmalani@umich.edu)
Cefepime v. Ceftriaxone for Nursing Home–Acquired Pneumonia: In six skilled-nursing facilities, cefepime proved a cost-effective alternative to ceftriaxone among 69 older residents with pneumonia that was managed without hospitalization (pp. 651-7). Comparing once-daily 1-gram doses of the two intramuscular agents, the authors found: “Patients were predominately female (76%). They had a mean age ± standard deviation of 85 ± 6, with a mean 5.8 ± 1.9 comorbidities; they had age-appropriate renal dysfunction, with a mean estimated creatinine clearance of 35 ± 7 mL/min. Clinical success occurred in 78% of cefepime- and 66% of ceftriaxone-treated patients (P = .39). Fifty-seven patients (93%) were switched to oral antibiotics after 3 days. Antibiotic-related adverse events occurred in 5% of patients. Seven patients (11.5%) were hospitalized. The overall mortality rate was 8%. Mean antibiotic costs were $117 ± 40 for cefepime- and $215 ± 68 for ceftriaxone-treated patients (P <.001). Cost-effectiveness analysis of total costs showed that cefepime would cost $597 and ceftriaxone $1,709 per expected successfully treated patient. One- and two-way sensitivity analyses using a generic price for ceftriaxone and improving its comparative efficacy revealed that the results were robust.” (J. Paladino, CPL Associates, LLC, Buffalo, N.Y.; paladino@cplassociates.com)
Pharmaceutical Care & Appropriate Prescribing: Added to Geriatric Evaluation and Management care, pharmaceutical care significantly improved the appropriateness of prescribing in a study of 203 patients aged 70 or older (pp. 658-65). Comparing patients who received pharmaceutical care from admission to the GEM unit to discharge with those who received GEM care only, the investigators determined: “Intervention patients were significantly more likely than control patients to have an improvement in the [Medication Appropriateness Index] and in the [Assessing Care of Vulnerable Elders] underuse criteria from admission to discharge (odds ratio (OR) = 9.1, 95% confidence interval (CI) = 4.2–21.6 and OR = 6.1, 95% CI = 2.2–17.0, respectively). The control and intervention groups had comparable improvements in the Beers criteria.” (A. Spinewine, Université catholique de Louvain, Bruxelles, Belgium; anne.spinewine@facm.ucl.ac.be)

>>>PNN NewsWatch
* FDA has warned pharmaceutical manufacturers, suppliers, drug repackers, and health professionals who compound medications to be especially vigilant in assuring that glycerin is not contaminated with diethylene glycol (DEG). The agency is issuing guidance to industry recommending methods of testing glycerin and other controls to identify any contamination with DEG before use in the manufacture or preparation of pharmaceutical products. In an article published on Sunday, the New York Times reported that 365 deaths in Panama may have resulted from exposure to DEG in pharmaceuticals, including 100 confirmed fatalities, and that the poison was sold by the barrel as glycerin by a Chinese company.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
May 9, 2007 * Vol. 14, No. 90
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
May 9 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2007; 297).
Cardioprotective Aspirin Doses: Doses higher than 75–81 mg daily are not supported by currently available evidence on the use of aspirin for prevention of cardiovascular disease, according to an systematic review (pp. 2018-24). “Although pharmacodynamic data demonstrate that long-term aspirin dosages as low as 30 mg/d are adequate to fully inhibit platelet thromboxane production, dosages as high as 1,300 mg/d are approved for use,” the authors write. “In the United States, 81 mg/d of aspirin is prescribed most commonly (60%), followed by 325 mg/d (35%). The available evidence, predominantly from secondary-prevention observational studies, supports that dosages greater than 75 to 81 mg/d do not enhance efficacy, whereas larger dosages are associated with an increased incidence of bleeding events, primarily related to gastrointestinal tract toxicity.” (C. L. Campbell, clcampbell@uky.edu)
Preparing for Influenza Pandemics: After reviewing the prospects for accurately predicting the possibility of an impending influenza pandemic, NIH authors advise these precautions (pp. 2025-7): “It is essential that while carefully monitoring current and identifiable risks, pandemic prevention strategies must also be based on expecting the unexpected and being capable of reacting accordingly. In addition to enhanced surveillance, it will be important to expand research on vaccine design, accelerated development of new classes of antiviral drugs, and improved diagnostics. These efforts will be of immediate benefit in the control of seasonal influenza and will simultaneously help to preemptively prepare for the next pandemic.” (D. M. Morens, dmorens@niaid.nih.gov)

>>>Psychiatry Report
Source:
May issue of the American Journal of Psychiatry (http://ajp.psychiatryonline.org/current.dtl; 2007; 164).
Drugs v. Therapy for Depression: Two reports explore differences and similarities in treatment of depression with medications versus cognitive–behavioral therapy.
Following failure of an initial trial of citalopram, patients with major depressive disorder benefited in similar proportions from either an alternative antidepressant or CBT (pp. 739-52). In a report from the STAR*D trial, these results were observed in the one-third of patients who agreed to randomization after the initial citalopram trial: “Those who received cognitive therapy (either alone or in combination with citalopram) had similar response and remission rates to those assigned to medication strategies [sertraline, bupropion, or venlafaxine]. For those who continued on citalopram, medication augmentation resulted in significantly more rapid remission than augmentation with cognitive therapy. Among those who discontinued citalopram, there were no significant differences in outcome, although those who switched to a different antidepressant reported significantly more side effects than those who received cognitive therapy alone.” (M. E. Thase)
Glucose metabolism, measured with positron emission tomography, was lowered in prefrontal brain regions in patients with major depressive disorder treated with either venlafaxine or CBT, investigators report (pp. 778-88). Comparing scans taken before and 16 weeks after treatment, the researchers found: “Response rates were comparable between the CBT (7/12) and venlafaxine (9/12) groups. Response to either treatment modality was associated with decreased glucose metabolism bilaterally in the orbitofrontal cortex and left medial prefrontal cortex, along with increased metabolism in the right occipital-temporal cortex. Changes in metabolism in the anterior and posterior parts of the subgenual cingulate cortex and the caudate differentiated CBT and venlafaxine responders.” (S. H. Kennedy)

>>>PNN NewsWatch
* Further limitations (see PNN, Mar. 12) in FDA-recommended uses of
erythropoietin-stimulating agents may be on the way. The agency yesterday released a report to an advisory committee that meets tomorrow, and it calls for the panel to consider whether approved indications should be narrowed and dosing limited in patients with cancer. The New York Times reports today on manufacturer payments to physicians based on prescribing of ESAs.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
May 10, 2007 * Vol. 14, No. 91
Providing news and information about medications and their proper use

>>>FDA Approves Rotigotine Patches for PD
Rotigotine (Neupro, Schwarz Pharma), a dopamine agonist formulated in a transdermal patch, has been approved by FDA for treatment of the signs and symptoms of early-stage idiopathic Parkinson’s disease. Applied once daily, the patch will be available in three strengths, 2, 4, and 6 mg. The drug was approved in Europe in Mar. 2006 and is currently available in 14 countries there.
The effectiveness of rotigotine was demonstrated in one fixed-dose response study and two flexible-dose studies. The parallel group studies were randomized, double-blinded, and placebo-controlled, and involved 1,154 patients with early Parkinson’s disease who were not taking other antiparkinsonian medications. The trials demonstrated safety and efficacy of the drug and indicated a low potential for drug interactions.
The most common adverse effects in rotigotine clinical trials included skin reactions at the patch site, dizziness, nausea, vomiting, drowsiness, and insomnia, most of which are typical of this class of drugs. Other potential safety concerns include sleep attacks (sudden onset of sleep while engaged in routine activities, including driving or operating machinery), hallucinations, and postural hypotension.

>>>NEJM Highlights
Source:
May 10 New England Journal of Medicine (http://content.nejm.org/current.shtml; 2007; 356).
Human Papillomavirus Vaccine: Several research studies, Perspective articles, and editorials in this issue assess the utility of the marketed quadrivalent human papillomavirus vaccine and its opportunities and challenges.
In the Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE) II trial, young women aged 15 to 26 years who were previously uninfected with HPV-16 or HPV-18 had significantly lower 3-year frequencies of high-grade cervical intraepithelial neoplasia when they had received the HPV vaccine than when they received placebo (pp. 1915-27; L. A. Koutsky,
kouts@u.washington.edu). A second article presents data from the FUTURE I trial, concluding that use of the “quadrivalent vaccine significantly reduced the incidence of HPV-associated anogenital diseases in young women” (pp. 1928-43; S. M. Garland, Royal Women’s Hosp., Carlton, Victoria, Australia; suzanne.garland@rch.org.au). A third study, relying on case–control data from 100 patients with newly diagnosed oropharyngeal cancer and 200 control patients without cancer, shows that oral HPV infection “is strongly associated with oropharyngeal cancer among subjects with or without the established risk factors of tobacco and alcohol use” (pp. 1944-56; M. L. Gillison, Johns Hopkins U., Baltimore; gillima@jhmi.edu).
In one of the editorials, writers describe the dilemma posed by availability of HPV vaccine (pp. 1991-3): “Policymakers, clinicians, and parents have a keen sense of urgency about HPV vaccination. On one hand, the vaccine has high efficacy against certain HPV types that cause life-threatening disease, and it appears to be safe; delaying vaccination may mean that many women will miss an opportunity for long-lasting protection. On the other hand, a cautious approach may be warranted in light of important unanswered questions about overall vaccine effectiveness, duration of protection, and adverse effects that may emerge over time. HPV vaccination has the potential for profound public health benefit if the most optimistic scenario of effectiveness is realized.” (G. F. Sawaya, UCSF)

>>>PNN NewsWatch
* The Senate yesterday passed sweeping reform legislation that, if signed into law, would remake FDA and its mission and operating procedures. The bill, approved in a 93–1 bipartisan vote, calls for FDA to focus just as much on a drug’s postmarketing phase as on the decision to approve the agent initially. The House is considering similar legislation, and FDA reauthorization is one of a handful of must-pass bills in the current Congressional session, as the agency’s user fees will otherwise expire.
* FDA has asked for more data on a
prostate-cancer vaccine, a request that delays an approval decision by 2 years, the Wall Street Journal reports this morning. An FDA advisory panel recommended in late March that Dendreon’s Provenge be approved, voting 13–4 at the end of a meeting attended by a strong faction of patients advocating for the vaccine.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
May 11, 2007 * Vol. 14, No. 92
Providing news and information about medications and their proper use

>>>JAPhA Highlights
Source:
May/June issue of the Journal of the American Pharmacists Assoc. (www.japha.org; 2007; 47).
Decision Support Tool for Product Substitution: A decision support tool was designed by an APhA advisory panel to assist pharmacists in determining when product substitution is appropriate (pp. 328-47). The tool balances a number of factors, including therapeutic , legal, patient, and practice concerns. The author notes: “The U.S. health care system and patients rely on pharmacists as medication use experts to ensure that prescription drug product substitutions are appropriate. Pharmacists must be able to efficiently determine therapeutic equivalence, identify situations where further research is required, have access to timely resources for gathering information, and effectively communicate with patients and physicians about substitution issues. The prescription drug product substitution tool and related resources presented are intended to assist pharmacists in making and communicating clinically sound product substitution decisions that are patient centered, evidence based, consistent with state and federal laws and regulations, and reflective of the realities of health care today.” (P. G. Manolakis, Charlotte, N.C.; pmanolakis@comcast.net)
Drug Importation: Presenting five “tiers” of pharmaceutical products with varying levels of risk if Congress relaxes drug importation statutes, an editorialist concludes that such a law would create a global competitive environment that would put patients at risk (pp. 319-27). Adding that the personal drug importation could “devastate” patient care, the author concludes: “It is not too late for U.S. community pharmacists, owners, and pharmacy associations to get involved and monitor the progress of drug importation legislation. This is no time to sit back and watch the deliberations. I encourage you, state pharmacy associations and societies and national pharmacy associations leaders, to take an active role in this legislative agenda. Community pharmacists have much to offer legislators and their constituencies. More importantly, community pharmacy has much to lose if you do not get involved.” (M.D. Shepherd, marvshepherd@mail.utexas.edu)

>>>PNN NewsWatch
* Consumers should not purchase or use “True Man” or “Energy Max” products, FDA warned yesterday. Promoted and sold as dietary supplements throughout the U.S. as sexual enhancement products and treatments for erectile dysfunction, these are illegal drug products that contain potentially harmful, undeclared ingredients, including analogues of sildenafil.
* The
Purdue Frederick Company and three current or former executives are paying more than $700 million to resolve criminal charges and civil liabilities in connection with several illegal schemes to promote, market, and sell OxyContin, FDA said in a news release on Thursday. The agency, in cooperation with other federal and state agencies, uncovered an extensive, long-term conspiracy by the company to generate the maximum amount of revenues possible from the sale of OxyContin through various illegal schemes, FDA said. To further this goal, FDA said that Purdue trained its sales representatives to make false representations to health care providers about the difficulty of extracting oxycodone from the OxyContin tablet; trained its sales force to represent to health care providers that OxyContin did not cause euphoria and was less addictive than immediate-release opiates; and allowed health care providers to entertain the erroneous belief that OxyContin was less addictive than morphine. In addition, FDA said that Purdue falsely labeled OxyContin as providing “fewer peaks and valleys than with immediate-release oxycodone,” and by representing that “…delayed absorption as provided by OxyContin Tablets is believed to reduce the abuse liability of the drug.”
*
Clarification: E-mail programs of several PNN recipients apparently removed a dash from the cardioprotective aspirin article in Wednesday’s edition. As shown in the PDF file distributed with the May 9 e-mail message, the dosage of aspirin mentioned in the first sentence was 75 to 81 mg, not 7581 mg. Also, the programs that removed the dash additionally removed quotation marks throughout that issue. Readers should note that many passages in PNN are quotes, usually from abstracts of journal articles, and that the PDF file correctly reflects the quoted material.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
May 14, 2007 * Vol. 14, No. 93
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
May 12 issue of BMJ (www.bmj.org; 2007; 334).
Low-Dose Aspirin for Cognition: In the Women’s Health Study, long-term use of aspirin 100 mg every other day provided no benefit for cognition among 6,377 women aged 65 years or older (pp. 987 ff). Administered for a mean of 9.6 years, low-dose aspirin produced these results: “At the initial assessment (mean 5.6 years after randomisation) cognitive performance in the aspirin group was similar to that of the placebo group (mean difference in global score –0.01, 95% confidence interval –0.04 to 0.02). Mean decline in the global score from the first to the final cognitive assessment was also similar in the aspirin compared with placebo groups (mean difference 0.01, –0.02 to 0.04). The risk of substantial decline (in the worst 10th centile of decline) was also comparable between the groups (relative risk 0.92, 0.77 to 1.10). Findings were similar for verbal memory; however, a 20% lower risk was observed for decline in category fluency with aspirin (relative risk 0.80, 0.67 to 0.97).” (J. H. Kang, nhjhk@channing.harvard.edu)

>>>Lancet Highlights
Source:
Early-release articles from and May 12 issue of Lancet (www.thelancet.com; 2007; 369).
Aspirin for Colorectal Cancer Prevention: Daily use of aspirin 300 mg for 5 years is associated with reduced risk of colorectal cancer, according to data from the British Doctors Aspirin Trial and the UK-TIA Aspirin Trial (pp. 1603-13). Analyzing data on nearly 7,500 patients, the researchers found: “In the randomised trials, allocation to aspirin reduced the incidence of colorectal cancer (pooled HR 0.74, 95% CI 0.56–0.97, p = 0.02 overall; 0.63, 0.47–0.85, p = 0.002 if allocated aspirin for 5 years or more). However, this effect was only seen after a latency of 10 years (years 0–9: 0.92, 0.56–1.49, p = 0.73; years 10–19: 0.60, 0.42–0.87, p = 0.007), was dependent on duration of scheduled trial treatment and compliance, and was greatest 10–14 years after randomisation in patients who had had scheduled trial treatment of 5 years or more (0.37, 0.20–0.70, p = 0.002; 0.26, 0.12–0.56, p = 0.0002, if compliant). No significant effect on incidence of non-colorectal cancers was recorded (1.01, 0.88–1.16, p = 0.87). In 19 case-control studies (20,815 cases) and 11 cohort studies (1,136,110 individuals), regular use of aspirin or NSAID was consistently associated with a reduced risk of colorectal cancer, especially after use for 10 years or more, with no difference between aspirin and other NSAIDs, or in relation to age, sex, race, or family history, site or aggressiveness of cancer, or any reduction in apparent effect with use for 20 years or more. However, a consistent association was only seen with use of 300 mg or more of aspirin a day, with diminished and inconsistent results for lower or less frequent doses.” (P. M. Rothwell, Radcliffe Infirmary, Oxford, U.K.; peter.rothwell@clneuro.ox.ac.uk)
Snus & Pancreatic Cancer: Use of Scandinavian moist snuff (snus) is linked to increased risk of pancreatic cancer in a study 279,897 Swedish men in 1978 through 1992 (DOI:10.1016/S0140-6736(07)60678-3). Based on follow-up through 2004 using population and health registries, use of snus by the 125,576 men, all construction workers, who never used tobacco showed these trends: “60 cases of oral, 154 of lung, and 83 of pancreatic cancer were recorded in never-smokers. Snus use was independently associated with increased risk of pancreatic cancer (relative risk for ever-users of snus 2.0; 95% CI 1.2–3.3, compared with never-users of any tobacco), but was unrelated to incidence of oral (0.8, 95% CI 0.4–1.7) and lung cancer (0.8, 0.5–1.3).” (O. Nyrén, Karolinska Institutet, Stockholm; lof.nyren@ki.se">olof.nyren@ki.se)

>>>PNN JournalWatch
* Implications and Treatment of Acute Hyperglycemia in the Setting of Acute Myocardial Infarction, in Circulation, 2007; 115: e436–9. Reprints: R. W. Nesto, Lahey Clinic Med. Ctr.; richard.w.nesto@lahey.org
* Noneosinophilic Asthma: A Distinct Clinical and Pathologic Phenotype, in
Journal of Allergy and Clinical Immunology, 2007; 119: 1043–52. Reprints: I. D. Pavord, Glenfield Hosp., Leicester, U.K.
* What’s More Dangerous, Your Aspirin or Your Car? Thinking Rationally About Drug Risks (and Benefits), in
Health Affairs, 2007; 26: 636–46. Reprints: J. T. Cohen.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
May 15, 2007 * Vol. 14, No. 94
Providing news and information about medications and their proper use

>>>Internal Medicine Report I
Source:
May 15 issue of the Annals of Internal Medicine (www.annals.org; 2007; 146).
Pharmacist Intervention in HF: In a randomized controlled trial of 314 patients with heart failure, pharmacists’ interventions improved medication adherence to cardiovascular medications and lowered health care use and costs (pp. 714-25). However, the researchers added, constant intervention is likely needed, as the these benefits disappeared within 3 months after the intervention was stopped. The study was conducted at a university-affiliated, inner-city ambulatory clinic, and researchers report these results: “During the 9-month intervention period, medication adherence was 67.9% and 78.8% in the usual care and intervention groups, respectively (difference, 10.9 percentage points [95% CI, 5.0 to 16.7 percentage points]). However, these salutary effects dissipated in the 3-month postintervention follow-up period, in which adherence was 66.7% and 70.6%, respectively (difference, 3.9 percentage points [CI, –5.9 to 6.5 percentage points]). Medications were taken on schedule 47.2% of the time in the usual care group and 53.1% of the time in the intervention group (difference, 5.9 percentage points [CI, 0.4 to 11.5 percentage points]), but this effect also dissipated at the end of the intervention (48.9% vs. 48.6%, respectively; difference, 0.3 percentage point [CI, –5.9 to 6.5 percentage points]). Emergency department visits and hospital admissions were 19.4% less (incidence rate ratio, 0.82 [CI, 0.73 to 0.93]) and annual direct health care costs were lower ($–2960 [CI, $–7603 to $1338]) in the intervention group.” (M. D. Murray, U. North Carolina, Chapel Hill)

>>>Internal Medicine Report II
Source:
May 14 issue of the Archives of Internal Medicine (http://archinte.ama-assn.org; 2007; 167).
Calcium/Vitamin D for Weight Maintenance: In a study of 36,282 postmenopausal women, use of calcium plus cholecalciferol supplements had “a small effect on the prevention of weight gain, which was observed primarily in women who reported inadequate calcium intakes” (pp. 893-902). Previous research had shown that intake of foods rich in calcium and vitamin D helped patients with weight management, but the current comparison of daily doses of elemental calcium 1,000 mg plus cholecalciferol 400 IU or placebo showed these results over a mean time period of 7 years: “Women receiving calcium plus cholecalciferol supplements vs women receiving placebo had a minimal but consistent favorable difference in weight change (mean difference, –0.13 kg; 95% confidence interval, –0.21 to –0.05; P = .001). After 3 years of follow-up, women with daily calcium intakes less than 1200 mg at baseline who were randomized to supplements were 11% less likely to experience small weight gains (1–3 kg) and 11% less likely to gain more moderate amounts of weight (>3 kg) (P for interaction for baseline calcium intake = .008).” (B. Caan, bjc@dor.kaiser.org)
Fiber, Magnesium Intake & Diabetes Risk: Risk of developing type 2 diabetes is lowered by increased intake of cereal fiber and magnesium, concludes a prospective cohort study of 9,702 men and 15,365 women aged 35 to 65 years in Germany (pp. 956-65). Based on 844 cases of incident diabetes occurring in 1994 to 2005, European Prospective Investigation Into Cancer and Nutrition–Potsdam investigators found: “Higher cereal fiber intake was inversely associated with diabetes risk (RR for extreme quintiles, 0.72 [95% confidence interval [CI], 0.56–0.93]), while fruit fiber (0.89 [95% CI, 0.70–1.13]) and vegetable fiber (0.93 [95% CI, 0.74–1.17]) were not significantly associated. Meta-analyses showed a reduced diabetes risk with higher cereal fiber intake (RR for extreme categories, 0.67 [95% CI, 0.62–0.72]), but no significant associations for fruit (0.96 [95% CI, 0.88-1.04]) and vegetable fiber (1.04 [95% CI, 0.94-1.15]). Magnesium intake was not related to diabetes risk in the European Prospective Investigation Into Cancer and Nutrition–Potsdam (RR for extreme quintiles, 0.99 [95% CI, 0.78-1.26]); however, meta-analysis showed a significant inverse association (RR for extreme categories, 0.77 [95% CI, 0.72-0.84]).” (M. B. Schulze, German Inst. of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany; mschulze@dife.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
May 16, 2007 * Vol. 14, No. 95
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
May 16 issue of JAMA (http://jama.ama-assn.org; 2007; 297).
Exercise, Weight, & Hypertension in Women: A graded dose–response change in fitness was observed across three levels of physical activity among 464 previously sedentary, overweight, or obese postmenopausal women with systolic blood pressures of 120 to 159.9 mm Hg, but elevated blood pressures did not improve in a 6-month study (pp. 2081-91). Compared with a nonexercise control group, patients in 4, 8, and 12 kcal/kg/week exercise groups showed these changes in peak absolute oxygen consumption (Vo2abs): “The mean (SD) baseline Vo2abs values were 1.30 (0.25) L/min. The mean (SD) minutes of exercising per week were 72.2 (12.3) for the 4-kcal/kg, 135.8 (19.5) for the 8-kcal/kg, and 191.7 (33.7) for the 12-kcal/kg per week exercise groups. After adjustment for age, race/ethnicity, weight, and peak heart rate, the exercise groups increased their Vo2abs compared with the control group by 4.2% in the 4-kcal/kg, 6.0% in the 8-kcal/kg, and 8.2% in the 12-kcal/kg per week groups (P <.001 for each vs control; P for trend <.001). There was no treatment X subgroup interaction for age, body mass index, weight, baseline Vo2abs, race/ethnicity, or baseline hormone therapy use. There were no significant changes in systolic or diastolic blood pressure values from baseline to 6 months in any of the exercise groups vs the control group.” (T. S. Church, Louisiana State U. System, Baton Rouge; tim.church@pbrc.edu)
“Even a little is good,” an editorialist writes of physical activity, but “more is better”: (pp. 2137-9): “Although the trial by Church et al shows a linear dose-response relation between physical activity and improvements in physical fitness, with benefit observed beginning at 72 minutes a week of moderate activity, it is limited in its ability to provide direct answers for other patterns of physical activity. Understandably, because of cost and feasibility reasons, the trial mimicked only 3 physical activity patterns that can occur; in real life, there are infinitely more. For example, this trial does not provide information about whether vigorous activities, such as running, can improve the cardiovascular risk factors that the moderate cycling and walking, carried out by participants, did not. And, as for typical patterns of activity in everyday life, eg, accumulated bouts of cycling or walking in commuting, or walking the dog, will fitness improve to the extent seen in the trial if the physical activity was not conducted in a single session but was broken up over the day? Or, if rather than the average 2.6 to 3.1 sessions a week of physical activity undertaken by study participants, the activity was conducted in 1 to 2 sessions over the weekend (weekend warrior) by busy, working adults? These questions ask about dose(s) of physical activity, with dose(s) referring to additional components of activity apart from the component studied, total energy expended in moderate activity.... An important unanswered question is, what is the dose–response for adverse health effects—at what activity level do harmful effects negate beneficial health effects?” (I-M Lee,
ilee@rics.bwh.harvard.edu)
Changing Perceptions of the U.S. Health Care System: Playing off George Carlin’s 1970s-era seven words that you can’t say on television, the author of a commentary explores changes in politically acceptable ways in which the U.S. health care system can be described to the American public (pp. 2131-3). His conclusion is that three once-standard phrases “can no longer be said about the US health care system without qualification, embarrassment, criticism, or even denunciation: ‘The United States has the best health care system in the world,’ ‘Health care is special,’ and ‘New is better.’” The writer concludes: “The evolution in what can and cannot be said on TV regarding the US health care system confirms and reinforces that there is an important change occurring in how many Americans view the health care system. The change in language suggests Americans now recognize that the system has deep structural problems. While this recognition is no guarantee of change, it does constitute a critical precondition for comprehensive reform of the system. Reform cannot occur without acknowledging that there is a problem. The next step is for the public to see a solution that they think offers a realistic chance of making the system better. Maybe this will become something that not only can be said on TV, but certainly will deserve to be emphasized.” (E. J. Emanuel, eemanuel@nih.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
May 17, 2007 * Vol. 14, No. 96
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
May 17 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2007; 356).
Treating Mild Asthma: Two research studies and related articles examine best treatments for mild persistent asthma.
In the Leukotriene or Corticosteroid or Corticosteroid–Salmeterol (LOCSS) trial, patients with well-controlled, mild persistent asthma were switched from twice-daily to once-daily inhaled fluticasone plus salmeterol without increased rates of treatment failure, but a switch to montelukast increased the rate of treatment failure and decreased asthma control (pp. 2027-39). Doses of the drugs for the 500 patients in the trial were inhaled fluticasone 100 mcg twice daily, montelukast 5 or 10 mg each night, and fluticasone 100 mcg plus salmeterol 50 mcg each night. Over the 16-week trial, these results were recorded: “Approximately 20% of patients assigned to receive continued fluticasone or switched to treatment with fluticasone plus salmeterol had treatment failure, as compared with 30.3% of subjects switched to montelukast. The hazard ratio for both comparisons was 1.6 (95% confidence interval, 1.1 to 2.6; P = 0.03). The percentage of days on which patients were free of asthma symptoms (78.7 to 85.8%) was similar across the three groups.” (J. T. Holbrook, Am. Lung Assoc. Asthma Clinical Research Ctr. Data Coordinating Ctr., Baltimore;
jholbroo@jhsph.edu)
A second trial, the Beclomethasone plus Salbutamol Treatment (BEST) study, shows that intermittent, symptom-driven use of inhaled beclomethasone 250 mcg and albuterol 100 mcg in a single inhalers was just as effective as regular use of inhaled beclomethasone 250 mcg twice daily (pp. 2040-52). Adding that the cumulative steroid dose over the 6-month trial was significantly lower with intermittent use, the investigators write: “In 455 patients with mild asthma who had a forced expiratory volume in 1 second of 2.96 liters (88.36% of the predicted value), the morning peak expiratory flow rate during the last 2 weeks of the 6-month treatment was higher (P = 0.04) and the number of exacerbations during the 6-month treatment was lower (P = 0.002) in the as-needed combination therapy group than in the as-needed albuterol therapy group, but the values in the as-needed combination therapy group were not significantly different from those in the groups receiving regular beclomethasone therapy or regular combination therapy. The cumulative dose of inhaled beclomethasone was lower in the as-needed combination therapy group than in the groups receiving regular beclomethasone therapy or regular combination therapy (P <0.001 for both comparisons).” (L. M. Fabbri, Università di Modena e Reggio Emilia, Modena, Italy;
fabbri.leonardo@unimore.it)
The
Journal introduces a new interactive feature with these asthma articles (pp. 2096-100). Clinical Decisions describes a case vignette and asks readers to vote on which of three options—derived from the research presented in the two above studies—they would recommend for the patient, and to make comments.
Disease-Modifying HIV Vaccine: While vaccines have traditionally provided long-lasting and completely preventive measures for the target microorganisms, researchers are beginning to view an HIV vaccine, at least in its early stages of development, as one that might modify rather than prevent the disease, authors of a review article write (pp. 2073-81). Such a product “would need to be delivered in the context of a comprehensive HIV-prevention program,” the writers note, adding: “A vaccine that conforms to the classic paradigm of viral vaccines remains the goal of efforts to develop an HIV vaccine. Such a vaccine would induce immune responses that prevented the establishment of HIV infection by clearing virus before latent viral reservoirs were produced. This goal may not be realized with first-generation vaccines. The development of an HIV vaccine may diverge from the classic paradigm for viral vaccines. There is optimism that even a less-than-perfect vaccine could benefit both individual recipients and the at-risk community. By blunting the initial burst of viremia and reducing virus levels, such a vaccine could prolong the disease-free period and also reduce transmission. If licensed, such a vaccine will have to be delivered as part of a comprehensive, multifaceted, prevention program.” (A. S. Fauci, afauci@niaid.nih.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
May 18, 2007 * Vol. 14, No. 97
Providing news and information about medications and their proper use

>>>Infectious Diseases Report
Source:
Articles scheduled for printing in the June 15 issue of Clinical Infectious Diseases (www.journals.uchicago.edu/CID/home.html; 2007; 44).
Strengthening Adult, Adolescent Immunization Coverage: Administration of vaccines by nonphysicians at schools, pharmacies, and walk-in clinics is one of several recommendations made by the Infectious Diseases Society of America in a set of policy principles on how to strengthen adult and adolescent immunization coverage in the U.S. The principles and examples of strategies for accomplishing them are as follows (N. A. Halsey, Johns Hopkins U., Baltimore; nhalsey@jhsph.edu):
* Increase demand for adult and adolescent immunization by improving public and provider awareness—encourage and educate medical providers; immunize health workers.
* Strengthen the health care system’s capacity to deliver vaccines to adults and adolescents—increase hospitals’ attention to immunization of eligible patients.
* Expand provision of vaccines to adults and adolescents in public and private health insurance programs—assure payment for all recommended adult and adolescent vaccines.
* Promote adult and adolescent immunization as an important measure of health care quality in managed care and other health care organizations—enhance quality assurance metrics and Joint Commission standards with regard to vaccinations.
* Monitor and improve the performance of the nation’s vaccine delivery and safety monitoring systems for adults and adolescents—focus on CDC surveillance of vaccine-preventable diseases.
* Assure adequate support for research regarding adult and adolescent vaccine-preventable diseases and vaccines—target funding by NIH, CDC, FDA, VA, other federal agencies, and vaccine manufacturers.
Lessons can be learned from childhood vaccination programs, write editorialists who maintain, “We know what to do. We just have to do it.” They add: “Minimum actions include an increase in Section 317 appropriations, with an earmark for adult immunizations; establishment and/or enhancement of public sector infrastructure for promoting/coordinating adult immunizations; assurance of adequate reimbursement for vaccine administration; measurement of and publicity for adult immunization coverage rates, by state and locality, to track progress and to identify good performers and areas that need improvement; and establishment of a culture of immunization among those who provide care to adults. In addition to these minimum actions, we believe that a Vaccines For Uninsured Adults Program would be highly beneficial.” (A. R. Hinman, Public Health Informatics Inst., Decatur, Ga.;
ahinman@taskforce.org)
Ischemic Heart Disease with HAART: While HIV-infected patients receiving highly active antiretroviral therapy are at increased risk for development of ischemic heart disease, their “relative risk is stable up to 8 years after treatment initiation,” according to a study of 3,953 patients in Denmark. Comparing patients’ rates of first hospitalization for ischemic heart disease during the 1995–2004 period with rates in 373,856 people in a population-based control group, the investigators found: “Although the difference was not statistically significant, patients with HIV infection who had not initiated HAART were slightly more likely to be hospitalized for the first time with ischemic heart disease than were control subjects (adjusted relative risk, 1.39; 95% confidence interval, 0.81–2.33). After HAART initiation, the risk increase became substantially higher (adjusted relative risk, 2.12; 95% confidence interval, 1.62–2.76), but the relative risk did not further increase in the initial 8 years of HAART.” (N. Obel, Rigshospitalet, Copenhagen)
Vancomycin for MRSA: A point–counterpoint exchange debates the utility of vancomycin in treating methicillin-resistant Staphylococcus aureus. An opponent maintains that alternative agents should be considered in such cases, describing vancomycin as entering obsolescence and stating that neither dose escalation or combination therapy is effective (S. Deresinski, Santa Clara Valley Med. Ctr., San Jose, Calif.). Proponents counter that resistance is a continuous rather than categorical phenomenon, and use of loading doses and development of more logical categorical breakpoints could permit vancomycin use (J. F. Mohr, U. Tex., Houston).

PNN Pharmacotherapy Line is published via e-mail each business day except 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
May 21, 2007 * Vol. 14, No. 98
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Early-release articles from and May 19 issue of Lancet (www.thelancet.com; 2007; 369).
Antiplatelet Agents for Prevention of Pre-eclampsia: Antiplatelet agents, particularly low-dose aspirin, administered during pregnancy lower women’s risk of pre-eclampsia, birth before 34 weeks’ gestation, and having a pregnancy with a serious adverse outcome, according to results of a meta-analysis of 32,217 women who delivered 21,819 babies during 21 randomized trials (doi: 10.1016/S0140-6736(07)60712-0). The authors report: “For women assigned to receive antiplatelet agents rather than control, the relative risk of developing pre-eclampsia was 0.90 (95% CI 0.84–0.97), of delivering before 34 weeks was 0.90 (0.83–0.98), and of having a pregnancy with a serious adverse outcome was 0.90 (0.85–0.96). Antiplatelet agents had no significant effect on the risk of death of the fetus or baby, having a small for gestational age infant, or bleeding events for either the women or their babies. No particular subgroup of women was substantially more or less likely to benefit from antiplatelet agents than any other.” (L. M Askie, U. Sydney, Camperdown, New South Wales, Australia; laskie@ctc.usyd.edu.au)
Papilloma Vaccine & Genital Lesions: Vaccination of young women with the quadrivalent human papilloma virus vaccine prevents high-grade vulval and vaginal lesions associated with HPV16 and HPV18 infections, according to a placebo-controlled study of women aged 16 to 26 years in Finland (pp. 1693-702). Focusing on the occurrence of high-grade vulval intraepithelial neoplasia (VIN2–3) and vaginal intraepithelial neoplasia (VaIN2–3) that precede cancers, the researchers found these results over a mean follow-up period of 3 years: “Among women naive to HPV16 or HPV18 through 1 month after dose three (per-protocol population; vaccine n = 7,811; placebo n = 7,785), the vaccine was 100% effective (95% CI 72–100) against VIN2–3 or VaIN2–3 associated with HPV16 or HPV18. In the intention-to-treat population (which included 18,174 women who, at day 1, could have been infected with HPV16 or HPV18), vaccine efficacy against VIN2–3 or VaIN2–3 associated with HPV16 or HPV18 was 71% (37–88). The vaccine was 49% (18–69) effective against all VIN2–3 or VaIN2–3, irrespective of whether or not HPV DNA was detected in the lesion. The most common treatment-related adverse event was injection-site pain.” (J. Paavonen, U. Central Hosp., Helsinki; jorma.paavonen@hus.fi)
LHRH Agonists for Premenopausal Breast Cancer: Luteinizing-hormone-releasing hormone agonists provide an alternative for treating hormone-receptor–positive breast cancer in premenopausal women, according to a meta-analysis of 16 trials that included 11,906 patients (pp. 1711-23). “When used as the only systemic adjuvant treatment, LHRH agonists did not significantly reduce recurrence (28.4% relative reduction, 95% CI consistent with 50.5% reduction to 3.5% increase, p = 0.08) or death after recurrence (17.8%, 52.8% reduction to 42.9% increase, p = 0.49) in hormone-receptor-positive cancers. Addition of LHRH agonists to tamoxifen, chemotherapy, or both reduced recurrence by 12.7% (2.4–21.9, p = 0.02); and death after recurrence by 15.1% (1.8–26.7, p = 0.03). LHRH agonists showed similar efficacy to chemotherapy (recurrence 3.9% increase, 7.7% reduction to 17.0% increase; death after recurrence 6.7% reduction, 20.7% reduction to 9.6% increase; both not significant). No trials had assessed an LHRH agonist versus chemotherapy with tamoxifen in both arms. LHRH agonists were ineffective in hormone-receptor-negative tumours.” (J. Cuzick, U. London, London; jack.cuzick@cancer.org.uk)

>>>PNN JournalWatch
* Treatment of Hypertension in the Prevention and Management of Ischemic Heart Disease. A Scientific Statement From the American Heart Association Council for High Blood Pressure Research and the Councils on Clinical Cardiology and Epidemiology and Prevention, in Circulation, 2007; doi: 10.1161/CIRCULATIONAHA.107.183885. Reprints: 800-242-8721; Am. Heart Assoc., Public Information, 7272 Greenville Ave, Dallas, TX 75231-4596.
* Genital Herpes and Its Management, in
BMJ, 2007; 334: 1048–52. Reprints: S. Barton, Chelsea and Westminster Hosp. Foundation NHS Trust, London; simon.barton@chelwest.nhs.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
May 22, 2007 * Vol. 14, No. 99
Providing news and information about medications and their proper use

>>>Cardiovascular Safety Issues Raised for Rosiglitazone
Risks of myocardial infarction and death from cardiovascular causes are increased among patients taking the antidiabetic agent rosiglitazone, according to a meta-analysis posted yesterday to the New England Journal of Medicine Web site. Editorialists commented that Congress needs to incorporate a “true life-cycle approach” into the FDA reauthorization legislation now being considered, FDA issued an alert to clinicians, and Avandia manufacturer GlaxoSmithKline disputed the study findings.
Data for the meta-analysis came from 42 randomized studies of rosiglitazone with durations of more than 24 weeks that were available in the published literature, on the FDA Web site, and in a clinical trials registry maintained by GSK (doi: 10.1056/NEJMoa072761). “Data were combined by means of a fixed-effects model,” the authors write. “In the 42 trials, the mean age of the subjects was approximately 56 years, and the mean baseline glycated hemoglobin level was approximately 8.2%. In the rosiglitazone group, as compared with the control group, the odds ratio for myocardial infarction was 1.43 (95% confidence interval [CI], 1.03 to 1.98; P = 0.03), and the odds ratio for death from cardiovascular causes was 1.64 (95% CI, 0.98 to 2.74; P = 0.06).” (S. E. Nissen, Cleveland Clinic, Cleveland;
nissens@ccf.org)
Reflecting on the pharmacovigilance challenges presented by medications in general clinical use,
NEJM editorialists point Congress toward Institute of Medicine recommendations regarding drug safety (doi: 10.1056/NEJMe078099): “On May 10, 2007, the Senate passed the Food and Drug Administration Revitalization Act. Although the Senate bill has many strengths, including the allocation of new authority to the FDA, none of its provisions would necessarily have identified the cardiovascular risks of rofecoxib or rosiglitazone in a timely fashion. One section of the bill (title II, subtitle A) focuses largely on the mitigation of known risks at the time of approval. In contrast, a true life-cycle approach, as advocated by the Institute of Medicine, would continue the evaluation of both efficacy and safety after approval, convert surrogate end points into clinically meaningful outcomes, integrate new information about health benefits and risks, and communicate those findings effectively to patients and physicians. The health of the public would benefit from additional revisions to the drug-safety legislation as it moves through the House of Representatives.” (B. M. Psaty, U. Washington, Seattle)
FDA issued a safety alert based on the new findings and encouraged prescribers and patients to “make individualized treatment decisions,” taking into consideration both this study as well as contradictory findings from other trials. “Pending questions include whether the other approved treatment from the same class of drugs, pioglitazone, has less, the same or greater risks,” FDA emphasized in a news release. “Furthermore, there is inherent risk associated with switching patients with diabetes from one treatment to another even in the absence of specific risks associated with particular treatments. For these reasons, FDA is not asking GlaxoSmithKline ... to take any specific action at this time.”
In its own news release, GSK said that it “strongly disagrees with the conclusions reached in the
NEJM article, which are based on incomplete evidence and a methodology that the author admits has significant limitations.” The company pointed to other published trials in defending its product and noted that large, long-term clinical trials would provide higher-quality evidence regarding rosiglitazone’s safety than does this meta-analysis.

>>>PNN NewsWatch
* Potential subpotency resulted in a nationwide recall of three Spectrum Laboratory Product lots of Caffeine Citrated, Powder, Purified (TS0225, UK0821, V11203). Remaining product should not be used in compounding of admixtures since premature infants might have subtherapeutic caffeine levels and increased risk of respiratory depression. The company can be contacted at 800/772-8786 for information on credits and returns.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
May 23, 2007 * Vol. 14, No. 100
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
May 23 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2007; 297).
Malaria Chemoprophylaxis for Travelers: The difficulties of sorting out the “controversies and misconceptions” about malaria chemoprophylaxis in travelers are explored in a review article, one of several related papers in this theme issue on malaria (pp. 2251-63). “Gaps and conflicts exist among current guidelines,” write the authors. “Health authorities vary in the chemoprophylaxis drugs they recommend, the indications for continuous prophylaxis vs no prophylaxis, and the use of standby emergency treatment. Despite widespread reports on the adverse effects of mefloquine, controlled studies found that serious neuropsychiatric adverse events occur at rates comparable with or lower than other chemoprophylaxis drugs. Moreover, mefloquine does not appear to impair performance while driving, flying, or diving. Vivax malaria causes significant illness in travelers, but current first-line chemoprophylaxis agents do not prevent relapses of vivax malaria. Although not licensed in most countries as primary prophylaxis, primaquine effectively prevents relapses of vivax malaria.” (L. H. Chen, lchen@hms.harvard.edu)
Malaria Treatment in U.S.: For clinicians practicing in the U.S., “malaria remains a diagnostic and treatment challenge” as they treat patients who travel to and emigrate from malarious areas, note authors of a systematic review (pp. 2264-77). They add: “Important measures to reduce morbidity and mortality from malaria in the United States include the following: obtaining a travel history, considering malaria in the differential diagnosis of fever based on the travel history, and prompt and accurate diagnosis and treatment. Chloroquine remains the treatment of choice for Plasmodium falciparum acquired in areas without chloroquine-resistant strains. In areas with chloroquine resistance, a combination of atovaquone and proguanil or quinine plus tetracycline or doxycycline or clindamycin are the best treatment options. Chloroquine remains the treatment of choice for all other malaria species, with the exception of P vivax acquired in Indonesia or Papua New Guinea, in which case atovaquone-proguanil is best, with mefloquine or quinine plus tetracycline or doxycycline as alternatives. Quinidine is currently the recommended treatment for severe malaria in the United States because the artemisinins are not yet available. Severe malaria occurs when a patient with asexual malaria parasitemia, and no other confirmed cause of symptoms, has 1 or more designated clinical or laboratory findings. The only adjunctive measure recommended in severe malaria is exchange transfusion.” (M. E. Parise, MParise@cdc.gov)

>>>PNN NewsWatch
* FDA yesterday approved the first continuous-use oral contraceptive, Lybrel (Wyeth), for marketing. The product contains levonorgestrel 90 mcg and ethinyl estradiol 20 mcg in a 28-day pack with all active tablets. Continuous use of the product eliminates menstrual periods for most women; in 1-year clinical studies of Lybrel, 59% of women on active drug had no bleedings or spotting during the final month. Because of the lack of menstrual periods, women who think they may be pregnant should take a pregnancy test.
* Cases of acute renal failure, some fatal, have been reported during postmarketing use of
deferasirox (Exjade), Novartis and FDA warned yesterday. Most fatalities occurred in patients with multiple comorbidities and who were in advanced stages of their hematologic disorders when they received this medication for iron overload. Additionally, cytopenias, including agranulocytosis, neutropenia, and thrombocytopenia occurred in patients treated with deferasirox, and some of the patients died. The relationship of these episodes to treatment with deferasirox is uncertain. Most of these patients had preexisting hematologic disorders frequently associated with bone marrow failure. Further, cases of leukocytoclastic vasculitis, urticaria, and hypersensitivity reactions (including anaphylaxis and angioedema) were reported. The MedWatch notice calls for health professionals to monitor serum creatinine in patients who are at increased risk of complications, having preexisting renal conditions, are elderly, have comorbid conditions, or are receiving medications that depress renal function. Blood counts should also be monitored regularly and treatment should be interrupted in patients who develop unexplained cytopenia.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
May 24, 2007 * Vol. 14, No. 101
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
May 24 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2007; 356).
Aspirin’s Effects on Colorectal Cancer: Cyclooxygenase-2 expression by colorectal tumors determines whether they are prevented by aspirin prophylaxis, report authors of a cohort study (pp. 2131-42). Based on data provided in questionnaires every 2 years by two large cohorts of patients, the investigators determined: “During 2,446,431 person–years of follow-up of 82,911 women and 47,363 men, we found 636 incident colorectal cancers that were accessible for determination of COX-2 expression. Of the tumors, 423 (67%) had moderate or strong COX-2 expression. The effect of aspirin use differed significantly in relation to COX-2 expression (P for heterogeneity = 0.02). Regular aspirin use conferred a significant reduction in the risk of colorectal cancers that overexpressed COX-2 (multivariate relative risk, 0.64; 95% confidence interval [CI], 0.52 to 0.78), whereas regular aspirin use had no influence on tumors with weak or absent expression of COX-2 (multivariate relative risk, 0.96; 95% CI, 0.73 to 1.26). The age-standardized incidence rate for cancers that overexpressed COX-2 was 37 per 100,000 person–years among regular aspirin users, as compared with 56 per 100,000 person–years among those who did not use aspirin regularly; in contrast, the rate for cancers with weak or absent COX-2 expression was 27 per 100,000 person–years among regular aspirin users, as compared with 28 per 100,000 person–years among nonregular aspirin users.” (A. T. Chan, achan@partners.org)
An editorialist describes the challenges of applying these findings in clinical practice (pp. 2195-8): “The findings of Chan et al. pose the further challenge of identifying persons in whom COX inhibitors would have the highest likelihood of conferring protection from the development of colon cancer. Such an ‘individualized medicine’ approach will first require evidence that certain persons reproducibly demonstrate high COX-2 expression in independent adenomas or cancers, because of genetic predisposition or environmental exposures. It will also be necessary to extend the findings of Chan et al. by demonstrating that prevention of colon adenomas by aspirin or COX-2 inhibitors also involves blocking the development of the highest COX-2–expressing lesions.” (S. D. Markowitz, Case Western Reserve U., Cleveland)
Government in Medicine: Commenting on two Perspectives articles, one on a recent Supreme Court decision on abortion (pp. 2125-8) and the other on “the intimidation of American physicians,” a journal editor expresses this concern about interference of government in medical decisions (pp. 2195): “It is not that physicians do not want oversight and open discussion of delicate matters but, rather, that we want these discussions to occur among informed and knowledgeable people who are acting in the best interests of a specific patient. Government regulation has no place in this process. In 1997, another editor of the Journal, Jerome Kassirer, took Congress to task for practicing medicine without a license. He cited a number of instances, including the passage of a forerunner of the bill that the Supreme Court upheld last week. With Gonzales v. Carhart, the judicial branch has regrettably joined the legislative branch in practicing medicine without a license.” (J. M. Drazen)

>>>PNN NewsWatch
* A new boxed warning is being mandated by FDA on the product labeling of all gadolinium-based contrast agents used to enhance the quality of magnetic resonance imaging (MRI). The warning will state that patients with severe kidney insufficiency who receive gadolinium-based agents are at risk for developing nephrogenic systemic fibrosis (NSF), a debilitating and potentially fatal disease. In addition, the warning cautions that patients who have undergone or are about to undergo liver transplantation, or those with chronic liver disease, are also at risk for developing NSF if they are experiencing kidney insufficiency of any severity. Five gadolinium-based contrast agents have been approved for use in the United States: Magnevist (gadopentetate dimeglumine), Omniscan (gadodiamide), OptiMARK (gadoversetamide), MultiHance (gadobenate dimeglumine), and ProHance (gadoteridol).

PNN Pharmacotherapy Line is published via e-mail each business day except 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
May 25, 2007 * Vol. 14, No. 102
Providing news and information about medications and their proper use

>>>DDW Highlights
More than 16,000 physicians and researchers have been in Washington, D.C., for Digestive Disease Week (www.ddw.org), a convention cosponsored by the American Gastroenterological Assoc. and three other GI groups. Here are some of the highlights of this year’s meeting:
* Prevention and treatment of inflammatory bowel disease was a hot topic, with dozens of studies presented. Rosiglitazone, also in the news this week because of cardiovascular problems reported in a study released by the
New England Journal of Medicine (see PNN, May 22), was shown to be an effective treatment for patients with mild to moderate ulcerative colitis who did not respond to first-line agent 5-aminosalicylic acid. Lewis et al. of U. Penn. reported on outcomes of a randomized, placebo-controlled trial of 105 patients. After 12 weeks of therapy, clinical response was achieved in 23 patients (44%) treated with rosiglitazone 4 mg twice daily and 12 patients (23%) treated with placebo. Patients treated with peroxisome proliferators-activated receptor ligand had higher rates of clinical remission, but not endoscopic remission. Furthermore, patients who took rosiglitazone also experienced improvement in endoscopic appearance, stool frequency, bleeding rates and the physician’s global assessment. Clinical improvement was evident as early as 4 weeks. While the patients’ quality of life was not improved at week 4 or 12, significant changes were seen at week 8.
* Patients with moderately to severely active ulcerative colitis who had responded to infliximab in the blinded phase of the ACT trials (Active Ulcerative Colitis 1 and 2) maintained improvement in their clinical symptoms for up to 2 years, reported Sandborn of the Mayo Clinic and Reinisch of U. Hosp. Vienna. For patients who completed follow-up through week 56 of the extension trials, 92% of 229 responder patients reported mild or no disease activity, as measured by the Physician’s Global Assessment (PGA). For patients followed through 104 weeks, 97% reported mild or no disease activity.
* A survey of 1,000 patients who rated their ulcerative colitis symptoms on a scale of 1 to 5, with 5 being very severe, showed that patients with more severe disease reported greater disability, significantly more days missed from work and significantly more days of reduced productivity, compared with patients with less severe disease. In fact, reported Geswell of the Crohn’s & Colitis Foundation of America, 19% of patients with the most severe disease were on long- or short-term medical leave from work, compared with less than 7% of patients whose disease was less severe. Of patients who were employed, those with the most severe disease missed an average of 19 days of work in the past year, compared with 1 day for those with the mildest disease. Furthermore, even when at work, patients who rated their disease as more severe reported being less productive on more than 30 days in the past year, underscoring the negative impact of ulcerative colitis on patients’ ability to function in the workplace.
* Use of peginterferon alone, or in combination with ribavirin, points to a cure for hepatitis C, according to Shiffman et al. of the Virginia Commonwealth University. Overall, 99% of 997 patients with hepatitis C who were treated successfully with peginterferon alone, or in combination with ribavirin, had no detectable virus up to 7 years later. During a mean follow-up period of 4.1 years, 989 maintained undetectable levels of HCV. The remaining 8 patients tested positive for HCV at an average of 2 years following treatment completion. The study found that these eight patients exhibited no consistency in age, gender or HCV genotype, and the investigators have not determined if these patients experienced a relapse or if they were re-infected with HCV. The researchers said these data validate the use of the word “cure” when describing hepatitis C treatment as successful treatment is defined as having undetectable hepatitis C virus in the blood 6 months following treatment.

>>>PNN NewsWatch
* PNN will not be published on Mon., May 28, Memorial Day.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 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
May 29, 2007 * Vol. 14, No. 103
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
May 26 issue of BMJ (www.bmj.com/content/vol334/issue7603/index.dtl; 2007; 334).
Pharmacists’ Home Visits for HF: While well received by 293 patients with heart failure, home visits by 17 community pharmacists failed to reduce hospital admissions or mortality to the degree observed in other studies involving specialist nurses (pp. 1098 ff). The authors conclude that these findings are problematic for policy makers in the U.K. who had hoped that “skilled community pharmacists” could help reduce the need for hospitalizations in this patient population. Results showed: “136 (91%) intervention patients received one or two visits. 134 admissions occurred in the intervention group compared with 112 in the control group (rate ratio = 1.15, 95% confidence interval 0.89 to 1.48; P = 0.28, Poisson model). 30 intervention patients died compared with 24 controls (hazard ratio = 1.18, 0.69 to 2.03; P = 0.54). Although EQ-5D scores favoured the intervention group, Minnesota living with heart failure questionnaire scores favoured controls; neither difference was statistically significant.” (R. Holland, U. East Anglia, Norwich, U.K.; r.holland@uea.ac.uk)
Pharmacists’ Consultations with Old–Old Patients: “The advice giving role of pharmacists ... has the potential to undermine and threaten the patients’ assumed competence, integrity, and self governance,” investigators conclude based on analysis of discourse during home medication reviews for patients aged 80 years or more who had been hospitalized (pp. 1101 ff). In a follow-up to the HOMER trial (Home Based Medication Review by Pharmacists), researchers identified these problems in an analysis of 29 taped consultations lasting about 45 minutes each: “Pharmacists found many opportunities to offer advice, information, and instruction. These advice giving modes were rarely initiated by the patients and were given despite a no problem response and deliberate displays of competence and knowledge by patients. Advice was often resisted or rejected and created interactional difficulties and awkward moments during the consultations.” (C. Salter, U. East Anglia, Norwich, U.K.; c.salter@uea.ac.uk)

>>>Internal Medicine Report
Source:
May 28 issue of the Archives of Internal Medicine (http://archinte.ama-assn.org/current.dtl; 2007; 167).
Surgical Medication Assessments by Pharmacists: Postoperative medication discrepancies related to patients’ home use of medications were reduced when pharmacists obtained medication histories from surgical patients and generated a postoperative medication order form (pp. 1034-40). In the Surgical Pharmacist in Preadmission Clinic Evaluation (SPPACE) study, these results were recorded: “Between April 19, 2005, and June 3, 2005, a total of 464 patients were enrolled in the study, of which 227 and 237 patients were randomized to the intervention and standard care [nurse-conducted medication histories and surgeon-generated medication orders] arms, respectively. In the intervention arm, 41 (20.3%) of 202 patients had at least 1 postoperative medication discrepancy related to home medications, compared with 86 (40.2%) of 214 patients in the standard care arm (P <.001). In the intervention arm, 26 (12.9%) of 202 patients had at least 1 postoperative medication discrepancy with the potential to cause possible or probable harm, compared with 64 (29.9%) of 214 patients in the standard care arm (P <.001). These were mostly omissions of reordering home medications.” (O. A. Fernandes, U. Health Network, Toronto; lavo.fernandes@uhn.on.ca">olavo.fernandes@uhn.on.ca)

>>>PNN JournalWatch
* Acute and Chronic Complications of Type 2 Diabetes Mellitus in Children and Adolescents, in Lancet, 2007; 369: 1823–31. Reprints: O. Pinhas-Hamiel, Sheba Med. Ctr., Tel-Hashomer, Ramat-Gan, Israel; rithami@sheba.health.gov.il">orithami@sheba.health.gov.il
* Evaluation of Serious Adverse Drug Reactions: A Proactive Pharmacovigilance Program (RADAR) vs Safety Activities Conducted by the Food and Drug Administration and Pharmaceutical Manufacturers, in
Archives of Internal Medicine, 2007; 167: 1041–9. Reprints: C. L. Bennett, cbenne@northwestern.edu
* Effect of Soy Nuts on Blood Pressure and Lipid Levels in Hypertensive, Prehypertensive, and Normotensive Postmenopausal Women, in
Archives of Internal Medicine, 2007; 167: 1060–7. Reprints: F. K. Welty, fwelty@bidmc.harvard.edu
* National Standards for Diabetes Self-Management Education, in
Diabetes Care, 2007; 30: 1630–7. Reprints: M. M. Funnell, mfunnell@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
May 30, 2007 * Vol. 14, No. 104
Providing news and information about medications and their proper use

>>>Diabetes Care Highlights
Source:
June issue of Diabetes Care (http://care.diabetesjournals.org/current.shtml; 2007; 30).
Telmisartan, Ramipril, & Renal Endothelial Function: Nitric oxide activity was significantly increased in the renal endothelium in patients treated with either telmisartan 40/80 mg or ramipril 5/10 mg once daily for 9 weeks (pp. 1351-6). Comparing the effects of renin–angiotensin blockade with these two agents, the investigators found similar changes in key parameters of renal endothelial function, leading them to conclude that either the ACE inhibitor or the ARB should “support the preservation of cardiovascular and renal function.” (R.E. Schmieder, Universitätsklinikum Erlangen, Erlangen, Germany; roland.schmieder@rzmail.uni-erlangen.de)
Diabetes Care in Extended-Care Facilities: Care of institutionalized elderly patients fails to meet ADA standards of care for outpatient adults, conclude authors who conducted a retrospective chart review of 108 residents at 11 Midwestern extended health care facilities (pp. 1454-8). “Blood glucose was monitored in 98% of the subjects, and 38% met glucose goals,” the trio writes. “A1C goal was achieved in 67% of patients. Blood pressure was monitored in 94% of patients, with 55% meeting goal. Thirty-one percent of patients had yearly lipids checked, 37% had annual electrocardiograms, 7% had urine analyzed for microalbuminuria, 42% were on aspirin, 87% received foot exams, 42% received dilated eye exams, 89% received influenza vaccinations, and 46% received pneumococcal vaccinations.” (R. M. Holt, Ohio U. College of Osteopathic Med., Athens, Ohio; rh185305@ohio.edu)
Once-Weekly Exenatide: Use of a long-acting release formulation of exenatide provided 24-hour glycemic control and weight reduction in a Phase II trial involving 45 patients with type 2 diabetes (pp. 1487-93). Over the 15 weeks of the study, these results were noted with exenatide LAR 0.8 or 2.0 mg subcutaneously once weekly: “From baseline to week 15, exenatide LAR reduced mean ± SE A1C by –1.4 ± 0.3% (0.8 mg) and –1.7 ± 0.3% (2.0 mg), compared with +0.4 ± 0.3% with placebo LAR (P < 0.0001 for both). A1C of 7% was achieved by 36 and 86% of subjects receiving 0.8 and 2.0 mg exenatide LAR, respectively, compared with 0% of subjects receiving placebo LAR. Fasting plasma glucose was reduced by –2.4 ± 0.9 mmol/l (0.8 mg) and –2.2 ± 0.5 mmol/l (2.0 mg) compared with +1.0 ± 0.7 mmol/l with placebo LAR (P < 0.001 for both). Exenatide LAR reduced self-monitored postprandial hyperglycemia. Subjects receiving 2.0 mg exenatide LAR had body weight reductions (–3.8 ± 1.4 kg) (P < 0.05), whereas body weight was unchanged with both placebo LAR and the 0.8-mg dose. Mild nausea was the most frequent adverse event. No subjects treated with exenatide LAR withdrew from the study.” (D. Kim, MD, dkim@amylin.com)

>>>PNN NewsWatch
* FDA has announced its intention to take action against companies that market unapproved timed-release guaifenesin products. Only Adams Respiratory Therapeutics’ Mucinex and Humibid products are approved. Some 20 other firms make timed-release products containing guaifenesin that have not undergone FDA review and as a result are considered by the agency to be unapproved drugs. This action does not affect products containing guaifenesin in immediate-release form, but rather affects only timed-release (extended-release, long-acting, or sustained-release) forms. Companies marketing unapproved products containing guaifenesin in timed-release form are expected to stop manufacturing them within 90 days and must cease shipping them in interstate commerce within 180 days, FDA said. A small amount of these products is expected to be available after these dates until supplies are exhausted.
*
Advanced Medical Optics has recalled Complete MoisturePlus Multi Purpose Solution because of reports of rare but serious eye infections involving the parasite Acanthamoeba keratitis. FDA and CDC said that consumers should stop using the product, discard partially used or unopened bottles, and ask their physician about an appropriate alternative cleaning/disinfecting product. They should also seek immediate treatment if they have symptoms of eye infection (eye pain or redness, blurred vision, light sensitivity, sensation of something in the eye, or excessive tearing).

PNN Pharmacotherapy Line is published via e-mail each business day except 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
May 31, 2007 * Vol. 14, No. 105
Providing news and information about medications and their proper use

>>>Temsirolimus Approved for Renal Cell Carcinoma
FDA yesterday approved temsirolimus (Torisel, Wyeth) for treatment renal cell carcinoma, which accounts for 85% of cases of kidney cancer. The mammalian target of rapamycin (mTOR) kinase inhibitor prolonged survival of patients with this condition.
In a news release, FDA noted that the approval of temsirolimus follows the December 2005 approval of sorafenib based on delay in progression of disease. In January 2006, sunitinib received accelerated approval based on durable response rate, or tumor size reduction, and was later demonstrated to delay tumor progression.
The safety and effectiveness of temsirolimus were demonstrated in a clinical trial of 626 patients who received temsirolimus, interferon alfa, or both drugs. The group of patients who received temsirolimus alone showed a significant improvement in overall median survival and progression-free survival (see next article for results of the pivotal clinical trial).
The most common adverse reactions, occurring in at least 30% of temsirolimus-treated patients, were rash, fatigue, mouth sores, nausea, edema, and loss of appetite. The most common laboratory abnormalities were hyperglycemia (which may require treatment with insulin or oral hypoglycemic agents), elevated blood lipids and triglycerides, elevated liver and kidney blood tests, and low red cell, white cell, and platelet counts. The drug can induce immunosuppression, and patients should be monitored for opportunistic infections. Hypersensitivity reactions manifested by symptoms—including anaphylaxis, dyspnea, flushing, and chest pain—have been observed with temsirolimus. Live vaccinations and close contact with those who received live vaccines should be avoided. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant. Rare but serious adverse effects associated with temsirolimus therapy include interstitial lung disease, bowel perforation, renal failure, abnormal wound healing, and in patients with central nervous system tumors and/or taking anticoagulants, intracerebral bleeding.

>>>NEJM Highlights
Source:
May 31 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2007; 356).
Temsirolimus for Metastatic Renal-Cell Carcinoma: Patients with metastatic renal-cell carcinoma and a poor prognosis had significantly increased median overall survival and progression-free survival when treated with the just-approved kinase inhibitor temsirolimus (see above article), compared with interferon-alfa (pp. 2271-81). The pivotal Phase III trial included 626 patients with previously untreated, poor-prognosis metastatic renal-cell carcinoma, and they received intravenous temsirolimus 25 mg weekly, interferon alfa 3 million units(with an increase to 18 million units) subcutaneously three times weekly, or combination therapy with temsirolimus 15 mg weekly plus interferon alfa 6 million units three times weekly.
Results showed the following: “Patients who received temsirolimus alone had longer overall survival (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.58 to 0.92; P = 0.008) and progression-free survival (P <0.001) than did patients who received interferon alone. Overall survival in the combination-therapy group did not differ significantly from that in the interferon group (hazard ratio, 0.96; 95% CI, 0.76 to 1.20; P = 0.70). Median overall survival times in the interferon group, the temsirolimus group, and the combination-therapy group were 7.3, 10.9, and 8.4 months, respectively. Rash, peripheral edema, hyperglycemia, and hyperlipidemia were more common in the temsirolimus group, whereas asthenia was more common in the interferon group. There were fewer patients with serious adverse events in the temsirolimus group than in the interferon group (P = 0.02).” (G. Hudes, Fox Chase Cancer Ctr., Philadelphia;
gary.hudes@fccc.edu)
Urea-Cycle Disorders: In 299 patients with urea-cycle disorders, catabolism was prevented through prompt recognition and treatment with sodium phenylacetate and sodium benzoate therapy (Ammonul, Ucyclyd Pharma; pp. 2282-92). Results are presented from an open-label, 25-year, uncontrolled study of 1,181 episodes of acute hyperammonemia in the patients. (G. M. Enns, greg.enns@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
June 1, 2007 * Vol. 14, No. 106
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
June issue of Pharmacotherapy (www.pharmacotherapy.org; 2007; 27).
Pharmacist-Run Teriparatide Clinic: Significant increases in bone mineral density in total hip and spinal sites occurred among 60 patients with osteoporosis who were seen in a pharmacist-run teriparatide clinic (pp. 779-88). However, BMDs in patients’ wrists were significantly reduced during the 2002–03 time period of this prospective observational study. Patients were referred to the clinic by endocrinologists because of fractures or adverse events occurring during antiresorptive therapy. The authors report: “Patients’ BMDs for the hip significantly increased by 3.5% at 1 year and by 3.9% at 2 years. In addition, BMD for the spine significantly increased by 7.2% at 1 year and 10.9% at 2 years. In 56 (93%) patients, BMD for the spine increased after 2 years of treatment. For the wrist, BMD decreased by 0.75% at 1 year and by 2.4% at 2 years, but the change was only significant at 2 years (p = 0.011). At both 1 and 2 years, T scores for the total hip and spine significantly improved from baseline (p ≤0.019), whereas T scores for the wrist significantly declined after 2 years of therapy (p <0.003). No new fractures were documented in any of the patients.” (J. S. Stroup, jeffrey.stroup@okstate.edu)
4-Aminopyridine Therapy in Spinal Cord Injury: Long-term administration of 4-aminopyridine significantly improved glucose tolerance among 31 patients with spinal cord injury, (pp. 789-92). Concluding that the therapy should be studied in randomized controlled trials for this common complication of spinal cord injury, investigators provide these findings from this prospective study blinded to dosage levels: “Of the 31 patients, 29 (94%) had impaired glucose tolerance at baseline. After 6 months of treatment with 4-aminopyridine, 12 (41%) of the 29 patients had a 2-hour postprandial glucose level that no longer supported a diagnosis of impaired glucose tolerance. No significant changes or clinically important trends were seen in fasting blood glucose concentrations or in other glucokinetic parameters in these patients.” (J. L. Segal, Harbor–UCLA Med. Ctr., Torrance, Calif.; Segaljl@earthlink.net)
Posaconazole–Immunosuppressant Interaction: Consistent with recommendations for other azole antifungal agents, the dosages of cyclosporine and tacrolimus should be reduced when either drug is used concomitantly with posaconazole, based on data from four patients with heart transplants and 36 healthy volunteers (pp. 825-34). “Coadministration of posaconazole increased cyclosporine exposure and necessitated dosage reductions of 14–29% for cyclosporine in three subjects,” the authors write. “Posaconazole increased the maximum blood concentration and the area under the concentration–time curve for tacrolimus by 121% and 358%, respectively, on day 14 compared with day 1 (both p = 0.001). In both studies, posaconazole pharmacokinetics were unaffected.” (A. Sansone-Parsons, Schering-Plough Corp., Kenilworth, N.J.; angela.sansone@spcorp.com)
Statin Therapy in HCV-Positive Men: Statins were effective and safe with regard to hepatotoxicity among 146 men who were seropositive for hepatitis C virus (pp. 845-51). Retrospective review of a registry of patients with HCV at a VA medical center between 1995 and 2003 showed these monitoring patterns and clinical outcomes: “Demographic and clinical data were collected for each patient; lipid and alanine aminotransferase (ALT) levels at baseline (within 6 mo of starting a statin), at 3 and 6 months after starting a statin, and at long-term follow-up (mean 22 mo) were also recorded. The primary efficacy end point was a significant decrease from baseline to long-term follow-up low-density lipoprotein cholesterol (LDL) level; the primary safety end point was a significant increase from baseline in ALT level. The mean change in LDL level was a reduction of 22% (p <0.01). No significant increases in ALT levels were observed; only one patient discontinued therapy due to ALT level elevations greater than 3 times the upper limit of normal.” (M. Segarra-Newnham, marisel.segarra-newnham@med.va.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
June 4, 2007 * Vol. 14, No. 107
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
June 2 Lancet and early-release article from Lancet Oncology (www.thelancet.com; 2007; 369).
Papillomavirus Vaccine & Cervical Cancer: The risk of cervical precancers and cancer associated with human papilloma viruses 16 and 18 can be substantially reduced through use of the quadrivalent HPV (6/11/16/18) vaccine in HPV-naive women and those who are already sexually active (pp. 1861-8). This conclusion comes from the Future II Study Group, which administered the vaccine or placebo to 10,583 women aged 16–26 years and monitored them with periodic Papanicolaou testing. “Mean follow-up was 3.0 years (SD 0.66) after first dose,” the group reports. “In women negative for HPV16 or HPV18 infection during the vaccination regimen (n = 17,129, per protocol), vaccine efficacy was 99% for the primary endpoint (95% CI 93–100), meeting the statistical criterion for success. In an intention-to-treat analysis of all randomised women (including those who were HPV16/18 naive or HPV16/18-infected at day 1), efficacy was 44% (95% CI 31–55); all but one case in vaccine recipients occurred in women infected with HPV16 or HPV18 before vaccination. In a second intention-to-treat analysis we noted an 18% reduction (95% CI 7–29) in the overall rate of [cervical intraepithelial neoplasia] 2/3 or AIS due to any HPV type.” (K. A. Ault, kevin.ault@emory.edu)
Folic Acid for Stroke Prevention: Folic acid supplementation for purposes of reducing cardiovascular risk through primary prevention is an effective strategy for reducing the risk of stroke in patients, according to a meta-analysis of eight randomized trials (pp. 1876-82): “Folic acid supplementation significantly reduced the risk of stroke by 18% (RR 0.82, 95% CI 0.68–1.00; p = 0.045). In the stratified analyses, a greater beneficial effect was seen in those trials with a treatment duration of more than 36 months (0.71, 0.57–0.87; p = 0.001), a decrease in the concentration of homocysteine of more than 20% (0.77, 0.63–0.94; p = 0.012), no fortification or partly fortified grain (0.75, 0.62–0.91; p = 0.003), and no history of stroke (0.75, 0.62–0.90; p = 0.002). In the corresponding comparison groups, the estimated RRs were attenuated and insignificant.” (X. Wang, Children’s Memorial Hosp., Chicago; xbwang@childrensmemorial.org)
Sertraline in Advanced Cancer: Sertraline, compared with placebo in 189 patients with advanced cancer but not major depression, did not improve symptoms, well being, or survival in a double-blinded trial that was stopped early because of lack of benefit (doi: 10.1016/S1470-2045(07)70148-1). Using doses of sertraline of 50 mg/day, the researchers found: “Sertraline had no significant effect (scale, benefit over placebo [95% CI]) on depression ([Centre for Epidemiologic Studies Depression scale] 0.4 [−2.6 to 3.4]), anxiety ([Hospital Anxiety and Depression Scales] 2.0 [−1.5 to 5.5]), fatigue ( Functional Assessment of Cancer Therapy–Fatigue 0.3 [−4.3 to 4.9]), overall quality of life ([Functional Assessment of Cancer Therapy–General] 1.7 [−1.3 to 4.7]), or clinicians’ ratings (SQLI 2.0 [−2.5 to 6.5]), and the 95% CI ruled out a clinically significant benefit for all main outcomes. Sertraline was discontinued more often and earlier than was placebo (hazard ratio 1.46 [1.03–2.06], p = 0.03). Recruitment was stopped after the first planned interim analysis in February 2006 showed that survival was longer in patients assigned placebo than in patients assigned sertraline (unadjusted hazard ratio 1.60 [95% CI 1.04–2.45], log-rank p = 0.04; n = 150; and adjusted for other independently significant baseline prognostic factors adjusted hazard ratio 1.62 [1.06–2.41, Cox model p = 0.02). However, at the final analysis in July 2006 of all patients and with longer follow-up, survival did not differ between the treatment groups (unadjusted hazard ratio 1.35 [0.95–1.91], log-rank p = 0.09; and after adjustment for independently significant prognostic factors adjusted hazard ratio 1.27 [0.87–1.84], Cox model p = 0.20).” (M. R. Stockler, U. Sydney, Camperdown, New South Wales, Australia; stockler@med.usyd.edu.au)

>>>PNN JournalWatch
* Rape and Sexual Assault, in BMJ, 2007; 334: 1154–8. Reprints: J. Welch, King’s College Hospital, London; jan.welch@kingsch.nhs.uk
* Acute Myopericarditis After Multiple Vaccinations in an Adolescent: Case Report and Review of the Literature, in
Pediatrics, 2007; 119: e1400–3. Reprints: M. T. Thanjan, Mount Sinai Med. Ctr., 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
June 5, 2007 * Vol. 14, No. 108
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
June 5 issue of the Annals of Internal Medicine (www.annals.org/current.shtml; 2007; 146).
Mortality with Antipsychotic Drug Use in Older Patients with Dementia: In a population-based, retrospective, matched-cohort study of older patients with dementia, use of conventional or atypical antipsychotic agents was associated with an increased risk of mortality (pp. 775-86). Considering both community-dwelling and institutionalized patients in Ontario, the investigators found these associations in the 1997–2003 data: “A total of 27,259 matched pairs were identified. New use of atypical antipsychotics was associated with a statistically significant increase in the risk for death at 30 days compared with nonuse in both the community-dwelling cohort (adjusted hazard ratio, 1.31 [95% CI, 1.02 to 1.70]; absolute risk difference, 0.2 percentage point) and the long-term care cohort (adjusted hazard ratio, 1.55 [CI, 1.15 to 2.07]; absolute risk difference, 1.2 percentage points). Excess risk seemed to persist to 180 days, but unequal rates of censoring over time may have affected these results. Relative to atypical antipsychotic use, conventional antipsychotic use was associated with a higher risk for death at all time points. Sensitivity analysis revealed that unmeasured confounders that increase the risk for death could diminish or eliminate the observed associations.”
Placing these results in perspective, the authors provide these “implications for clinical practice”: “First, conventional antipsychotics seem to be associated with a higher risk for death than are atypical antipsychotics. Second, the estimated mortality rate among study participants was high, especially in the long-term care setting (as one might expect among vulnerable older adults with dementia). Despite these high mortality rates, we can still detect excess mortality associated with exposure to antipsychotics. In ... U.S. FDA and Health Canada reviews, the risk for death seemed to be a class effect with all atypical antipsychotics studied, and 2 meta-analyses confirmed these findings. Thus, switching between individual atypical antipsychotics in an attempt to modify the risk for death cannot be recommended. Finally, and perhaps most complex, the role of atypical antipsychotics in the management of behavioral and psychological symptoms of dementia must be carefully reviewed.” (S. S. Gill, St. Mary’s of the Lake Hosp., Kingston, Ont., Canada)
Vitamins, Homocysteine, & VTE: Despite a reduction in homocysteine levels associated with daily supplements of folic acid 2.5 mg, vitamin B6 50 mg, and vitamin B12 1 mg, patients’ risk for venous thromboembolism was not significantly different from those taking placebo in the 5-year study (pp. 761-7). The Heart Outcomes Prevention Evaluation 2 (HOPE-2) trial included 5,522 patients aged 55 years or older with known cardiovascular disease or diabetes mellitus and at least 1 other risk factor for vascular disease were followed at 145 centers in 13 countries, and reports these results: “The geometric mean homocysteine level decreased by 2.2 µmol/L in the vitamin therapy group and increased by 0.80 µmol/L in the placebo group. Venous thromboembolism occurred in 88 participants during a mean follow-up of 5 years. The incidence rate of venous thromboembolism was the same in the vitamin therapy group and the placebo group (0.35 per 100 person–years; hazard ratio, 1.01 [95% CI, 0.66 to 1.53]). Vitamin therapy did not reduce the risk for deep venous thrombosis (hazard ratio, 1.04 [CI, 0.63 to 1.72]), pulmonary embolism (hazard ratio, 1.14 [CI, 0.57 to 2.28]), or unprovoked venous thromboembolism (hazard ratio, 1.21 [CI, 0.66 to 2.23]).” (J. G. Ray, St. Michael’s Hosp., Toronto; rayj@smh.toronto.on.ca)
Assessment of Rheumatoid Arthritis: Autoantibodies against cyclic citrullinated peptide “are more specific than [rheumatoid factor] for diagnosing rheumatoid arthritis and may better predict erosive disease,” conclude researchers who conducted a meta-analysis of 87 studies (pp. 797-808; K. Nishimura, knishimu@hsph.harvard.edu)

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

PNN Pharmacotherapy Line
June 6, 2007 * Vol. 14, No. 109
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
June 6 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2007; 297).
Folic Acid for Preventing Colorectal Adenomas: In a 10-year, double-blind, placebo-controlled, randomized clinical trial, folic acid in doses of 1 mg/day failed to reduce colorectal adenoma risk among 1,021 men and women with recent histories of colorectal adenomas and no history of invasive colon cancer (pp. 2351-9). Participants were randomized to either folate or placebo and were separately randomized to aspirin 81 or 325 mg/day or placebo, with these results: “During the first 3 years, 987 participants (96.7%) underwent colonoscopic follow-up, and the incidence of at least 1 colorectal adenoma was 44.1% for folic acid (n = 221) and 42.4% for placebo (n = 206) (unadjusted risk ratio [RR], 1.04; 95% confidence interval [CI], 0.90–1.20; P = .58). Incidence of at least 1 advanced lesion was 11.4% for folic acid (n = 57) and 8.6% for placebo (n = 42) (unadjusted RR, 1.32; 95% CI, 0.90–1.92; P = .15). A total of 607 participants (59.5%) underwent a second follow-up, and the incidence of at least 1 colorectal adenoma was 41.9% for folic acid (n = 127) and 37.2% for placebo (n = 113) (unadjusted RR, 1.13; 95% CI, 0.93–1.37; P = .23); and incidence of at least 1 advanced lesion was 11.6% for folic acid (n = 35) and 6.9% for placebo (n = 21) (unadjusted RR, 1.67; 95% CI, 1.00–2.80; P = .05). Folic acid was associated with higher risks of having 3 or more adenomas and of noncolorectal cancers. There was no significant effect modification by sex, age, smoking, alcohol use, body mass index, baseline plasma folate, or aspirin allocation.” (B. F. Cole, bernard.cole@dartmouth.edu)
Editorialists write that “timing is everything” with respect to folate prevention of cancer (pp. 2408-9): “Because the timing of folate administration during carcinogenesis matters, the results from this trial do not provide data on primary prevention. However, they certainly provide a definitive answer that, among patients with resected adenoma, folic acid intake of 1 mg/d, which can be achieved with 2 multivitamins plus folic acid from fortified foods, is not beneficial for adenoma prevention. The results also highlight several important research needs on the role of folate in carcinogenesis.” These are a better understanding is needed about the dosage, duration, and timing effects of folic acid on the growth of early neoplastic lesions and slow-growing tumors, information on the effects of folic acid on patients with unresected colorectal polyps, and research into the effects of folate supplementation in patients with cancer. (C. M. Ulrich, Fred Hutchinson Cancer Research Ctr., Seattle;
nulrich@fhcrc.org)
Rectal Artemisinin Derivatives for Malaria: While available rectal preparations of artemisinin derivatives differ importantly in bioavailability, artesunate and artemisinin have acceptable therapeutic efficacy in malaria, including in severe cases, according to a review article (pp. 2381-90). “Thirty-two studies provided valid clinical efficacy data: 19 of artesunate, 10 of artemisinin, 2 of dihydroartemisinin, and 1 of artemether,” the authors write. “All demonstrated prompt parasite clearance, with evidence of a dose-dependent effect for artesunate. Mortality rates in severe malaria (weighted means, 0%–13%) were consistent with those expected. Eight studies compared rectal artemisinin with conventional parenteral treatment (quinine, artemether, or artesunate) for severe malaria. Despite similar clinical outcomes, rectal artemisinin derivatives initiated parasite clearance more rapidly than parenteral treatment (percentage of baseline at 12 hours, 27% vs 56%, respectively). Eighteen pharmacokinetic studies were identified, including 13 of artesunate. There was marked interindividual variability in most pharmacokinetic variables, but artesunate achieved an earlier Tmax and higher Cmax and area under the plasma concentration–time curve than other artemisinin derivatives.” (T. M. E. Davis, Fremantle Hosp., Fremantle, Western Australia, Australia; tdavis@cyllene.uwa.edu.au)

>>>PNN NewsWatch
* The STS-7 Continuous Glucose Monitoring System (DexCom), approved this week by FDA, measures glucose levels every 5 minutes throughout a 7-day period.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
June 7, 2007 * Vol. 14, No. 110
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Early-release articles from and the June 7 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2007; 356).
Interim Rosiglitazone Analysis: No significant differences in overall risk of hospitalization or death from cardiovascular causes were found among patients taking rosiglitazone in an unplanned interim analysis of data from the RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes) trial, but an increased risk of heart failure was associated with the embattled antidiabetic drug (doi: 10.1056/NEJMoa073394). The randomized, open-label, noninferiority trial, which is ongoing, includes 4,447 patients with type 2 diabetes who had inadequate glycemic control while receiving metformin or sulfonylurea. Comparing safety aspects of add-on rosiglitazone with metformin plus sulfonylurea, the investigators found: “Because the mean follow-up was only 3.75 years, our interim analysis had limited statistical power to detect treatment differences. A total of 217 patients in the rosiglitazone group and 202 patients in the control group had the adjudicated primary end point [hospitalization or death from cardiovascular causes] (hazard ratio, 1.08; 95% confidence interval [CI], 0.89 to 1.31). After the inclusion of end points pending adjudication, the hazard ratio was 1.11 (95% CI, 0.93 to 1.32). There were no statistically significant differences between the rosiglitazone group and the control group regarding myocardial infarction and death from cardiovascular causes or any cause. There were more patients with heart failure in the rosiglitazone group than in the control group (hazard ratio, 2.15; 95% CI, 1.30 to 3.57).” (P. D. Home, Med. Sch., Framlington Place, Newcastle upon Tyne, U.K.; philip.home@newcastle.ac.uk)
Continuing what some
media have portrayed as an effort to influence the current debate of FDA reauthorization legislation on Capitol Hill, NEJM released three editorials expressing concerns over the safety of rosiglitazone. Journal editors discuss “continued uncertainty about the cardiovascular safety of rosiglitazone” (doi: 10.1056/NEJMe078118; J. M. Drazen). David M. Nathan of Harvard Medical School adds (doi: 10.1056/NEJMe078117): “It is reasonable to ask whether physicians should feel comfortable using a drug that might have an 8% excess risk of severe cardiovascular disease or death from cardiovascular causes. Given the other choices of therapy available, including pioglitazone, which has limited clinical trial data suggesting a protective cardiovascular effect (albeit in a study that has been criticized for its design and its analysis), the answer should be no. Unless further studies can provide convincing assurance that treatment with rosiglitazone does not increase the risk of cardiovascular disease, the largely circumstantial evidence of the meta-analyses and the nonsignificant trend in the current report from the RECORD trial must be taken seriously.” Bruce M. Psaty of U. Wash. and Curt D. Furberg of Wake Forest U. write (doi: 10.1056/NEJMe078116): “Patients and physicians will need to weigh the benefits and risks of treatment with rosiglitazone. Glycemic control and durability appear to be the major benefits. Rosiglitazone is also associated with significant weight gain, an adverse effect on low-density lipoprotein cholesterol, an increased risk of heart failure, an increased risk of fractures in women, and an apparent increase in the risk of myocardial infarction. Patients should not stop treatment on their own, but if they have concerns, they should consult their physicians. Together, patients and physicians can decide whether they wish to suspend the use of rosiglitazone.”
Eprodisate for Renal Disease in AA Amyloidosis: In 183 patients with amyloid A amyloidosis, eprodisate slowed the decline in renal function during a 24-month trial (pp. 2349-60). “Disease was worsened in 24 of 89 patients who received eprodisate (27%) and 38 of 94 patients given placebo (40%, P = 0.06); the hazard ratio for worsening disease with eprodisate treatment was 0.58 (95% confidence interval, 0.37 to 0.93; P = 0.02). The mean rates of decline in creatinine clearance were 10.9 and 15.6 ml per minute per 1.73 m2 of body-surface area per year in the eprodisate and the placebo groups, respectively (P = 0.02). The drug had no significant effect on progression to end-stage renal disease (hazard ratio, 0.54; P = 0.20) or risk of death (hazard ratio, 0.95; P = 0.94).” (L. M. Dember, Boston U., Boston; ldember@bu.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
June 8, 2007 * Vol. 14, No. 111
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
June 12 issue of the Journal of the American College of Cardiology (http://content.onlinejacc.org/current.dtl; 2007; 49).
Adjunctive Enoxaparin During PCI: In an issue focused on substudies from the ExTRACT-TIMI 25 (Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment–Thrombolysis In Myocardial Infarction 25) trial, two articles examine use of enoxaparin when added to other drug therapies in patients with ST-segment elevation myocardial infarction who underwent percutaneous coronary intervention.
“The strategy of ENOX support for fibrinolytic therapy followed by PCI is superior to [unfractionated heparin] and provides a seamless transition from the medical management to the interventional management phase of STEMI without the need for introducing a second anticoagulant in the cardiac catheterization laboratory,” investigators conclude in the first report (pp. 2238-46). Among 20,479 patients with STEMI who received fibrinolytic therapy, ENOX was administered throughout hospitalization or UFH for at least 48 hours, and the blinded study drug was continued if PCI was performed. Examining a primary end point of death or recurrent MI through 30 days among the 4,676 patients who underwent PCI, the researchers found: “After initial fibrinolysis, fewer patients underwent PCI through 30 days in the ENOX versus the UFH group (22.8% vs. 24.2%; p = 0.027). Among patients who underwent PCI by 30 days, the primary end point occurred in 10.7% of ENOX and 13.8% of UFH patients (0.77 relative risk; p < 0.001). There were no differences in major bleeding for ENOX versus UFH (1.4% vs. 1.6%; p = NS). Results were similar when PCI was carried out in patients receiving blinded study drug during PCI (n = 2,178).”
The benefits of EXOX were evident in ExTRACT-TIMI 25 regardless of clopidogrel administration, the second report explains (pp. 2256-63): “Enoxaparin significantly reduced the rate of the composite of death, recurrent myocardial infarction, myocardial ischemia, or stroke, compared with UFH, both in patients (n = 2,173) treated with clopidogrel (10.8% vs. 13.9%, adjusted odds ratio [OR
adj] 0.70, p = 0.013) and in patients (n = 12,918) not treated with clopidogrel (13.3% vs. 15.3%, ORadj 0.85, p = 0.003) with no evidence of heterogeneity (pinteraction = 0.21). The excess risk of TIMI major bleeding with ENOX versus UFH was numerically but not statistically significantly higher in patients treated with clopidogrel (2.7% vs. 1.0%) versus those who were not (2.1% vs. 1.2%) (pinteraction = 0.61). Net clinical benefit (MACE and major bleeding) favored treatment with ENOX over UFH, either with concomitant clopidogrel (absolute risk reduction 2.4%, 95% confidence interval [CI] –0.5% to 5.3%) or without (absolute risk reduction 1.7%, 95% CI 0.5% to 3.0%) (pinteraction = 0.61). (E. M. Antman, eantman@rics.bwh.harvard.edu)
CoQ10 in Statin Myopathy: Noting that coenzyme Q10 has “no known risks” but has shown some benefit in anecdotal and preliminary trials, authors of a state-of-the-art paper conclude, “CoQ10 can be tested in patients requiring statin treatment, who develop statin myalgia, and who cannot be satisfactorily treated with other agents” (pp. 2231-7). The writers note: “Statin treatment reduces circulating levels of CoQ10. The effect of statin therapy on intramuscular levels of CoQ10 is not clear, and data on intramuscular CoQ10 levels in symptomatic patients with statin-associated myopathy are scarce. Mitochondrial function may be impaired by statin therapy, and this effect may be exacerbated by exercise. Supplementation can raise the circulating levels of CoQ10, but data on the effect of CoQ10 supplementation on myopathic symptoms are scarce and contradictory. We conclude that there is insufficient evidence to prove the etiologic role of CoQ10 deficiency in statin-associated myopathy and that large, well-designed clinical trials are required to address this issue. The routine use of CoQ10 cannot be recommended in statin-treated patients.... CoQ10 can be tested in patients requiring statin treatment, who develop statin myalgia, and who cannot be satisfactorily treated with other agents. Some patients may respond, if only via a placebo effect.” (P. D. Thompson, Hartford Hosp., Hartford, Conn.; pthomps@harthosp.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
June 11, 2007 * Vol. 14, No. 112
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Early-release articles from and June 9 issue of Lancet (www.thelancet.com; 2007; 369).
Statin Safety: Safe and well tolerated, statins in widespread use have the potential for “a major effect on the global burden of cardiovascular disease,” concludes the author of a review article (doi: 10.1016/S0140-6736(07)60716-8). “Adverse effects from some statins on muscle, such as myopathy and rhabdomyolysis, are rare at standard doses, and on the liver, in increasing levels of transaminases, are unusual,” the paper notes. “Myopathy—muscle pain or weakness with blood creatine kinase levels more than ten times the upper limit of the normal range—typically occurs in fewer than one in 10,000 patients on standard statin doses. However, this risk varies between statins, and increases with use of higher doses and interacting drugs. Rhabdomyolysis is a rarer and more severe form of myopathy, with myoglobin release into the circulation and risk of renal failure. Stopping statin use reverses these side-effects, usually leading to a full recovery. Asymptomatic increases in concentrations of liver transaminases are recorded with all statins, but are not clearly associated with an increased risk of liver disease.” (J. Armitage, U. Oxford Old Road Campus, Oxford, U.K.; jane.armitage@ctsu.ox.ac.uk)
Administration Route for Misoprostol Abortion: When misoprostol is used for medical abortion, the administration interval can vary between 3 and 12 hours with vaginal administration, but dosing intervals of 3 hours are needed with sublingual doses (pp. 1938-46). Adverse effects are more frequent with sublingual dosing, the authors note, adding these details from a study of 2,066 healthy pregnant women who requested medical abortion during the first 63 days of gestation: “Complete abortion rates at 2-week follow-up were recorded for 431 (84%) in the sublingual and for 434 (85%) women in the vaginal group when misoprostol was given at 3-h intervals (difference 0.4%, 95% CI −4.0 to 4.9, p = 0.85 equivalence shown), and for 399 (78%) in the sublingual and for 425 (83%) in the vaginal 12-h groups (4.6%, −0.2 to 9.5, p = 0.06, equivalence not shown). In the 3-h groups, pregnancy continued in 29 (6%) women after sublingual and in 20 (4%) women after vaginal administration (difference 1.8%, 95% CI −0.8 to 4.4, p = 0.19, equivalence shown); in the 12-h groups it continued in 47 (9%) after sublingual and in 25 (5%) after vaginal administration (4.4%, 1.2–7.5, p = 0.01, vaginal better than sublingual). Differences for complete abortion between intervals for sublingual and vaginal routes were 6% (95% CI 1.0–10.6, p = 0.02, 3 h better than 12 h) and 2% (−2.9 to 6.1, p = 0.49, equivalence not shown), respectively; for continuing pregnancies they were 4% (0.4–6.8, p = 0.03, 3 h better than 12 h) and 1% (−1.5 to 3.5, p = 0.44, equivalence shown), respectively.” (H. von Hertzen, vonhertzenh@who.int)

>>>BMJ Highlights
Source:
Early-release article from BMJ (www.bmj.org; 2007; 334).
CBT Plus SSRIs for Adolescent Depression: Cognitive–behavioral therapy and SSRIs were no better among 208 adolescents with moderate to severe major depression than SSRIs plus usual clinical care in a 28-week trial (doi: 10.1136/bmj.39224.494340.55). Assessing a primary outcome of change in score on the Health the Nation instrument, the authors report: “At 12 weeks the treatment effect for the primary outcome was –0.64 (95% confidence interval –2.54 to 1.26, P = 0.50). In a longitudinal analysis, there was no difference in effectiveness of treatment for the primary (average treatment effect 0.001, –1.52 to 1.52, P = 0.99) or secondary outcome measures. On average there was a decrease in suicidal thoughts and self harm. There was no evidence of a protective effect of cognitive behaviour therapy on suicidal thinking or action. By 28 weeks, 57% were much or very much improved with 20% remaining unimproved.” (I. Goodyer, Cambridge U., Cambridge, U.K.; ig104@cam.ac.uk)

>>PNN JournalWatch
* Neuroleptic Malignant Syndrome, in American Journal of Psychiatry, 2007; 164: 870–6. Reprints: J. R. Strawn.
* The Challenges Posed by Reemerging
Clostridium difficile Infection, in Clinical Infectious Diseases, 2007; 45. Reprints: D. B. Blossom, CDC, Atlanta.
* Advances in Allergic Skin Disease, Anaphylaxis, and Hypersensitivity Reactions to Foods, Drugs, and Insects, in
Journal of Allergy and Clinical Immunology, 2007; 119: 1462–9. Reprints: S. H. Sicherer, Mount Sinai Hosp., New York; scott.sicherer@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
June 12, 2007 * Vol. 14, No. 113
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
June 11 issue of the Archives of Internal Medicine (http://archinte.ama-assn.org/current.dtl; 2007; 167).
Cardiovascular & Kidney Disease: Two articles and an editorial explore the relationship between cardiovascular and kidney diseases.
In the Kidney Early Evaluation Program (KEEP), anemia, estimated glomerular filtration rate, and microalbuminuria are independently associated with cardiovascular disease (pp. 1122-9). When all three factors were present in a cohort of 37,153 persons screened in the National Kidney Foundation’s Kidney Early Evaluation Program and followed for a median of 16 months, CVD was common and survival was reduced, the investigators noted, adding these results: “The mean ± SD age was 52.9 ± 15.9 years, and 68.7% were female. A total of 1,835 (4.9%) had a self-reported history of myocardial infarction, 1,336 (3.6%) had a history of stroke, and 2897 (7.8%) had a history of myocardial infarction or stroke. Multivariate analysis controlling for age demonstrated that the following were independently associated with CVD: male sex (odds ratio [OR], 1.64; P <.001), smoking (OR, 1.73; P <.001), body mass index (OR, 1.01; P = .03), diabetes mellitus (OR, 1.66; P <.001), hypertension (OR, 1.77; P <.001), eGFR of 30 to 59 mL/min per 173 m
3 (OR, 1.37; P = .001), hemoglobin level of 12.8 g/dL or less (OR, 1.45; P <.001), and microalbuminuria of greater than 30 mg/L (OR, 1.28; P = .01). Survival analysis found CVD (OR, 3.02; P = .003), chronic kidney disease (OR, 1.98; P = .05), and the combination (OR, 3.80; P <.001) to be independent predictors of mortality. Persons with a combination of all 3 chronic kidney disease measures (anemia, microalbuminuria, and eGFR of <60 mL/min per 1.73 m2) had the lowest survival of about 93% by the end of 30 months.” (P. A. McCullough, William Beaumont Hosp., Royal Oak, Mich.; pmc975@yahoo.com)
CVD can also be a cause of renal decline, conclude authors who analyzed data from two longitudinal studies, the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study (pp. 1130-6): “Among 13,826 individuals, the mean ± SD baseline serum creatinine level was 0.9 ± 0.2 mg/dL (79.6 ± 17.7 µmol/L), and the mean ± SD baseline eGFR was 89.8 ± 20.1 mL/min per 1.73 m
2. In serum creatinine level–based models, 520 individuals (3.8%) experienced kidney function decline, and 314 individuals (2.3%) developed kidney disease during a mean ± SD of 9.3 ± 0.9 years of follow-up. Baseline CVD, present in 1787 individuals (12.9%), was associated with an increased risk of all outcomes (odds ratio, 1.70; 95% confidence interval, 1.36–2.13), an odds ratio of 1.75 (95% confidence interval, 1.32–2.32) for serum creatinine level, and odds ratios of 1.28 (95% confidence interval, 1.13–1.45) and 1.54 (95% confidence interval, 1.26–1.89) for eGFR for kidney function decline and development of kidney disease, respectively.” (D. E. Weiner, Tufts–New England Med. Ctr., Boston; dweiner@tufts-nemc.org)
Editorialists add these perspectives on CKD/CVD (pp. 1113-5): “The presence of atherosclerotic CVD should now be recognized as an independent risk factor for the development and progression of kidney disease. When caring for individuals with preexisting CVD and multiple CVD risk factors, primary care physicians and cardiologists should be vigilant in checking for the development and progression of CKD. Moreover, attention should be directed to the potential complications of kidney disease that may require consultation by a nephrologist. Surveys have suggested that primary care physicians do not routinely screen for CKD those patients with diabetes or hypertension; and fewer than 33% of patients with CKD receive angiotensin-converting enzyme inhibitors. It is reasonable to encourage screening for most patients in such high-risk groups. Late referral to nephrology is common, especially among young African American men. Such data suggest that we have a serious problem with quality of care for CKD in the United States.... The potential for achieving current treatment goals in individuals at risk for nephropathy and CVD using a more focused approach promises greater reductions in future CVD and ESRD events.” (T. D. DuBose, Jr., Wake Forest U., Winston-Salem, N.C.;
tdubose@wfubmc.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 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
June 13, 2007 * Vol. 14, No. 114
Providing news and information about medications and their proper use

>>>Psychiatry Highlights
Source:
June issue of the American Journal of Psychiatry (http://ajp.psychiatryonline.org/current.dtl; 2007; 164).
Treatment for Pediatric Depression After Suicidality Warnings: Aggregate rates of diagnosis and treatment of depression in pediatric patients fell significantly following the 2003 warnings by FDA of suicidality associated with use of SSRIs in this age group, researchers report (pp. 884-91). From a national claims database, a large pediatric cohort with newly diagnosed episodes of depression was identified over the Oct. 1998 to Sept. 2005 time period. Experiences in the 65,349 patients showed the following: “From 1999 to 2004, pediatric diagnoses of depression increased from 3 to 5 per 1,000. After the FDA advisory was issued, the national rate decreased to 1999 levels, a significant deviation from the historical trend. Pediatricians and nonpediatrician primary care physicians accounted for the largest reductions in new diagnoses. Among patients with depression, the proportion receiving no antidepressant increased to three times the rate predicted by the preadvisory trend, and SSRI prescription fills were 58% lower than predicted by the trend. There was no evidence of a significant increase in use of treatment alternatives (psychotherapy, atypical antipsychotics, and anxiolytics).” (A. M. Libby)
Augmentation of Antidepressants in Older Adults: In 195 older adults with major depression who responded inadequately to paroxetine plus interpersonal psychotherapy, augmentation of treatment with bupropion, nortriptyline, or lithium produced recoveries in one-half of the patients (pp. 892-9). Overall, 105 (53.8%) of patients required augmentation because of inadequate response (77 patients) or relapse after recovery (36), and 69 of these patients received augmentation. Based on recovery in one-half of those patients, the investigators make these observations: “Need for augmentation presages slower recovery in patients showing initial inadequate response; those requiring it after early relapse recovered more quickly. Strategies to further improve the likelihood and speed of recovery after initial treatment failure are needed.” (M. A. Dew)
Duloxetine for Depression: In a randomized trial conducted in 311 elderly patients with recurrent major depressive disorder, duloxetine improved cognition, depression, and some pain measures (pp. 900-9). Comparing duloxetine 60 mg/day and placebo for 8 weeks, the authors found: “Patients had a median age of 72 years (range = 65–90). Duloxetine demonstrated significantly greater improvement in the composite cognitive score versus placebo (least-squares mean change from baseline to endpoint: 1.95 versus 0.76), driven by improved verbal learning and memory. Duloxetine treatment showed significantly greater baseline-to-endpoint reductions in both Hamilton depression scale (–6.49 versus –3.72) and Geriatric Depression Scale (–4.07 versus –1.34) total scores compared with placebo. Hamilton depression scale response (37.3% versus 18.6%) and remission (27.4% versus 14.7%) rates at endpoint were significantly higher for duloxetine than for placebo. Duloxetine significantly improved Visual Analogue Scale scores for back pain and time in pain while awake versus placebo. Significantly fewer patients receiving duloxetine withdrew from the study because of lack of efficacy (2.9% versus 9.6%); the incidences of discontinuation due to adverse events were similar for duloxetine and placebo (9.7% versus 8.7%).” (J. Raskin)

>>>PNN NewsWatch
* The APhA Foundation presented the 10th annual Pinnacle Awards last night in Washington, D.C. Honored in the individual category was Dennis K. Helling, PharmD, DSc, FCCP, FASHP, Executive Director, Pharmacy Operations and Therapeutics, Kaiser Permanente–Colorado Region, and Clinical Professor, U. Colorado School of Pharmacy, Denver, Colo. University of Southern California Community Pharmacy Group, Los Angeles, Calif., received the 2007 award in the Group Practice/Health System/Corporation Category. In the Government Agencies/Nonprofit Organizations Category, the National Coordinating Council for Medication Error Reporting and Prevention, Rockville, Md., was honored.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
June 14, 2007 * Vol. 14, No. 115
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
June 14 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2007; 356).
Treating Invasive Candidiasis: Two articles and an editorial examine use of antifungal agents in adults and preterm neonates.
For treating invasive candidiasis in adult patients, anidulafungin was noninferior to fluconazole (pp. 2472-82). Participants received one of the two study drugs, administered first intravenously and then as tolerated by mouth, with these results: “Eighty-nine percent of the 245 patients in the primary analysis had candidemia only.
Candida albicans was isolated in 62% of the 245 patients. In vitro fluconazole resistance was infrequent. Most of the patients (97%) did not have neutropenia. At the end of intravenous therapy, treatment was successful in 75.6% of patients treated with anidulafungin, as compared with 60.2% of those treated with fluconazole (difference, 15.4 percentage points; 95% confidence interval [CI], 3.9 to 27.0). The results were similar for other efficacy end points. The statistical analyses failed to show a ‘center effect’; when data from the site enrolling the largest number of patients were removed, success rates at the end of intravenous therapy were 73.2% in the anidulafungin group and 61.1% in the fluconazole group (difference, 12.1 percentage points; 95% CI, –1.1 to 25.3). The frequency and types of adverse events were similar in the two groups. The rate of death from all causes was 31% in the fluconazole group and 23% in the anidulafungin group (P = 0.13).” (A. C. Reboli, Cooper U. Hosp., Camden, N.J.; reboli-annette@cooperhealth.edu)
Among 322 preterm infants weighing less than 1,500 grams at birth, prophylactic fluconazole reduced the incidence of colonization and invasive candida infection (pp. 2483-95). Fluconazole 3 or 6 mg/kg or placebo was administered randomly from birth until day 30 of life (day 45 for neonates weighing less than 1,000 grams at birth), and weekly surveillance cultures and systematic fungal susceptibility testing revealed the following: “Among infants receiving fluconazole, fungal colonization occurred in 9.8% in the 6-mg group and 7.7% in the 3-mg group, as compared with 29.2% in the placebo group (P <0.001 for both fluconazole groups vs. the placebo group). The incidence of invasive fungal infection was 2.7% in the 6-mg group and 3.8% in the 3-mg group, as compared with 13.2% in the placebo group (P = 0.005 for the 6-mg group and P = 0.02 for the 3-mg group vs. the placebo group). The use of fluconazole did not modify the relationship between colonization and the subsequent development of invasive fungal infection. Overall mortality was similar among groups, as was the incidence of cholestasis. No evidence for the emergence of resistant
Candida species was observed, but the study did not have substantial power to detect such an effect.” (P. Manzoni, Sant’Anna Hosp., Turin, Italy; paolomanzoni@hotmail.com)
All things considered, fluconazole remains the drug of choice for first-line therapy, write editorialists, with echinocandins used initially in specific clinical situations (pp. 2525-6): “In spite of the clinical results with echinocandins in candidemia studies, there is absolutely no justification for abandoning fluconazole, given its safety, overall efficacy, and low cost. The price of echinocandins has dropped substantially but remains severalfold higher than that of generic fluconazole. Moreover, there are clinical scenarios in which azoles may be more effective than echinocandins on the basis of pharmacokinetic considerations, such as in meningitis, endophthalmitis, and candiduria. Likewise, relapse rates of
Candida esophagitis appear to be higher with echinocandins, as compared with azoles. However, in critically ill patients who are hemodynamically unstable and have candidemia, especially when the infection is associated with previous or concurrent exposure to azoles, echinocandins appear to be the drugs of first choice. Several studies have concluded that sequential exchange among drug classes is feasible and safe and that patients started on parenteral polyenes or echinocandins can successfully complete therapy with the use of an oral triazole.” (J. D. Sobel, Wayne State U., Detroit)

>>>PNN NewsWatch
* An FDA advisory panel yesterday voted unanimously to recommend rejection of a new drug application for Sanofi-Aventis’s rimonabant (Acomplia). Psychiatric adverse events were major concerns.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
June 15, 2007 * Vol. 14, No. 116
Providing news and information about medications and their proper use

>>>Geriatrics Highlights
Source:
June issue of the Journal of the American Geriatrics Society (www.blackwell-synergy.com/toc/jgs/55/6; 2007; 55).
Rimantadine-Resistant Influenza: Consistent with later recommendations of the CDC, influenza virus treated with rimantadine quickly developed resistance in a 50-bed nursing unit during the 2004–05 season (pp. 923-6). “A total of 15 symptomatic cases were identified over 8 days,” the authors report. “Amantadine sensitivity was determined in five cases. Three initial cases were sensitive to rimantadine, whereas two cases identified after 6 days of rimantadine prophylaxis were resistant to rimantadine.” While rimantadine treatment is no longer recommended by CDC, the authors hold out the possibility of future utility of the drug: “If reemergence of sensitivity follows discontinuation of rimantadine use, using rimantadine as prophylaxis and oseltamivir for treatment of symptomatic cases might be efficacious and economical on a national scale.” P. J. Drinka, Wisc. Veterans Home, King, Wisc.; Paul.Drinka@dva.state.wi.us)
Depression & Bone Loss: Rates of bone loss at the hip were higher among older women with depression in a population-based prospective cohort study conducted at four U.S. clinical centers (pp. 824-31). Based on depressive symptoms as measured with the Geriatric Depression Scale, investigators found these results among 4,177 community-dwelling women aged 69 years or older: “In age-adjusted models, mean total hip BMD decreased 0.69%/year in 3,977 women with a GDS score of less than 6, compared with 0.96%/year in 200 women with a GDS score of 6 or greater (P <.01). Results were not substantially altered when adjusted for potential confounders and when users of antidepressants were excluded from the analysis.” (S. J. Diem, U. Minnesota, Minneapolis; sdiem@umn.edu)

>>Pediatrics Report
Source:
June issue of Pediatrics (http://pediatrics.aappublications.org/current.shtml; 2007; 119).
Sleep Medications in Hospitalized Pediatric Patients: Despite a lack of FDA-approved medications and consensus guidelines, researchers found that medications are being prescribed for sleep in hospitalized children, especially those with psychiatric diagnoses (pp. 1047-55). Based on a chart review of 26 randomly selected days in 2004, investigators report these results for 9,440 patients (54.5% boys; mean age, 7.0 years; 63% white): “Overall, 6.0% of all hospitalized children (3% of all medically hospitalized children, excluding children with a psychiatric diagnosis) were prescribed medications for sleep, with antihistamines the most frequently prescribed medication (36.6%), followed by benzodiazepines (19.4%); hypnotic agents were the least frequently prescribed (2.2%). Significant differences were found in both the frequency of sleep-medication prescriptions and the types of medications used across hospitals, as well as for age, length of hospitalization, and service that the child was discharged from. Children with a psychiatric diagnosis were more likely to receive a sleep medication, with 22% of children on a psychiatric service receiving a sleep-related medication.” (L. J. Meltzer, Children’s Hosp., Philadelphia)
Zinc, Childhood Diarrhea, and Respiratory Illnesses: In 17 studies assessed using meta-analysis, zinc supplementation reduced significantly the frequency and severity of diarrhea and respiratory illnesses and the duration of diarrheal morbidity (pp. 1120-30). “Children who received a zinc supplement had fewer episodes of diarrhea (rate ratio: 0.86) and respiratory tract infections (rate ratio: 0.92) and significantly fewer attacks of severe diarrhea or dysentery (rate ratio: 0.85), persistent diarrhea (rate ratio: 0.75), and lower respiratory tract infection or pneumonia (rate ratio: 0.80) than did those who received placebo,” the researchers write. “They also had significantly fewer total days with diarrhea (rate ratio: 0.86) but not days with respiratory illness (rate ratio: 0.95). Published studies showed a publication bias and significant heterogeneity; however, no cause for the latter could be identified.” (R. Aggarwal, Sanjay Gandhi Postgraduate Inst. of Med. Sci., Lucknow, India)

PNN Pharmacotherapy Line is published via e-mail each business day except 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
June 18, 2007 * Vol. 14, No. 117
Providing news and information about medications and their proper use

>>>Ambrisentan Approved for Pulmonary Arterial HTN
FDA on Friday approved ambrisentan (Letairis, Gilead) 5 mg and 10 mg tablets. The endothelin receptor antagonist (ERA), reviewed on a priority basis and also approved as an orphan drug, is indicated for once-daily treatment of pulmonary arterial hypertension (WHO Group 1) in patients with WHO Functional Class II or III symptoms to improve exercise capacity and delay clinical worsening.
Gilead noted in a news release that Letairis will be available early this week. Because of the risks of liver injury and birth defects, the product will be distributed on a restricted basis through the Letairis Education and Access Program (LEAP).
The safety and effectiveness of ambrisentan were demonstrated in two international clinical trials involving 393 patients. The drug significantly improved physical activity capacity compared with placebo, as shown by significantly increased 6-minute walk distances after 4 and 12 weeks of treatment (median increases in the 30- to 60-meter ranges for the two approved dosages). Ambrisentan also delayed the worsening of pulmonary hypertension, defined as death, lung transplantation, hospitalization for PAH, atrial septostomy, study withdrawal due to the addition of other PAH therapeutic agents, or study withdrawal due to early escape (progressive disease).
The most common adverse effects in patients using ambrisentan included peripheral edema (6%), nasal congestion (4%), sinusitis (3%), flushing (3%), and palpitations (3%). Most adverse drug reactions were mild or moderate in severity, and only nasal congestion was dose-dependent.
Because of teratogenicity, ambrisentan should not be used by women who are pregnant or may become pregnant. Patients taking ambrisentan must have monthly blood tests to check for potential liver injury.

>>>Lancet Highlights
Source:
June 16 issue of Lancet (www.thelancet.com; 2007; 369).
Alcohol & Deaths of Russian Men: Consumption of alcohol, including nonbeverage sources of the drug, account for almost one-half of all deaths among working-age men in Russian cities, according to a case–control study conducted in Izhevsk (pp. 2001-9). Comparing characteristics of 1,750 men who died at ages 25–54 years in 2003–05 with those of an equal number of controls, the researchers found: “751 (51%) cases were classed as problem drinkers or drank non-beverage alcohol, compared with 192 (13%) controls. The mortality odds ratio (OR) for these men, compared with those who either abstained or were non-problematic beverage drinkers, was 6.0 (95% CI 5.0–7.3) after adjustment for smoking and education. The mortality ORs for drinking non-beverage alcohol in the past year (yes vs no) was 9.2 (7.2–11.7) after adjustment for age. Adjustment for volume of ethanol consumed from beverages lowered the OR to 8.3 (6.5–10.7), and further adjustment for education and smoking reduced it to 7.0 (5.5–9.0). A strong direct gradient with mortality was seen for frequency of non-beverage alcohol drinking independent of volume of beverage ethanol consumed. 43% of mortality was attributable to hazardous drinking (problem drinking or non-beverage alcohol consumption, or both) adjusted for smoking and education.” (D. A. Leon, London Sch. of Hygiene and Tropical Med., London; david.leon@lshtm.ac.uk)

>>>BMJ Highlights
Source:
June 16 issue of BMJ (www.bmj.org; 2007; 334).
Rosiglitazone & Pharmacovigilance: Focusing on the different reactions of the European Medicines Agency and FDA to previous reports and studies of cardiovascular effects of rosiglitazone, an editorialist calls for “a radical change ... in the culture of existing regulatory institutions that regard postmarketing surveillance as their secondary mandate” (pp. 1233-4). The writer adds that physicians should consider replacing rosiglitazone with cheaper and safer alternatives, keeping in mind the associated risks of changing treatments and the “fragility of the available evidence.” (D. Kazi, London Sch. of Economics, London; d.s.kazi@lse.ac.uk)

>>>PNN JournalWatch
* New Therapies for Treatment of Rheumatoid Arthritis, in Lancet, 2007; doi: 10.1016/S0140-6736(07)60784-3. Reprints: J. S. Smolen, Medical U., Vienna; josef.smolen@wienkav.at

PNN Pharmacotherapy Line is published via e-mail each business day except 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
June 19, 2007 * Vol. 14, No. 118
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
June 19 issue of the Annals of Internal Medicine (www.annals.org; 2007; 146).
Adalimumab Induction Therapy for Infliximab-Treated Crohn Disease: In 301 adult patients with Crohn disease who could not tolerate infliximab or had symptoms despite receiving infliximab therapy, adalimumab induced remissions more frequently than did placebo in a 4-week, randomized, double-blind, placebo-controlled trial (pp. 829-38). Looking at a primary end point of induction of remission at week 4 of the moderate or severe symptoms present at baseline, researchers in the Gauging Adalimumab Efficacy in Infliximab Nonresponders (GAIN) trial found: “Twenty-one percent (34 of 159) of patients in the adalimumab group versus 7% (12 of 166) of those in the placebo group achieved remission at week 4 (P < 0.001). The absolute difference in clinical remission rates was 14.2 percentage points (95% CI, 6.7 to 21.6 percentage points). A 70-point response occurred at week 4 in 52% (82 of 159) of patients in the adalimumab group versus 34% (56 of 166) of patients in the placebo group (P = 0.001). The absolute difference in 70-point response rates was 17.8 percentage points (CI, 7.3 to 28.4 percentage points). Two of 159 patients in the adalimumab group and 4 of 166 patients in the placebo group discontinued treatment because of adverse events. No patients in the adalimumab group and 4 of 166 patients in the placebo group had a serious infection.” (W. J. Sandborn, sandborn.william@mayo.edu)
An editorialist analyzes these results within a broader context of research challenges with Crohn disease (pp. 888-90): “The message of the GAIN trial is that clinicians can use adalimumab as a treatment for patients who were previously responsive to infliximab but now are refractory to or intolerant of it. However, fewer patients will respond than those who responded to infliximab initially and only a minority will achieve remission. The medical management of Crohn disease after the patient becomes refractory to anti–TNF-alpha antibodies is a major challenge for the inflammatory bowel disease research community. We will succeed only when we more fully understand the biological mechanisms at play in resurgent inflammatory disease.” (P. Mannon, NIH, Bethesda, Md.)
Genistein in Osteopenic Postmenopausal Women: Bone mineral density improved during 24 months of treatment with the isoflavone phytoestrogen genistein, report investigators who conducted a double-blind, placebo-controlled trial in 389 postmenopausal women with osteopenia (pp. 839-47). All patients received calcium and vitamin D supplements, with these results: “At 24 months, BMD had increased in genistein recipients and decreased in placebo recipients at the anteroposterior lumbar spine (change, 0.049 g/cm2 [95% CI, 0.035 to 0.059] vs. –0.053 g/cm2 [CI, –0.058 to –0.035]; difference, 0.10 g/cm2 [CI, 0.08 to 0.12]; P < 0.001) and the femoral neck (change, 0.035 g/cm2 [CI, 0.025 to 0.042] vs. –0.037 g/cm2 [CI, –0.044 to –0.027]; difference, 0.062 g/cm2 [CI, 0.049 to 0.073]; P < 0.001). Genistein statistically significantly decreased urinary excretion of pyridinoline and deoxypyridinoline, increased levels of bone-specific alkaline phosphatase and insulin-like growth factor I, and did not change endometrial thickness compared with placebo. More genistein recipients than placebo recipients experienced gastrointestinal side effects (19% vs. 8%; P = 0.002) and discontinued the study.” (F. Squadrito, Azienda Ospedaliera Universitaria Policlinico “G. Martino,” Messina, Italy; Francesco.Squadrito@unime.it)
Antithrombotic Therapy in Nonvalvular Atrial Fibrillation: In a meta-analysis of antithrombotic therapy for stroke prevention in patients with nonvalvular atrial fibrillation, warfarin was 40% more effective than antiplatelet therapies (pp. 857-67). Looking at data from 29 trials of 28,044 mostly older patients, the authors found: “Compared with the control, adjusted-dose warfarin (6 trials, 2,900 participants) and antiplatelet agents (8 trials, 4,876 participants) reduced stroke by 64% (95% CI, 49% to 74%) and 22% (CI, 6% to 35%), respectively. Adjusted-dose warfarin was substantially more efficacious than antiplatelet therapy (relative risk reduction, 39% [CI, 22% to 52%]) (12 trials, 12,963 participants). Other randomized comparisons were inconclusive. Absolute increases in major extracranial hemorrhage were small (0.3% per year) on the basis of meta-analysis.” (R. G. Hart, hartr@uthscsa.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
June 20, 2007 * Vol. 14, No. 119
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
June 20 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2007; 297).
“Widely Covered” Medicare Part D Drugs: While a few generic drugs are included in most Medicare Part D formularies, few brand-name drugs are widely covered, and physicians need to check for coverage before prescribing (pp. 2596-602). That conclusion comes from an analysis of Part D formularies in California and Hawaii with attention on inclusion of 75 specific agents in eight treatment classes (ACE inhibitors, angiotensin II receptor blockers, beta-blockers, calcium-channel blockers, loop diuretics, SSRIs, statins, and thiazide diuretics). Defining “widely covered” as inclusion in 90% or more of formularies, the investigators found: “For California, coverage for the 75 drugs examined ranged from 7% to 100%. Despite this variation, 7 of 8 classes (excluding angiotensin II receptor blockers) had at least 1 widely covered drug. Of the 34 widely covered drugs (45%), all but 2 were generic. Restricting widely covered to include 95% or more of formularies at co-payments of $15 or less still resulted in 7 of 8 classes with at least 1 widely covered drug. Overall, 73% of generic drugs and 6% of brand-name drugs were widely covered. Findings were similar for Hawaii.” (C-W Tseng, Pacific Health Res. Inst., Honolulu, Hawaii; cwtseng@hawaii.edu)
Malaria Prevention During Pregnancy: Use of sulfadoxine–pyrimethamine is increasingly being restricted to intermittent preventive therapy (IPT) during pregnancy and for infants, note authors of a systematic review on the combination’s efficacy for malaria control during pregnancy (pp. 2603-16). The effort “may reduce drug pressure and may prolong longevity of this valuable drug,” the writers note, adding these details from their literature review: “Four trials compared 2-dose IPT with sulfadoxine–pyrimethamine to case management or placebo in women during their first or second pregnancy. The IPT reduced placental malaria (relative risk [RR], 0.48; 95% CI, 0.35–0.68), low birth weight (RR, 0.71; 95% CI, 0.55–0.92), and anemia (RR, 0.90; 95% CI, 0.81–0.99). The effect did not vary by sulfadoxine–pyrimethamine resistance levels (range, 19%–26%). Efficacy of IPT with sulfadoxine–pyrimethamine was lower among women using insecticide-treated nets. Three trials compared 2-dose with monthly IPT with sulfadoxine–pyrimethamine during pregnancy. Among HIV-positive women in their first or second pregnancy, monthly IPT resulted in less placental malaria (RR, 0.34; 95% CI, 0.18–0.64) and higher birth weight (mean difference, 112 g; 95% CI, 19–205 g) over the range of sulfadoxine–pyrimethamine resistance tested (8%–39%). Among HIV-negative women, there was no conclusive additional effect of monthly dosing (2 trials; 24% and 39% resistance).” (F. O. ter Kuile, Liverpool School of Tropical Med., Liverpool, U.K.; terkuile@liv.ac.uk)

>>>PNN NewsWatch
* Several clusters of patients have experienced chills, fever, and body aches shortly after receiving propofol for sedation or general anesthesia, FDA warns. The agency has tested multiple units of propofol vials and lots used in patients who have experienced these symptoms, but to date, these tests have not identified any vials contaminated with bacteria or endotoxins. FDA recommends that health professionals carefully follow the recommendations for handling and use found in propofol’s current product labeling and report to the MedWatch program patients who have received propofol for sedation or general anesthesia and subsequently experienced fever, chills, body aches, or other symptoms of an acute febrile reaction.
*
Long Weekend—sold as a dietary supplement through mail orders and retailers located nationwide, and in Puerto Rico, Canada, the United Kingdom, Russia, and China—has been recalled because it contains undeclared tadalafil. Long Weekend, which is not approved by FDA, poses a safety risk to patients taking nitrates, as they may experience low blood pressure secondary to interactions between tadalafil and the nitrates. Consumers should discontinue use of Long Weekend and consult health professionals about approved treatments for erectile dysfunction, FDA suggests.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
June 21, 2007 * Vol. 14, No. 120
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
June 21 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2007; 356).
Estrogen Therapy & Coronary-Artery Calcification: While their complex biological actions complicate clinical use, estrogens produced a lower calcified-plaque burden in coronary arteries in a subanalysis from the Women’s Health Initiative (pp. 2591-602). Doses of conjugated equine estrogens 0.625 mg/day were compared with placebo in 1,064 women aged 50–59 years at randomization who had undergone hysterectomy, and computed tomography of the heart showed these results: “The mean coronary-artery calcium score after trial completion was lower among women receiving estrogen (83.1) than among those receiving placebo (123.1) (P = 0.02 by rank test). After adjustment for coronary risk factors, the multivariate odds ratios for coronary-artery calcium scores of more than 0, 10 or more, and 100 or more in the group receiving estrogen as compared with placebo were 0.78 (95% confidence interval, 0.58 to 1.04), 0.74 (0.55 to 0.99), and 0.69 (0.48 to 0.98), respectively. The corresponding odds ratios among women with at least 80% adherence to the study estrogen or placebo were 0.64 (P = 0.01), 0.55 (P <0.001), and 0.46 (P = 0.001). For coronary-artery calcium scores of more than 300 (vs. <10), the multivariate odds ratio was 0.58 (P = 0.03) in an intention-to-treat analysis and 0.39 (P = 0.004) among women with at least 80% adherence.” (J. E. Manson, jmanson@rics.bwh.harvard.edu)
Editorialists (pp. 2639-41) comment that this analysis “lends further support to recent consensus statements from two large societies of menopause practitioners, which strongly endorse the timing hypothesis and recognize the potentially beneficial cardiovascular effects of hormone-replacement therapy in younger menopausal women receiving the therapy for symptoms. These potential benefits will be explored further in ongoing clinical trials ... and in future studies of the effects of new hormone-replacement formulations on cardiovascular end points. The translation of basic research to the bedside and to public guidelines requires a collaborative and interactive process conducted with patience and persistence. Just such an iterative process has enabled our emerging appreciation for the potential cardiovascular benefits of hormone-replacement therapy in younger women who have recently undergone menopause. As Schopenhauer observed: ‘Opinion is like a pendulum and obeys the same law. If it goes past the centre of gravity on one side, it must go a like distance on the other; and it is only after a certain time that it finds the true point at which it can remain at rest.’” (M. E. Mendelsohn, Tufts U., Boston)
Entecavir Effects on HIV-1 Replication, Resistance: Caution is needed when entecavir is used to treat chronic hepatitis B virus infection in patients coinfected with HIV, write authors of a brief report (pp. 2614-21). Based on three case reports and phenotypic and PCR analysis of patient blood samples, the investigators conclude: “Entecavir, at doses used to treat chronic hepatitis B, is a potent partial inhibitor of HIV-1 replication and can select for the M184V resistance mutation in HIV-1 reverse transcriptase. Since the full extent of HIV-1 reverse-transcriptase mutations selected by entecavir monotherapy is not known, caution should be used in treating chronic hepatitis B with entecavir in HIV-1–infected patients who are not receiving fully suppressive antiretroviral regimens. Furthermore, these data underscore the importance of a careful study of agents with potential for anti–HIV-1 activity before licensure.” (C. L. Thio, Johns Hopkins U., Baltimore; cthio@jhmi.edu)
Natalizumab for Multiple Sclerosis: A case report of use of natalizumab in a woman with multiple sclerosis is presented, along with recommendations to use this drug only in patients with recent inflammatory disease activity and insufficient response or poor tolerance to other medications (pp. 2622-9). They add: “Patients beginning treatment with natalizumab should have taken no immunosuppressive medications in the preceding 3 months, they should have no condition that compromises cell-mediated immunity..., and their leukocyte counts, at minimum, should be normal. They should also be able to provide informed consent and to comply with the requirements of the mandatory monitoring program.” (R. M. Ransohoff, Cleveland Clinic, Cleveland; ransohr@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
June 22, 2007 * Vol. 14, No. 121
Providing news and information about medications and their proper use

>>>Chest Highlights
Source:
June issue of Chest (http://www.chestjournal.org/current.shtml; 2007; 131).
HIT in Teaching Hospital: Heparin-induced thrombocytopenia occurred in 0.2% of patients receiving heparin in a large, tertiary-care hospital during a 1-year period, with a 0.76% incidence in those patients receiving therapeutic-dose intravenous heparin (pp. 1644-9). A retrospective review of hospital records of patients receiving heparin or a direct thrombin inhibitor showed these results: “A total of 58,814 patient admissions occurred with an estimated 24,068 patients being exposed to unfractionated heparin. DTI therapy was administered to 133 patients. Of these, 49 new HIT cases and 15 cases of suspected HIT (unconfirmed) were identified. The overall incidence of recognized new HIT was 0.2%. New HIT occurred in 0.76% of patients receiving therapeutic-dose IV heparin and in <0.1% of patients receiving antithrombotic prophylaxis (subcutaneous heparin). Forty-nine percent of all new HIT cases were in coronary artery bypass and/or valve replacement surgery patients, while no cases were identified in hip/knee arthroplasty patients.” (M. A. Smythe, Wayne State U., Detroit; msmythe@beaumont.edu)
Childhood Asthma & Early Antibiotic Use: A longitudinal study reports that use of antibiotics, especially broad-spectrum cephalosporins, in early life is associated with development of childhood asthma (pp. 1753-9). Looking at use of antibiotics during the first year of life and presence of asthma at age 7 for a 1995 birth cohort of 13,116 children in Manitoba, investigators found: “Independent of well-known asthma risk factors, asthma was significantly more likely to develop in children who had received antibiotics in the first year of life at age 7 years. The association with asthma was observed for antibiotic use in non-respiratory tract infections (adjusted odds ratio [OR], 1.86; 95% confidence interval [CI], 1.02 to 3.37). The risk of asthma was highest in children receiving more than four courses of antibiotics (adjusted OR, 1.46; 95% CI, 1.14 to 1.88), especially among rural children, and in the absence of maternal asthma or a dog in the birth year. Broad-spectrum cephalosporin use was more common in these subpopulations of children.” (A. Kozyrskyj, kozyrsk@cc.umanitoba.ca)
2Tone Trainer for MDI Education: Asthma quality of life was significantly improved when patients used the 2Tone Trainer device (Canday Medical Ltd.; Newmarket, U.K.) following metered-dose inhaler training (pp. 1776-82). In this 6-week, 107-patient study, those with suboptimal MDI technique who received verbal training plus the 2T device scored higher on clinical and QOL measures than did patients receiving verbal training only. (H. Chrystyn, U. Bradford, Bradford, U.K.; h.chrystyn@brad.ac.uk)

>>>PNN NewsWatch
* Following a priority review, FDA on Thursday approved pregabalin (Lyrica, Pfizer) for the additional indication of management of fibromyalgia. The first agent indicated for fibromyalgia, pregabalin was previously approved for management of neuropathic pain associated with diabetic peripheral neuropathy and postherpetic neuralgia and for the adjunctive therapy for adult patients with partial onset seizures. In two double-blind trials of 1,800 patients, fibromyalgia symptoms such as poor sleep, stiffness, fatigue, deep tenderness, soreness, and flu-like aching were relieved by 300- and 450-mg daily doses of the drug. The most common adverse effects of pregabalin were dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, constipation, euphoric mood, balance disorder, increased appetite, and thinking abnormally (primarily difficulty with concentration/attention).
*
FDA also yesterday cleared for marketing the INRange Systems’ Electronic Medication Management Assistant (EMMA), a programmable device that stores and dispenses prescription medication for patients’ use in the home. The computerized medication box was designed to be used under the supervision of a licensed health care provider. EMMA can reduce drug identification and dosing errors, and allow health professionals to monitor patient adherence to medication regimens in an outpatient setting. FDA said that the device may be especially useful for aging patients, as well as those with complex medication regimens such as patients with HIV.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
June 25, 2007 * Vol. 14, No. 122
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
June 23 issue of Lancet (www.thelancet.com; 2007; 369).
Benefits of Lowering Blood Pressure: Diastolic function is improved equally well by inhibitors of the renin–angiotensin–aldosterone system and other antihypertensive agents, conclude authors of a research study (pp. 2079-87). Since ventricular hypertrophy and myocardial fibrosis are reduced by angiotensin blockade, the investigators measured diastolic relaxation velocity between baseline and 38 weeks of treatment with valsartan or placebo along with concomitant antihypertensive agents that lowered blood pressure to less than 135/80 mm Hg. Results showed the following: “186 patients were randomly assigned to receive valsartan; 198 were randomly assigned to receive placebo. 43 patients were lost to follow-up or discontinued the assigned intervention. Over 38 weeks, there was a 12.8 (SD 17.2)/7.1 (9.9) mm Hg reduction in blood pressure in the valsartan group and a 9.7 (17.0)/5.5 (10.2) mm Hg reduction in the placebo group. The difference in blood pressure reduction between the two groups was not significant. Diastolic relaxation velocity increased by 0.60 (SD 1.4) cm/s from baseline in the valsartan group (p <0.0001) and 0.44 (1.4) cm/s from baseline in the placebo group (p <0.0001) by week 38. However, there was no significant difference in the change in diastolic relaxation velocity between the groups (p = 0.29).” (S. D. Solomon, ssolomon@rics.bwh.harvard.edu)
Gene Therapy in PD: In 11 men and 1 woman with advanced Parkinson’s disease, gene therapy directed at the subthalamic nucleus was safe and effective (pp. 2097-105). In an open-label, safety and tolerability trial, investigators assessed the transfer of glutamic acid decarboxylase (GAD) gene using adeno-associated virus (AAV) and looked for differences in the Unified Parkinson’s Disease Rating Scale (UPDRS), scales of activities of daily living (ADL), neuropsychological testing, and PET imaging with 18F-fluorodeoxyglucose: “All patients who enrolled had surgery, and there were no dropouts or patients lost to follow-up. There were no adverse events related to gene therapy. Significant improvements in motor UPDRS scores (p = 0.0015), predominantly on the side of the body that was contralateral to surgery, were seen 3 months after gene therapy and persisted up to 12 months. PET scans revealed a substantial reduction in thalamic metabolism that was restricted to the treated hemisphere, and a correlation between clinical motor scores and brain metabolism in the supplementary motor area.” (M. J. During, uring.1@osu.edu">During.1@osu.edu)

>>>PNN NewsWatch
* FDA on Friday announced a long-awaited final rule establishing regulations to require current good manufacturing practices (cGMP) for dietary supplements. Under the final rule, which takes effect on Aug. 24, manufacturers are required to evaluate the identity, purity, strength, and composition of their dietary supplements. If dietary supplements contain contaminants or do not contain the dietary ingredient they are represented to contain, FDA would consider those products to be adulterated or misbranded. The agency also issued an interim final rule that outlines a petition process for manufacturers to request an exemption to the cGMP requirement for 100% identity testing of specific dietary ingredients used in the processing of dietary supplements. Comments on this proposal can be made until Sept. 24.

>>>PNN JournalWatch
* Diagnosis and Treatment of Sciatica, in BMJ, 2007; 334: 1313–7. Reprints: B. W. Koes, Erasmus Med. Ctr., Rotterdam, the Netherlands; b.koes@erasmusmc.nl
* Colonoscopy: A Tarnished Gold Standard [editorial]?, in
Gastroenterology, 2007; 132: 2588–90. Reprints: G. Cooper, University Hospitals Case Medical Center, Cleveland; greg.cooper@case.edu
* Treatment of Proximal Deep-Vein Thrombosis With the Oral Direct Factor Xa Inhibitor Rivaroxaban (BAY 59-7939). The ODIXa-DVT (Oral Direct Factor Xa Inhibitor BAY 59-7939 in Patients With Acute Symptomatic Deep-Vein Thrombosis) Study, in
Circulation, 2007; doi: 10.1161/CIRCULATIONAHA.106.668020. Reprints: G. Agnelli, U.Perugia, Perugia, Italy; agnellig@unipg.it

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 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
June 26, 2007 * Vol. 14, No. 123
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
June 25 issue of the Archives of Internal Medicine (http://archinte.ama-assn.org/current.dtl; 2007; 167).
Antidepressants & BMD: Two research studies and an editorial examine the effects of antidepressants on bone mineral density.
SSRIs but not tricyclic antidepressants increase the rate of bone loss at the hip, according to a study of 2,722 older community-dwelling women (mean age, 78.5 years) (pp. 1240-5). In the prospective Study of Osteoporotic Fractures, hip BMD was measured at the sixth examination and an average of 4.9 years later at the eighth examination. Categorizing the women into users of SSRIs (n = 198), TCAs (n = 118), or neither (n = 2,406), the researchers found: “After adjustment for potential confounders, including the Geriatric Depression Scale score, mean total hip BMD decreased 0.47% per year in nonusers compared with 0.82% in SSRI users (P <.001) and 0.47% in TCA users (P = .99). Higher rates of bone loss were also observed at the 2 hip subregions for SSRI users. Results were not substantially altered when women who scored at least 6 on the Geriatric Depression Scale were excluded from the analysis.” (S. J. Diem,
sdiem@umn.edu)
Similar results come from a study of older men (pp. 1246-51). In the prospective cohort Osteoporotic Fractures in Men Study, a cross-sectional analysis of data from 5,995 men 65 years and older showed these patterns in BMD at the femoral neck, greater trochanter, and lumbar spine: “In adjusted analyses, mean BMD among SSRI users (n = 160) was 3.9% lower at the total hip and 5.9% lower at the lumbar spine compared with BMD in men reporting no antidepressant use (n = 5,708 [P = .002 for total hip; P <.001 for lumbar spine]). There was no significant difference among users of trazodone hydrochloride (n = 52) or tricyclic antidepressants (n = 99) compared with nonusers. Adjusting for variables that could be associated with BMD and/or SSRI use did not significantly alter these results. The observed difference in BMD for SSRIs is similar to that seen with glucocorticoids.” (E. M. Haney, Oregon Health & Sci. U., Portland;
haneye@ohsu.edu)
An editorialist advises clinicians to “mend the mind but mind the bones” and summarizes implications of the above studies (pp. 1231-2): “First, the accumulating data are compelling, and a number of the Bradford–Hill requirements for establishing causal relationships in observational studies hold true. Despite the methodological limitations noted and the absence of a dose response (because neither study quantitated the dose of antidepressant used), the biological plausibility, the consistency of these 2 studies with each other and with previous studies, and the magnitude of the associations partially support a causal relationship. Second, as suggested in the study by Haney and colleagues, the fact that the magnitude of the SSRI bone effect appeared similar to that observed with glucocorticoids is of clinical concern. Similar to the way glucocorticoids are prescribed, there is some unnecessary use of SSRIs in the general medical community, and the indications for starting and continuing SSRI therapy now should be even more carefully scrutinized. Analogous to the necessity for using glucocorticoids in persons with certain serious inflammatory disorders, those who truly need SSRIs should continue to receive them despite potential bone concerns.” (K. Saag, U. Ala., Birmingham;
ksaag@uab.edu)
Low-Dose Rosiglitazone: Rosiglitazone in doses of 2 mg/day proved an equally effective adjunct to insulin therapy as 4 mg/day doses of the drug in a 24-week, 630-patient trial (pp. 1284-90). In patients whose type 2 diabetes mellitus was not adequately controlled by insulin therapy, rosiglitazone in either dose produced significant improvements in mean glycated hemoglobin concentrations, C-reactive protein levels, and fibrinogen levels, compared with placebo and baseline. Only the higher dose of rosiglitazone significantly reduced matrix metalloproteinase 9 levels, and adverse event profiles were similar in all treatment groups, including frequency of hypoglycemia and edema. (P. Hollander, Priscilh@baylorhealth.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
June 27, 2007 * Vol. 14, No. 124
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
June 27 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2007; 297).
Weight Management in Overweight Children: Body composition and insulin resistance were improved in 209 overweight children and sustained for up to 12 months through a weight-management program (pp. 2697-704). The Bright Bodies program included exercise classes twice weekly and nutrition/behavior modification classes once weekly for 6 months. The program showed these changes in study outcome measures for intervention versus control patients: weight, +0.3 kg (95% CI, –1.4 to 2.0) vs +7.7 kg (5.3 to 10.0); BMI, –1.7 (–2.3 to –1.1) vs +1.6 (0.8 to 2.3); body fat, –3.7 kg (–5.4 to –2.1) vs +5.5 kg (3.2 to 7.8); and homeostasis model assessment of insulin resistance, –1.52 (–1.93 to –1.01) vs +0.90 (–0.07 to 2.05). The researchers conclude: “While the program was very successful in treating overweight children, the expense incurred in operating such a program is substantial. Future work for our group includes cost-benefit analyses, as this would be helpful for pediatric clinicians or health management organizations that are considering offering similar services to overweight children and adolescents.” (M. Savoye, mary.savoye@yale.edu)

>>>ASHP Holds Summer Meeting in San Francisco
With 5,000 pharmacists, technicians, and exhibitors in attendance, ASHP this week hosted its 2007 Summer Meeting in San Francisco. Among the highlights of the meeting, which closes today, are the following:
* The Society currently has a five-pronged
Leadership Agenda, ASHP’s presidential officers shared during a news conference on Monday. The specific goals are to improve medication-use safety in hospitals and health systems; expand access to the patient care services of hospital and health-system pharmacists; foster an adequate supply of qualified practice managers, pharmacists, and pharmacy technicians; foster evidence-based medication use in hospitals and health systems; and help hospital and health-system pharmacists deal with the affordability and accessibility of pharmaceuticals.
* Installed as 2007–08 President of ASHP was Janet Silvester, MBA, FASHP, of Martha Jefferson Hosp., Charlottesville, Va. In her inaugural address delivered on Tuesday, Silvester recalled two specific patients from early in her career with whom she developed a close relationship. She learned from them, “When you can touch people in that way, they touch you back.” She emphasized the value of pharmacists beyond technical expertise and the increasing trend toward collaboration of pharmacists with physicians and other health professionals, noting that those trends add meaning to ASHP’s new tag line, “Together we make a great team.” Reflecting on the name of a video describing for patients the roles of pharmacists in hospitals, Silvester added, “We can no longer be the ‘invisible ingredient’ if we want to advance pharmacy practice. We each have to be the voice that fights for safer medication-use systems, for access to care, for quality standards, and for our place as the medication-use expert wherever that is required.”
* Direct-to-consumer advertising of dietary supplements and advocacy for a fully funded Medicare prescription drug benefit were two of more than two dozen policies considered by the
ASHP House of Delegates. The House also approved a resolution calling for, by 2020, completion of an ASHP-accredited postgraduate year 1 residency by all new pharmacy graduates who will be providing direct patient care. Re-elected Chair of the House for the coming year was Teresa J. Hudson, PharmD, BCPP, FASHP, of Little Rock, Ark. Paul Abramowitz of the University of Iowa Hospitals was elected the new Treasurer of the Society.
* The 2007 Harvey A. K. Whitney Lecture Award went to Henri R. Manasse, Jr., PhD, ScD, ASHP Executive Vice President and CEO. In his address, “Ideals and Idealists: Striving to Achieve our Societal Imperative,” Manasse explored three areas “deeply in need of attention”: quality and competence of the pharmacy workforce; genomics, pharmacogenomics, and proteomics; and global connections in a flat world.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
June 28, 2007 * Vol. 14, No. 125
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
June 28 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2007; 356).
Teratogenicity of SSRIs: Two research articles and an editorial assess birth defects in women taking SSRIs during the first trimester of pregnancy.
While some SSRIs may be linked to increased risks of specific birth defects, three types—craniosynostosis, omphalocele, and heart defects—did not occur more frequently with SSRI use overall, according to data on 9,849 infants with and 5,860 infants without birth defects (pp. 2675-83). Furthermore, note investigators from the Slone Epidemiology Center Birth Defects Study, the identified defects are rare and the absolute risks small: “Overall use of SSRIs was not associated with significantly increased risks of craniosynostosis (115 subjects, 2 exposed to SSRIs; odds ratio, 0.8; 95% confidence interval [CI], 0.2 to 3.5), omphalocele (127 subjects, 3 exposed; odds ratio, 1.4; 95% CI, 0.4 to 4.5), or heart defects overall (3724 subjects, 100 exposed; odds ratio, 1.2; 95% CI, 0.9 to 1.6). Analyses of the associations between individual SSRIs and specific defects showed significant associations between the use of sertraline and omphalocele (odds ratio, 5.7; 95% CI, 1.6 to 20.7; 3 exposed subjects) and septal defects (odds ratio, 2.0; 95% CI, 1.2 to 4.0; 13 exposed subjects) and between the use of paroxetine and right ventricular outflow tract obstruction defects (odds ratio, 3.3; 95% CI, 1.3 to 8.8; 6 exposed subjects). The risks were not appreciably or significantly increased for other defects or other SSRIs or non-SSRI antidepressants. Exploratory analyses involving 66 comparisons showed possible associations of paroxetine and sertraline with other specific defects.” (C. Louik, Slone Epidemiology Ctr., Boston;
clouik@slone.bu.edu)
Data on 9,622 case infants with major birth defects and 4,092 control infants born from 1997 through 2002 from the National Birth Defects Prevention Study show no significantly increased risk of congenital heart defects and most other categories of birth defects, but three specific types of problems were identified (pp. 2684-92). Based on exposure to SSRIs from 1 month before to 3 months after conception, the authors report: “There were no significant associations between maternal use of SSRIs overall during early pregnancy and congenital heart defects or most other categories or subcategories of birth defects. Maternal SSRI use was associated with anencephaly (214 infants, 9 exposed; adjusted odds ratio, 2.4; 95% confidence interval [CI], 1.1 to 5.1), craniosynostosis (432 infants, 24 exposed; adjusted odds ratio, 2.5; 95% CI, 1.5 to 4.0), and omphalocele (181 infants, 11 exposed; adjusted odds ratio, 2.8; 95% CI, 1.3 to 5.7).” (J. Reefhuis,
JReefhuis@cdc.gov)
“Patients and physicians alike would prefer it if there were clear lines separating ‘risk’ and ‘no risk’ and if all studies gave consistent results pointing in the same direction,” writes an editorialist (pp. 2732-3). “Unfortunately, this is often not the case, and the data to inform potential risks of SSRIs are no exception. The two reports in this issue of the
Journal, together with other available information, do suggest that any increased risks of these malformations in association with the use of SSRIs are likely to be small in terms of absolute risks.” (M. F. Greene, Mass. Genl. Hosp., Boston)
Disclosing Harmful Medical Errors to Patients: Standards and legal developments regarding disclosure of harmful medical errors to patients are reviewed (pp. 2713-9). “Disclosure programs and practices are in their infancy,” the authors write. “The fast pace at which they have developed over the past 5 years appears to be set to continue and perhaps even accelerate during the next 5 years. There will be ongoing experimentation with disclosure by health care delivery organizations and some malpractice insurers. This work will yield useful information about the impact of various disclosure approaches on key outcomes such as patient satisfaction and the rates and cost of litigation. Insights gained by institutions that use standard quality-improvement techniques to track, test, and refine their disclosure strategies will be especially valuable. Disclosure activities continue apace outside the United States. Canada’s recently formed Canadian Patient Safety Institute, for example, is set to release new national disclosure guidelines, and some Canadian provinces have adopted legislation concerning apology and disclosure.” (T. H. Gallagher, thomasg@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
June 29, 2007 * Vol. 14, No. 126
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
July issue of Diabetes Care (http://care.diabetesjournals.org/current.shtml; 2007; 30).
All-Cause Mortality with Oral Hypoglycemics: Compared with oral sulfonylurea monotherapy, metformin, metformin plus sulfonylurea, and thiazolidinediones had no significant effect on all-cause mortality, according to a retrospective cohort analysis of data from the Veterans Health Administration Diabetes Epidemiology Cohort (pp. 1689-93). Investigators report: “A total of 39,721 patients with diabetes were included in the study. Adjusted odds ratios and 95% CIs for all-cause mortality were 0.87 (0.68–1.10) for metformin monotherapy users, 0.92 (0.82–1.05) for metformin plus sulfonylurea users, and 1.04 (0.75–1.46) for TZD users, relative to sulfonylurea monotherapy users.” (K. H. Kahler, kristijan.kahler@novartis.com)
Telmisartan Effects on Endothelial Dysfunction: In patients with type 1 diabetes, telmisartan acts as an antioxidant similar in effect to vitamin C (pp. 1694-8). In addition, researchers report, combining the normalization of glycemia with an antioxidant can normalize endothelial function, adding these details from a study of 36 patients with diabetes and 12 control participants: “Neither normalization of glycemia nor vitamin C treatment alone was able to normalize endothelial dysfunction or oxidative stress. Combining insulin and vitamin C normalized endothelial dysfunction and decreased oxidative stress to normal levels. Telmisartan significantly improved basal endothelial function and decreased nitrotyrosine plasma levels. In patients treated with telmisartan, a near normalization of both flow-mediated vasodilation and oxidative stress was achieved when glycemia was normalized, whereas adding vitamin C infusion did not show further effect on endothelial function or nitrotyrosine plasma levels.” (A. Ceriello, Warwick Med. Sch., Coventry, U.K.; antonio.ceriello@warwick.ac.uk)
Inhaled Insulin in COPD: Patients with chronic bronchitis or pulmonary emphysema tolerated short-term exposure to the AIR brand of inhaled insulin, but insulin absorption and metabolic effects were reduced, compared with healthy subjects (pp. 1777-82). Three nonsmoking groups of 15 participants each received AIR inhaled insulin 12 units equivalent and subcutaneous insulin lispro 12 units. Insulin exposure was significantly lower with inhaled insulin in the groups with one of the types of chronic obstructive pulmonary disorder, and total insulin effect was reduced significantly, compared with healthy participants. No such differences were noted with subcutaneous insulin, and glucodynamic variability ranged from 17% to 52% across the three groups. (K. Rave, Profil Institut für Stoffwechselforschung, Neuss, Germany; klaus.rave@profil-research.de)

>>>PNN NewsWatch
* Use of “average glucose” units to report the results of A1C assays could enable patients to better relate results of that test to their self-monitoring of blood glucose, researchers reported this week at the American Diabetes Association’s 67th Annual Scientific Sessions in Chicago. The International A1C-AG Study, scheduled for completion in Sept., is comparing A1C results to thousands of blood glucose values measured in each participant over a 4-month period. Results from the first 250 participants have confirmed a close relationship between A1C and AG. If confirmed in 450 other patients, analyzers could soon be reprogrammed to report results as A1C-derived average glucose, or ADAG, in mg/dL in the U.S.
* Statins and fibrates significantly lower the risk of developing
peripheral sensory diabetic neuropathy, according to a study of 1,294 patients with type 2 diabetes reported at ADA. In a subgroup of 531 people followed longitudinally over 6 years, time to development of newly diagnosed peripheral neuropathy as lowered by 48% and 35% by fibrates and statins, respectively. Beneficial effects of the drugs were independent of each other, indicating that the drugs may work through different mechanisms.
*
FDA is looking into a possible link between use of a pharmacy-prepared colistimethate solution for inhalation via nebulizer and death of a patient with cystic fibrosis.

PNN Pharmacotherapy Line is published via e-mail each business day except 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.