PNN Quarterly File—Second Quarter 2006

PNN Pharmacotherapy Line
Apr. 3, 2006 Vol. 13, No. 63
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Early-release articles and Apr. 1 issue of Lancet (www.thelancet.com; 2006; 367).
Antioxidants in Pre-eclampsia: High-dose antioxidant vitamins provided no protection against pre-eclampsia in a trial of 2,410 women, but vitamin C and E supplements did increase the rate of babies born with low birthweights (DOI: 10.1016/S0140-6736(06)68433-X). Women received vitamin C 1,000 mg plus vitamin E 400 IU or placebo daily from the second trimester of pregnancy until delivery. The authors report these results: “Of 2,404 patients treated, we analysed 2,395 (99.6%). The incidence of pre-eclampsia was similar in treatment and placebo groups (15% [n = 181] vs 16% [n = 187], RR 0.97 [95% CI 0.80-1.17]). More low birthweight babies were born to women who took antioxidants than to controls (28% [n = 387] vs 24% [n = 335], 1.15 [1.02-1.30]), but small size for gestational age did not differ between groups (21% [n = 294] vs 19% [n = 259], 1.12 [0.96-1.31]).” (L. Poston, King's College, London; lucilla.poston@kcl.ac.uk)
Decline in HIV Transmission: Reporting a one-third decline in prevalence of HIV among young women in south India, researchers attribute the improving transmission picture to increased condom use by men and female sex workers, resulting in less transmission to wives (DOI: 10.1016/S0140-6736(06)68435-3). “The age-standardised HIV-1 prevalence in women aged 15–24 years in southern states fell from 1.7% to 1.1% in 2000-04 (relative reduction 35%; ptrend < 0.0001, yearly reduction 11%), but did not fall significantly in women aged 25-34 years. Reductions in women aged 15-24 years were seen in key demographic groups and were similar in sites tested continuously or in all sites. Prevalence in the north was about a fifth of that in the south, with no significant decreases (or increases) in 2000-04. Prevalence fell in men aged 20-29 years attending STI clinics in the south (ptrend < 0.0001), including those with ulcerative STIs (ptrend = 0.0008), but reductions were more modest in their northern counterparts.” (P. Jha, prabhat.jha@utoronto.ca)
Postinfection Emboli: Acute infections should be added to the list of conditions that can precipitate venous thromboembolism, according to authors of a case series of first episodes of deep-vein thrombosis in 7,278 patients and pulmonary embolism in 3,755 patients (pp. 1075-9). “The risks of DVT and PE were significantly raised, and were highest in the first two weeks, after urinary tract infection,” note the investigators. “The incidence ratio for DVT was 2.10 (95% CI 1.56-2.82), and that for PE 2.11 (1.38-3.23). The risk gradually fell over the subsequent months, returning to the baseline value after 1 year. The risk of DVT was also higher after respiratory tract infection, but possible diagnostic misclassification precluded a reliable estimate of the risk of PE after respiratory infection.” (L. Smeeth, London Sch. of Hygiene and Tropical Med., London; liam.smeeth@lshtm.ac.uk)

>>>BMJ Highlights
Source:
Apr. 1 issue of BMJ (www.bmj.org; 2006; 332).
Neuroleptic Use in Nursing Homes: In 12 nursing homes for people with dementia, training and support of staff enabled a significant reduction in the use of neuroleptics over a 12-month period (pp. 756-61). “At 12 months the proportion of residents taking neuroleptics in the intervention homes (23.0%) was significantly lower than that in the control homes (42.1%): average reduction in neuroleptic use 19.1% (95% confidence interval 0.5% to 37.7%),” write the researchers. “No significant differences were found in the levels of agitated or disruptive behaviour between intervention and control homes.” (R. Howard, King's College, London; r.howard@iop.kcl.ac.uk)

>>>PNN JournalWatch
* Asthma Control in Adults, in BMJ, 2006; 332: 767–71. Reprints: www.bmj.org; J. Rees, King's College, London; john.rees@kcl.ac.uk
* Pancreas and Islet Transplantation in Type 1 Diabetes, in
Diabetes Care, 2006; 29: 935. Reprints: care.diabetesjournals.org; American Diabetes Assn.
* Gastrointestinal Complications of Dual Antiplatelet Therapy, in
Circulation, 2006; 113: e655–8. Reprints: circ.ahajournals.org; doi: 10.1161/CIRCULATIONAHA.105.590612; N. G. Vallurupalli.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, 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, 2006 Vol. 13, No. 64
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Apr. 4 issue of the Annals of Internal Medicine (www.annals.org; 2006; 144).
Quality of Care of Chronic Lifestyle Diseases: Despite improvements in the “diabetes processes of care and intermediate outcomes” in the U.S. over the past decade, “2 in 5 persons with diabetes still have poor LDL cholesterol control, 1 in 3 persons still has poor blood pressure control, and 1 in 5 persons still has poor glycemic control,” according to an analysis of national data (pp. 465-74). Based on data from the National Health and Nutrition Examination Survey (1988-1994 and 1999-2002) and the Behavioral Risk Factor Surveillance System (1995 and 2002), investigators report: “In the past decade, the proportion of persons with diabetes with poor glycemic control (hemoglobin A1c > 9%) showed a nonstatistically significant decrease of 3.9% (95% CI, -10.4% to 2.5%), while the proportion of persons with fair or good lipid control (LDL cholesterol level < 3.4 mmol/L [<130 mg/dL]) had a statistically significant increase of 21.9% (CI, 12.4% to 31.3%). Mean LDL cholesterol level decreased by 0.5 mmol/L (18.8 mg/dL). Although mean hemoglobin A1c did not change, the proportion of persons with hemoglobin A1c of 6% to 8% increased from 34.2% to 47.0%. The blood pressure distribution did not change. Annual lipid testing, dilated eye examination, and foot examination increased by 8.3% (CI, 4.0% to 12.7%), 4.5% (CI, 0.5% to 8.5%), and 3.8% (CI, -0.1% to 7.7%), respectively. The proportion of persons reporting annual influenza vaccination and aspirin use improved by 6.8 percentage points (CI, 2.9 percentage points to 10.7 percentage points) and 13.1 percentage points (CI, 5.4 percentage points to 20.7 percentage points), respectively.” (J. B. Saaddine, jsaaddine@cdc.gov)
Clinicians generally made therapy modifications when patients had poor control of hypertension, dyslipidemia, and diabetes, report authors who conducted a retrospective cohort study of Kaiser Permanente of Northern California members in 2002 and 2003 (pp. 475-84). “A total of 64% of patients experienced modifications in therapy for poorly controlled systolic blood pressure, 71% for poorly controlled diastolic blood pressure, 56% for poorly controlled low-density lipoprotein cholesterol level, and 66% for poorly controlled hemoglobin A1c level,” the researchers write. “Most frequent modifications were increases in number of drug classes (from 70% to 84%) and increased dosage (from 15% to 40%). An additional 7% to 11% of those with poorly controlled blood pressure, but only 3% to 4% of those with elevated low-density lipoprotein cholesterol level or hemoglobin A1c level, returned to control without therapy modification. Patients with more than 1 of the 3 conditions, higher baseline values, and target organ damage were more likely to receive appropriate care.’” (N. Rodondi, U. Lausanne, Lausanne, Switzerland;
nicolas.rodondi@hospvd.ch)
Asking what will it take to overcome “clinical inertia” in managing metabolic conditions, editorialists make this challenge (pp. 525-7): “We ... offer a modest but achievable proposal for every health care professional, every practice, and every private and public health care system. First, review your own data and processes of care for diabetes. Second, use the principles of evidence-based medicine to identify the highest-priority goals and treatment strategies. Third, develop actionable plans to increase the proportion of clinical encounters in which clinicians take appropriate action. Fourth, systematically track progress toward achieving treatment goals. Fifth, give feedback to those who are making patient care decisions. We must recognize the deadly consequences of clinical inertia and commit ourselves to the task of overcoming it in our own practices. If we succeed, we will improve the prospect of healthier lives for tens of millions of Americans.” (L. M. Pogach,
leonard.pogach@med.va.gov)
Sirolimus-Associated Pneumonitis: Cough, fatigue, fever, and dyspnea were common in 24 transplant patients who developed pneumonitis during sirolimus therapy (pp. 505-9). Symptoms resolved within 6 months of dechallenge. (E. Morelon, Université Claude Bernard Lyon, Lyon, France; emmanuel.morelon@chu-lyon.fr)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, 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, 2006 Vol. 13, No. 65
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Apr. 4 issue of JAMA (www.jama.com; 2006; 295).
Fondaparinux in STEMI: As reported last month at the American College of Cardiology meeting (see PNN, Mar. 15), fondaparinux significantly reduced mortality and reinfarction among 12,092 patients with ST-segment elevation myocardial infarction, especially those who were not undergoing percutaneous coronary interventions (pp. 1519-30). In the OASIS-6 (Organization for the Assessment of Strategies for Ischemic Syndromes) trial, patients with STEMI received usual care or add-on therapy with this factor Xa inhibitor initiated early and continued for up to 8 days. Death or reinfarction at 30 days was reduced significantly in the fondaparinux group (9.7%, compared with 11.2% among those receiving placebo; hazard ratio, 0.86; 95% CI, 0.77-0.96). In an analysis of patients undergoing PCI, no difference between the groups was evident. Another subgroup analysis, this one of patients for whom unfractionated heparin was indicated, showed lower death or reinfarction rates with fondaparinux at 30 days (HR, 0.82; 95% CI, 0.66-1.02) and at 3-6 months (HR, 0.77; 95% CI, 0.64-0.93). (S. Yusuf, yusufs@mcmaster.ca)
An editorialist makes this assessment of the OASIS-6 results (pp. 1579-80): “The multiple permutations and combinations of antithrombotic drugs are increasingly confusing to clinicians seeking the best options for their patients. How do physicians find a way out of this maze? Hopefully, the era in which individual clinical trials are considered to be the definitive answer to questions of clinical practice is coming to an end. Rather, clinical practices should be organized in a manner that allows for continuous learning based on observation of practice through collection of data, with randomized trials embedded within observational databases to answer specific questions about pragmatic choices in medical care. Just a few years ago, this would have seemed impossible but the impending widescale availability of electronic health records and professional databases promises to make the data readily available—the challenges are no longer technical. The largest advances in STEMI treatment are the findings that reperfusion is beneficial, that direct PCI is superior to lysis, and that treatment with aspirin, beta-blockers, and angiotensin-system modulators in appropriate patients all save lives.” (R. M. Califf,
robert.califf@duke.edu)
Abciximab for ACS: Among patients with non-ST-segment elevation acute coronary syndromes who are undergoing percutaneous coronary interventions, abciximab reduced the risk of adverse events, but the benefit was limited to patients with elevated troponin levels (pp. 1531-8). Patients were pretreated with clopidogrel and monitored for a primary end point of death, myocardial infarction, or urgent target vessel revascularization, with these results: “The primary end point was reached in 90 patients (8.9%) assigned to abciximab vs 120 patients (11.9%) assigned to placebo, a 25% reduction in risk with abciximab (relative risk [RR], 0.75; 95% CI, 0.58-0.97; P = .03). Among patients without an elevated troponin level, there was no difference in the incidence of primary end point events between the abciximab group (23/499 patients [4.6%]) and the placebo group (22/474 patients [4.6%]) (RR, 0.99; 95% CI, 0.56-1.76; P = .98), whereas among patients with an elevated troponin level, the incidence of events was significantly lower in the abciximab group (67/513 patients [13.1%]) compared with the placebo group (98/536 patients [18.3%]), which corresponds to an RR of 0.71 (95% CI, 0.54-0.95; P = .02) (P = .07 for interaction). There were no significant differences between the 2 groups regarding the risk of major and minor bleeding as well as need for transfusion.” (A. Kastrati, Deutsches Herzzentrum, Munich, Germany; kastrati@dhm.mhn.de)
Editorialists support the use of abciximab in PCI patients (pp. 1581-2): “All heparin-treated patients undergoing PCI for treatment of ACS with elevated troponin levels should receive adjunctive Gp IIa/IIIb antagonists, irrespective of whether the patient has also received adequate pretreatment with clopidogrel. Whether there is additional clinical benefit to administering clopidogrel in addition to a Gp IIa/IIIb antagonist ... remains to be prospectively studied.” (S. R. Steinhubl,
steinhubl@uky.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 © 2006, 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, 2006 Vol. 13, No. 66
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Apr. 6 issue of the New England Journal of Medicine (content.nejm.org; 2006: 354).
Pneumococcal Vaccine: After licensing of the pneumococcal conjugate vaccine for use in young children in 2000, the rate of antibiotic-resistant invasive pneumococcal infections decreased in both young children and older persons (pp. 1455-63). Using data from the Active Bacterial Core surveillance project for 1996 through 2004, the investigators report: “Rates of invasive disease caused by penicillin-nonsusceptible strains and strains not susceptible to multiple antibiotics peaked in 1999 and decreased by 2004, from 6.3 to 2.7 cases per 100,000 (a decline of 57 percent; 95 percent confidence interval, 55 to 58 percent) and from 4.1 to 1.7 cases per 100,000 (a decline of 59 percent; 95 percent confidence interval, 58 to 60 percent), respectively. Among children under two years of age, disease caused by penicillin-nonsusceptible strains decreased from 70.3 to 13.1 cases per 100,000 (a decline of 81 percent; 95 percent confidence interval, 80 to 82 percent). Among persons 65 years of age or older, disease caused by penicillin-nonsusceptible strains decreased from 16.4 to 8.4 cases per 100,000 (a decline of 49 percent). Rates of resistant disease caused by vaccine serotypes fell 87 percent. An increase was seen in disease caused by serotype 19A, a serotype not included in the vaccine (from 2.0 to 8.3 per 100,000 among children under two years of age).” (C. G. Whitney, cwhitney@cdc.gov)
Despite the benefits of such “herd” effects, an editorialist notes that these are no substitute for direct vaccination (pp. 1522-4): “The herd effect, although important from an epidemiologic perspective, is much less strongly protective than is the direct effect of vaccination. I regularly receive calls from parents who, having delayed vaccinating their children because of widely prevalent but erroneous concepts about the adverse effects of vaccination, are now concerned because an active case of infection has surfaced and their child has been exposed. These parents may have been counting on the benefits of the herd effect. Unfortunately, once there is a direct exposure, the herd effect is no longer applicable. Our task, as physicians, is to ensure that our colleagues and patients understand the complex individual and societal benefits of vaccinations, in order to optimize adherence to vaccination recommendations.” (D. M. Musher, Baylor Coll. of Med., Houston)
Fondaparinux in ACS: In patients with acute coronary syndromes, fondaparinux is as effective as and safer than enoxaparin, according to findings from the Fifth Organization to Assess Strategies in Acute Ischemic Syndromes (OASIS-5) trial (pp. 1464-76). Reported initially at the American College of Cardiology meeting last month, the study shows these effects on a primary outcome of death, myocardial infarction, or refractory ischemia at 9 days among 20,078 patients: “The number of patients with primary-outcome events was similar in the two groups (579 with fondaparinux [5.8 percent] vs. 573 with enoxaparin [5.7 percent]; hazard ratio in the fondaparinux group, 1.01; 95 percent confidence interval, 0.90 to 1.13), satisfying the noninferiority criteria. The number of events meeting this combined outcome showed a nonsignificant trend toward a lower value in the fondaparinux group at 30 days (805 vs. 864, P = 0.13) and at the end of the study (1,222 vs. 1,308, P = 0.06). The rate of major bleeding at nine days was markedly lower with fondaparinux than with enoxaparin (217 events [2.2 percent] vs. 412 events [4.1 percent]; hazard ratio, 0.52; P < 0.001). The composite of the primary outcome and major bleeding at nine days favored fondaparinux (737 events [7.3 percent] vs. 905 events [9.0 percent]; hazard ratio, 0.81; P < 0.001). Fondaparinux was associated with a significantly reduced number of deaths at 30 days (295 vs. 352, P = 0.02) and at 180 days (574 vs. 638, P = 0.05).” (S. Yusuf, Hamilton Genl. Hosp., Hamilton, Ont., Canada)
Also in this issue are results of the Enoxaparin and Thrombosis Reperfusion for Acute Myocardial Infarction Treatment: Thrombosis in Myocardial Infraction (ExTRACT-TIMI 25) study (pp. 1477-88; see PNN, Mar. 15). Editorialists comment on this and the OASIS-5 trial (pp. 1524-7; R. J. Gibbons, Mayo Clinic, Rochester, Minn.).

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, 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. 7, 2006 Vol. 13, No. 67
Providing news and information about medications and their proper use

>>>Pharmacotherapy Update
Source:
Apr. issue of Pharmacotherapy (www.pharmacotherapy.org; 2006; 26).
Bivalirudin for HIT: Low doses of bivalirudin are required in treatment of heparin-induced thrombocytopenia to achieve activated partial thromboplastin times of 1.5-2.5 times baseline, concludes a study of patients in intensive care units with hepatic and/or renal dysfunction (pp. 452-60). The retrospective cohort analysis included 18 patients, 12 of whom had compromised liver and kidney function (group 1), four with hepatic dysfunction only (group 2), and two with renal dysfunction only (group 3). The authors report these results: “Mean bivalirudin doses were 0.06 ± 0.15 mg/kg/hour (median 0.03 mg/kg/hr), 0.14 ± 0.05 mg/kg/hour (median 0.14 mg/kg/hr), and 0.05 ± 0.01 mg/kg/hour (median 0.05 mg/kg/hr) for patients in groups 1, 2, and 3, respectively. Ten patients receiving continuous venovenous hemofiltration with or without dialysis received a mean dose of 0.04 ± 0.03 mg/kg/hour (median 0.03 mg/kg/hr). In the 18 patients, mean bivalirudin duration was 15 ± 17 days, aPTT was 69 ± 22 seconds, and international normalized ratio was 2.2 ± 0.8. Supratherapeutic aPTTs were most common on days 1 (22%) and 2 (28%) when bivalirudin doses were highest. Clinically significant bleeding did not occur in any patient. Thrombosis occurred in one patient (6%) while receiving bivalirudin. (T. H. Kiser, ty.kiser@uchsc.edu)
A 42-patient study compares the available direct thrombin inhibitors in treating HIT, concluding that all are effective but that bivalirudin costs less per day, compared with argatroban and lepirudin (pp. 461-8). “Patients receiving bivalirudin who reached therapeutic aPTTs attained them sooner than those receiving either argatroban or lepirudin (8.5 vs 14 and 24 hrs, respectively, p = 0.124). Average percentage of therapeutic aPTTs/patient was greatest in the argatroban group (62%), followed by the bivalirudin (57%) and lepirudin (29%) groups (p = 0.062). Average drug cost/day/patient was greater in the lepirudin group than the other groups, whereas average laboratory costs were similar among groups. Treatment duration was longer with argatroban than with bivalirudin or lepirudin. Bleeding rates were similar in the argatroban and bivalirudin groups, but higher than in the lepirudin group. A composite of clinical outcomes (deep vein thrombosis, nonfatal myocardial infarction, nonfatal stroke, limb amputation, and all-cause mortality) were similar among the three groups.” (J. M. Nappi,
nappijm@musc.edu)
Effectiveness of Rosuvastatin: In a comparison of statin effectiveness in the usual care setting, rosuvastatin provided greater reductions in LDL cholesterol, triglycerides (except compared with atorvastatin), and total cholesterol levels (pp. 469-78). The retrospective, longitudinal, cohort study included 8,251 patients who were beginning statin therapy in 2003-04. Based on managed care records, the investigators report: “Absolute and percent reductions in LDL, triglyceride, and total cholesterol levels were significantly greater with rosuvastatin than with other statins (all p < 0.05 except for triglyceride reduction vs atorvastatin). After adjustment for age, sex, and baseline LDL, percent LDL reductions still were significantly greater with rosuvastatin than with other statins (p < 0.05). Changes in high-density lipoprotein cholesterol were not significant. Goal attainment was higher with rosuvastatin than with other statins after adjustment for age, sex, baseline LDL, risk status, dose, and duration of therapy (p < 0.05). Dose-stratified analysis showed that LDL goal attainment was significantly higher with rosuvastatin 10 mg than with atorvastatin 10 or 20 mg.” (M. F. Bullano, HealthCore, Inc., Wilmington, Del.; mbullano@healthcore.com)
Adherence & Antihypertensives: Older patients, women, African Americans, and those without depression are more likely to adhere to antihypertensive therapy, according to a study of 492 patients at a primary care center (pp. 483-92). Self-reported adherence and refill records provided “complementary information” regarding adherence and were linked to lower blood pressures. (M. D. Murray, mick@unc.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 © 2006, 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, 2006 Vol. 13, No. 68
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from BMJ (www.bmj.org; 2006; 332).
Tobacco Smoke & Glucose Intolerance: Young adults exposed actively or passively to tobacco smoke were significantly more likely to develop glucose intolerance over a 15-year period, reports a study of 1,386 current smokers, 621 previous smokers, 1,452 never smokers exposed to secondhand smoke, and 1,113 never smokers without smoke exposure (doi: 10.1136/bmj.38779.584028.55). The prospective cohort study was launched in 1985-86 in Birmingham, Chicago, Minneapolis, and Oakland, and the authors report these results: "Median age at baseline was 25, 55% of participants were women, and 50% were African-American. During follow-up, 16.7% of participants developed glucose intolerance. A graded association existed between smoking exposure and the development of glucose intolerance. The 15 year incidence of glucose intolerance was highest among smokers (21.8%), followed by never smokers with passive smoke exposure (17.2%), and then previous smokers (14.4%); it was lowest for never smokers with no passive smoke exposure (11.5%). Current smokers (hazard ratio 1.65, 95% confidence interval 1.27 to 2.13) and never smokers with passive smoke exposure (1.35, 1.06 to 1.71) remained at higher risk than never smokers without passive smoke exposure after adjustment for multiple baseline sociodemographic, biological, and behavioural factors, but risk in previous smokers was similar to that in never smokers without passive smoke exposure." (T. K. Houston; thouston@uab.edu)

>>>Lancet Highlights
Source:
Early-release articles from Lancet (www.thelancet.com; 2006; 367).
Papillomavirus Vaccine: A three-dose series of a bivalent human papillomavirus vaccine proved highly immunogenic and safe, with protection evident for up to 4.5 years after vaccination (DOI:10.1016/S0140-6736(06)68439-0). Compared with placebo in 776 women, the HPV 16/18 viruslike particle AS04 vaccine produced these results: “More than 98% seropositivity was maintained for HPV-16/18 antibodies during the extended follow-up phase. We noted significant vaccine efficacy against HPV-16 and HPV-18 endpoints: incident infection, 96.9% (95% CI 81.3-99.9); persistent infection: 6 month definition, 94.3 (63.2-99.9); 12 month definition, 100% (33.6–100). In a combined analysis of the initial efficacy and extended follow-up studies, vaccine efficacy of 100% (42.4-100) against cervical intraepithelial neoplasia (CIN) lesions associated with vaccine types. We noted broad protection against cytohistological outcomes beyond that anticipated for HPV 16/18 and protection against incident infection with HPV 45 and HPV 31. The vaccine has a good long-term safety profile.” (D. M. Harper, Dartmouth Med. Sch., Lebanon, N.H.; diane.m.harper@dartmouth.edu)

>>>PNN NewsWatch
* Pfizer has added hypersensitivity to pegaptanib sodium or any product excipient to the contraindications section of the Macugen labeling. The agent, indicated for treatment of neovascular (wet) age-related macular degeneration, is administered once every 6 weeks by intravitreous injection.
* Daytrana is a
transdermal methylphenidate system from Shire that was approved last week by FDA. The once-daily patch is approved for treatment of attention-deficit/hyperactivity disorder and will be available in 10, 15, 20, and 30 mg strengths.

>>>PNN JournalWatch
* Recent Trends in Stimulant Medication Use Among U.S. Children, in American Journal of Psychiatry, 2006; 163: 579-85. Reprints: ajp.psychiatryonline.org; S. H. Zuvekas.
* The Folate Debate, in
Pediatrics, 2006; 117: 1418-9. Reprints: www.pediatrics.org; R. L. Brent, Thomas Jefferson U., Wilmington, Del.
* Extremity Magnetic Resonance Imaging in Rheumatoid Arthritis: Report of the American College of Rheumatology Extremity Magnetic Resonance Imaging Task Force. in
Arthritis & Rheumatism, 2006; 54: 1034-47. Reprints: www.rheumatology.org; S. Cohen, American College of Rheumatology, Atlanta.
* Minocycline for Short-Term Neuroprotection, in
Pharmacotherapy, 2006; 26: 515-21. Reprints: www.pharmacotherapy.org; Susan C. Fagan, U. Georgia, Augusta; sfagan@mail.mcg.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 © 2006, 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, 2006 Vol. 13, No. 69
Providing news and information about medications and their proper use

>>>Internal Medicine Update
Source:
Apr. 10 issue of Archives of Internal Medicine (www.archinternmed.com; 2006 166).
Maintaining Sinus Rhythm in AF: In patients with atrial fibrillation who have been cardioverted, class IA, IC, and III antiarrhythmic agents are effective for maintaining sinus rhythm, according to a systematic review of 44 trials, but class IA drugs also increase mortality (pp. 719-28). The authors write: “Several class IA (disopyramide phosphate, quinidine sulfate), class IC (flecainide acetate, propafenone hydrochloride), and class III (amiodarone, dofetilide, sotalol hydrochloride) drugs significantly reduced recurrence of atrial fibrillation (number needed to treat, 2-9), but all increased withdrawals due to adverse effects (number needed to harm [NNH], 9-27) and all but amiodarone and propafenone increased proarrhythmia (NNH, 17-119). Class IA drugs, pooled, were associated with increased mortality compared with controls (Peto odds ratio, 2.39; 95% confidence interval, 1.03-5.59; P = .04; NNH, 109). No other antiarrhythmic showed a significant effect on mortality compared with controls. We could not analyze other outcomes because data were lacking.” (C. Lafuente-Lafuente, MD, Hôpital Lariboisière, Paris; c.lafuente@nodo3.net)
Fibrates, Lipids, & Metabolic Syndrome: The fibric acid derivative bezafibrate attenuated the development of insulin resistance among patients with coronary artery disease in a 2-year trial (pp. 737-41). Assessing effectiveness by monitoring homeostatic indexes of insulin resistance (HOMA-IRs), the investigators report: “Both the patients taking bezafibrate (n = 1,262) and those taking placebo (n = 1,242) displayed similar baseline characteristics. The HOMA-IRs significantly correlated at baseline and during follow-up with glucose (r = 0.35 and 0.31, respectively) and triglycerides (r = 0.16 and 0.19, respectively). In a subgroup of 351 patients with diabetes, HOMA-IR at baseline was 88% higher than in their counterparts with normal glucose levels (P < .001). In the placebo group, during follow-up there was a significant 34.4% rise in HOMA-IR. In contrast, in the bezafibrate group there was only a nonsignificant 6.6% change in HOMA-IR. The intergroup differences in percentage changes of HOMA-IR were in favor of bezafibrate (P < .001).” (A. Tenenbaum, Chaim Sheba Med. Ctr., Tel-Hashomer, Israel)
During 18 years of follow-up in the Helsinki Heart Study, lower mortality was evident among 4,081 dyslipidemic middle-aged men who were treated early with gemfibrozil, especially when the lipid disorders involved factors related to metabolic syndrome (pp. 743-8). During the 5-year study, patients were randomized to either placebo or gemfibrozil; after the study, they were invited to continue in the follow-up phase of gemfibrozil treatment at no charge. Looking at the original placebo (OP) and original gemfibrozil (OG) groups, the researchers found these relative risks: “During the follow-up until 1995, subjects in the OG group had a 32% lower RR of CHD mortality (P = .03) compared with those in the OP group, and when followed up until 2000, the RR was 23% lower (P = .05). Overall, there were no differences in all-cause or cancer mortality. However, those in the OG group with both body mass index and triglyceride level in the highest tertiles had a 71% lower RR of CHD mortality (P < .001), a 33% lower RR of all-cause mortality (P = .03), and a 36% lower RR of cancer mortality (P = .22) compared with those in the OP group.” (L. Tenkanen, Helsinki Heart Study, Helsinki, Finland;
leena.tenkanen@uta.fi)
An editorialist writes that statins have more evidence supporting their use, but “fibrates may be down, but they are not out” (pp. 715-6): “For patients similar to those enrolled in [these studies] and especially for those with features of the metabolic syndrome, gemfibrozil is a very reasonable and less expensive alternative to statins. The other fibrates, bezafibrate (available outside the U.S.) and fenofibrate, have yet to prove their efficacy in reducing major cardiac events. The most pressing question now is whether adding fibrates to statin therapy is safe and reduces cardiovascular events above and beyond what can be achieved with statins alone. This will hopefully be answered, at least for fenofibrate, by the ACCORD trial.” (H. E. Bloomfield,
bloom013@tc.umn.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, 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, 2006 Vol. 13, No. 70
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Apr. 12 issue of JAMA (www.jama.com; 2006; 295).
Estrogens & Breast Cancer: In postmenopausal women with prior hysterectomy, treatment with conjugated equine estrogens for 5 years did not increase the risk of breast cancer during 7.1 years of follow-up, but the need for mammography screening was greater, according to data from the Women’s Health Initiative Estrogen-Alone trial (pp. 1647-57). The study included 10,739 postmenopausal women aged 50 to 79 years who were treated with CEE 0.625 mg/day or placebo from 1993 until 1998. “After a mean (SD) follow-up of 7.1 (1.6) years, the invasive breast cancer hazard ratio (HR) for women assigned to CEE vs placebo was 0.80 (95% confidence interval [CI], 0.62-1.04; P = .09) with annualized rates of 0.28% (104 cases in the CEE group) and 0.34% (133 cases in the placebo group),” the authors report. “In exploratory analyses, ductal carcinomas (HR, 0.71; 95% CI, 0.52-0.99) were reduced in the CEE group vs placebo group; however, the test for interaction by tumor type was not significant (P = .054). At 1 year, 9.2% of women in the CEE group had mammograms with abnormalities requiring follow-up vs 5.5% in the placebo group (P < .001), a pattern that continued through the trial to reach a cumulative percentage of 36.2% vs 28.1%, respectively (P < .001); however, this difference was primarily in assessments requiring short interval follow-up.” (M. L. Stefanick, stefanick@stanford.edu)
Estrogen-Receptor Status & Chemotherapy: In an analysis of data from breast cancer treatment trials, biweekly doxorubicin/cyclophosphamide plus paclitaxel was superior to low-dose cyclophosphamide, doxorubicin, and fluorouracil among patients with node-positive tumors, estrogen-receptor-negative breast cancer, reducing rates of recurrence and death by more than 50% (pp. 1658-67). Data from these Cancer and Leukemia Group B and U.S. Breast Cancer Intergroup regimens were assessed: (1): three regimens of cyclophosphamide, doxorubicin, and fluorouracil (Jan. 1985 to Apr. 1991); (2) three doses of doxorubicin concurrent with cyclophosphamide, with or without subsequent paclitaxel (May 1994 to Apr. 1997); (3) sequential doxorubicin, paclitaxel, and cyclophosphamide with concurrent doxorubicin and cyclophosphamide followed by paclitaxel, and also 3-week vs 2-week cycles (Sept. 1997 to Mar. 1999). The investigators report: “For ER-negative tumors, chemotherapy improvements reduced the relative risk of recurrence by 21%, 25%, and 23% in the 3 studies, respectively, and 55% comparing the lowest dose in the first study with biweekly cycles in the third study. Corresponding relative risk reductions for ER-positive tumors treated with tamoxifen were 9%, 12%, and 8% in the 3 studies, and 26% overall. The overall mortality rate reductions associated with chemotherapy improvements were 55% and 23% among ER-negative and ER-positive patients, respectively. All individual ER-negative comparisons and no ER-positive comparisons were statistically significant. Absolute benefits due to chemotherapy were greater for patients with ER-negative compared with ER-positive tumors: 22.8% more ER-negative patients survived to 5 years disease-free if receiving chemotherapy vs 7.0% for ER-positive patients; corresponding improvements for overall survival were 16.7% vs 4.0%.” (D. A. Berry, dberry@mdanderson.org)
Herd Immunity with Pneumococcal Vaccine: The frequency of invasive pneumococcal disease has declined among neonates and young infants in the years since introduction of the heptavalent pneumococcal conjugate vaccine even though the product is used only in older infants and children (pp. 1668-74). This evidence of a “herd immunity” with use of the vaccine comes from a prospective, population-based study in eight U.S. states with data from 1997 to 2004. A total of 146 IPD cases were recorded, 89 in the 3 years before PCV7 was introduced and 57 in the 3 years after PCV7 introduction. Among all the infants aged 0 to 90 days, the average rate of IPD decreased significantly from 11.8 per 100,000 live births in the pre-PCV7 years to 7.2 per 100,000 live births in the post-PCV7 years. The average rate of IPD decreased by 39%, 45%, and 32% for infants aged 0 to 30 days, 31 to 60 days, and 61 to 90 days, respectively. (K. Poehling, katherine.poehling@vanderbilt.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 © 2006, 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, 2006 Vol. 13, No. 71
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Apr. 13 issue of the New England Journal of Medicine (content.nejm.org; 2006; 354).
Homocysteine & Cardiovascular Disease: As reported in PNN on Mar. 13, two studies released at the American College of Cardiology meeting show no reductions in cardiovascular events as a result of lowering of serum homocysteine levels. In the Heart Outcomes Prevention Evaluation (HOPE) 2 trial, dietary supplements containing folic acid and vitamins B6 and B12 failed to reduce the risk of death and myocardial infarction among 5,522 patients with vascular disease or diabetes (pp. 1567-77). “Mean plasma homocysteine levels decreased by 2.4 µmol per liter (0.3 mg per liter) in the active-treatment group and increased by 0.8 µmol per liter (0.1 mg per liter) in the placebo group,” HOPE 2 investigators write. “Primary outcome events occurred in 519 patients (18.8 percent) assigned to active therapy and 547 (19.8 percent) assigned to placebo (relative risk, 0.95; 95 percent confidence interval, 0.84 to 1.07; P = 0.41). As compared with placebo, active treatment did not significantly decrease the risk of death from cardiovascular causes (relative risk, 0.96; 95 percent confidence interval, 0.81 to 1.13), myocardial infarction (relative risk, 0.98; 95 percent confidence interval, 0.85 to 1.14), or any of the secondary outcomes. Fewer patients assigned to active treatment than to placebo had a stroke (relative risk, 0.75; 95 percent confidence interval, 0.59 to 0.97). More patients in the active-treatment group were hospitalized for unstable angina (relative risk, 1.24; 95 percent confidence interval, 1.04 to 1.49).” (E. Lonn, lonnem@mcmaster.ca)
The second study supports the HOPE 2 findings, concluding that these supplements are not beneficial and may in fact be harmful (pp. 1578-88). Study participants received either placebo, vitamin B
6 alone, folic acid plus vitamin B12, or folic acid plus vitamins B6 and B12. As in the HOPE 2 trial, plasma homocysteine levels were lowered significantly, but this provided no significant effect on a composite primary end point of recurrent MI, stroke, and sudden death attributed to coronary artery disease. Furthermore, the investigators add, the group receiving folic acid plus vitamins B6 and B12 had a trend toward increased risk of this end point (relative risk, 1.22; 95 percent confidence interval, 1.00 to 1.50; P = 0.05). (K. H. Bønaa, U. Tromsø, Tromsø, Norway; kaare.bonaa@stolav.no)
An editorialist adds that progress will depend on exploration of new methods for changing the hepatic conversion and/or urinary excretion of homocysteine (pp. 1629-32): “The straightforward but incorrect view that folic acid can decrease homocysteine levels and, thus, reduce the risk of atherosclerosis effectively may be an unintended consequence of oversimplifying a complicated metabolic network. Further exploration of the relations among the intermediates in this metabolic pathway and their association with atherothrombotic mediators will be needed.” (J. Loscalzo, Harvard Med. Sch., Boston)
Telithromycin & Asthma: For unclear reasons, the antibiotic telithromycin improves lung function among patients with acute exacerbations of asthma (pp. 1589-600). In a study of 278 adults, 10 days of telithromycin 800 mg/day significantly decreased symptom scores, compared with placebo. While 61% of patients had evidence of infection, clinical results did not correlate with presence of organisms such as Chlamydophila pneumoniae or Mycoplasma pneumoniae. (S. L. Johnston, Imperial Coll., London; s.johnston@imperial.ac.uk)

>>>PNN NewsWatch
* Reversing a February 2006 ruling, CMS has announced that the prescription niacin products Niaspan (Kos) and Niacor (Upsher-Smith) will continue to be reimbursable under the Medicare Part D benefit. CMS had ruled that prescription niacin products were essentially vitamins and thus not covered under Part D. Coverage had been assured through May 31 but was to have ended after that date. Because of the earlier ruling, prescription drug plans will not be required to add or restore the products to formularies for the balance of this year. For 2007, CMS indicated that prescription niacin products should be considered by PDPs for formulary inclusion.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, 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. 14, 2006 Vol. 13, No. 72
Providing news and information about medications and their proper use

>>>Rheumatology Update
Source:
Apr. issue of Arthritis & Rheumatism (www.rheumatology.org/publications; 2006; 54).
Etanercept, MTX for RA: The combination of etanercept plus methotrexate reduced disease activity, slowed radiographic progression, and improved function significantly more than either agent administered alone in a 2-year study of 686 patients with rheumatoid arthritis (pp. 1063-74). Comparing doses of etanercept 25 mg subcutaneously twice weekly and methotrexate orally up to 20 mg weekly, the investigators found: “A total of 503 of 686 patients continued into year 2 of the study. During the 2 years, significantly fewer patients receiving combination therapy withdrew from the study (29% of the combination therapy group, 39% of the etanercept group, and 48% of the MTX group).... The [American College of Rheumatology] 20% improvement (ACR20), ACR50, and ACR70 responses and the remission rates (based on a [Disease Activity Score] of < 1.6) were significantly higher with combination therapy than with either monotherapy (P < 0.01). Similarly, improvement in disability (based on the Health Assessment Questionnaire) was greater with combination therapy (P < 0.01). The combination therapy group showed significantly less radiographic progression than did either group receiving monotherapy (P < 0.05); moreover, radiographic progression was significantly lower in the etanercept group compared with the MTX group (P < 0.05). For the second consecutive year, overall disease progression in the combination therapy group was negative, with the 95% confidence interval less than zero. Adverse events were similar in the 3 treatment groups.” (D. van der Heijde, U. Hosp., Maastricht, the Netherlands; dhe@sint.azm.nl)
SNPs & MTX: Patient genotypes can be used to predict improvement versus adverse effects with methotrexate among patients with rheumatoid arthritis (pp. 1087-95). After 6 months of MTX therapy, combined most of the time with folate supplementation, those among 205 patients with a certain single nucleotide polymorphism had improvements, while those with another SNP developed more adverse drug effects. (J. A. M. Wessels, Leiden U. Med. Ctr., Leiden, The Netherlands; j.a.m.wessels@lumc.nl)

>>>PNN NewsWatch
* A once-monthly injectable naltrexone formulation (Vivitrol; Alkermes, Cephalon) was approved yesterday by FDA for treatment of alcohol dependence. It is indicated for alcohol-dependent patients who are able to abstain from drinking in an outpatient setting and are not actively drinking when initiating treatment. Treatment should be used in combination with psychosocial support, such as counseling or group therapy.
*
Bausch & Lomb has asked retailers to stop sales of the contact-lens solution Renu with MoistureLoc pending the outcome of a CDC investigation into a rash of cases of fungal keratitis. A total of 109 cases of suspected Fusarium keratitis are under investigation by CDC and public health authorities in 17 states. Some patients have reported a significant loss of vision, resulting in the need for a corneal transplant. Of the 30 patient cases fully investigated so far, 28 wore soft contact lenses and 2 reported no contact lens use. Twenty-six of the soft contact lens users who remembered which solution they used during the month before the infection onset reported using a Bausch & Lomb ReNu brand contact lens solution or a generic brand manufactured by the same company. Five patients reported using other solutions in addition to the ReNu brand, and 9 patients reported wearing contact lenses overnight, a known risk factor for microbial keratitis.
*
MiniMed Paradigm Real-Time Insulin Pump and Continuous Glucose Monitoring System (Medtronic) has been approved by FDA. The system has two components. The Real-Time CGM System relays glucose readings every 5 minutes from a glucose sensor to the insulin pump, which displays up to 288 readings a day, allowing patients to take immediate action to improve their glucose control after taking a confirmatory fingerstick. The Real-Time CGM System component is indicated for any patient 18 years of age or older, and insulin pump therapy is approved for all patients requiring insulin.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, 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, 2006 Vol. 13, No. 73
Providing news and information about medications and their proper use

>>>Chest Highlights
Source:
Apr. issue of Chest (www.chestjournal.org; 2006; 129).
Smoking After 9/11: Patient history of smoking and presence of withdrawal symptoms should be used in determining the number and dose of nicotine-replacement products and the duration of combination treatment should exceed 3 months, concludes the New York City Fire Department World Trade Center Tobacco Cessation Study (pp. 979-87). Tobacco use among firemen increased after the Sept. 11, 2001, attacks despite acute respiratory symptoms and health concerns among many of the rescue workers, the authors report. To counter this, a no-cost, quit-smoking program, “Tobacco Free With FDNY,” was instituted, and these results were noted for 220 cigarette smokers in 2002: “At study enrollment, the mean (± SD) tobacco use was 20 ± 7 cigarettes per day, and the mean tobacco dependency, as assessed by a modified Fagerstrom test score, was 6.7 ± 2.5 (maximum score, 10). Based on tobacco use, 20% of enrollees used three types of nicotine medications, 64% used two types, 14% used one type, and 3% used no medications. Additionally, 14% of enrollees used bupropion sustained release. The confirmed continuous abstinence rates were 47%, 36%, and 37%, respectively, after 3 months of treatment and at the 6-month and 12-month follow-up. Abstinence rates did not correlate with the history of tobacco use but correlated inversely with tobacco dependency. Adverse events and maximal nicotine medication use were unrelated, and no one experienced a serious adverse event.” (D.J. Prezant, Prezand@fdny.nyc.gov)
Docetaxel for Second-Line NSCLC Treatment: Among patients with nonsmall-cell lung cancer who fail platinum-based chemotherapy, weekly docetaxel provides less myelosuppression and better adherence and responses rates than do less frequent regimens of the drug (pp. 1031-8). Response rates among 161 patients were 17.2% among those who received docetaxel 35 mg/sq m on days 1, 8, and 15 every 4 weeks (D35); 10.9% with docetaxel 40 mg/sq m on days 1 and 8 every 3 weeks (D40); and 6.1% with docetaxel 75 mg/sq m on day 1 every 3 weeks (D75). The authors add, “Grades 3/4 leukopenia and neutropenia were significantly higher in the D75 arm of the study (p < 0.001). Drug-induced pneumonitis occurred more frequently in patients on a weekly schedule than in those on a schedule of every 3-weeks (p = 0.05). The median survival times were as follows: D35 group, 8.4 months; D40 group, 7.2 months; and D75 group, 9.5 months (p = 0.855). The 1-year survival rates were 32.8%, 31.9%, and 28.7%, respectively.” (Y-M Chen, Taipei Veterans Genl. Hosp., Taipei, Taiwan; ymchen@vghtpe.gov.tw)

>>>Lancet Highlights
Source:
Early-release article from Lancet (www.thelancet.com; 2006; 367).
Drug Control Policy in Romania: Reform of antidrug regulations was required in Romania to facilitate adequate pain management, and such efforts are needed in many countries of the world, conclude authors who address unrelieved pain from cancer and HIB/AIDS, calling it “a substantial worldwide public-health problem” (doi: 10.1016/S0140-6736(06)68482-1): “Romania’s drug-control policies are more than 35 years old and impose an antiquated regulatory system that is based on inpatient post-surgical management of acute pain that restricts prescription authority and makes access to opioid treatment difficult for outpatients with severe chronic pain due to cancer or HIV/AIDS. A Ministry of Health palliative-care commission used WHO guidelines to assess and recommend changes to Romania’s national drug control law and regulations. The Romanian parliament has adopted a new law that will simplify prescribing requirements and allow modern pain management.” (K. M. Ryan, kmryan2@wisc.edu)

>>>PNN JournalWatch
* Systemic Lupus Erythematosus in BMJ, 2006; 332: 890-4. Reprints: www.bmj.org; D. P. D’Cruz, St. Thomas Hosp., London; david.d’cruz@kcl.ac.uk
* Methods for Evaluating Patient Adherence to Antidepressant Therapy: A Real-World Comparison of Adherence and Economic Outcomes in
Medical Care, 2006; 44: 300-3. Reprints: www.lww-medicalcare.com; C. R. Cantrell.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, 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, 2006 Vol. 13, No. 74
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release article from and the Apr. 18 issue of the Annals of Internal Medicine (www.annals.org; 2006; 144).
Impact of Health Technology: A systematic review of literature finds improving quality and efficiency with implementation of health technology, but most studies are from four benchmark research institutions, leaving investigators to wonder “whether and how other institutions can achieve similar benefits, and at what costs” (early-release article). Looking systematically at the literature published through Jan. 2004 on technologies such as electronic health records, computerized provider order entry, mobile computing, decision support, and knowledge-retrieval systems, the researchers found: “257 studies met the inclusion criteria. Most studies addressed decision support systems or electronic health records. Approximately 25% of the studies were from 4 academic institutions that implemented internally developed systems; only 9 studies evaluated multifunctional, commercially developed systems. Three major benefits on quality were demonstrated: increased adherence to guideline-based care, enhanced surveillance and monitoring, and decreased medication errors. The primary domain of improvement was preventive health. The major efficiency benefit shown was decreased utilization of care. Data on another efficiency measure, time utilization, were mixed. Empirical cost data were limited.” (B. Chaudhry, BChaudhry@mednet.ucla.edu)
Tea, Coffee, & Diabetes: Consumption of green but not black tea, coffee, and total caffeine was associated with a lower risk of diabetes in a retrospective cohort study conducted in Japan (pp. 554-62). In 25 communities across the island nation, 6,727 men and 10,686 women aged 40-65 years reported these outcomes: “During the 5-year follow-up, there were 444 self-reported new cases of diabetes in 231 men and 213 women (5-year event rates, 3.4% and 2.0%, respectively). Consumption of green tea and coffee was inversely associated with risk for diabetes after adjustment for age, sex, body mass index, and other risk factors. Multivariable odds ratios for diabetes among participants who frequently drank green tea and coffee (6 cups of green tea per day and 3 cups of coffee per day) were 0.67 (95% CI, 0.47 to 0.94) and 0.58 (CI, 0.37 to 0.90), respectively, compared with those who drank less than 1 cup per week. No association was found between consumption of black or oolong teas and the risk for diabetes. Total caffeine intake from these beverages was associated with a 33% reduced risk for diabetes. These inverse associations were more pronounced in women and in overweight men.” (H. Iso, Osaka U., Osaka, Japan; iso@pbhel.med.osaka-u-ac.jp)

>>>PNN NewsWatch
* Initial results of the Study of Tamoxifen and Raloxifene (STAR) show that raloxifene works as well as tamoxifen in reducing breast cancer risk for postmenopausal women at increased risk of the disease. STAR, one of the largest breast cancer prevention clinical trials ever conducted, enrolled 19,747 postmenopausal women who were at increased risk of the disease. Participants were randomly assigned to receive either raloxifene 60 mg or tamoxifen 20 mg daily for 5 years. In STAR, both drugs reduced the risk of developing invasive breast cancer by about 50%, the National Cancer Institute announced yesterday. In addition, women who were prospectively and randomly assigned to take raloxifene daily, and who were followed for an average of about 4 years, had 36% fewer uterine cancers and 29% fewer blood clots than the women who were assigned to take tamoxifen. Uterine cancers, especially endometrial cancers, are a rare but serious side effect of tamoxifen. Both tamoxifen and raloxifene are known to increase a woman’s risk of blood clots. Lilly, which markets raloxifene as Evista, indicated that it would seek FDA approval of the drug for this added indication.
* The majority of American adults believe that drugs for
attention-deficit/hyperactivity disorder are overused in children younger than 13, and 56% are not sure how effective stimulants such as amphetamines and methylphenidate are. A Wall Street Journal/Harris Interactive survey shows 68% of adults support stronger warnings on the products’ labels.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, 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, 2006 Vol. 13, No. 75
Providing news and information about medications and their proper use

>>>Circulation Highlights
Source:
Apr. 18 issue of Circulation (circ.ahajournals.org; 2006; 113).
Anticoagulants & Transaminase Elevation: The epidemiology, diagnosis, and clinical management of elevations in hepatic transaminases during anticoagulant therapy are reviewed (pp. e698-702). While infrequently reported, anticoagulant-induced liver injury has been described in case reports, and the increasing number of patients on long-term anticoagulation is leading to increased attention to this possibility, the authors write. Warfarin has been associated with a 0.8% to 1.2% risk of transaminase elevations of 3 or more times the upper limit of normal; phenprocoumon, a structurally similar coumarin analogue commonly used in Europe, was linked to a 2% incidence of hepatitis and 0.2% incidence of liver failure in a retrospective registry; and the direct thrombin inhibitor ximelagatran, when used long-term, was associated with a 7.9% increase in transaminase levels, a 1.1% incidence of hepatitis, and a 1 in 2,000 risk of death from liver failure.
The authors make these recommendations for clinical management of patients with elevated transaminase levels: “If no other cause is apparent and if ALT or AST is elevated to >3 ULN in any patient on anticoagulant therapy, close follow-up is recommended. If the trend shows a persistent rise, switch to another class of anticoagulant agent. If the bilirubin is elevated to >2 ULN and if there is a strong suspicion of the anticoagulant medication being the culprit, discontinue the anticoagulant immediately.
“Fulminant hepatic failure can develop within 2 weeks of onset of hepatocellular injury. If there is evidence of encephalopathy with persistent jaundice and coagulopathy (as measured by an INR of 1.5 or greater) even after discontinuation of the anticoagulant, consider transferring the patient to a liver transplantation center. Corticosteroid treatment may be used in patients with evident hypersensitive reactions, although controlled trials have not proven the efficacy of such treatment for the hepatotoxic adverse reactions of other drugs. A cautious repeat challenge can be performed if the association is highly questionable and if no other drug is available for the treatment of a potentially life-threatening disorder.” (S. Z. Goldhaber,
sgoldhaber@partners.org)

>>>JAMA Highlights
Source:
Apr. 19 issue of JAMA (www.jama.com; 2006; 295).
Estrogens & Migraine: Pharmacologic studies designed to explore the link between estrogens and migraine are justified based on epidemiologic, pathophysiologic, and clinical evidence, concludes an author of a review article (pp. 1824-30). “The influence of estrogen on migraine is evident by a 3-fold greater prevalence among women compared with men, and by significant changes in migraine incidence with changes in female reproductive status,” the writer notes. “Menstrual migraines are usually more resistant to treatment, generally not associated with aura, of longer duration, and associated with more functional disability compared with attacks at other times of the month. Biochemical and genetic evidence suggest central and peripheral roles for estrogen in the pathophysiology of menstrual migraine, with potential interactions with excitatory circuits, including serotonergic components. Although evidence for estrogen as a preventive treatment for menstrual migraine is inconsistent, serotonin receptor agonists (triptans) provide acute relief and also may have a role in prevention.” (J. L. Brandes, jbrandes@nashvilleneuroscience.com)

>>>PNN NewsWatch
* Hospira Inc. will today announce the “first major overhaul of IV gear in more than 30 years,” reports this morning’s Wall Street Journal. The new bags and tubing will replace polyvinyl chloride with propylene, the newspaper notes, and will be made without the controversial component diethylhexylphthalate, linked in some studies to hormonal disruptions. Hospira is the second largest producer of IV products in the U.S.; the largest producer, Baxter, yesterday announced plans for a pilot program of a premium line of products that would be made without PVC and DHEP.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, 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, 2006 Vol. 13, No. 76
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Apr. 20 issue of the New England Journal of Medicine (content.nejm.org; 2006; 354).
Corticosteroids & ARDS: Methylprednisolone, while improving cardiopulmonary physiology, is not effective for treating acute respiratory distress syndrome, and treatment beginning more than 2 weeks after ARDS onset may increase mortality risk (pp. 1671-84). In a study of 180 patients with ARDS of at least 7 days’ duration, methylprednisolone or placebo produced these outcomes: “At 60 days, the hospital mortality rate was 28.6 percent in the placebo group (95 percent confidence interval, 20.3 to 38.6 percent) and 29.2 percent in the methylprednisolone group (95 percent confidence interval, 20.8 to 39.4 percent; P = 1.0); at 180 days, the rates were 31.9 percent (95 percent confidence interval, 23.2 to 42.0 percent) and 31.5 percent (95 percent confidence interval, 22.8 to 41.7 percent; P = 1.0), respectively. Methylprednisolone was associated with significantly increased 60- and 180-day mortality rates among patients enrolled at least 14 days after the onset of ARDS. Methylprednisolone increased the number of ventilator-free and shock-free days during the first 28 days in association with an improvement in oxygenation, respiratory-system compliance, and blood pressure with fewer days of vasopressor therapy. As compared with placebo, methylprednisolone did not increase the rate of infectious complications but was associated with a higher rate of neuromuscular weakness.” (K. P. Steinberg, steinkp@u.washington.edu)
Treating Prehypertension with ARBs: In the Trial of Preventing Hypertension (TROPHY), institution of candesartan therapy in patients with prehypertension reduced the risk of incident hypertension during a 2-year study period, compared with placebo (pp. 1685-97). Concluding that “treatment of prehypertension appears to be feasible,” TROPHY investigators report these results for these patients, who had systolic blood pressures of 130-139 mm Hg with diastolic readings below 90 mm Hg or SBPs below 140 mm Hg with DBPs of 85-89 mm Hg: “A total of 409 participants were randomly assigned to candesartan, and 400 to placebo. Data on 772 participants (391 in the candesartan group and 381 in the placebo group; mean age, 48.5 years; 59.6 percent men) were available for analysis. During the first two years, hypertension developed in 154 participants in the placebo group and 53 of those in the candesartan group (relative risk reduction, 66.3 percent; P < 0.001). After four years, hypertension had developed in 240 participants in the placebo group and 208 of those in the candesartan group (relative risk reduction, 15.6 percent; P < 0.007). Serious adverse events occurred in 3.5 percent of the participants assigned to candesartan and 5.9 percent of those receiving placebo.” (S. Julius, sjulius@umich.edu)
Ondansetron for Gastroenteritis: Among 215 children aged 6 months to 10 years who were treated in a pediatric emergency department for gastroenteritis and dehydration, a single oral dose of ondansetron helped decrease vomiting and thereby facilitate oral rehydration (pp. 1698-705). The researchers report: “As compared with children who received placebo, children who received ondansetron were less likely to vomit (14 percent vs. 35 percent; relative risk, 0.40; 95 percent confidence interval, 0.26 to 0.61), vomited less often (mean number of episodes per child, 0.18 vs. 0.65; P < 0.001), had greater oral intake (239 ml vs. 196 ml, P = 0.001), and were less likely to be treated by intravenous rehydration (14 percent vs. 31 percent; relative risk, 0.46; 95 percent confidence interval, 0.26 to 0.79). Although the mean length of stay in the emergency department was reduced by 12 percent in the ondansetron group, as compared with the placebo group (P = 0.02), the rates of hospitalization (4 percent and 5 percent, respectively; P = 1.00) and of return visits to the emergency department (19 percent and 22 percent, P = 0.73) did not differ significantly between groups.” (S. B. Freedman, Hosp. for Sick Children, Toronto, stephen.freedman@sickkids.ca)
Dual Antiplatelet Therapy: Results of the CHARISMA trial of clopidogrel plus aspirin, as reported in the Mar. 13 PNN, are published in full in this issue of NEJM (pp. 1706-17; E. Topol, eric.topol@case.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 © 2006, 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. 21, 2006 Vol. 13, No. 77
Providing news and information about medications and their proper use

>>>Gastroenterology Update
Source:
Apr. issue of Gastroenterology (www.gastrojournal.org; 2006; 130).
Infliximab Bridge for Crohn’s Disease: Addition of infliximab to azathioprine/6-mercaptopurine therapy can enable patients with Crohn’s disease to go off steroids, providing a bridge between steroid treatments or a parachute when steroids are not working (pp. 1054-61). This study included participants whose disease was not adequately treated with stable doses of AZA/6-MP for 6 months plus steroids (failure stratum) and patients who had not previously received AZA/6-MP (naive stratum). “Among the 113 enrolled patients (55 in the failure stratum), 57 were assigned to infliximab,” the researchers write. “At week 24, the success rate (intent-to-treat analysis) was higher in the infliximab group than in the placebo group (57% vs 29%; P = .003); at weeks 12 and 52, the corresponding rates were 75% vs 38% (P < .001) and 40% vs 22% (P = .04), respectively. In each stratum, the success rate was significantly higher in the infliximab group at weeks 12 and 24, and a trend was found at week 52. In the failure stratum, only 27% of the patients in the infliximab group were still in remission off steroids, compared with 52% in the naive stratum. Steroid resistance was less common and the cumulative dose of prednisone was lower in the infliximab group.” (M. Lemann, marc@lemann.com)
An editorialist provides this advice to clinicians (pp. 1354-7): “Infliximab induction in conjunction with AZA doubles the 12-month steroid-free remission rate in patients who are steroid dependent. This delays, but does not prevent relapse (the ‘parachute’ effect). Particular patients who benefit are those naive to thiopurines, those who are young (age <26), and who have colonic Crohn’s disease. Since 40% in steroid-free remission 1 year is at least as good as that achieved by infliximab in the ACCENT I study, this gives solace to those practitioners (largely in Europe) for whom maintenance infliximab is not readily available. The question now is whether regular infliximab with AZA-MP will do any better: results are expected in 2007. In the meantime, if infliximab is given to steroid-dependent patients, then azathioprine should be given as well.” (S. Travis, John Radcliffe Hosp., Oxford, U.K.;
simon.travis@orh.nhs.uk)
HCV Therapies: Two studies address how hepatitis C virus should be treated in difficult-to-treat patients.
Extended treatment duration should be reserved for patients with slow virologic responses, concludes a study of 455 treatment-naive patients with HCV (pp. 1086-97). Comparing outcomes with pegylated interferon alfa-2a in those treated for 48 weeks (group A) or 72 weeks (group B), the authors report: “Overall, no significant differences could be observed in the treatment outcome between both groups. End-of-treatment and [sustained virologic response] rates in groups A and B were 71% vs 63% and 53% vs 54%, respectively. Patients with undetectable HCV-RNA levels already at weeks 4 and 12 had excellent SVR rates ranging from 76% to 84% regardless of treatment group, whereas patients shown to be still HCV-RNA positive at week 12 achieved significantly higher SVR rates when treated for 72 instead of 48 weeks (29% vs 17%, P = .040). A particular benefit from extended treatment duration was seen in patients with low-level viremia (<6000 IU/mL) at week 12. The frequency and intensity of adverse events was similar between the 2 groups.” (T. Berg,
thomas.berg@charite.de)
Among multiexperienced and difficult-to-treat nonresponding patients with HCV, retreatment with pegylated interferon-alpha-2b plus ribavirin produced a “very promising SVR,” reports a second study (pp. 1098-106). The investigators note: “By intent-to-treat analysis, 20% of patients achieved ... SVR. SVR of genotype 1 patients was 19%. Independent predictors of SVR were low gamma-glutamyltransferase levels (OR, 22.9; 95% CI: 6.6-79.6) and low viral load (OR, 3.8; 95% CI: 1.1-12.6). Twelve (23%) out of 51 patients who were HCV RNA positive after 24 weeks of therapy achieved a late virologic response (after week 24) and 5 (10%) of them, all with genotype 1, achieved an SVR. Genotype was not associated with response (P = .2) or with early response (P = .3).” (G. Taliani,
gloria.taliani@uniroma1.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 © 2006, 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, 2006 Vol. 13, No. 78
Providing news and information about medications and their proper use

>>>
Lancet Highlights
Source:
Early-release article from Lancet (www.thelancet.com; 2006; 367).
European Preparedness for Avian Influenza: Despite strong governmental commitment to preparing for a possible avian influenza pandemic, gaps remain and countries vary considerably in their preparedness, report authors who analyzed 21 national plans (DOI:10.1016/S0140-6736(06)68511-5). “Although preparation for surveillance, planning and coordination, and communication were good, maintenance of essential services, putting plans into action, and public-health interventions were probably inadequate,” the investigators note. “Few countries have addressed in their plans the need for collaboration with adjacent countries, despite this being an acknowledged imperative. Similarly, plans for the timely distribution of available medical supplies are notably absent.” (R. J. Coker, London Sch. of Hygiene and Tropical Med., London; richard.coker@lshtm.ac.uk)
Commenting on potential problems in a pandemic situation, a
Lancet editorialist write: “Other problems—medical, distribution of medical supplies, essential services, quarantine, civil order—may be listed under the broad umbrella of confidence. These are grey areas in countries’ plans, yet it is here that the public’s confidence in governments and agencies can be easily eroded, particularly in a rapidly evolving situation. Failure to have financial contingencies in place, or appearance of counterfeit medicines, will exacerbate any such erosion.” (K. F. Shortridge, U. Auckland, Auckland, New Zealand; kennedyfs@xtra.co.nz)

>>>BMJ Highlights
Source:
Apr. 22 issue of BMJ (www.bmj.org; 2006; 332).
Atorvastatin & Nightmares: Extreme nightmares in a 72-year-old woman began 5 days after starting atorvastatin and continued for 2.5 weeks, stopped upon dechallenge, and recurred on rechallenge, according to a Drug Points article (p. 950). The internist reporting the case notes: “A possible relation between nightmares and statins has previously been reported with the use of simvastatin and metoprolol. To my knowledge, no recounts of nightmares with the use of atorvastatin have been reported to Pfizer or have been published.
“The nightmares could be a direct effect of atorvastatin on the central nervous system. But the mechanism may be pharmacokinetic (CYP3A4) or a pharmacodynamic interaction.
“Although it seems that nightmares are an occasional adverse effect of statins, this is relevant for the patient and should be recognised by the treating doctor since it is easily corrected by stopping statins.” (P. J. H. Gregoor, Albert Schweitzer Hosp., Dordrecht, the Netherlands;
p.smakgregoor@asz.nl

>>>PNN NewsWatch
* A Government Accountability Office report due out today reportedly criticizes FDA for its handling of problems with Vioxx, Bextra, Arava, and Propulsid. The Washington Post reports that GAO concludes that FDA lacks “criteria for determining what safety actions to take and when to take them.” The Wall Street Journal adds, “The GAO report focused on the relationship between the FDA’s Office of New Drugs, which reviews medicines before they go on the market and has primary responsibility for them, and the Office of Drug Safety, which focuses on safety of medicines after they are approved. The report said the safety office served as a ‘consultant’ to the new-drugs office, with no ‘independent decision-making responsibility.’ Some drug-safety staff told the investigators their recommendations fell into a ‘black hole’ or an ‘abyss.’”

>>>PNN JournalWatch
* Recommendations from an International Expert Panel on the Use of Neoadjuvant (Primary) Systemic Treatment of Operable Breast Cancer: An Update, in Journal of Clinical Oncology, 2006; 24: 1940-9. Reprints: www.jco.org/cgi/content/abstract/24/12/1940; M. Kaufmann, J.W. Goethe-U. Hosp., Frankfurt, Germany; M.Kaufmann@em.uni-frankfurt.de
* Ins and Outs Modulating Hepatic Triglyceride and Development of Nonalcoholic Fatty Liver Disease, in
Gastroenterology, 2006; 130: 1343-6. Reprints: www.gastrojournal.org/article/PIIS0016508506004744/fulltext; I J. Goldberg, ijg3@columbia.edu

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, 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, 2006 Vol. 13, No. 79
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Apr. 24 issue of Archives of Internal Medicine (www.archinternmed.com; 2006; 166).
Preventing Relapse After Smoking Cessation: Skills training and other interventions designed to help patients avoid relapse after smoking cessation are as yet unproven, according to a systematic review of 42 randomized or quasi-randomized controlled trials of 6 months or more in duration (pp. 828-35). “The most common interventions were skills training to identify and resolve tempting situations and extended treatment contact,” report the researchers. “A few studies tested pharmacotherapy. We separately analyzed studies that randomized abstainers and those that randomized participants before their quit date. Within subgroups of trials, pooled odds ratios ranged from 0.86 to 1.30, and in most analyses, 95% confidence intervals included 1. Most studies had limited power to detect moderate differences between interventions.” (T. Lancaster, U. Oxford, Oxford, U.K.; tim.lancaster@dphpc.ox.ac.uk)
Oxycodone for Cancer-Related Pain: In patients with cancer-related pain, oral oxycodone is comparable with oral morphine and oral hydromorphone, conclude authors who conducted a meta-analysis of available trials (pp. 837-43). Focusing only on use of the analgesics as single agents (not in combination with acetaminophen), the authors found: “Four studies, comparing oral oxycodone with either oral morphine (n = 3) or oral hydromorphone (n = 1), were suitable for meta-analysis. Standardized mean differences in pain scores comparing oxycodone with control groups were pooled using random-effects models. Overall, there was no evidence that mean pain scores differed between oxycodone and control drugs (pooled standardized mean difference, 0.04; 95% confidence interval [CI], –0.29 to 0.36; P = .8; I2 = 62%). In meta-regression analyses, pain scores were higher for oxycodone compared with morphine (0.20; 95% CI, –0.04 to 0.44) and lower compared with hydromorphone (–0.36; 95% CI, –0.71 to 0.00), although these effect sizes were small. The efficacy and tolerability of oxycodone are similar to morphine, supporting its use as an opioid for cancer-related pain.” (C. M. Reid, Colette.reid@bristol.ac.uk)
Bleeding with Ximelagatran, Warfarin: Patients with nonvalvular atrial fibrillation had lower risks of bleeding while taking ximelagatran 36 mg twice daily, compared with warfarin dosed to an INR of 2.0-3.0 (pp. 853-9). These data come from a pooled analysis of 7,329 patients in the Stroke Prevention Using Oral Thrombin Inhibitor in Atrial Fibrillation III and V trials: “Annual incidence of any bleeding was 31.75% with ximelagatran and 38.82% with warfarin (relative risk reduction, 18.2%; 95% confidence interval [CI], 13.0-23.1; P < .001). Annual incidence of major bleeding was 2.01% with ximelagatran and 2.68% with warfarin (relative risk reduction, 25.1%; 95% CI, 3.2-42.1; P = .03). Case-fatality rate of bleeding was comparable in ximelagatran- and warfarin-treated patients (8.16% vs 8.09%; P = .98). Cumulative incidence of major bleeding was higher with warfarin than ximelagatran after 24 months of treatment (4.7% vs 3.7%; P = .04). Anatomic sites of bleeding were comparable with both treatments. Risk factors for bleeding with ximelagatran were as follows (hazard ratios and 95% CIs in parentheses): diabetes mellitus (1.81; 1.19-2.77; P = .006), previous stroke or transient ischemic attack (1.78; 1.16-2.73; P = .008), age 75 years or greater (1.70; 1.33-2.18; P < .001), and aspirin use (1.68; 1.08-2.59; P = .02). Risk factors for bleeding in warfarin-treated patients were previous liver disease (4.88; 1.55-15.39; P = .007); aspirin use (2.41; 1.69-3.43; P < .001); and age 75 years or greater (1.26; 1.03-1.52; P = .02).” (J. D. Douketis, jdouket@mcmaster.ca)
Calcium & Adherence: A 5-year study of 1,460 older women shows that calcium is ineffective for preventing clinical fractures because many patients do not adhere to and persist with the intervention (pp. 869-75). Considering all patients, the risk of fracture was reduced by a nonsignificant 13%, but among 830 patients who took 80% or more of their active or placebo tablets, the incidence of fracture was significantly reduced, by 44%, with active therapy. (R. L. Prince, Sir Charles Gairdner Hosp., Nedlands, W. Australia, Australia; rlprince@cyllene.uwa.edu.au)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, 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, 2006 Vol. 13, No. 80
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Apr. 26 issue of JAMA (www.jama.com; 2006; 295).
Diabetes Guidelines for Older Adults: Clinical use of the “Guidelines for Improving the Care of the Older Person with Diabetes Mellitus” is described in three case presentations (pp. 1935-40). Developed by a California Health Care Foundation/American Geriatrics Society panel and published in a 2003 supplement of the Journal of the American Geriatrics Society (www.blackwell-synergy.com; 5 suppl; pp. S265-80), the guidelines considered “the heterogeneity of health status of the older adult diabetic population and asked (1) what are the major health threats to older diabetic patients and (2) how might physicians prioritize health care recommendations for patients at the extremes of health status and for those in between,” the author notes. “[These] are the first guidelines to specifically address [the] complexity [of older patients’ clinical conditions] and provide guidance to physicians who must prioritize therapies and goals for older adults with diabetes, comorbid medical conditions, and geriatric syndromes. By providing a rationale for prioritizing recommendations and the inclusion of geriatric syndromes that impact the patient’s overall health and diabetic care, these guidelines may serve as a model for the development of other guidelines targeting older adults with complex health status.” (S. C. Durso, Johns Hopkins U., Baltimore; sdurso@jhmi.edu)
Physician-Assisted Suicide: A legal perspective explores whether physician-assisted suicide is a “legitimate medical practice” (pp. 1941-3). After analyzing the recent Gonzales v. Oregon decision issued by the U.S. Supreme Court that prevents the Attorney General from using the Controlled Substances Act to stop state-permissible assisted suicide, the author concludes: “In many ways, discussion of physician-assisted suicide masks a far more important problem—the need to reliably and safely achieve effective relief of pain and suffering near the end of life. Multiple forces have stood in the way of effective palliative care such as physician training (stressing intervention over palliation), a rescue imperative, and the burgeoning development and promotion of life-saving technologies. Physicians have also feared criminal or civil liability for hastening a patient’s death. Commenting on Gonzales v Oregon, President George W. Bush expressed disappointment at the erosion of a ‘culture of life.’ However, deep caring and relief of suffering by physicians at the bedside of dying patients may be a far greater affirmation of life. Modern medicine must evolve to constructively support patients in the dying process—a time of incomparable meaning and importance to the human condition.” (L. O. Gostin, gostin@law.georgetown.edu)
FDA Experts’ Conflicts of Interest: Nearly three quarters of FDA advisory committees that met during 2001 through 2004 included at least one voting member who disclosed financial conflicts of interest, according to an analysis of committee agendas and meetings, but only a weak relationship between conflicts and votes was detected (pp. 1921-8). “A total of 221 meetings held by 16 advisory committees were included in the study. In 73% of the meetings, at least 1 advisory committee member or voting consultant disclosed a conflict; only 1% of advisory committee members were recused. For advisory committee members (n = 1957) and voting consultants combined (n = 990), 28% (n = 825) disclosed a conflict. The most commonly specified conflicts were consulting arrangements, contracts/grants, and investments. Nineteen percent of consulting arrangements involved over $10,000, 23% of contracts/grants exceeded $100,000, and 30% of investments were over $25,000. The meeting-level analysis did not show a statistically significant relationship between conflict rates (‘index conflict,’ ‘competitor conflict,’ or ‘any conflict&rsquoWinking and voting patterns, but a weak, statistically significant positive relationship was apparent for competitor conflict and any conflict.” (P. Lurie, Public Citizen’s Health Research Group, Washington, D.C.; plurie@citizen.org)

>>>PNN NewsWatch
* Promethazine hydrochloride should not be used in children younger than 2 years of age because of potentially fatal respiratory depression, FDA has warned, and the drug should be used cautiously in older children.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, 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, 2006 Vol. 13, No. 81
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Apr. 27 issue of the New England Journal of Medicine (content.nejm.org; 2006; 354).
Thyroxine & Acid Secretion: Patients with Helicobacter pylori or other types of gastritis that interfere with normal acid secretion in the stomach require an increased dose of thyroxine, according to a 248-patient study (pp. 1787-95). Doses of thyroxine required to attain a low thyrotropin level were compared in 135 patients with goiter and no gastric disorders, 53 patients with H. pylori-associated gastritis, and 60 patients with atrophic gastritis of the body of the stomach; 11 patients were studied more closely in a prospective part of the study. Results showed the following: “The daily requirement of thyroxine was higher (by 22 to 34 percent) in patients with H. pylori–related gastritis, atrophic gastritis, or both conditions than in the reference group. In prospective studies, the occurrence of H. pylori infection in the 11 patients treated with thyroxine led to an increase in the level of serum thyrotropin (P = 0.002), an effect that was nearly reversed on eradication of H. pylori infection. In a similar way, omeprazole treatment was associated with an increase in the level of serum thyrotropin in all 10 patients treated with thyroxine, an effect that was reversed by an increase in the thyroxine dose by 37 percent.” (M. Centanni, Policlinico Umberto I, Rome; marco.centanni@uniroma1.it)
Pregnancy & Antioxidant Vitamins: Similar to results reported recently in Lancet (see PNN, Apr. 3), daily supplements of vitamin C 1,000 mg and vitamin E 400 IU failed to reduce the risks of preeclampsia in nulliparous women, intrauterine growth restriction, and death or other serious outcomes in infants (pp. 1796-806). Comparing vitamin supplements with placebo in 1,877 women, the investigators found: “There were no significant differences between the vitamin and placebo groups in the risk of preeclampsia (6.0 percent and 5.0 percent, respectively; relative risk, 1.20; 95 percent confidence interval, 0.82 to 1.75), death or serious outcomes in the infant (9.5 percent and 12.1 percent; relative risk, 0.79; 95 percent confidence interval, 0.61 to 1.02), or having an infant with a birth weight below the 10th percentile for gestational age (8.7 percent and 9.9 percent; relative risk, 0.87; 95 percent confidence interval, 0.66 to 1.16).” (C. A. Crowther, U. Adelaide, North Adelaide, Australia; caroline.crowther@adelaide.edu.au)
Editorialists support further testing of antioxidant vitamins but not routine use in clinical practice: “Until more data are available, given the scant evidence of benefit and the potential for harm, supplemental antioxidant therapy for the prevention of preeclampsia should be limited to women enrolled in randomized trials and should not be prescribed as part of routine practice” (pp. 1841-3). The writers provide this update on ongoing clinical trials: “The Maternal–Fetal Medicine Units Network of the National Institute of Child Health and Human Development is currently conducting a multicenter trial in the United States of supplementation with vitamin C and vitamin E for the prevention of preeclampsia, with an anticipated sample of 10,000 low-risk women. The data safety monitoring committee has decided to continue this trial without modification, after reviewing the results provided [in the
Lancet study mentioned above]. There are also ongoing international trials of antioxidant therapy to prevent preeclampsia, some involving women in developing nations, where the intake of antioxidants may be less and the benefit of supplementation may be greater than in developed nations. (A. Jeyabalan, U. Pittsburgh, Pittsburgh)
HBV Resistance to Adefovir: Three cases of hepatitis B virus resistant to adefovir but sensitive to tenofovir are reported (pp. 1807-12). When lamivudine resistance develops, patients are often switched to adefovir, but these cases indicate when a rare HVB variant with a valine at position 233 of the reverse transcriptase domain is present, tenofovir would be a better second-line choice. In addition, adefovir has the disadvantage of being given as a fixed doses, while tenofovir doses can be increased 10-fold. (W. H. Gerlich, Inst. of Medical Virology, Giessen, Germany; wolfram.h.gerlich@viro.med.uni-giessen.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 © 2006, 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. 28, 2006 Vol. 13, No. 82
Providing news and information about medications and their proper use

>>>
Diabetes Highlights
Source:
May issue of Diabetes Care (care.diabetes.journals.org; 2006; 29).
Antihypertensives & Incident Diabetes: A higher risk of new-onset diabetes was observed among patients taking thiazide diuretics and beta-blockers for hypertension, according to a new analysis of data from the Nurses’ Health Study I and II and the Health Professionals Follow-up Study (pp. 1065-70). Based on biennial questionnaires completed by 41,193 older women, 14,151 younger women, and 19,472 men who had hypertension but not diabetes at baseline, the authors report these results after 8, 10, and 16 years of monitoring, respectively: “We documented 3,589 incident cases of diabetes. After adjustment for age, [body mass index], physical activity, the use of other antihypertensive medications, and other risk factors, the multivariate relative risk (RR) of incident diabetes in participants taking a thiazide diuretic compared with those not taking a thiazide was 1.20 (95% CI 1.08-1.33) in older women, 1.45 (1.17-1.79) in younger women, and 1.36 (1.17-1.58) in men. The multivariate RR in participants taking a beta-blocker compared with those not taking a beta-blocker was 1.32 (1.20–1.46) in older women and 1.20 (1.05–1.38) in men. ACE inhibitors and calcium channel blockers were not associated with risk.” (E. N. Taylor, entaylor@partners.org)
In an accompanying editorial, this advice is offered for incorporating these findings into daily clinical practice (pp. 1167-9): “Clinically, physicians and health care professionals should focus on achievement of glucose, lipid, and blood pressure goals, since only 7.3% of those with diabetes achieve all three guideline goals. While cost of medications and preexisting conditions of the patients (i.e., other cardiovascular risk factors) should be considered when prescribing medications, these concerns need to be tempered by the cardiovascular/renal benefits of achieving guideline goals. Agents that do not predispose to the development of diabetes should be preferred in those with metabolic syndrome, but a diuretic will be needed in almost everyone as a second agent to achieve further blood pressure reduction. This is due to the increased sodium reabsorption and volume expansion that results from high circulating insulin levels in people with metabolic syndrome and type 2 diabetes. Beta-blockers can be avoided more easily as first-line agents in patients predisposed to develop diabetes but may be needed for specific indications in some people. In such circumstances, it is important to use the appropriate agents while ensuring that guideline goals are achieved.” (G. L. Bakris, Rush U. Med. Ctr., Chicago;
gbakris@earthlink.net)
Meal Bolus Alarms on CSII Pumps: Among 48 children with type 1 diabetes who were using continuous subcutaneous insulin infusion pumps, meal bolus alarms had only a transient, modest effect in improving suboptimal glycemic control (pp. 1012-5). “After 3 months of study, the number of missed meal boluses per week was significantly lower in the experimental group (from 4.9 ± 3.7 to 2.5 ± 2.5; P = 0.0005) but not significantly lower in the control group (from 4.3 ± 2.7 to 4.2 ± 3.9; P = 0.7610),” the authors report. “Also after 3 months, the mean A1C value of the experimental group declined significantly (from 9.32 ± 1.12 to 8.86 ± 1.10; P = 0.0430). No significant decline in A1C was present for the control group (from 8.93 ± 1.04 to 8.67 ± 1.17; P = 0.1940). After 6 months of study, the significant decline in A1C from baseline in the experimental group was no longer present. Pooling of all available data from the control and experimental groups showed that at baseline and 3 and 6 months, the number of missed meal boluses per week was significantly correlated with A1C values.” (H. P. Chase, Barbara Davis Ctr. for Childhood Diabetes, Aurora, Colo.; peter.chase@uchsc.edu)
Candy v. Potato Chips: Adolescents with type 1 diabetes are replacing dietary carbohydrates with fats, according to a study of 132 patients with type 1 diabetes and 131 adolescents without diabetes (pp. 982-7). Those with diabetes took in less energy overall than recommended, but still consumed more than recommended amounts of fat. Boys were especially at risk for increased fat consumption. (V. S. Helgeson, Carnegie Mellon U., Pittsburgh; vh2e@andrew.cmu.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 © 2006, 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, 2006 Vol. 13, No. 83
Providing news and information about medications and their proper use

>>>Alglucosidase Alfa OK’d For Pompe Disease
FDA on Friday granted marketing approval for alglucosidase alfa (Myozyme, Genzyme) for treatment of patients with Pompe disease, an orphan disease that produces muscle weakness and associated breathing problems in infants with inherited deficiency of acid alpha-glucosidase (AAG). This enzyme-replacement therapy improves ventilator-free survival in patients with infantile-onset Pompe disease, compared with an untreated historical control patients. Alglucosidase alfa has not been adequately studied in patients with other forms of Pompe disease, but studies are underway in other patient groups.
Pompe disease manifests as a broad spectrum of clinical symptoms. All patients typically experience progressive muscle weakness and breathing difficulty, but the rate of disease progression can vary widely depending on the age of onset and the extent of organ involvement. When symptoms appear within a few months of birth, babies frequently display a markedly enlarged heart and die within the first year of life. When symptoms appear during childhood, adolescence, or adulthood, patients may experience steadily progressive debilitation and premature mortality due to respiratory failure. They often require mechanical ventilation to assist with breathing and wheelchairs to assist with mobility.
Clinical trials of this agent included 39 infantile-onset patients with Pompe disease who ranged in age from 1 month to 3.5 years at study admission. Administered as intravenous infusions, alglucosidase alfa produced severe or significant hypersensitivity reactions in 8 of 280 (3%) patients in clinical studies or expanded access programs. The most common reactions to the drug included pneumonia, respiratory failure and distress, infections, and fever.

>>>Lancet Highlights
Source:
Early-release article from Lancet (www.thelancet.com; 2006; 367).
Addressing Malaria: The World Bank, while well funded with an annual operating budget of $20 billion, is the wrong agency to try to address the problem of malaria around the globe, argue authors of an analysis of financial and statistical measures of the disease and research into its treatment (DOI: 10.1016/S0140-6736(06)68545-0). Writing about the Global Strategy & Booster Program, the Bank’s plan for controlling malaria in 2005-10, the authors note: “We believe this plan is inadequate to reverse the Bank’s troubling history of neglect for malaria. In the past 5 years, the Bank has failed to uphold a pledge to increase funding for malaria control in Africa, has claimed success in its malaria programmes by promulgating false epidemiological statistics, and has approved clinically obsolete treatments for a potentially deadly form of malaria. Crucially, the Bank also downsized its malaria staff, so that it cannot swiftly execute the restoration it plans under the Global Strategy & Booster Program. [In this article,] we summarise the evidence, show that the Bank possesses demonstrably little expertise in malaria, and argue that the Bank should relinquish its funding to other agencies better placed to control the disease.” (A. Attaran, aataran@uottawa.ca)

>>>PNN JournalWatch
* Efficacy of Lipid Lowering Drug Treatment for Diabetic and Non-diabetic Patients: Meta-analysis of Randomised Controlled Trials, in BMJ, 2006; doi:10.1136/bmj.38793.468449.AE. Reprints: http://bmj.bmjjournals.com/cgi/content/abstract/bmj.38793.468449.AEv2; A. V. Cameiro, U. Lisbon, Lisbon, Portugal; avc@fm.ul.pt
* Diagnosis and Treatment of Chronic Hepatitis C Infection, in
BMJ, 2006; 332:-1013-7. Reprints: http://bmj.bmjjournals.com/cgi/content/extract/332/7548/1013; J. G. McHutchison, mchut001@mc.duke.edu
* Glucose Abnormalities in Patients with Hepatitis C Virus Infection: Epidemiology and Pathogenesis, in
Diabetes Care, 2006; 29: 1140-9. Reprints: http://care.diabetesjournals.org/cgi/content/extract/29/5/1140; R. Simó, Hospital Vall d’Hebron, Barcelona, Spain; rsimo@ir.vhebron.net
* Diabetic Ketoacidosis in Infants, Children, and Adolescents: A Consensus Statement from the American Diabetes Association in
Diabetes Care, 2006; 29: 1150-9. Reprints: http://care.diabetesjournals.org/cgi/content/extract/29/5/1150; M. A. Sperling, Children’s Hosp., Pittsburgh; masp+@pitt.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 © 2006, 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, 2006 Vol. 13, No. 84
Providing news and information about medications and their proper use

>>>Psychiatry Highlights
Source:
May issue of the American Journal of Psychiatry (ajp.psychiatryonline.org/current.shtml; 2006; 163).
Preemptive Use of Antipsychotic Agents: Low power may be to blame for a study’s failure to reach statistical significance in lowering the conversion-to-psychosis rate among a group of 60 adolescents with prodromal symptoms of schizophrenia (pp. 790-9). In the Prevention Through Risk Identification, Management, and Education project, outpatients received olanzapine 5–15 mg/day or placebo during a 1-year double-blind treatment period and no treatment during a 1-year follow-up period. The authors report these results: “During the treatment year, 16.1% of olanzapine patients and 37.9% of placebo patients experienced a conversion to psychosis, a nearly significant difference. The hazard of conversion among placebo patients was about 2.5 times that among olanzapine-treated patients, which also approached significance. In the follow-up year, the conversion rate did not differ significantly between groups. During treatment, the mean score for prodromal positive symptoms improved more in the olanzapine group than in the placebo group, and the mixed-model repeated-measures least-squares mean score showed significantly greater improvement between weeks 8 and 28 with olanzapine. The olanzapine patients gained significantly more weight (mean = 8.79 kg, SD = 9.05, versus mean = 0.30 kg, SD = 4.24).” (T. H. McGlashan)
Light Therapy for SAD: Compared with fluoxetine in treatment of winter seasonal affective disorder, light therapy produced earlier onset of action and fewer rates of some adverse effects (pp. 805-12). Concluding that the data demonstrate that patient preferences should prevail in selecting first-line treatment for SAD, the investigators note the following findings for the 96-patient study: “Intent-to-treat analysis showed overall improvement with time, with no differences between treatments. There were also no differences between the light and fluoxetine treatment groups in clinical response rates (67% for each group) or remission rates (50% and 54%, respectively). Post hoc testing found that light-treated patients had greater improvement at 1 week but not at other time points. Fluoxetine was associated with greater treatment-emergent adverse events (agitation, sleep disturbance, palpitations), but both treatments were generally well-tolerated with no differences in overall number of adverse effects.” (R. W. Lam)
Calling a Spade a Spade: Use of the term “dependence” rather than “addiction” in recent iterations of the Diagnostic and Statistical Manual was “a serious mistake,” write editorialists (pp. 764-5). Noting the distinct differences between physician dependence and addiction and calling for correction of this terminology in DSM-V, now in the planning stages, the authors note: “Addiction is a perfectly acceptable word. It is used by the American Society of Addiction Medicine, the American Association of Addiction Psychiatrists, the American Journal on Addictions, and the oldest journal in the field, simply known as Addiction. It is clear that any harm that might occur because of the pejorative connotation of the word ‘addiction’ would be completely outweighed by the tremendous harm that is now being done to the patients who have had needed medication withheld because their doctors believe that they are addicted simply because they are dependent.” (C. P. O’Brien, brien@mail.trc.upenn.edu">obrien@mail.trc.upenn.edu)

>>>PNN NewsWatch
* In today’s Annals of Internal Medicine, an 80-patient study indicates that laparoscopic gastric banding was significantly more effective at helping patients lose weight and keep the weight off over a 2-year period than an intervention of caloric restriction, weight loss medications, and counseling (www.annals.org; p. 625). At 6 months, both groups lost 13.8% of initial weight; at 24 months, patients who had gastric banding lost an average of 21.6% of initial body weight compared with 5.5% in the nonsurgical group. Noting that the surgery was performed on mild to moderately obese people for whom current recommendations for weight loss do not include surgery, editorialists point out that primary care providers or their patients should not “overlook the positive health benefits of a 5% to 10% weight loss [that can be] achieved with lifestyle modification” (p. 689).

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, 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, 2006 Vol. 13, No. 85
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
May 3 issue of JAMA (www.jama.com; 2006; 295).
Treating Alcohol Dependence: While approved by FDA for treatment of alcohol dependence, acamprosate was no more effective than placebo in a 16-week trial of 1,383 recently alcohol-abstinent volunteers (pp. 2003-17). The Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) study included nine groups that received naltrexone 100 mg/day or acamprosate 3 grams/day, both drugs, one or both placebos, with or without combined behavioral intervention, or CBI only with no drugs or placebos. The investigators concluded that no treatment worked better than naltrexone or CBI alone based on these results: “All groups showed substantial reduction in drinking. During treatment, patients receiving naltrexone plus medical management (n = 302), CBI plus medical management and placebos (n = 305), or both naltrexone and CBI plus medical management (n = 309) had higher percent days abstinent (80.6, 79.2, and 77.1, respectively) than the 75.1 in those receiving placebos and medical management only (n = 305), a significant naltrexone X behavioral intervention interaction (P = .009). Naltrexone also reduced risk of a heavy drinking day (hazard ratio, 0.72; 97.5% CI, 0.53-0.98; P = .02) over time, most evident in those receiving medical management but not CBI. Acamprosate showed no significant effect on drinking vs placebo, either by itself or with any combination of naltrexone, CBI, or both. During treatment, those receiving CBI without pills or medical management (n = 157) had lower percent days abstinent (66.6) than those receiving placebo plus medical management alone (n = 153) or placebo plus medical management and CBI (n = 156) (73.8 and 79.8, respectively; P < .001). One year after treatment, these between-group effects were similar but no longer significant.” (R. F. Anton, antonr@musc.edu)
These results open the door to primary care treatment of patients with alcohol dependence, notes an editorialist (pp. 2075-6): “Patients who decline an offer of pharmacological treatment to reduce their drinking can be referred for intensive behavioral treatment. Notably, however, the beneficial effects of naltrexone were seen in the context of medical management similar to what is routinely available in primary care practice. This offers the prospect that an efficacious treatment for alcohol dependence can be made as widely available as are current treatments for smoking cessation and major depression.” (H. R. Kranzler, U. Conn., Farmington;
kranzler@psychiatry.uchc.edu)
Nonhormonal Therapies for Menopausal Hot Flashes: While nonhormonal agents show efficacy for treatment of menopausal symptoms, none is as effective as estrogen, concludes a review article (pp. 2057-71). “From 4,249 abstracts, 43 trials met inclusion criteria, including 10 trials of antidepressants, 10 trials of clonidine, 6 trials of other prescribed medications, and 17 trials of isoflavone extracts,” the article explains. “The number of daily hot flashes decreased compared with placebo in meta-analyses of 7 comparisons of selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) (mean difference, -1.13; 95% confidence interval [CI], -1.70 to -0.57), 4 trials of clonidine (–0.95; 95% CI, -1.44 to -0.47), and 2 trials of gabapentin (-2.05; 95% CI, -2.80 to -1.30). Frequency was not reduced in meta-analysis of trials of red clover isoflavone extracts and results were mixed for soy isoflavone extracts. Evidence of the efficacy of other therapies is limited due to the small number of trials and their deficiencies. Trials do not compare different therapies head-to-head and relative efficacy cannot be determined.” (H. D. Nelson, nelsonh@ohsu.edu)
“Nonhormonal alternatives are less effective than estrogen, generally have more symptomatic adverse effects, and long-term adverse effects are not as well documented,” editorialists add (pp. 2076-8). “With all medicines or dietary supplements used for symptomatic treatment, the lowest effective dose should be used and stopped as soon as symptoms improve or resolve. A better understanding of the pathophysiology of hot flashes will likely be necessary for the development of nonhormonal therapies that equal or surpass the efficacy of hormones.” (J. A. Tice,
jeff.tice@ucsf.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 © 2006, 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, 2006 Vol. 13, No. 86
Providing news and information about medications and their proper use

>>>FDA Approves MDS Drug
Decitabine injection (Dacogen, MGI Pharma) has been approved by FDA for treatment of myelodysplastic syndromes, including previously treated and untreated, de novo, and secondary MDS of all French-American-British (FAB) subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia), and Intermediate-1, Intermediate-2, and High-Risk International Prognostic Scoring System groups. A new molecular entity, decitabine was designated an orphan drug since new cases of MDS occur annually in only 7,000 to 12,000 people in the United States.
The bone marrow of patients with MDS does not produce enough mature blood cells. This causes a lack of healthy blood cells that can function properly in the body. Decitabine is thought to work by promoting normal development of blood cells. MDS can develop following treatment with drugs or radiation therapy for other diseases, or it can develop without any known cause. Some forms of MDS can progress to acute myeloid leukemia, in which too many white blood cells are made. Although MDS occurs in all age groups, the highest prevalence is in people older than 60 years of age. Typical symptoms include weakness, fatigue, infections, easy bruising, bleeding, and fever.
Results from a Phase III clinical trial demonstrated an overall response rate of 21% in decitabine-treated patients considered evaluable for response, defined as those patients with pathologically confirmed MDS at baseline who received at least two cycles of treatment, compared with no patients in the supportive care arm. All patients who responded to decitabine treatment became or remained transfusion independent during the time of the response. Patients should be treated with decitabine for a minimum of four cycles, and treatment may continue as long as the patient continues to benefit.
The most commonly occurring adverse reactions with decitabine are neutropenia, thrombocytopenia, anemia, pyrexia, fatigue, nausea, cough, petechiae, hyperglycemia, constipation, and diarrhea.

>>>NEJM Highlights
Source:
May 4 issue of the New England Journal of Medicine (content.nejm.org; 2006; 354).
Stents for PAD: In 104 patients with severe claudication or chronic limb ischemia secondary to stenosis or occlusion of the superficial femoral artery, primary implantation of a nickel-titanium stent proved superior to the currently recommended approach of balloon angioplasty with optional stenting (pp. 1879-88). The investigators describe these results at 6 and 12 months: “Secondary stenting was performed in 17 of 53 patients (32 percent) in the angioplasty group, in most cases because of a suboptimal result after angioplasty. At 6 months, the rate of restenosis on angiography was 24 percent in the stent group and 43 percent in the angioplasty group (P = 0.05); at 12 months the rates on duplex ultrasonography were 37 percent and 63 percent, respectively (P = 0.01). Patients in the stent group were able to walk significantly farther on a treadmill at 6 and 12 months than those in the angioplasty group.” (M. Schillinger, Med. U., Vienna; martin.schillinger@meduniwien.ac.at)
An editorialist describes the use of nitinol stents as “a potentially important therapeutic advance” in treatment of PAD but notes that more research is needed to define the “relative risk and benefit, durability, and cost” of the various medical and endovascular interventions for this disease (pp. 1944-7): “To offer a true therapeutic choice, we will need knowledge from clinical trials that define the potential risks and benefits of each treatment. Combinations of exercise, medication, and revascularization therapies have rarely been evaluated in populations of patients with peripheral arterial disease. The Claudication: Exercise versus Endoluminal Revascularization (CLEVER) trial—sponsored by the National Heart, Lung, and Blood Institute and currently under way—is a prospective, multicenter clinical investigation that will compare the safety and efficacy of supervised exercise, endovascular stenting, and optimal pharmacotherapy for patients with aortoiliac peripheral arterial disease.” (A. T. Hirsch, U. Minnesota, Minneapolis)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, 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 5, 2006 Vol. 13, No. 87
Providing news and information about medications and their proper use

>>>Pharmacotherapy Update
Source:
May issue of Pharmacotherapy (www.pharmacotherapy.org; 2006; 26).
Hospital ADRs: For targeting monitoring and management programs, pharmacists can use a list of high-risk diagnoses and drug classes developed through an analysis of adverse drug reactions among 8.2 million Medicare patients who were hospitalized in 1998 (pp. 601-8). Focusing on the 141,398 (1.73%) patients who experienced ADRs, the investigators note the following: “The most common drug classes associated with ADRs were cardiotonic glycosides, adrenal corticosteroids, antineoplastic agents, anticoagulants, and analgesics. The most common associated diagnoses were hypertension, congestive heart failure, atrial fibrillation, volume depletion disorders, and atherosclerotic heart disease. In patients who experienced an ADR, death rates were 19.18% higher with 1,971 excess deaths (odds ratio 1.208, 95% confidence interval 1.184–1.234), and length of hospital stay was 8.25% higher with 77,769 excess patient-days (Mann-Whitney U test [U] = 200078720610, p < 0.0001). Charges for patients with an ADR were increased as follows: total Medicare 19.86% ($339,496,598, U = 200089611739, p < 0.0001), drugs 9.15% ($24,744,650, U = 208719928502, p < 0.0001), and laboratory charges 2.82% ($6,221,512, U = 195143498450, p < 0.0001).” (C. A. Bond, cab.bond@ttuhsc.edu)
Antithrombotic Therapy in Nonurgent PCI: Bivalirudin with provisional therapy with glycoprotein IIb/IIIa inhibitors is the most cost-effective strategy for antithrombotic therapy in patients undergoing nonurgent percutaneous coronary interventions, concludes an analysis that used a literature-based decision model (pp. 609-18). The model included patients data from four clinical trials of unfractionated heparin and routine GP IIb/IIIa treatment with eptifibatide or abciximab, and the authors report these findings: “We included patient populations undergoing contemporary nonurgent PCI to identify probabilities of success or complications (myocardial infarction, urgent revascularization, thrombocytopenia, and major or minor bleeding at 30 days). Costs were assigned to each outcome by incorporating diagnosis-related group– and/or Current Procedural Terminology–associated costs, institutional drug acquisition costs, and unit replacement costs of platelets and red blood cells. In the base-case analysis, the use of bivalirudin with provisional GP IIb-IIIa inhibitor therapy dominated the UFH and planned GP IIb-IIIa inhibitor approach: UFH with eptifibatide was $74 more expensive and 1.2% less effective, and UFH with abciximab was $777 more expensive and 2.3% less effective. Sensitivity analyses indicated that the model results were robust, but also revealed that bivalirudin lost its cost-effectiveness, resulting in UFH with eptifibatide becoming more cost-effective, when two or more vials of bivalirudin were necessary in greater than 27% of cases or when the use of provisional GP IIb-IIIa inhibitor therapy exceeded 20%.” (M. A. Crouch, macrouch@vcu.edu)
Herbal–Drug Interactions in the ED: Potential interactions among prescription drugs and complementary and alternative medicines occur commonly in the emergency department, including some interactions that are clinically relevant (pp. 634-40). This conclusion comes from a survey of 404 adult patients who visited an Australian ED over a 14-month period in 2002–2003. “Mean ± SD patient age was 50.6 ± 20.0 years; 220 patients were men (54.5%, 95% confidence interval [CI] 49.5–59.4%),” write the authors. “When asked about use during the previous year, 275 patients (68.1%, 95% CI 63.2–72.5%) reported having taken a CAM; of these, 138 were also taking a prescription drug. We identified 15 documented potential drug-CAM interactions in nine patients (3.3% of CAM users, 95% CI 1.6–6.3%) and 97 theoretical potential drug-CAM interactions in 51 patients (18.6% of CAM users, 95% CI 14.2– 23.8%). Aspirin and warfarin were the most commonly involved drugs. Of CAM users, 197 (71.6%, 95% CI 65.9–76.8%) never informed their physician about CAM use, most frequently because they were not asked.” (D. Taylor, Royal Melbourne Hosp., Parkville, Victoria, Australia; avid.Taylor@mh.org.au">David.Taylor@mh.org.au)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, 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, 2006 Vol. 13, No. 88
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
May 6 issue of Lancet (www.thelancet.com; 2006; 367).
Prognosis for Kaposi’s Sarcoma: In patients with AIDS who develop Kaposi’s sarcoma, four factors can be used to determine a patient’s prognosis and guide therapy, according to a regression analysis of data from 5,873 patients (pp. 1495-502). “In the primary model, we developed a prognostic score from 0 to 15 starting at 10,” the authors write in describing the outcomes of the 6% of study participants who developed Kaposi’s sarcoma. “Having Kaposi’s sarcoma as the AIDS-defining illness (−3 points) and increasing CD4 count (−1 point for every complete 100 cells per mm3) improved prognosis; age of 50 years or older (2 points) and having another AIDS-associated illness at the same time (3 points) conveyed a poorer prognosis. In individuals with prognostic scores of 0, 5, 10, and 15, probability of survival at 1-year was 0.993, 0.967, 0.834, and 0.378, and at 5 years was 0.984, 0.918, 0.631, and 0.084, respectively. Increasing prognostic score by 1 increased 1-year death hazard ratio by 40% (95% CI 28-53%; bootstrapped hazard ratio 1.39, 1.25-1.51). The index had concordance of 76.8% (71.7-82.3).” (J Stebbing, Chelsea and Westminster Hosp., London; justinstebbing@gmail.com)
Vitamins & IVF: Supplementation of foods in the U.K. with folate could lead to an increased number of twins born following in vitro fertilization, conclude researchers who conducted a prospective cohort study of 602 women undergoing fertility treatment (pp. 1513-9). Based on information provided by study participants on a questionnaire and plasma and RBC concentrations of folate and vitamin B12, the investigators determined: “The likelihood of a twin birth after IVF rose with increased concentrations of plasma folate (1.52, 1.01-2.28; p = 0.032) and red-cell folate (1.28, 1.00-1.65; p = 0.039). There was no association between folate and vitamin B12 levels and likelihood of a successful pregnancy. Women homozygous for the 1298 CC variant of methylenetetrahydrofolate reductase (MTHFR), rather than the AA variant, were less likely to produce a livebirth after IVF (0.24, 0.08-0.71; p = 0.003) or to have had a previous pregnancy (0.42, 0.21-0.81; p = 0.008).” (P. Haggarty, Aberdeen U., Aberdeen, U.K.; p.haggarty@abdn.ac.uk)

>>>BMJ Highlights
Source:
Early-release article from BMJ (www.bmj.org; 2006; 332).
ADRs to Cardiovascular Meds: Ethnic and racial differences in rates of adverse drug reactions to cardiovascular medications were evident in a systematic review and meta-analysis of 24 studies (doi: 10.1136/bmj.38803.528113.55). The authors report: “In pooled analyses the relative risk of angio-oedema from angiotensin converting enzyme (ACE) inhibitors in black compared with non-black patients was 3.0 (95% confidence interval 2.5 to 3.7); the relative risk of cough from ACE inhibitors was 2.7 (1.6 to 4.5) in East Asian compared with white patients; and the relative risk of intracranial haemorrhage with thrombolytic therapy was 1.5 (1.2 to 1.9) in black compared with non-black patients.” (R. E. Ferner, City Hosp., Birmingham, U.K.; r.e.ferner@bham.ac.uk)

>>>PNN JournalWatch
* Metabolic Acidosis of CKD: Diagnosis, Clinical Characteristics, and Treatment, in American Journal of Kidney Diseases, 2006; 45: 978-93. Reprints: http://www.ajkd.org/article/PIIS0272638605004300/abstract; J. Kraut, jkraut@ucla.edu
* Home Blood Pressure Monitoring in CKD, in
American Journal of Kidney Diseases, 2006; 45: 994-1001. Reprints: http://www.ajkd.org/article/PIIS0272638605002854/abstract; R. Agarwal, Indiana U., Indianapolis; ragarwal@iupui.edu
* The Risk of Suicide with Selective Serotonin Reuptake Inhibitors in the Elderly, in
American Journal of Psychiatry, 2006; 163: 813-21. Reprints: http://ajp.psychiatryonline.org/cgi/content/abstract/163/5/813; D. N. Juurlink.
* Pemtrexed, a Novel Antifolate Therapeutic Alternative for Cancer Chemotherapy, in
Pharmacotherapy, 2006; 26: 641-54. Reprints: www.pharmacotherapy.org; S. R. Shah, sachin.shah@ttuhsc.edu
* American College of Clinical Pharmacy’s Vision of the Future: Postgraduate Pharmacy Residency Training as a Prerequisite for Direct Patient Care Practice, in
Pharmacotherapy, 2006; 26: 722-33. Reprints: www.pharmacotherapy.org or www.accp.com; Am. Coll. of Clin. Pharm., accp@accp.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 © 2006, 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, 2006 Vol. 13, No. 89
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
May 8 issue of the Archives of Internal Medicine (www.archinternmed.com; 2006; 166).
Clinical Pharmacists & Inpatient Care: Improved care with no evidence of harm was produced through clinical pharmacists’ inclusion in care of inpatients, according to a systematic review of reports published between 1985 and 2005 (pp. 955-64). The researchers gathered data on types of intervention, study designs, and outcomes such as adverse drug events, medication appropriateness, and resource use, and report these results: “Thirty-six studies met inclusion criteria, including 10 evaluating pharmacists’ participation on rounds, 11 medication reconciliation studies, and 15 on drug-specific pharmacist services. Adverse drug events, adverse drug reactions, or medication errors were reduced in 7 of 12 trials that included these outcomes. Medication adherence, knowledge, and appropriateness improved in 7 of 11 studies, while there was shortened hospital length of stay in 9 of 17 trials. No intervention led to worse clinical outcomes and only 1 reported higher health care use. Improvements in both inpatient and outpatient outcome measurements were observed.”
The group concludes: “More research is needed to better understand the role of clinical pharmacists, clinical areas most likely to benefit, and patient-specific factors associated with improvements. Cost-effectiveness can also be improved by identifying pharmacist duties most beneficial to patients and determining whether less skilled and costly personnel can perform other duties. Future studies should describe interventions in sufficient detail that they can be reproduced, and outcomes such as medication appropriateness and adherence should be measured using validated instruments. Last, larger, multicenter, randomized, controlled trials should be conducted to prove that benefits of pharmacist interventions are generalizable across institutions and to quantify the value to the health care system.” (P. J. Kaboli,
peter-kaboli@uiowa.edu)
Telephonic Delivery of Anticoagulation Care: For managing patients on long-term anticoagulation therapy, interactions via telephone were just as effective as face-to-face contact in a VA study of 192 patients over 36 months (pp. 997-1002). Usual-care patients met with anticoagulation management service (AMS) clinicians in every-4-week visits, while those assigned to the interim telephone (IT) group completed a self-assessment form and if it indicated no problems upon review by a clinic nurse, were allowed to leave and were contacted by telephone within 24 hours by an AMS clinician. The investigators report: “We found no statistically significant difference between the 2 groups in the percentage of time maintained within INR target range overall (55.1% for AMS; 57.8% for IT; P = .28) nor over the course of the study. There were no statistically significant differences in the rate of thromboembolic or serious bleeding events between IT and AMS participants. Nevertheless, we did note differences related to intensity of anticoagulation. The IT group receiving treatment at a higher intensity (INR, 2.5-3.5) experienced greater anticoagulation control (P = .04) and fewer complications than the AMS group. The IT participants, however, reported a significantly higher rate of minor bleeding events, experienced mainly by those at an INR range of 2.0 to 3.0.” (C. A. Sorkness, sorkness@wisc.edu)
Reducing Warfarin–Medication Interactions: Medication error alerts “modestly reduced” coprescribing of warfarin and interacting medications, but additional efforts are needed, conclude authors of a study of computerized decision support in a health-maintenance organization (pp. 1009-15). Prescribing patterns were assessed at 15 primary care clinics where 239 prescribers received alerts when orders included warfarin plus acetaminophen, NSAIDs, fluconazole, metronidazole, and/or sulfamethoxazole; 7 clinics also received academic detailing. “Coinciding with the alerts, there was an immediate and continued reduction in the warfarin-interacting medication prescription rate (from 3294.0 to 2804.2), resulting in a 14.9% relative reduction (95% confidence interval, –19.5 to –10.2) at 12 months. Group academic detailing did not enhance alert effectiveness.” (A. C. Feldstein, Kaiser Permanente, Portland; Adrianne.C.Feldstein@kpchr.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 © 2006, 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, 2006 Vol. 13, No. 90
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
May 16 issue of the Journal of the American College of Cardiology (www.cardiosource.com; 2006; 47).
Rimonabant Review: Rimonabant, a promising but not-yet-approved agent, “has a potential to be a useful adjunct to lifestyle and behavior modification in treatment of multiple cardiometabolic risk factors, including abdominal obesity and smoking,” concludes a state-of-the-art paper (pp. 1919-26). “Rimonabant is a first selective blocker of the cannabinoid receptor type 1 (CB1) being developed for the treatment of multiple cardiometabolic risk factors, including abdominal obesity and smoking,” the authors write. “In four large trials, after one year of treatment, rimonabant 20 mg led to greater weight loss and reduction in waist circumference compared with placebo. Therapy with rimonabant is also associated with favorable changes in serum lipid levels and an improvement in glycemic control in prediabetes patients and in type 2 diabetic patients. At the same dose, rimonabant significantly increased cigarette smoking quit rates as compared with placebo. Rimonabant seems to be well tolerated, with a primary side effect of mild nausea.” (C. P. Cannon, cpcannon@partners.org)
Thrombi with Sirolimus-Eluting Stents: Subclinical thrombus formation is identified as the result of incomplete neointimal coverage within 3-6 months of implantation of sirolimus-eluting stents (pp. 2108-11). In patients receiving 37 consecutive stents for coronary artery lesions, angioscopy revealed these findings in those receiving SES or bare-metal stents: “Thrombi were identified in eight stented segments, tended to be more common with SES (p = 0.14), but were not seen on angiography. Three of the 15 SES (20%) had grade 0 neointimal coverage, and only 2 SES (13.3%) had complete coverage (grades 2/3). In contrast, all 22 BMS showed complete intimal coverage (grades 2/3). Thrombi were more common in stents with incomplete neointimal coverage (p = 0.09).” (J. Kotani, Kansai Rosai Hosp., Amagasaki, Japan; shamallv8@aol.com)
Multi-multitasking: The JACC editor describes the perils of eating lunch at one’s desk while processing manuscripts online and participating in a conference call simultaneously (pp. 2116-7): “As part of an obsession to get the maximal productivity out of every moment, I had become a habitual multitasker; in fact, a multi-multitasker. I was somewhat chagrined to see how this behavior had become so ingrained into my life. It had become so routine I barely thought about it. Moreover, it was obvious that this behavior was part of a deep trend in society, perhaps expressed just a bit more in medicine. Whether in conference rooms, restaurants, or airports, we seem to have become slaves to the goal of productivity and of making every second count. There is just no room for ‘down time.’ This is best exemplified by the plethora of devices and technology that have been developed enabling us to continuously function despite time, place, or accompanying persons [especially the cell phone]....
“Although we have acquired a great deal of technology to make life easier and more satisfying, I am inclined to believe that in many ways it has had the opposite effect. For me, at least, the time has come to put the quest for even greater productivity into perspective. I cannot help but believe that a little down time for contemplation and relaxation will ultimately produce a better result in whatever I undertake. For sure, it will be more enjoyable.” (A. N. DeMaria,
ademaria@acc.org)

>>>PNN NewsWatch
* Acute phosphate nephropathy results rarely from use of oral sodium phosphates (OSPs) for bowel cleansing, FDA warns. Individuals at increased APN risk include those of advanced age, with kidney disease or decreased intravascular volume, or using medications that affect renal perfusion or function (diuretics, ACE inhibitors, angiotensin II receptor blockers, and NSAIDs). Documented cases of APN include 21 patients who used an OSP solution (such as Fleet Phospho-soda or Fleet ACCU-PREP) and one patient who used OSP tablets (Visicol). No cases of APN or acute renal failure have been associated with OsmoPrep, a recently approved OSP tablet used for bowel preparation, FDA added.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, 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, 2006 Vol. 13, No. 91
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
May 11 issue of the New England Journal of Medicine (content.nejm.org; 2006; 354).
Inhaled Steroids in Pediatrics: Three articles examine use of inhaled corticosteroids in preschool children at high risk of asthma and infants with episodic wheezing.
No disease-modifying effect of inhaled corticosteroids was detected in a study of 285 children with a positive asthma predictive index at ages 2 to 3 (pp. 1985-97). Study participants received either placebo or fluticasone propionate 88 mcg twice daily by inhalation for 2 years followed by a treatment-free year, with these results: “During the observation year, no significant differences were seen between the two groups in the proportion of episode-free days, the number of exacerbations, or lung function. During the treatment period, as compared with placebo use, use of the inhaled corticosteroid was associated with a greater proportion of episode-free days (P = 0.006) and a lower rate of exacerbations (P < 0.001) and of supplementary use of controller medication (P < 0.001). In the inhaled-corticosteroid group, as compared with the placebo group, the mean increase in height was 1.1 cm less at 24 months (P < 0.001), but by the end of the trial, the height increase was 0.7 cm less (P = 0.008). During treatment, the inhaled corticosteroid reduced symptoms and exacerbations but slowed growth, albeit temporarily and not progressively.” (T. W. Guilbert,
guilbert@arc.arizona.edu)
In the second study, intermittent inhaled budesonide 400 mcg per day had no effect on progression from episodic to persistent wheezing (pp. 1998-2005). Infants, aged 1 month, received 2-week courses of steroid or placebo following 3-day episodes of wheezing and were followed for 3 years. Among 411 infants, including 294 who received budesonide initially, the researchers found: “The proportion of symptom-free days was 83 percent in the budesonide group and 82 percent in the placebo group (absolute difference, 1 percent; 95 percent confidence interval, –4.8 to 6.9 percent). Twenty-four percent of children in the budesonide group had persistent wheezing, as compared with 21 percent in the placebo group (hazard ratio, 1.22; 95 percent confidence interval, 0.71 to 2.13)—a finding that was unaffected by the presence or absence of atopic dermatitis. The mean duration of the acute episodes was 10 days in both groups and was independent of respiratory viral status. Height and bone mineral density were not affected by treatment.” (H. Bisgaard, Copenhagen U. Hosp., Gentofte, Copenhagen, Denmark)
Noting the adverse effects of corticosteroids on height and alveolar development in infants and young children, editorialists provide this perspective (pp. 2058-60): “These two clinical studies add to the evidence that although inhaled corticosteroids may control persistent or severe wheezing, such drugs should not be used in the hope of altering the course of asthma in childhood. Given the potential risks of therapy in early life, prolonged treatment for toddlers under the age of two years should be highly selective. While we await better criteria for the selection of young children who are likely to respond to therapy, there is no substitute for clinical judgment in deciding whether and for how long to use corticosteroids in very young children.” (D. R. Gold, Brigham and Women’s Hosp., Boston)
Imatinib & Phosphate: Routine monitoring of serum phosphate and vitamin D may be advisable during imatinib therapy, based on findings of hypophosphatemia among 16 patients with chronic myelogenous leukemia or gastrointestinal stromal tumors (pp. 2006-13). Comparing those patients with 8 others with normal levels, the authors report: “Patients in the low-phosphate group (median serum phosphate level, 2.0 mg per deciliter [0.6 mmol per liter]; normal level, >2.5 mg per deciliter [0.8 mmol per liter]) had elevated parathyroid hormone levels and low-to-normal serum calcium levels, were younger, and were receiving a higher dose of imatinib than patients in the normal-phosphate group (median level, 3.2 mg per deciliter [1.0 mmol per liter]). Both groups had high levels of phosphate excreted in the urine and markedly decreased serum levels of osteocalcin and N-telopeptide of collagen cross-links.” (E. Berman, Memorial Sloan-Kettering Cancer Ctr., New York, bermane@mskcc.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 © 2006, 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 12, 2006 Vol. 13, No. 92
Providing news and information about medications and their proper use

>>>Varenicline Approved for Smoking Cessation
FDA has approved varenicline tartrate, a new prescription drug that will be marketed by Pfizer as Chantix for smoking cessation. The new chemical entity acts by activating nicotinic receptors, which provides two benefits. In abstinent patients, nicotinic stimulation decreases craving for cigarettes and blocks withdrawal symptoms. Further, if patients resume smoking, presence of varenicline in the nicotinic receptors prevents nicotine from stimulating them further, thereby diminishing the sense of satisfaction associated with smoking.
Varenicline’s approval was based four pivotal trials involving more than 2,000 cigarette smokers. Study participants had smoked an average of 21 cigarettes per day for a mean of approximately 25 years. In two identically designed studies, patients receiving a 12-week course of varenicline 1 mg twice daily nearly quadrupled the likelihood of quitting, compared with those taking placebo, and had nearly twice the likelihood of quitting compared with patients taking bupropion 150 mg twice daily. All participants received educational materials.
Patients in these two trials were followed for an additional 40 weeks without treatment. After 1 year, approximately 20% of patients who received the 12-week course of varenicline remained abstinent. For those patients who quit at the end of 12 weeks, an additional course of 12 weeks treatment with varenicline resulted in a greater likelihood of long-term success in quitting smoking.
Varenicline was generally well tolerated, with overall discontinuation rates similar to placebo. The most common adverse effects were nausea, constipation, flatulence, vomiting, changes in dreaming, insomnia, and dysgeusia (change in taste perception).

>>>Pediatrics Highlights
Source:
May issue of Pediatrics (www.pediatrics.org; 2006; 117).
Dichloroacetate for Congenital Lactic Acidosis: Oral dichloroacetate was safe and partially effective in a group of 43 infants, children, and adolescents with persistent or intermittent hyperlactemia, reducing postprandial increases in lactate but failing to improve neurologic and other outcomes (pp. 1519-31). Most study participants, ranging in age from 0.9 to 19 years, had severe psychomotor delay. After preconditioning on placebo for 6 months, patients were randomly assigned to receive placebo or DCA 12.5 mg/kg every 12 hours. The authors report these results: “There were no significant differences in Global Assessment of Treatment Efficacy scores, linear growth, or the frequency or severity of intercurrent illnesses. DCA significantly decreased the rise in blood lactate caused by carbohydrate feeding. Chronic DCA administration was associated with a fall in plasma clearance of the drug and with a rise in the urinary excretion of the tyrosine catabolite maleylacetone and the heme precursor gamma-aminolevulinate.” (P. W. Stacpoole, U. Fla., Gainesville)
Timing of Vancomycin, Cephalosporin Doses: Among children with pneumococcal meningitis, early empiric vancomycin therapy was associated with hearing loss and no clinical benefits, according to a retrospective analysis of patients treated in 1991–2001 (pp. 1688-94). “Of 114 subjects, 109 received empiric vancomycin therapy in combination with cefotaxime or ceftriaxone,” the investigators report. “Ten subjects (9%) died, whereas 37 (55%) of 67 survivors who underwent audiometry had documented hearing loss, and 14 (13%) of 104 survivors were discharged with other neurologic deficits. Subjects with hearing loss had a significantly shorter median vancomycin start time than did those with normal hearing (<1 vs 4 hours). Vancomycin start time was not significantly associated with death or other neurologic deficits in univariate or multivariate analyses. Multiple logistic regression revealed that hearing loss was independently associated with vancomycin start time <2 hours, blood leukocyte count <15000/µL, and cerebrospinal fluid glucose concentration <30 mg/dL.” The authors conclude, “It may be prudent to consider delaying the first dose of vancomycin therapy until ≥2 hours after the first dose of parenteral cephalosporin in children beginning therapy for suspected or confirmed pneumococcal meningitis.” (S. C. Buckingham, U. Tennessee Health Science Ctr., Memphis)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, 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, 2006 Vol. 13, No. 93
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Early-release articles from Lancet (www.thelancet.com; 2006; 367).
Avian Influenza Vaccine: A two-dose regimen of an avian influenza vaccine was “safe and showed an immune response consistent with European regulatory requirements for licensure of seasonal influenza vaccine,” conclude authors of a 300-participant study (DOI: 10.1016/S0140-6736(06)68656-X). In the randomized, open-label, noncontrolled Phase I trial, volunteers aged 18 to 40 years received one of six influenza A/Vietnam/1194/2004 (H5N1) influenza vaccine formulations, with these results: “All formulations were well tolerated, with no serious adverse events, few severe reactions, and no oral temperatures of more than 38°C. All formulations induced an immune response, and responses were detectable in some individuals after only one dose. The adjuvanted 30 µg formulation induced the greatest response (67% haemagglutinin-inhibition seroconversion rate after two vaccinations). Adjuvant did not improve the response to the lower doses. Two vaccinations of non-adjuvanted 7.5 µg, adjuvanted 15 µg, or non-adjuvanted 15 µg seroconverted more than 40% of participants (haemagglutinin-inhibition test only). Haemagglutinin inhibition and neutralising results were comparable.” (M. Saville, Melanie.Saville@sanofipasteur.com)
Editorialists provide this commentary on preparations for an avian influenza pandemic (DOI: 10.1016/S0140-6736(06)68657-1): “Important considerations for pandemic vaccine development include optimising prime-boost strategies, cost-effectiveness, ease and speed of manufacture, cross-protection against variant strains by the induction of cross-reactive antibodies and/or T cells, universal vaccines that induce protective antibodies and/or cytotoxic T cells against highly conserved proteins, stockpiling, cold-storage considerations, and the ability to confer protection in populations of all ages. The recently issued guidelines from the US Food and Drug Administration for fast-tracking promising candidates through licensing are very timely.12 Will we be ready in time? History will judge our global efforts.” (S. Sambhara,
ssambhara@cdc.gov)

>>>PNN NewsWatch
* A new meta-analysis conducted by GlaxoSmithKline shows increased suicidal behavior and ideation, particularly in young adults, during paroxetine therapy of conditions ranging from depression to panic disorder. GSK is changing the product labeling for Paxil and sending a letter to health professionals about the findings. All patients should be monitored carefully while on paroxetine therapy regardless of the condition being treated, FDA noted in a MedWatch item posted on its Web site. The meta-analysis included placebo-controlled clinical trials of paroxetine in adult patients with psychiatric disorders including major depressive disorder, other depression, and nondepression disorders such as dysthymia, panic disorder, generalized anxiety disorder, and obsessive-compulsive disorder. A higher frequency of suicidal behavior was evident among young adults treated with paroxetine compared with placebo. Further, in the analysis of adults with MDD (all ages), the frequency of suicidal behavior was higher in patients treated with paroxetine compared with placebo. This difference was statistically significant; however, as the absolute number and incidence of events are small, these data should be interpreted with caution, FDA suggested. The agency added that all of the reported events of suicidal behavior in the adult patients with MDD were nonfatal suicide attempts, and the majority of these attempts (8 of 11) were in younger adults aged 18-30. These MDD data suggest that the higher frequency observed in the younger adult population across psychiatric disorders may extend beyond the age of 24.

>>>PNN JournalWatch
* Community Pharmacy-Based Implementation and Evaluation of an Osteoporosis Self-Assessment Tool for Asians, in Journal of the American Pharmacists Association, 2006; 46: 391-6. Reprints: www.japha.org; Correspondence: N. Chaiyakunapruk, Naresuan U., Phitsanulok, Thailand; nui@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 © 2006, 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, 2006 Vol. 13, No. 94
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
May 16 issue of the Annals of Internal Medicine (www.annals.org; 2006; 144).
Cardiac Benefits of Benznidazole Treatment of Chagas Disease: A randomized controlled trial of benznidazole in patients with chronic Chagas disease should be conducted based on findings from an unblinded trial of 566 patients with nonacute disease and no initial heart failure (pp. 724-34). At a Buenos Aires center caring for patients with the trypanosomal disease, oral benznidazole 5 mg/kg/day for 30 days was compared with no treatment: “Fewer treated patients had progression of disease (12 of 283 [4%] vs. 40 of 283 [14%]; adjusted hazard ratio, 0.24 [95% CI, 0.10 to 0.59]; P = 0.002) or developed abnormalities on electrocardiography (15 of 283 [5%] vs. 45 of 283 [16%]; adjusted hazard ratio, 0.27 [CI, 0.13 to 0.57]; P = 0.001) compared with untreated patients. Left ventricular ejection fraction (hazard ratio, 0.97 [CI, 0.94 to 0.99]; P < 0.002) and left ventricular diastolic diameter (hazard ratio, 2.45 [CI, 1.53 to 3.95]; P < 0.001) were also associated with disease progression. Conversion to negative results on serologic testing was more frequent in treated patients than in untreated patients (32 of 218 [15%] vs. 12 of 212 [6%]; adjusted hazard ratio, 2.1 [CI, 1.06 to 4.06]; P = 0.034).” (R. Viotti, Hosp. Eva Perón, Buenos Aires; peron@millicom.com.ar)
Differentiating Between Stress & Urge Incontinence: Three questions can help clinicians differentiate between stress and urge incontinence, a pair of conditions that sound similar but have different treatments, according to a study of 301 women conducted at five academic medical centers (pp. 715-23). The 3 Incontinence Questions (3IQ) instrument asked patients about leakage of urine within the past 3 months, what activities the patients were doing when the leakage occurred or feelings of urgency, and whether urine most often leaked during physical activity, when the patient felt the need to urinate, or without any activity or sense of urgency.
Compared with evaluations by urologists, the instrument produced these results: “For classification of urge incontinence and with the extended evaluation as the gold standard, the 3IQ had a sensitivity of 0.75 (95% CI, 0.68 to 0.81), a specificity of 0.77 (CI, 0.69 to 0.84), and a positive likelihood ratio of 3.29 (CI, 2.39 to 4.51). For classification of stress incontinence, the sensitivity was 0.86 (CI, 0.79 to 0.90), the specificity was 0.60 (CI, 0.51 to 0.68), and the positive likelihood ratio was 2.13 (CI, 1.71 to 2.66).” (J. S. Brown,
brownj@obgyn.ucsf.edu)
Hepatitis C Infections: Reflecting on several Annals articles on hepatitis C infections, an editorialist writes (pp. 770-1): “[These] new data build on those reported previously to paint a vivid portrait of hepatitis C in the United States. A self-limited epidemic of injection drug use over several decades amplified the transmission of hepatitis C, and we are now seeing the delayed, bitter harvest of chronic liver disease. Between the declining frequency of new infections and the exciting advances in antiviral therapy, we can look forward to a time in the near future when this legacy of epidemic injection drug use—the hepatic (and less recognized renal) consequences of HCV infection—will be behind us.” (J. L. Dienstag, jdienstag@partners.org)

>>>PNN NewsWatch
* Bausch & Lomb yesterday recalled its ReNu with MoistureLoc product worldwide and said that it will not reintroduce the product. Since no contamination, tampering, or counterfeiting has been identified that might account for 122 reported cases of Fusarium keratitis, CEO Ron Zarrella wrote in a letter, “That leads us to conclude that there may be some aspect of the MoistureLoc formula, when combined with certain environmental factors, lens wear and care practices, and other factors, that might increase the risk of Fusarium infection in rare circumstances.”
*
Abuse of prescription drugs by teenagers continues to increase, according to results of an annual study conducted by the Partnership for a Drug-Free America. According to media reports that are appearing this morning, 20% of teenagers report abusing narcotic analgesics such as Vicodin and OxyContin, and the Partnership warns that teenage abuse of prescription drugs has become “an entrenched behavior.”

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, 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, 2006 Vol. 13, No. 95
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
May 17 issue of JAMA (www.jama.com; 2006; 295).
Policosanol & Lipid Levels: The Cuban sugar cane derivative policosanol provided no lipid-lowering effect among patients with hypercholesterolemia or combined hyperlipidemia beyond that provided by placebo, according to a German study (pp. 2262-9). Study participants took placebo and began dieting during a 6-week, open-label phase and then were randomized for 12 weeks to either placebo or various servings of the dietary supplement policosanol. Results showed the following: “A total of 143 patients were randomized to 5 equal groups and were analyzed on an intention-to-treat basis. In none of the 5 treatment groups did LDL-C levels decrease more than 10% from baseline. No statistically significant difference between policosanol and placebo was observed. A nonparametric test analyzing dose-dependency yielded nonsignificant results. In none of the secondary outcome measures, namely total cholesterol, high-density lipoprotein cholesterol (HDL-C), very low-density lipoprotein cholesterol, triglycerides, lipoprotein(a), and ratio of total or LDL-C to HDL-C, were there any significant effects of policosanol. Policosanol was tolerated well without serious adverse events.” (H. K. Berthold, Drug Commission of the German Medical Assoc., Berlin; berthold@uni-bonn.de)
Risks of Anti-TNF Antibody Therapy in Rheumatoid Arthritis: A systematic review and meta-analysis confirms an increased risk of serious infections and a dose-dependent increased risk of malignancies when anti-TNF antibody therapy is used for treating patients with rheumatoid arthritis (pp. 2275-85). Based on results from nine published studies of infliximab and adalimumab that were at least 12 weeks in duration, the authors report these risks for 5,005 study participants: “We calculated a pooled odds ratio (Mantel-Haenszel methods with a continuity correction designed for sparse data) for malignancies and serious infections (infection that requires antimicrobial therapy and/or hospitalization) in anti-TNF–treated patients vs placebo patients. We estimated effects for high and low doses separately. The pooled odds ratio for malignancy was 3.3 (95% confidence interval [CI], 1.2-9.1) and for serious infection was 2.0 (95% CI, 1.3-3.1). Malignancies were significantly more common in patients treated with higher doses compared with patients who received lower doses of anti-TNF antibodies. For patients treated with anti-TNF antibodies in the included trials, the number needed to harm was 154 (95% CI, 91-500) for 1 additional malignancy within a treatment period of 6 to 12 months. For serious infections, the number needed to harm was 59 (95% CI, 39-125) within a treatment period of 3 to 12 months.” (T. Bongartz, bongartz.tim@mayo.edu)
Funding Sources & Cardiovascular Study Results: Who’s paying for cardiovascular studies makes a difference in whether results are positive or negative, according to a review of 324 consecutive superiority trials published in 2000-2005 in three major medical weekly journals (pp. 2270-4). “Of the 104 trials funded solely by not-for-profit organizations, 51 (49%) reported evidence significantly favoring newer treatments over the standard of care, whereas 53 (51%) did not (P = .80),” the researchers write. “By contrast, 92 (67.2%) of 137 trials funded solely by for-profit organizations favored newer treatments over standard of care (P<.001). Among 62 jointly funded trials, 35 (56.5%), an intermediate proportion, favored newer treatments. For 205 randomized trials evaluating drugs, the proportions favoring newer treatments were 39.5%, not-for-profit; 54.4%, jointly funded; and 65.5%, for-profit trials (P for trend across groups = .002). For the 39 randomized trials evaluating cardiovascular devices, the proportions favoring newer treatments were 50.0%, not-for-profit; 69.2%, jointly funded; and 82.4%, for-profit trials (P for trend across groups = .07). Regardless of funding source, trials using surrogate end points, such as quantitative angiography, intravascular ultrasound, plasma biomarkers, and functional measures were more likely to report positive findings (67%) than trials using clinical end points (54.1%; P = .02).” (P. M Ridker, pridker@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 © 2006, 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, 2006 Vol. 13, No. 96
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
May 18 issue of the New England Journal of Medicine (content.nejm.org; 2006; 354).
HER2 & Chemotherapy: Studying breast cancer cells from 710 premenopausal women with node-positive tumors, researchers determined that those patients with amplification of the human epidermal growth factor receptor type 2 (HER2, also called HER2/neu) gene had better clinical responses to anthracycline-containing chemotherapy (pp. 2103-11). Patients were treated with cyclophosphamide, epirubicin, and fluorouracil (CEF) or cyclophosphamide, methotrexate, and fluorouracil (CMF), and those with amplified HER2 had poor prognoses regardless of treatment. CEF was superior to CMF in terms of relapse-free survival in women with amplified HER2 (hazard ratio, 0.52; 95% CI, 0.34-0.80; P = .003) and overall survival (HR, 0.65; 95% CI, 0.42-1.02; P = .06). These parameters were unchanged by CEF among women whose tumors did not have HER2 amplification. (K. I. Pritchard, kathy.pritchard@sunnybrook.ca)
Caffeine & Prematurity: Caffeine therapy, used in 2,006 infants with low birth weights (500-1,500 grams) for apnea of prematurity, reduced the rate of bronchopulmonary dysplasia (pp. 2112-21). “Of 963 infants who were assigned to caffeine and who remained alive at a postmenstrual age of 36 weeks, 350 (36 percent) received supplemental oxygen, as did 447 of the 954 infants (47 percent) assigned to placebo (adjusted odds ratio, 0.63; 95 percent confidence interval, 0.52 to 0.76; P < 0.001),” report the researchers. “Positive airway pressure was discontinued one week earlier in the infants assigned to caffeine (median postmenstrual age, 31.0 weeks; interquartile range, 29.4 to 33.0) than in the infants in the placebo group (median postmenstrual age, 32.0 weeks; interquartile range, 30.3 to 34.0; P < 0.001). Caffeine reduced weight gain temporarily. The mean difference in weight gain between the group receiving caffeine and the group receiving placebo was greatest after two weeks (mean difference, –23 g; 95 percent confidence interval, –32 to –13; P < 0.001). The rates of death, ultrasonographic signs of brain injury, and necrotizing enterocolitis did not differ significantly between the two groups.” (B. Schmidt, schmidt@mcmaster.ca)

>>>PNN NewsWatch
* Making recommendations for the “generally healthy population” of the U.S., an NIH panel yesterday concluded that multivitamins and minerals are largely unproven therapies that may be harming some consumers. “Half of American adults are taking MVMs and the bottom line is that we don’t know for sure that they’re benefiting from them. In fact, we’re concerned that some people may be getting too much of certain nutrients,” said panel chair J. Michael McGinnis, MD, MPP, senior scholar with the Institute of Medicine of the National Academy of Sciences. The panel recommended the combined use of calcium and vitamin D supplementation for postmenopausal women to protect bone health. The panel also advocated that antioxidants and zinc be considered for use by nonsmoking adults with early-stage, age-related macular degeneration. The panel supported previous recommendations by the CDC that women of childbearing age take daily folate to prevent neural tube defects in infants. Conversely, it found no evidence to recommend beta-carotene supplements for the general population, and strong evidence to caution smokers against taking them. Specifically, beta-carotene was linked to an increase in lung cancer among smokers who took the vitamin regularly. In looking specifically at MVMs for chronic disease prevention, however, the panel found that the available data are insufficient to make a firm recommendation for or against their use in the general population.
* Merck data show that patients taking
rofecoxib have elevated risks of cardiovascular events within the first 4 months of treatment, according to this morning’s Wall Street Journal. After reviewing a 107-page summary that Merck has provided to FDA, the newspaper noted that statistical significance was not achieved between Vioxx and placebo recipients in the first 4 months. But the article explains that previous data published as a graph in the New England Journal of Medicine had shown “essentially identical” lines “until 18 months, when they sharply diverged.”

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, 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 19, 2006 Vol. 13, No. 97
Providing news and information about medications and their proper use

>>>Rasagiline Approved for PD
FDA has approved a new chemical entity, rasagiline (Azilect, Teva), with indications for initial monotherapy of early Parkinson’s disease as well as adjunctive therapy to levodopa in patients having moderate to advanced disease. The product will be available in 8–10 weeks.
The safety and effectiveness of this medication were demonstrated in three 18- to 26-week controlled clinical trials. One of the studies compared the effects of rasagiline with the effects of placebo in 404 patients with early Parkinson’s disease. Compared with patients on placebo, the condition of patients on rasagiline showed significantly less worsening in their ability to perform mental and motor tasks as well as daily living activities.
The other two studies compared the effects of rasagiline with placebo when taken together with levodopa in more than 1,100 patients with more advanced Parkinson’s disease. In these studies, patients using rasagiline with levodopa had significantly less time per day with relatively poor function and mobility as compared with patients on levodopa and placebo.
Rasagiline may be associated with hypertensive crisis if patients also consume tyramine-rich foods, beverages, or dietary supplements or amines contained in many cough and cold medications. Therefore, patients will need to avoid these sources of tyramine and amines when taking rasagiline. As with most other medications for Parkinson’s disease, rasagiline has the potential to cause dyskinesias, hallucinations, and lowered blood pressure.
During development, melanoma was diagnosed in a small number of patients treated with rasagiline. Patients with Parkinson’s disease have an increased risk for this form of skin cancer, and FDA concluded that the data did not conclusively link rasagiline to a further increase in risk of melanoma. Teva will perform a Phase IV study to further assess any possible relationship, and the product labeling recommends that patients undergo periodic dermatologic examinations.

>>>Allergy/Immunology Update
Source:
May issue of the Journal of Allergy and Clinical Immunology (www.jacionline.org; 2006; 117).
CAM for Rhinitis, Asthma: While used extensively in treatment of allergic rhinitis and asthma, complementary and alternative medicines are not effective, according to currently available evidence (pp. 1054-62). This conclusion is reached in a review article in which authors note: “The methodology of clinical trials with complementary-alternative medicine was frequently inadequate. Meta-analyses provided no clear evidence for the efficacy of acupuncture in rhinitis and asthma. Some positive results were described with homeopathy in good-quality trials in rhinitis, but a number of negative studies were also found. Therefore it is not possible to provide evidence-based recommendations for homeopathy in the treatment of allergic rhinitis, and further trials are needed. A limited number of studies of herbal remedies showed some efficacy in rhinitis and asthma, but the studies were too few to make recommendations. There are also unresolved safety concerns.” (G. Passalacqua, U. Genoa, Genoa, Italy; passalacqua@unige.it)

>>>PNN NewsWatch
* The FDA vaccines advisory panel yesterday unanimously recommended approval of Gardasil, a quadrivalent vaccine for human papillomavirus being developed by Merck, for prevention of cervical cancer and for prevention of cervical, vulvar, and vaginal pre-cancers caused by HPV types 16 and 18 in females. The vaccine has been tested in girls and women aged 16 to 26 years as well as in men (HPV can produce genital warts and head and neck cancer in boys and men). Immunogenicity studies have been conducted in boys and girls aged 9 to 15 years, and the discussions and votes during the meeting indicate that FDA seems likely to approve the vaccine for use in girls and women aged 9 to 26 years. If it does, the vaccine could be added to the routine immunizations received by girls at ages 11 and 12.

* FDA reviewers are recommending new warnings about liver failure in the labeling of
telithromycin (Ketek, Sanofi Aventis), according to this morning’s Wall Street Journal.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, 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, 2006 Vol. 13, No. 98
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
May 20 issue of Lancet (www.thelancet.com; 2006; 367).
ASA Plus Dipyridamole for Ischemic Stroke: Following ischemic stroke of presumed arterial origin, aspirin plus dipyridamole is a better antithrombotic approach than is aspirin alone, according to results of the European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT; pp. 1665-73). A total of 2,739 patients randomly received aspirin 30-325 mg daily with or without dipyridamole 200 mg twice daily, with therapy beginning within 6 months of a transient ischemic attack or minor stroke of presumed arterial origin. Results showed the following: “Mean follow-up was 3.5 years (SD 2.0). Median aspirin dose was 75 mg in both treatment groups (range 30–325); extended-release dipyridamole was used by 83% (n = 1,131) of patients on the combination regimen. Primary outcome events arose in 173 (13%) patients on aspirin and dipyridamole and in 216 (16%) on aspirin alone (hazard ratio 0.80, 95% CI 0.66–0.98; absolute risk reduction 1.0% per year, 95% CI 0.1–1.8). Addition of the ESPRIT data to the meta-analysis of previous trials resulted in an overall risk ratio for the composite of vascular death, stroke, or myocardial infarction of 0.82 (95% CI 0.74–0.91). Patients on aspirin and dipyridamole discontinued trial medication more often than those on aspirin alone (470 vs 184), mainly because of headache.” (A. Algra, U. Med. Ctr., Utrecht, the Netherlands; A.Algra@umcutrecht.nl)

>>>BMJ Highlights
Source:
May 20 issue of BMJ (www.bmj.org; 2006; 332).
Pediatric Underdosing of Antiretroviral Meds: Among 615 children with HIV infection aged 2-12 years, underdosing with antiretroviral agents was common, generally resulting from largely inadvertent problems that are common in pediatrics (pp. 1183-7). Comparing doses at clinical centers in the U.K. and Ireland with those recommended in 2004 European guidelines, the authors found: “Actual doses standardised to weight or surface area varied widely across individual drugs, antiretroviral class, and calendar time, with children underdosed (prescribed less than 90% of current recommended doses) from 6-62% child time at risk. Three serious issues in prescribing antiretrovirals, which may also be relevant to paediatric prescribing in general, were identified. Firstly, dosing was inadequate before incorrect recommendations at licensing were later revised when important pharmacokinetic results emerged. Secondly, guidelines stating dosage alternatives (by weight/surface area) for the same drug led to different and inconsistent doses. And, thirdly, ongoing growth was not adjusted for.” (E. N. Menson, MRC Clinical Trials Unit, London)
Gabapentin & Visual Field Constriction: Used for treating neuropathic pain, gabapentin therapy was associated with reversible visual field constriction (p. 1193). Episodes of disturbed vision lasting 5-10 minutes and dizziness began in a 52-year-old woman 9 months after gabapentin was started, and ophthalmologic examination showed concentric visual field constriction. This worsened over the next 4 months, leading the clinicians to stop gabapentin. Over the 9 months, the constriction improved, and it disappeared completely after 5 years. (S. I. Bekkelund, U. Hosp. of North Norway, Tromsø, Norway; svein.ivar.bekkelund@unn.no)

>>>PNN JournalWatch
* Home Versus Outpatient Administration of Intravenous Steroids for Multiple-Sclerosis Relapses: A Randomised Controlled Trial, in Lancet Neurology, 2006; 367: DOI:10.1016/S1474-4422(06)70450-1. Reprints: www.thelancet.com/journals/laneur/article/PIIS1474442206704501; J. Chataway, Natl. Hosp. for Neurology and Neurosurgery, London; jeremychataway@fastmail.fm
* Sepsis-Associated Myocardial Dysfunction: Diagnostic and Prognostic Impact of Cardiac Troponins and Natriuretic Peptides, in
Chest, 2006; 129: 1349-66. Reprints: www.chestjournal.org/cgi/content/abstract/129/5/1349; M. Maeder, U. Hosp., Basel, Switzerland; micha.maeder@bluewin.ch
* The Antimicrobial Therapy Puzzle: Could Pharmacokinetic-Pharmacodynamic Relationships Be Helpful in Addressing the Issue of Appropriate Pneumonia Treatment in Critically Ill Patients?, in
Clinical Infectious Diseases, 2006; 42: 1764-71. Reprints: www.journals.uchicago.edu/CID/journal/issues/v42n12/38867/brief/38867.abstract.html; F. Pea, U. Udine, Udine, Italy.; federico.pea@med.uniud.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 © 2006, 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, 2006 Vol. 13, No. 99
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
May 22 issue of the Archives of Internal Medicine (www.archinternmed.com; 2006; 166).
Prescribing Safety Alerts: In a health-maintenance organization, prescribing of contraindicated medications for elderly patients was reduced by institution of an outpatient medical record with prescribing safety alerts (pp. 1098-104). Over a 39-month period, computerized alerts cautioned prescribers not to use certain agents in elderly patients, and researchers followed changes in prescribing patterns as compared with a previous time period. “Following the implementation of the drug-specific alerts, a large and persistent reduction (5.1 prescriptions per 10 000, P = .004), a 22% relative decrease from the month before alert implementation, in the exposure of elderly patients to nonpreferred medications was observed,” the authors report. “We found no evidence of a decrease in use of nonpreferred agents for nonelderly patients. The reduction seen in use of nonpreferred agents for elderly persons was driven primarily by decreases in dispensing for tertiary tricyclic agents.” (D. H. Smith, Kaiser Permanente Ctr. for Health Research, Portland, Oreg.; avid.H.Smith@kpchr.org">David.H.Smith@kpchr.org)
High-Dose Influenza Vaccine Doses for the Elderly: Use of high-dose influenza vaccine improved immunogenicity among a group of 202 patients older than 65 (pp. 1121-7). A single intramuscular injection of placebo or various doses of the 2001-2002 trivalent inactivated influenza vaccine, with these results: “Increasing dosages of vaccine elicited significantly higher serum antibody levels, frequencies of antibody responses, and putative protective titers after vaccination. Mean serum hemagglutination inhibition antibody titers 1 month after immunization in groups given 0-, 15-, 30-, and 60-µg dosages were 23, 37, 50, and 61 against influenza A/H1N1; 43, 86, 91, and 125 against influenza A/H3N2; and 10, 14, 18, and 24 against influenza B, respectively. Mean serum hemagglutination inhibition and neutralizing antibody levels against the 3 vaccine antigens in participants given the 60-µg dosage were 44% to 71% and 54% to 79%, respectively, higher than those in participants given the standard 15-µg dosage, and the 60-µg dosage level nearly doubled the frequency of antibody responses in those whose preimmunization antibody titers were in the lower half of the antibody range. Dose-related increases in the occurrence of injection site reactions were observed (P < .001), but all dosages were well tolerated.”
Authors of this study conclude: “The results of this study show that the highest dose (60 µg) was the most efficacious. Higher doses were not tested because of manufacturing considerations. The increased doses tested in this study were selected because they would not significantly affect projected future vaccine supply. Although adjuvant vaccine could potentially reduce the antigenic dose, adjuvant vaccines used for annual vaccination in elderly individuals present unknown risks compared with the safety record of nonadjuvant vaccines. Our findings provide a rationale for further, expanded trials designed to assess the effectiveness of immunization with enhanced-potency vaccines in the elderly population.” (W. A. Keitel, Baylor Coll. of Med., Houston;
wkeitel@bcm.tmc.edu)

>>>PNN NewsWatch
* Spectrum Laboratory Products has voluntarily recalled its active pharmaceutical ingredient (API) tacrolimus after learning some lots are subpotent. Furthermore, blood tacrolimus concentrations in some patients were significantly lower than would be expected based solely on the lower assay results. At least one injury associated with use of the product has been reported. Tacrolimus API is identified as Catalog Number T3192. Recalled lots include the following: TA1210, UD1060, UF0298, UL0964, and VB0031. Pharmacies should stop using these lots and contact Spectrum to make arrangements to return product. Tacrolimus API was distributed to pharmacies, one university (1 bottle), and one pharmacy distributor (2 bottles) for use in compounding. This recall does not apply to tacrolimus marketed in finished dosage forms as Prograf (Astellas) or to Prograf oral capsules that have been used for compounding.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, 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, 2006 Vol. 13, No. 100
Providing news and information about medications and their proper use

>>>
Infectious Diseases Update
Source:
June 15 issue of Clinical Infectious Diseases (www.journals.uchicago.edu/CID; 2006; 42).
Hepatitis C Among Incarcerated IDUs: Health professionals should intervene during incarceration of injection drug users who have acute hepatitis C virus infections to provide counseling about other blood-borne pathogens and offer immunizations and HCV treatment, argue authors of a pilot study (pp. 1663-70). Medical providers at correctional and detoxification facilities were instructed to refer all patients with hepatitis to a specialty clinic, where these results were noted: “Over a 30-month period, 21 patients received a diagnosis of acute hepatitis C, 3 received a diagnosis of hepatitis B, and 1 received a diagnosis of hepatitis A. Of the 21 patients with acute hepatitis C, 19 were identified in the prison setting shortly after incarceration. Of the 17 patients who were observed serially (mean duration of observation, 6.3 months), 8 had spontaneous virologic clearance. Early therapy with pegylated interferon was initiated for 5 patients with persistent viremia and led to a sustained virologic response in 2 individuals. All patients agreed to undergo human immunodeficiency virus counseling and testing, as well as to receive immunization for hepatitis A and B.” (B. McGovern, bmcgovern@tufts-nemc.org)
An editorialist supports increased attention to diagnosis and treatment of HCV (pp. 1671-3): “It has been 18 years since HCV was discovered, and there have been many advances, including elimination of transfusion transmission of HCV in the West. We now have treatments that can clear HCV infection in approximately one-half of those who receive them, and we have a number of potent anti-HCV compounds in various stages of development. However, current therapeutic strategies have done very little to reduce the global or even the US burden of HCV infection. As McGovern et al. show among IDUs, HCV infections still happen, and we clearly need better methods to prevent, detect, and treat acute HCV infection in this large segment of our population. If almost one-half of HCV-infected persons are in contact with correctional services each year, there is indeed a window of opportunity.” (D. L. Thomas, Johns Hopkins U., Baltimore)
Posaconazole for Serious Fungal Infections: An orally administered investigational triazole antifungal agent, posaconazole, was safe in a pair of Phase II/III open-label clinical trials (pp. 1726-34). Overall, 362 patients with invasive fungal infections and 66 patients with febrile neutropenia received the drug, and 109 of these patients were treated for periods exceeding 6 months. The authors report these safety results: “Treatment-emergent, treatment-related adverse events were reported in 38% of the overall patient population. The most common treatment-related adverse events were nausea (8%) and vomiting (6%). Treatment-related serious adverse events occurred in 8% of patients. Low rates of treatment-related corrected QT interval and/or QT interval prolongation (1%) and elevation of hepatic enzymes (2%) were reported as adverse events. Treatment-emergent, treatment-related adverse events occurred at similar rates in patients who received posaconazole therapy for <6 months and ≥6 months.” (I. I. Raad, iraad@mdanderson.org)
Lactobacillus in Preterm Neonates: The incidence and the intensity of enteric colonization by Candida among 80 very low birth weight neonates were significantly reduced by oral administration of a Lactobacillus product (pp. 1735-42). During the first 3 days of life, neonates received either a probiotic product containing Lactobacillus casei subspecies rhamnosus (Dicoflor, Dicoflor spa) or unsupplemented human milk. Use of the probiotic was associated with significant decreases in the incidence of fungal enteric colonization (23.1% vs. 48.8%; relative risk, 0.315, 95% CI, 0.120–0.826) and the numbers of fungal isolates from each neonate and from each colonized patient. Investigators noted that the Lactobacillus product was more effective in neonates with birth weights of 1,001–1,500 grams. No adverse effects attributable to the probiotic were observed. (P. Manzoni, Azienda Ospedaliera Regina Margherita–S. Anna, Torino, Italy; paolomanzoni@hotmail.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 © 2006, 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, 2006 Vol. 13, No. 101
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
May 25 issue of the New England Journal of Medicine (content.nejm.org; 2006; 354).
Surgery for Perforated Necrotizing Enterocolitis: Survival, dependence on total parenteral nutrition, and other clinical outcomes were unaffected by the type of surgery performed on 117 preterm neonates with birth weights of less than 1,500 grams and perforated necrotizing enterocolitis (pp. 2225-34). Comparing primary peritoneal drainage with a laparotomy and bowel resection procedure, the researchers found: “At 90 days postoperatively, 19 of 55 infants assigned to primary peritoneal drainage had died (34.5 percent), as compared with 22 of 62 infants assigned to laparotomy (35.5 percent, P = 0.92). The percentages of infants who depended on total parenteral nutrition were 17 of 36 (47.2 percent) in the peritoneal-drainage group and 16 of 40 (40.0 percent) in the laparotomy group (P = 0.53). The mean (± SD) length of hospitalization for the 76 infants who were alive 90 days after operation was similar in the primary peritoneal-drainage and laparotomy groups (126 ± 58 days and 116 ± 56 days, respectively; P = 0.43). Subgroup analyses stratified according to the presence or absence of radiographic evidence of extensive necrotizing enterocolitis (pneumatosis intestinalis), gestational age of less than 25 weeks, and serum pH less than 7.30 at presentation showed no significant advantage of either treatment in any group.” (R. L. Moss, larry.moss@yale.edu)
An editorialist, after noting limitations of the above study, concludes (pp. 2275-6): “The results strongly support the conclusion that, at least among neonates with birth weights of less than 1,000 g, there is no apparent difference in short-term survival, length of hospitalization, or requirement for parenteral nutrition between infants who undergo primary peritoneal drainage and those who undergo laparotomy. These results indicate that primary peritoneal drainage is a reasonable treatment approach in these very tiny patients with tenuous health.” (A. W. Flake, Children’s Hosp., Philadelphia)
Adaptive Immunity with Imatinib: A newly recognized type of immune cell, the interferon-producing killer dendritic cell (IKDC), may be responsible for the observation that some gastrointestinal stromal tumors are refractory in vitro to the antiproliferative effects of imatinib but sensitive to the drug in vivo (pp. 2282-4). Writing in a Clinical Implications of Basic Research article, an author explains: “It is not yet certain whether the immune surveillance of pathogens and tumors is a normal function of the IKDC. Tumor immunity may occur only when mice are treated with imatinib mesylate and interleukin-2. Certainly, under these circumstances, IKDCs proliferated and also infiltrated the regressing tumor beds. Since the IKDC does not express c-kit (to which imatinib mesylate binds), the mechanism by which imatinib mesylate potentiates IKDC function in vivo has yet to be discovered. Should these results be extrapolated to humans, however, there will be the opportunity to further improve and broaden the activity of the drug. A key challenge is to identify an equivalent cell in humans. If one exists, it will be important to determine the most effective way to stimulate IKDCs to generate an immune response to tumors.” (M. J. Smyth, Peter MacCallum Cancer Ctr., East Melbourne, Victoria, Australia)
LCMV Transmission by Organ Grafts: Two clusters of lymphocytic choriomeningitis virus transmission through organ transplantation are described (pp. 2235-49). “In both investigations, LCMV could not be detected in the organ donor. In the 2005 cluster, the donor had had contact in her home with a pet hamster infected with an LCMV strain identical to that detected in the organ recipients; no source of LCMV infection was found in the 2003 cluster. The transplant recipients had abdominal pain, altered mental status, thrombocytopenia, elevated aminotransferase levels, coagulopathy, graft dysfunction, and either fever or leukocytosis within three weeks after transplantation. Diarrhea, peri-incisional rash, renal failure, and seizures were variably present. Seven of the eight recipients died, 9 to 76 days after transplantation. One recipient, who received ribavirin and reduced levels of immunosuppressive therapy, survived.” (M. J. Kuehnert, mkuehnert@cdc.gov)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, 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 26, 2006 Vol. 13, No. 102
Providing news and information about medications and their proper use

>>>JAPhA Highlights
Source:
May/June Journal of the American Pharmacists Association (www.japha.org; 2006; 46).
Workforce Issues and MTM: Four reports from the 2004 National Pharmacist Workforce Study describe a trend toward increasing part-time employment for both men and women pharmacists, and several articles describe emerging services relevant to pharmacists who are launching medication therapy management services. “The imbalance between supply and demand of pharmacists since 1999 combined with the difficult economic times of the early 21st century appear to have increased the number of older men pharmacists—including many who might otherwise have retired—practicing in part-time positions,” notes the lead workforce article (pp. 322-30; D. A. Mott, damott@pharmacy.wisc.edu).
MTM-related contributions are highlighted by the editors (pp. 320-1): “Articles in this issue describe how pharmacists can segment women into groups based on their osteoporosis belief profiles and screen Asian women for this disease based on nothing more than their age and weight; how the gap in counseling on diet, exercise, and smoking cessation should be filled by pharmacists willing to leverage their accessibility and knowledge and how failure to do so makes all our efforts ‘like spitting into the wind’; how cardiovascular and diabetic screenings of high-risk individuals can be effective when conducted by pharmacists both in their practice settings and other locations in the community; and how pharmacists are making progress in documenting their ... MTM services.” (L. M. Posey,
mposey@aphanet.org)

>>>PNN NewsWatch
* APhA, ASHP, AMCP, and ACCP have responded to an emergency-contraception commentary in Obstetrics & Gynecology (www.greenjournal.org/cgi/content/abstract/107/5/1148; 2006; 107: 1148-51) that argued that “pharmacists ‘at the counter’ lack the fundamental prerequisites necessary for making clinically sound ethical decisions.” The authors, L. Lewis Wall, MD, DPhil, of Washington U., and Douglas Brown, PhD, of Mich. State U., examined pharmacists’ claim of a professional right of conscience in declining to dispense emergency postcoital contraceptives, reaching this bottom line: “We conclude that a policy that allows pharmacists to dispense or not dispense medications to patients on the basis of their personal values and opinions is inimical to the public welfare and should not be permitted.” Responding that this analysis compares apples with oranges, the pharmacy organizations wrote in a letter posted on the APhA Web site, “Serving our patients and helping them make the best use of their medication is pharmacists’ priority, which is why our organizations support the two-part policy stressing the need to assure patient access to legally prescribed, clinically appropriate therapy in a timely manner when a pharmacist steps away from working with a prescription based on personal beliefs. Our organizations oppose pharmacists using their position to berate, belittle, or lecture their patients. Our organizations oppose pharmacists obstructing patient access to therapy. We also oppose laws, regulations, and commentaries that compel pharmacists to dispense every legally valid, clinically safe prescription regardless of personal beliefs. Rather than designating professionals to be robots or automatons who subscribe to one set of beliefs, a different approach is available. And it works. It takes more time, and proactive implementation, but many of the best solutions do.”
*
Thalidomide (Thalomid, Celgene) has been approved for treatment of newly diagnosed multiple myeloma in combination with dexamethasone. FDA made the accelerated approval based on response rates rather than hard clinical outcomes such as survival rates.
* FDA yesterday approved an
extended-cycle oral contraceptive product, Seasonique (Duramed), which provides levonorgestrel 0.15 mg/ethinyl estradiol 0.03 mg for 84 days followed by ethinyl estradiol 0.01 mg for 7 days. Similar to Duramed’s Seasonale product launched in 2003, Seasonique reduces the number of menstrual periods from 12 to 4 per year, and the low estrogen doses limits hormonal fluctuations and decreases menstrual symptoms.
*
PNN will not be published on Mon., May 29, 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 © 2006, 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, 2006 Vol. 13, No. 103
Providing news and information about medications and their proper use

>>>FDA Licenses Zoster Vaccine
Merck’s Zoster Vaccine Live (Oka/Merck) has been licensed by FDA for prevention of herpes zoster (shingles) in individuals 60 years of age and older. Merck will market the vaccine under the tradename Zostavax. Since the target population for this new vaccine is similar to that for influenza vaccine, pharmacists could be in a prime position to ensure that older Americans are vaccinated against shingles.
The efficacy and safety of a single dose of Zostavax was evaluated in the Shingles Prevention Study (SPS) of 38,546 men and women aged 60 and older who had no previous history of shingles. In this randomized, double-blind, placebo-controlled study, participants were given either Zostavax (n = 19,270) or a placebo (n = 19,276) and followed for the development of shingles for a median of 3.1 years. Zostavax significantly reduced the risk of developing shingles compared with placebo by 51% (315 cases [5.4 cases per 1,000 person–years] vs. 642 cases [11.1 cases per 1,000 person–years], respectively;
P < .001) in the SPS. Efficacy of Zostavax for the prevention of shingles was highest for those 60 to 69 years of age and declined with increasing age.
Vaccine-related injection site and systemic adverse events seen in the first 42 days after vaccination in 1% or more of the individuals who received Zostavax (n = 3,345) included headache (1.4%) and these injection-site reactions: erythema (33.7%), pain/tenderness (33.4%), swelling (24.9%), hematoma (1.4%), pruritus (6.6%), and warmth (1.5%). Most of these adverse experiences were reported as mild in intensity.
In the entire SPS study population, the rates of overall cardiovascular events (0.4%) including coronary artery disease–related conditions (0.2%) were similar in those vaccinated with Zostavax or placebo. In the AEMS of the SPS, in the first 42 days after vaccination, the rate of overall cardiovascular events was higher after Zostavax (0.6%) than after placebo (0.4%), including the rate of coronary artery disease–related conditions (Zostavax, 0.3%; placebo, 0.2%).
Zostavax is contraindicated in persons with a history of anaphylactic/anaphylactoid reaction to gelatin, neomycin, or any other component of the vaccine; with a history of primary or acquired immunodeficiency states including leukemia, lymphomas of any type, or other malignant neoplasms affecting the bone marrow or lymphatic system; with AIDS or other clinical manifestations of infection with HIV; and with active untreated tuberculosis. It is also contraindicated in persons on immunosuppressive therapy, including high-dose corticosteroids, and in women who are or may be pregnant.

>>>BMJ Highlights
Source:
Early-release article from BMJ (www.bmj.org; 2006; 332).
Commercial Weight-Loss Programs: Patients motivated to lose weight did so on all four commercial weight-loss programs studied in this U.K. analysis (doi: 10.1136/bmj.38833.411204.80). In an unblinded, multicenter, randomized, controlled, 6-month trial, community-dwelling overweight and obese adults followed either Dr. Atkins’ new diet revolution, Slim-Fast plan, Weight Watchers pure points program, or Rosemary Conley’s eat yourself slim diet and fitness plan. The investigators report: “All diets resulted in significant loss of body fat and weight over six months. Groups did not differ significantly but loss of body fat and weight was greater in all groups compared with the control group. In an intention to treat analysis, average weight loss was 5.9 kg and average fat loss was 4.4 kg over six months. The Atkins diet resulted in significantly higher weight loss during the first four weeks, but by the end was no more or less effective than the other diets.” (H. Truby, U. Surrey, Guildford, U.K.; h.truby@surrey.ac.uk)

>>>PNN JournalWatch
* Management of Hypertrophic Cardiomyopathy, in BMJ, 2006; 332: 1251-5. Reprints: bmj.bmjjournals.com/cgi/content/extract/332/7552/1251; P. Spirito, Ente Ospedaliero Ospedali Galliera, Genoa, Italy; paolo.spirito@galliera.it
* Infections Due to Rapidly Growing Mycobacteria, in
Clinical Infectious Diseases, 2006; 42: 1756-63. Reprints: www.journals.uchicago.edu/CID/journal/issues/v42n12/38494/brief/38494.abstract.html; G. Huitt, Natl. Jewish Med. and Res. Ctr., Denver; huittg@njc.org

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, 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, 2006 Vol. 13, No. 104
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
June issue of Diabetes Care (care.diabetes.journals.org; 2006; 29).
Predicting Foot Ulcers: A1C levels, impaired vision, prior foot ulcer or amputation, monofilament insensitivity, and presence of tinea pedis or onychomycosis can be used to predict which patients with diabetes are likely to develop foot ulcers, according to a study of 1,285 veterans (pp. 1202-7). Noting that this readily available clinical information can be used to target patients at high risk for this complication, the authors note these findings: “At baseline, subjects were 62.4 years of age on average and 98% male. Mean follow-up duration was 3.38 years, during which time 216 foot ulcers occurred, for an incidence of 5.0/100 person-years. Significant predictors (P ≤ 0.05) of foot ulcer in the final model (hazard ratio, 95% CI) included A1C (1.10, 1.06–1.15), impaired vision (1.48, 1.00–2.18), prior foot ulcer (2.18, 1.61–2.95), prior amputation (2.57, 1.60–4.12), monofilament insensitivity (2.03, 1.50–2.76), tinea pedis (0.73, 0.54–0.98), and onychomycosis (1.58, 1.16–2.16).” (E. J. Boyko, eboyko@u.washington.edu)
New LDL-C Targets: In the Treating to New Targets (TNT) study, atorvastatin 80 mg daily significantly lowered risks of major cardiovascular events by 25% among patients with clinically evident coronary heart disease and diabetes, compared with 10-mg doses of that HMG-CoA reductase inhibitor (pp. 1220-6). The 1,501 patients included in this analysis had LDL cholesterol levels lower than 130 mg/dL at randomization and were followed for a median of 4.9 years. Results showed: “End-of-treatment mean LDL cholesterol levels were 98.6 mg/dl with atorvastatin 10 mg and 77.0 mg/dl with atorvastatin 80 mg. A primary event occurred in 135 patients (17.9%) receiving atorvastatin 10 mg, compared with 103 patients (13.8%) receiving atorvastatin 80 mg (hazard ratio 0.75 [95% CI 0.58–0.97], P = 0.026). Significant differences between the groups in favor of atorvastatin 80 mg were also observed for time to cerebrovascular event (0.69 [0.48–0.98], P = 0.037) and any cardiovascular event (0.85 [0.73–1.00], P = 0.044). There were no significant differences between the treatment groups in the rates of treatment-related adverse events and persistent elevations in liver enzymes.” (J. Shepherd, Royal Infirmary, Glasgow, U.K.; jshepherd@gri-biochem.org.uk)
Adjunctive Therapy with Inhaled Insulin: Premeal doses of inhaled insulin were more effective than adjunctive metformin when added to a sulfonylurea in 427 patients with poorly controlled type 2 diabetes but produced more cough as an adverse effect (pp. 1282-7). During this open-label, 24-week trial, patients were followed based on their initial A1C level, with these results: “In the A1C >9.5% arm, INH demonstrated a significantly greater reduction in A1C than metformin. Mean adjusted changes from baseline were –2.17 and –1.79%, respectively; between-treatment difference was –0.38% (95% CI –0.63 to –0.14, P = 0.002). In the A1C ≤ 9.5% arm, mean adjusted A1C changes were –1.94 and –1.87%, respectively (–0.07% [–0.33 to 0.19], P = 0.610), consistent with the noninferiority criterion. Hypoglycemia (events/subject-month) was greater in the INH (0.33) than in the metformin (0.15) group (risk ratio 2.16 [95% CI 1.67–2.78]), but there were no associated discontinuations. Other adverse events, except increased cough in the INH group, were similar. At week 24, changes in pulmonary function parameters were small and comparable between groups. Insulin antibody binding increased more with INH but did not have any associated clinical manifestations.” (A. H. Barnett, Birmingham Heartlands Hosp., Birmingham, U.K.; anthony.barnett@heartofengland.nhs.uk)

>>>PNN NewsWatch
* FDA has approved a closely watch follow-on version of growth hormone, the Wall Street Journal reports today. Omnitrope (Sandoz) was approved as equivalent to Genotropin (Pfizer), and the newspaper notes, “The approval ... is important because it confirms that the FDA has the scientific knowledge to approve a so-called ‘follow-on’ version of at least a simple biotechnology drug.” A recent article in the Journal of the American Pharmacists Association reviews this topic (www.japha.org; Devine et al.; 2006; 46: 193-204).

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, 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, 2006 Vol. 13, No. 105
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
June 1 issue of the New England Journal of Medicine (content.nejm.org; 2006; 354).
Caps on Medicare Drug Benefits: Poorer adherence and lack of control of blood pressure, lipids, and glucose levels were the result of a $1,000 cap on Medicare drug benefits, conclude authors who studied 157,275 Medicare–Choice benefits in 2003 with caps and 41,904 beneficiaries whose employers supplemented benefits to avoid the limits (pp. 2349-59). “After adjusting for individual characteristics, we found that subjects whose benefits were capped had pharmacy costs for drugs applicable to the cap that were lower by 31 percent than subjects whose benefits were not capped (95 percent confidence interval, 29 to 33 percent) but had total medical costs that were only 1 percent lower (95 percent confidence interval, –4 to 6 percent),” the researchers write. “Subjects whose benefits were capped had higher relative rates of visits to the emergency department (relative rate, 1.09 [95 percent confidence interval, 1.04 to 1.14]), nonelective hospitalizations (relative rate, 1.13 [1.05 to 1.21]), and death (relative rate, 1.22 [1.07 to 1.38]; difference, 0.68 per 100 person-years [0.30 to 1.07]). Among subjects who used drugs for hypertension, hyperlipidemia, or diabetes in 2002, those whose benefits were capped were more likely to be nonadherent to long-term drug therapy in 2003; the respective odds ratios were 1.30 (95 percent confidence interval, 1.23 to 1.38), 1.27 (1.19 to 1.34), and 1.33 (1.18 to 1.48) for subjects using drugs for hypertension, hyperlipidemia, and diabetes. In each subgroup, the physiological outcomes were worse for subjects whose drug benefits were capped than for those whose benefits were not capped; the odds ratios were 1.05 (95 percent confidence interval, 1.00 to 1.09), 1.13 (1.03 to 1.25), and 1.23 (1.03 to 1.46), respectively, for subjects with a systolic blood pressure of 140 mm Hg or more, a serum low-density-lipoprotein cholesterol level of 130 mg per deciliter or more, and a glycated hemoglobin level of 8 percent or more.” (J. Hsu, Kaiser Permanente, Oakland, Calif.; jth@dor.kaiser.org)
An editorialist notes the challenges to policymakers and benefits managers evident in these data (pp. 2385-6): “Effective strategies for reducing the level and growth of spending will need to rely on tools other than high-deductible plans and limits on benefits. With respect to the rise in spending, we need to address the rise in obesity head-on. Doing so will be neither easy nor likely to produce immediate results. However, the failure to include primary prevention and population-based approaches in the cost-containment tool kit will come at a price: a continued increase in obesity and in the prevalence of associated disease.
“In the near term, we can do a better job of treating chronically ill patients. Some major health systems, in particular the Veterans Health Administration, responded to this challenge by substantially improving clinical information systems and the treatment of chronic disease. Today, patients in the Veterans Health Administration receive better preventive care, and more recommended care for chronic disease, than do patients outside the system. Our attention needs to shift toward the reform of payment and delivery systems and away from the redesign of health insurance benefits.” (K. E. Thorpe, Emory U., Atlanta)
Medicare Part D: Two point–counterpoint Perspective articles review the performance of the Medicare Part D benefit in its initial months. Authors from CMS emphasize the positive results but notes the need to make choices available and easy to comprehend, ensure that formularies provide a broad range of choices at a reasonable cost, and work with physicians and other providers to reach beneficiaries with limited incomes (pp. 2312-4; M. B. McClellan, CMS, Baltimore). But a second article, from a Democratic representative from New York calls the benefit “the product of a broken process” (pp. 2314-5; L. M. Slaughter, House of Representatives, Washington).

>>>PNN NewsWatch
* Oracea (CollaGenex) has been approved by FDA for treatment of papules and pustules of rosacea in adults. The once-daily product contains doxycycline 40 mg in a combination immediate- and delayed-release formulation.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, 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 2, 2006 Vol. 13, No. 106
Providing news and information about medications and their proper use

>>>Pharmacotherapy Update
Source:
June issue of Pharmacotherapy (www.pharmacotherapy.org; 2006; 26).
ADRs in Hospitals: A variety of clinical pharmacy services have significant impacts on adverse drug reactions in hospitals, according to an analysis of 584 hospitals (pp. 735-47). Focusing on 35,193 Medicare patients who experienced one or more ADRs during hospitalization, the authors report: “Of ... 14 clinical pharmacy services, 12 were associated with reduced ADR rates. The most significant reductions occurred in hospitals offering pharmacist-provided admission drug histories (odds ratio [OR] 1.864, 95% confidence interval [CI] 1.765–1.968), drug protocol management (OR 1.365, 95% CI 1.335–1.395), and ADR management (OR 1.360, 95% CI 1.328–1.392). Multivariate analysis, performed to further evaluate these findings, showed that nine variables were associated with ADR rate: pharmacist-provided in-service education (slope –0.469, p = 0.018), drug information (slope –0.488, p = 0.005), ADR management (slope -0.424, p = 0.021), drug protocol management (slope –0.732, p = 0.002), participation on the total parenteral nutrition team (slope 0.384, p = 0.04), participation on the cardiopulmonary resuscitation team (slope –0.506, p = 0.008), medical round participation (slope –0.422, p = 0.037), admission drug histories (slope –0.712, p = 0.008), and increased clinical pharmacist staffing (slope –4.345, p = 0.009). As clinical pharmacist staffing increased from the 20th to the 100th percentile (from 0.93 ± 0.77/100 to 5.16 ± 4.11/100 occupied beds), ADRs decreased by 47.88%. In hospitals without pharmacist-provided ADR management, the following increases were noted: mean number of ADRs/100 admissions by 34.90% (OR 1.360, 95% CI 1.328–1.392), length of stay 13.64% (Mann-Whitney U test [U]=11047367, p = 0.017), death rate 53.64% (OR 1.574, 95% CI 1.423–1.731), total Medicare charges 6.88% (U=111298871, p = 0.018), and drug charges 8.16% (U=108979074, p < 0.001). Patients in hospitals without pharmacist-provided ADR management had an excess of 4266 ADRs, 443 deaths, 85,554 patient-days, $11,745,342 in total Medicare charges, and $1,857,744 in drug charges. The implications of these findings are significant for our health care system, especially considering that the study population represented 15.55% of 12,261,737 Medicare patients and 5.71% of the 34,345,436 patients admitted to all U.S. hospitals.” (C. A. Bond, cab.bond@ttuhsc.edu)
Pituitary Tumors & Second-Generation Antipsychotics: Use of risperidone and other atypical antipsychotic agents may be associated with development of pituitary tumors in people, a finding that would be consistent with studies of mice, report authors who analyzed reports submitted to FDA’s Adverse Event Reporting System (pp. 748-58). This pharmacovigilance study used the Multi-item Gamma Poisson Shrinker data mining algorithm to determine the Empiric Bayes Geometric Mean values for observed versus expected rates of adverse events. Results showed: “Risperidone had the highest adjusted reporting ratios for hyperprolactinemia (EBGM 34.9, 90% confidence interval [CI] 32.8–37.1]), galactorrhea (EBGM 19.9, 90% CI 18.6–21.4), and pituitary tumor (EBGM 18.7, 90% CI 14.9–23.3) among the seven antipsychotics, and one of the highest scores for all drugs in the AERS database. Some tumors were associated with visual field defects, hemorrhage, convulsions, surgery, and severe (> 10-fold) prolactin elevations. The EBGM values for risperidone for these adverse events were higher in women, but high EBGM values for these events were also seen in men and children. Moreover, the rank order of the EBGM values for pituitary tumors corresponded to the affinities of these seven drugs for D2 receptors. (A. Szarfman, szarfman@cder.fda.gov)
Drug Use Among the Elderly: Significant proportions of the elderly receive potentially inappropriate prescription medications, according to a longitudinal retrospective cohort analysis of the Medicare Expenditure Panel survey results, but health-related quality of life was not significantly affected by drug use (pp. 768-78). The authors conclude that a disease-specific HRQOL instrument may be needed to detect drug-related problems. (D. M. Franic, dfranic@rx.uga.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, 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, 2006 Vol. 13, No. 107
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from BMJ (www.bmj.org; 2006; 332).
Statin Guidelines: In a comparison of various countries’ guidelines on use of statins, Canadians fared best when the Australian and British recommendations were followed (doi: 10.1136/bmj.38849.487546.DE). Data for 6,760 men and women aged 20-74 years from the Canadian Heart Health Survey were used to estimate the number of people recommended for treatment with statins, the potential number of deaths from coronary heart disease avoided, and the number needed to treat to avoid one coronary heart disease death with 5 years of statin treatment if the recommendations from each guideline were fully implemented. Results were as follows: “When applied to the Canadian population, the Australian and British guidelines were the most effective, potentially avoiding the most deaths over five years (>15,000 deaths). The New Zealand guideline was the most efficient, potentially avoiding almost as many deaths (14,700) while recommending treatment to the fewest number of people (12.9% of people v 17.3% with the Australian and British guidelines). If their ‘optional’ recommendations are included, the US guidelines recommended treating about twice as many people as the New Zealand guidelines (24.5% of the population, an additional 1.4 million people) with almost no increase in the number of deaths avoided.” (D. G. Manuel, Inst. for Clinical Evaluative Sciences, Toronto; doug.manuel@ices.on.ca)

>>>Lancet Highlights
Source:
Early-release articles from Lancet (www.thelancet.com; 2006; 367).
Heroin Use in Switzerland: The medicalization of heroin use in Switzerland “seems to have contributed to the image of heroin as unattractive for young people,” according to authors who analyzed data for 7,256 patients in Zurich (doi: 10.1016/S0140-6736(06)68804-1). Switzerland has a liberal drug policy that includes approaches such as drug consumption rooms, needle-exchange services, low-threshold methadone programs, and heroin-assisted treatments. Focusing on experiences through March 2005, the authors report: “Every second person began their first [heroin] substitution treatment within 2 years of starting to use heroin regularly. Incidence of heroin use rose steeply, starting with about 80 people in 1975, culminating in 1990 with 850 new users, and declining substantially to about 150 users in 2002. Two-thirds of those who had left substitution treatment programmes re-entered within the next 10 years. The population of problematic heroin users declined by 4% a year. The cessation rate in Switzerland was low, and therefore, the prevalence rate declined slowly. Our prevalence model accords with data generated by different approaches.” (C. Nordt, Psychiatric U. Hosp., Militärstrasse, Zurich, Switzerland; cnordt@bli.unizh.ch)
>>>PNN JournalWatch
* Pharmacokinetics of Intravenous Immunoglobulin: A Systematic Review, in Pharmacotherapy, 2006; 26: 813-27. Reprints: www.pharmacotherapy.org; M. H. H. Ensom, Children’s and Women’s Health Ctr. of British Columbia, Vancouver.
* Update on Apomorphine for the Rapid Treatment of Hypomobility (“Off&rdquoWinking Episodes in Parkinson’s Disease, in
Pharmacotherapy, 2006; 26: 840-52. Reprints: www.pharmacotherapy.org; C. D. Obering, beringc@umkc.edu">oberingc@umkc.edu
* Vaccine Shortages: Why They Occur and What Needs to Be Done to Strengthen Vaccine Supply, in
Pediatrics, 2006; 117: 2269-75. Reprints: pediatrics.aappublications.org/cgi/content/extract/117/6/2269; J. O. Klein, Boston U., Boston.
* Pharmacologic Management of Insomnia in Children and Adolescents: Consensus Statement, in
Pediatrics, 2006; 117: e1223-32. Reprints: pediatrics.aappublications.org/cgi/content/abstract/117/6/e1223; J. A. Mindell, Children’s Hosp., Philadelphia.
* The Reduction of Inflammatory Biomarkers by Statin, Fibrate, and Combination Therapy Among Diabetic Patients With Mixed Dyslipidemia: The DIACOR Study, in
Journal of the American College of Cardiology, 2006; doi: 10.1016/j.jacc.2006.05.009. Reprints: content.onlinejacc.org/cgi/content/abstract/j.jacc.2006.05.009v1; J. B. Muhlestein, LDS Hosp., Salt Lake City; brent.muhlestein@intermountainmail.org
* Omega-3 Fatty Acids and Mood Disorders, in
American Journal of Psychiatry, 2006; 163: 969-78. Reprints: ajp.psychiatryonline.org/cgi/content/abstract/163/6/969; G. Parker.
* Omega-3 Treatment of Childhood Depression: A Controlled, Double-Blind Pilot Study, in
American Journal of Psychiatry, 2006; 163: 1098-100. Reprints: ajp.psychiatryonline.org/cgi/content/abstract/163/6/1098; H. Nemets.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, 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, 2006 Vol. 13, No. 108
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release articles and the June 6 issue of the Annals of Internal Medicine (www.annals.org; 2006; 144).
Long-Acting Beta-Agonists in Asthma: Severe, life-threatening asthma exacerbations and asthma-related deaths are increased with use of long-acting beta-agonists, according to a meta-analysis of 19 trials of 33,826 participants that were at least 3 months in duration and tested the effects of LABAs in patients with asthma (early-release article scheduled for print on June 20; pp. 904-12). “Long-acting beta-agonists increased exacerbations requiring hospitalization (OR, 2.6 [95% CI, 1.6 to 4.3]) and life-threatening exacerbations (OR, 1.8 [CI, 1.1 to 2.9]) compared with placebo,” the authors report. “Hospitalizations were statistically significantly increased with salmeterol (OR, 1.7 [CI, 1.1 to 2.7]) and formoterol (OR, 3.2 [CI, 1.7 to 6.0]) and in children (OR, 3.9 [CI, 1.7 to 8.8]) and adults (OR, 2.0 [CI, 1.1 to 3.9]). The absolute increase in hospitalization was 0.7% (CI, 0.1% to 1.3%) over 6 months. The risk for asthma-related deaths was increased (OR, 3.5 [CI, 1.3 to 9.3]), with a pooled risk difference of 0.07% (CI, 0.01% to 0.1%).” (S. R. Salpeter, salpeter@stanford.edu)
An editorialist notes how clinicians can use this information both now and in the future (pp. 936-7): “Although asthma treatment options have expanded, all of them have some risks, including the risk of not controlling asthma in a particular patient. With respect to LABAs, Salpeter and colleagues were not able to completely address the potential contribution of disease severity, co-treatments, adherence, and race to serious adverse outcomes. The report does, however, underscore the fact that LABAs are powerful and complex medications that we must use with care even as we await additional information to help us refine the decision to use them. Physicians must be alert to factors (for example, race) that may predict an unfavorable reaction to LABAs, carefully monitor patients receiving these drugs, and act promptly when patients do not respond favorably. Therapeutic decisions increasingly require tailoring therapy to individual needs and, some day perhaps, to pharmacogenomic profiles.” (J. Glassroth,
jeff.glassroth@tufts.edu)
Coffee, Napping, & Nighttime Driving: Driving impairment was reduced by either drinking coffee or napping, according to a study of 12 young men conducted in a sleep laboratory and on the open highway (pp. 785-91). Participants in the crossover study drank one-half cup of coffee containing caffeine 200 mg, drank decaffeinated coffee containing caffeine 15 mg, or slept for 30 minutes at 1 am. Evening driving periods without interventions and nighttime test periods showed the following: “Nighttime driving performance was similar to daytime performance (0 to 1 line crossing) for 75% of participants after coffee (0 or 1 line crossing), for 66% after the nap (P = 0.66 vs. coffee), and for only 13% after placebo (P = 0.041 vs. nap; P = 0.014 vs. coffee). The incidence rate ratios for having a line crossing after placebo were 3.7 (95% CI, 1.2 to 11.0; P = 0.001) compared with coffee and 2.9 (CI, 1.7 to 5.1; P = 0.021) compared with nap. A statistically significant interindividual variability was observed in response to sleep deprivation and countermeasures. Sleep latencies and efficiency during sleep after nighttime driving were similar in the 3 conditions.” (P. Philip, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France; pierrephilip@compuserve.com)

>>>PNN NewsWatch
* FDA yesterday approved an application for resumed marketing of natalizumab (Tysabri— Biogen Idec; Elan) subject to a special restricted distribution program. To decrease the possibility of patients developing progressive multifocal leukoencephalopathy, while also making natalizumab available to appropriate patients with multiple sclerosis, Biogen-Idec submitted and FDA approved a risk management plan, the TOUCH Prescribing Program, that restricts distribution of the drug and requires patients on natalizumab to be evaluated at 3 and 6 months after the first infusion and every 6 months after that, and their status reported regularly to Biogen Idec. Information on the TOUCH Prescribing Program is available from the companies by calling 1-800-456-2255.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, 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, 2006 Vol. 13, No. 109
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Early-release articles from JAMA (www.jama.com; 2006; 295).
SERMs & Breast Cancer Risk: In a comparison of selective estrogen receptor modulators, the second-generation agent raloxifene was as effective as tamoxifen for reducing the risk of invasive breast cancer, and it produced significantly fewer thromboembolic events and cataracts (doi: 10.1001/jama.295.23.joc60074). The risks of other cancers, fractures, ischemic heart disease, and stroke was similar for the two drugs among the 19,747 participants in the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) trial, but investigators did note a nonsignificant elevation in the risk noninvasive breast cancer with raloxifene, compared with tamoxifen. Preliminary results of the STAR trial were released earlier by the National Cancer Institute, sponsor of the study (see PNN, Apr. 18).
Specific results reported for the 6 years of monitoring include these: “There were 163 cases of invasive breast cancer in women assigned to tamoxifen and 168 in those assigned to raloxifene (incidence, 4.30 per 1000 vs 4.41 per 1,000; risk ratio [RR], 1.02; 95% confidence interval [CI], 0.82-1.28). There were fewer cases of noninvasive breast cancer in the tamoxifen group (57 cases) than in the raloxifene group (80 cases) (incidence, 1.51 vs 2.11 per 1,000; RR, 1.40; 95% CI, 0.98-2.00). There were 36 cases of uterine cancer with tamoxifen and 23 with raloxifene (RR, 0.62; 95% CI, 0.35-1.08). No differences were found for other invasive cancer sites, for ischemic heart disease events, or for stroke. Thromboembolic events occurred less often in the raloxifene group (RR, 0.70; 95% CI, 0.54-0.91). The number of osteoporotic fractures in the groups was similar. There were fewer cataracts (RR, 0.79; 95% CI, 0.68-0.92) and cataract surgeries (RR, 0.82; 95% CI, 0.68-0.99) in the women taking raloxifene. There was no difference in the total number of deaths (101 vs 96 for tamoxifen vs raloxifene) or in causes of death.” (V. G. Vogel, Magee-Womens Hosp., U. Pittsburgh, Pittsburgh;
vvogel@magee.edu)
A second article analyzes STAR data with respect to patient-reported symptoms and health-related quality of life, concluding that those in the tamoxifen reported better sexual function but more gynecological problems, vasomotor symptoms, leg cramps, and bladder control problems (doi: 10.1001/jama.295.23.joc60075). Women in the raloxifene group reported more musculoskeletal problems, dyspareunia, and weight gain, as reflected in these results: “Among women in the QOL analysis, mean [physical, mental, and depression] scores worsened modestly over the study’s 60 months, with no significant difference between the tamoxifen (n = 973) and raloxifene (n = 1,010) groups (P > .2). Sexual function was slightly better for participants assigned to tamoxifen (age-adjusted repeated measure odds ratio, 1.22%; 95% CI, 1.01-1.46). Of the women in the symptom assessment analyses, the 9,769 in the raloxifene group reported greater mean symptom severity over 60 months of assessments than the 9,743 in the tamoxifen group for musculoskeletal problems (1.15 vs 1.10, P = .002), dyspareunia (0.78 vs 0.68, P < .001), and weight gain (0.82 vs 0.76, P < .001). Women in the tamoxifen group reported greater mean symptom severity for gynecological problems (0.29 vs 0.19, P < .001), vasomotor symptoms (0.96 vs 0.85, P < .001), leg cramps (1.10 vs 0.91, P < .001), and bladder control symptoms (0.88 vs 0.73, P < .001).” (S. R. Land,
land@pitt.edu)
Editorialists laud both STAR drugs but worry about the study’s impact (doi:10.1001/jama.295.23.jed60037): “The breast cancer chemoprevention sky now includes 2 shining STARs—tamoxifen and raloxifene. Although neither is a supernova, their benefits include prevention of breast cancer in postmenopausal women at increased risk and, in the case of raloxifene, reduction of fractures related to osteoporosis. Perhaps because the clear benefits are limited to these end points, the relatively modest adverse event profiles and minimally impaired quality of life experienced by these women still may not be enough to convince primary care physicians to be more aggressive than they have been to date in breast cancer chemoprevention. Time will tell.” (W. J. Gradishar,
w-gradishar@northwestern.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 © 2006, 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, 2006 Vol. 13, No. 110
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
June 8 issue of the New England Journal of Medicine (content.nejm.org; 2006; 354).
ACE Inhibitors & Congenital Malformations: ACE inhibitors, already contraindicated in the second and third trimesters of pregnancy, produce congenital malformations during the first trimester, according to a cohort study of the Tennessee Medicaid database (pp. 2443-51). From 29,507 infants born between 1985 and 2000, investigators identified 209 infants with exposure to ACE inhibitors in the first trimester alone and 202 infants with first-trimester exposure to other antihypertensive medications. The authors report: “Infants with only first-trimester exposure to ACE inhibitors had an increased risk of major congenital malformations (risk ratio, 2.71; 95 percent confidence interval, 1.72 to 4.27) as compared with infants who had no exposure to antihypertensive medications. In contrast, fetal exposure to other antihypertensive medications during only the first trimester did not confer an increased risk (risk ratio, 0.66; 95 percent confidence interval, 0.25 to 1.75). Infants exposed to ACE inhibitors were at increased risk for malformations of the cardiovascular system (risk ratio, 3.72; 95 percent confidence interval, 1.89 to 7.30) and the central nervous system (risk ratio, 4.39; 95 percent confidence interval, 1.37 to 14.02).” Malformations found in the study included atrial and ventricular septal defects, patent ductus arteriosus, spina bifida, microcephaly, and renal dysplasia. (W. O. Cooper, william.cooper@vanderbilt.edu)
An editorialist describes the quandary that these data create for women who are pregnant with a baby that has been exposed to these drugs (pp. 2498-500): “Further study is needed to determine the precise risk and its relationship to individual drugs, but the increase appears to be great enough to require discussion with all women of reproductive age who are prescribed ACE inhibitors. Detailed fetal ultrasonography and echocardiography at about 18 weeks of gestation should be offered to women who have taken such drugs during the first trimester of pregnancy. A woman who learns that she is pregnant while taking an ACE inhibitor should immediately be switched to another antihypertensive agent to minimize the risk of fetopathy. If we knew that a particular ACE inhibitor posed a teratogenic risk and that other effective antihypertensive agents did not, physicians could avoid the use of the potentially teratogenic drug in women of reproductive age, and especially in those who were planning to become pregnant. Unfortunately, however, insufficient data are available to determine the teratogenic risk for 39 of the 47 other oral antihypertensive drugs listed in the ‘Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.’ Therapeutic doses of eight drugs (chlorothiazide, chlorthalidone, hydrochlorothiazide, atenolol, acebutolol, pindolol, nifedipine, and reserpine) are considered unlikely to pose a substantial teratogenic risk, but each drug raises concerns of other kinds. Moreover, the data available on teratogenicity are no better than fair for any of these agents.” (J. M. Friedman, U. British Columbia, Vancouver)
Azithromycin for Cholera: Single-dose azithromycin proved better than ciprofloxacin for treatment of severe cholera in adults (pp. 2452-62). Given in single doses of 1 gram, the antibiotics produced these results: “Therapy was clinically successful in 71 of 97 patients receiving azithromycin (73 percent) and in 26 of 98 patients receiving ciprofloxacin (27 percent) (P < 0.001) and bacteriologically successful in 76 of 97 patients receiving azithromycin (78 percent) and in 10 of 98 patients receiving ciprofloxacin (10 percent) (P < 0.001). Patients who were treated with azithromycin had a shorter duration of diarrhea than did patients treated with ciprofloxacin (median, 30 vs. 78 hours); a lower frequency of vomiting (43 percent vs. 67 percent); fewer stools (median, 36 vs. 52); and a lower stool volume (median, 114 vs. 322 ml per kilogram of body weight). The median minimal inhibitory concentration of ciprofloxacin for the 177 isolates of V. cholerae O1 was 0.25 µg per milliliter, which was 11 to 83 times as high as that in previous studies at this site.” (D. Saha, International Ctr. for Diarrhoeal Disease Research, Dhaka, Bangladesh; dsaha@icddrb.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 © 2006, 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 9, 2006 Vol. 13, No. 111
Providing news and information about medications and their proper use

>>>Cervical Cancer Vaccine Licensed by FDA
Merck Vaccine’s Gardasil (Quadrivalent Human Papillomavirus [Types 6, 11, 16, 18] Recombinant Vaccine) has been licensed by FDA. It is indicated for use in girls and women aged 9 to 26 years for prevention of cervical cancer; cervical precancers (cervical intraepithelial neoplasia [CIN] 2/3 and adenocarcinoma in situ [AIS]); vulvar precancers (vulvar intraepithelial neoplasia [VIN] 2/3); vaginal precancers (vaginal intraepithelial neoplasia [VaIN] 2/3) caused by HPV types 16 and 18; and genital warts and low-grade cervical lesions (CIN 1) caused by HPV types 6, 11, 16 and 18.
Efficacy and safety of Gardasil, administered in three intramuscular injections in the upper arm over a 6-month period, were studied in four Phase II and III studies and in combined analyses and measured starting after a month 7 visit. The combined analyses showed the following:
*
Cervical Cancer: Gardasil prevented 100% of HPV 16- and 18-related cervical precancers and noninvasive cervical cancers (CIN 2/3, and AIS, or adenocarcinoma in situ ). No cases occurred among 8,487 women who received Gardasil, while 53 cases were identified in 8,460 women on placebo.
*
Cervical Intraepithelial Neoplasia: Gardasil prevented 95% of low-grade cervical dysplasia (low grade lesions) and precancers (CIN 2/3 or AIS) caused by HPV 6, 11, 16 or 18. Among the 7,858 women who received Gardasil, 4 cases of CIN occurred, compared with 83 cases among 7,861 women who received placebo.
*
Genital Warts: Gardasil prevented 99% of cases of genital warts caused by HPV 6 or 11. The 7,897 women who received Gardasil had 1 case of genital warts, compared with 91 cases among 7,899 women who received placebo.
Gardasil also prevented 100% of HPV 16- and 18-related vulvar and vaginal precancers (VIN 2/3 or VaIN 2/3) in women not previously exposed to the relevant HPV types. No cases occurred among 8,641 women who received Gardasil, compared with 24 cases among 8,667 women receiving placebo.
Gardasil was generally well tolerated and few subjects (0.1%) discontinued injections because of adverse events. Vaccine-related adverse experiences observed in clinical trials at a frequency of at least 1.0% among recipients of Gardasil and also greater than those observed among recipients of placebo, respectively, were pain (83.9% vs. 75.4%), swelling (25.4% vs. 15.8%), erythema (24.6% vs. 18.4%), fever (10.3% vs. 8.6%), and pruritus (3.1% vs. 2.8%). Most injection-site reactions were reported to be mild to moderate in intensity.
Merck will conduct several studies following licensure, including additional studies to further evaluate general safety and long-term effectiveness. The company will also monitor the pregnancy outcomes of women who receive Gardasil while unknowingly pregnant. Also, Merck is conducting a study to evaluate the safety and effectiveness of Gardasil in boys and men.
Gardasil is now available from Merck at a catalogue price of $120 per dose. The CDC Advisory Committee on Immunization Practices will consider adding Gardasil to the routine pediatric immunization schedule for girls at its meeting on June 29. While the CDC panel is expected to support inclusion of the vaccine, some states may be reluctant to add it the mandatory school vaccinations list, partially because of pressure from conservative groups disturbed by the association between sexual activity and HPV transmission and their preference for abstinence-based messages to the nation’s youth.

>>>PNN NewsWatch
* FDA has requested removal from the market of a variety of unapproved products containing the antihistamine carbinoxamine. At least 120 products are involved in the market removal, as only one company has FDA approval for formulations of this agent. Mikart Inc. of Atlanta manufactures carbinoxamine tablets and oral solution that are approved for treatment of allergic reactions or their symptoms (Palgic Carbinoxamine, PamLab; Carbinox, Physicians Total Care).
* FDA will today order wholesalers to begin
tracking their pharmaceutical products, the Wall Street Journal reports. The action would take effect on Dec. 2.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, 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, 2006 Vol. 13, No. 112
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
June 10 issue of Lancet (www.thelancet.com; 2006; 367).
Anticoagulation in AF: Oral anticoagulation targeted at an INR of 2.0–3.0 was superior to clopidogrel 75 mg daily plus aspirin 75–100 mg daily for preventing vascular events among 6,706 patients with atrial fibrillation plus one or more risk factors for stroke (pp. 1903-12). Looking at a primary outcome of first occurrence of stroke, non-CNS systemic embolus, myocardial infarction, or vascular death, the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W) investigators report: “The study was stopped early because of clear evidence of superiority of oral anticoagulation therapy. There were 165 primary events in patients on oral anticoagulation therapy (annual risk 3.93%) and 234 in those on clopidogrel plus aspirin (annual risk 5.60%; relative risk 1.44 (1.18–1.76; p = 0.0003). Patients on oral anticoagulation therapy who were already receiving this treatment at study entry had a trend towards a greater reduction in vascular events (relative risk 1.50, 95% CI 1.19–1.89) and a significantly (p = 0.03 for interaction) lower risk of major bleeding with oral anticoagulation therapy (1.30; 0.94–1.79) than patients not on this treatment at study entry (1.27, 0.85–1.89 and 0.59, 0.32–1.08, respectively).” (S. J. Connolly, Hamilton Health Sciences Corp., Hamilton, Ont., Canada; connostu@phri.ca)

>>>BMJ Highlights
Source:
Early-release article from BMJ (www.bmj.org; 2006; 332).
Aggressive Cholesterol Lowering: Recent recommendations to more aggressively use statins in treating patients ignore the reality that little is known about adverse effects of the drugs at such high doses, argue authors of a commentary article (doi:10.1136/bmj.332.7553.1330). Noting that American recommendations for LDL cholesterol “could put most of the Western world’s adult population on statins,” the authors discussed results of the Treating to New Targets (TNT) trial: “Overall mortality was not reduced because the smaller number of cardiovascular deaths in the 80 mg atorvastatin group was offset by increased deaths from other causes leaving a benefit of 250 (5%) fewer non-fatal cardiovascular events. Because many non-fatal events resolve with little residual damage or discomfort, meticulous recording of all possible adverse side effects is mandatory. However, the authors have not provided adequate information on adverse events.” (U. Ravnskov, Lund, Sweden; ravnskov@tele2.se)

>>>Diabetes Meeting Underway
The 66th annual scientific sessions of the American Diabetes Association are underway in Washington, D.C. (http://scientificsessions.diabetes.org/). Here are some highlights:
* One polypill per day plus a commitment to better diabetes care could prevent many heart attacks and other events among patients with diabetes and reduce health care costs by billions, argued Robert A. Rizza, MD, ADA president for medicine and science. The polypill would contain metformin 100 mg, aspirin 75 mg, a generic statin, and a generic ACE inhibitor.
* Physicians are not intensifying therapy in patients with type 2 diabetes and hypertension or hyperglycemia, according to four reports. Craig A. Plauschinat, PharmD, MPH, of Novartis, reported a mean of 240 days from start of treatment with oral antidiabetic agents to therapy intensification among 9,416 newly diagnosed patients. During this time, mean A1C levels rose from 8.4% to 8.5%, with 67% of patients beginning with A1C levels above 9.5% and ending up with levels above 10%.

>>>PNN JournalWatch
* Serum Cholesterol, Haemorrhagic Stroke, Ischaemic Stroke, and Myocardial Infarction: Korean National Health System Prospective Cohort Study, in BMJ, 2006; doi:10.1136/bmj.38855.610324.80. Reprints: http://bmj.bmjjournals.com/cgi/content/abstract/bmj.38855.610324.80v1; J. Sung, Kangwon Natl. U., Kangwon-Do, Korea; sungjohn@kangwon.ac.kr
* Macrolide Antibiotics and Asthma Treatment, in
Journal of Allergy and Clinical Immunology, 2006; 117: 1233-6. Reprints: www.jacionline.org/article/PIIS009167490600741X/abstract; S. L. Johnston, Imperial College, London; s.johnston@imperial.ac.uk
* Are Phosphodiesterase 4 Inhibitors Just More Theophylline? in
Journal of Allergy and Clinical Immunology, 2006; 117: 1237-43. Reprints: www.jacionline.org/article/PIIS0091674906006348/abstract; C. P. Page, King’s College London; clive.page@kcl.ac.uk

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, 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, 2006 Vol. 13, No. 113
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
June 12 issue of Archives of Internal Medicine (www.archinternmed.com; 2006; 166).
Sex Differences in MI Treatment: In Michigan, rates of adherence to evidence-based medicine increased with use of the American College of Cardiology’s Acute Myocardial Infarction Guidelines Applied in Practice (GAP; http://www.acc.org/gap/gap.htm) program, but the tool was used less often in women, according to an analysis of experiences of that state’s Medicare patients (pp. 1164-70). “Use of evidence-based care, including use of beta-blockers and aspirin in men and women at hospital discharge and lipid-lowering agent use in men, was higher in the post-GAP sample (P < .01 for all),” write the investigators. “Use of the discharge tool promoted by the GAP program was independently protective against death at 1 year in women (adjusted odds ratio, 0.46; 95% confidence interval, 0.27-0.79), and a trend existed for similar results in men (adjusted odds ratio, 0.62; 95% confidence interval, 0.36-1.06). However, the tool was used slightly less often with women (27.9% vs 33.96%; P=.003).” (K. A. Eagle, keagle@umich.edu)
Exogenous Insulin & Hypertension: Patients with type 2 diabetes who use insulin are at higher risk for development of hypertension, conclude authors who studied 87,850 Taiwanese (pp. 1184-9). Using national health insurance records, the researchers found: “There were 5,927 insulin users, who were characterized by being 1 year older in age, female preponderance, longer duration of diabetes, slightly lower body mass index, and less smoking but higher prevalence of hypertension with higher blood pressure. After adjustment for age, sex, body mass index, duration of diabetes, smoking, and parental hypertension, the odds ratios (95% confidence interval [CI]) for hypertension for patients using insulin for less than 5 years, 5 to 9 years, and 10 years or more were 1.14 (95% CI, 1.06-1.23), 1.35 (95% CI, 1.18-1.54), and 1.46 (95% CI, 1.24-1.74), respectively, compared with nonusers. In insulin users who did not have hypertension at the start of insulin use, the respective odds ratios for those using insulin for 5 to 9 years and 10 years or more were 1.5 (95% CI, 1.25-1.80) and 2.15 (95% CI, 1.72-2.70), respectively, compared with those using insulin for less than 5 years.” (C-H Tseng, National Taiwan U. Hosp., Taipei, Taiwan; ccktsh@ms6.hinet.net)
Cost-Effectiveness of Osteoporosis Treatments: Alendronate treatment of severe osteoporosis was cost-effective, with a cost of $11,600 per quality-adjusted life-year, in an analysis conducted from the societal perspective (pp. 1209-17). Noting that the cost of sequential teriparatide/alendronate therapy was $156,500 per QALY, compared with usual care, the investigators conclude, “Therapy with teriparatide alone is more expensive and produces a smaller increase in QALYs than therapy with alendronate. Sequential teriparatide/alendronate therapy appears expensive but could become more cost-effective with reductions in teriparatide price, with restriction to use in exceptionally high-risk women, or if short courses of treatment have comparable efficacy to that observed in clinical trials.” (H. Liu, hauliu@stanford.edu)

>>>Diabetes Meeting Update
The 66th annual scientific sessions of the American Diabetes Association (http://scientificsessions.diabetes.org/) close today in Washington, D.C. Here are highlights of Monday’s presentations:
* In a study of 7,061 men and women in Sweden, three genes increased the future risk of developing type 2 diabetes: the T-alleles of both
TCF7L2 rs1255372 (OR, 1.40) and rs7903146 (OR, 1.52); KCNJ11 K-allele (OR, 1.23); and PPARG PP-genotype (OR, 1.20).
* Depression followed diabetes, rather than the opposite, in a study of 443 adults conducted by Lawrence S. Phillips, MD, of Emory U., Atlanta. Awareness of the health risks of diabetes may contribute to depression, and the presenter recommended that newly diagnosed patients with diabetes be counseled and monitored for depression.
* Hyperglycemia was an independent predictor of mortality in a study of 216,000 critically ill patients conducted by the VA Inpatient Evaluation Ctr. Mortality rates varied with patient disease, with some risks elevated 15-fold.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, 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, 2006 Vol. 13, No. 114
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
June 14 issue of JAMA (www.jama.com; 2006; 295)
Fluoxetine, Weight, & Anorexia Nervosa: Following weight restoration in 93 patients with anorexia nervosa, fluoxetine failed to delay time to relapse (pp. 2605-12). Patients had received intensive therapy as inpatients or day-program patients at psychiatric facilities, enabling them to regain weight to a body mass index of 19.0, after which they randomly received fluoxetine or placebo for 1 year along with cognitive behavioral therapy. Results showed the following: “Similar percentages of patients assigned to fluoxetine and to placebo maintained a body mass index of at least 18.5 and remained in the study for 52 weeks (fluoxetine, 26.5%; placebo, 31.5%; P = .57). In a Cox proportional hazards analysis, with prerandomization body mass index, site, and diagnostic subtype as covariates, there was no significant difference between fluoxetine and placebo in time-to-relapse (hazard ratio, 1.12; 95% CI, 0.65-2.01; P = .64).” (B. T. Walsh, btw1@columbia.edu)
An editorialist describes these findings as “important but disappointing” (pp. 2659-60): “The study by Walsh et al is an important contribution that addresses a major gap in research on anorexia nervosa and provides vital information about a fairly common treatment practice for this illness. Unfortunately, it appears that fluoxetine provides no benefit in the relapse prevention treatment of anorexia nervosa. Despite a prevalence rate similar to many other psychiatric illnesses, and particularly in light of the high mortality associated with anorexia nervosa, there is a serious underrepresentation of anorexia nervosa in biomedical research. Much more information is needed on the treatment of individuals with anorexia nervosa while they are at low weight. In addition, strategies must be developed to help individuals who recover to stay in recovery.” (S. J. Crow,
crowx002@umn.edu)
Fish Oil & Ventricular Arrhythmias: Very-long-chain n-3 polyunsaturated fatty acids, or omega-3 PUFAs, failed to protect against ventricular tachyarrhythmias among 546 patients with implantable cardioverter defibrillators (pp. 2613-9). In the Study on Omega-3 Fatty Acids and Ventricular Arrhythmia (SOFA) trial, participants at 26 European cardiology clinics were recruited if they had ICDs plus prior documented malignant ventricular tachycardia or ventricular fibrillation. They received fish oil 2 grams/day or placebo for a median period of 356 days, with these results: “The primary end point occurred in 81 (30%) patients taking fish oil vs 90 (33%) patients taking placebo (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.64-1.16; P = .33). In prespecified subgroup analyses, the HR was 0.91 (95% CI, 0.66-1.26) for fish oil vs placebo in the 411 patients who had experienced VT in the year before the study, and 0.76 (95% CI, 0.52-1.11) for 332 patients with prior myocardial infarctions.” (I. A. Brouwer, Wageningen Ctr. for Food Sciences, Wageningen, the Netherlands; ingeborg.brouwer@wur.nl)

>>>PNN NewsWatch
* The APhA Foundation’s 9th annual Pinnacle Awards were presented last night in Washington, D.C. Honored in the individual category for his clinical research in cardiovascular therapeutics and antithrombotic therapy was Henry I. Bussey Jr., PharmD, of the University of Texas at Austin and the ClotCare Online Resource. His work was instrumental in adoption of the international normalized ratio (INR) for warfarin monitoring. Kerr Drug, Inc. Clinical Services, Raleigh, N.C., received a Pinnacle Award in the Group Practice/Health System/Corporation category. The chain’s services—including weight-management clinics and other in-pharmacy medication therapy management efforts—have redefined community pharmacy practice and improved patient care, presenters noted. In the Government Agencies/Nonprofit Organizations category, KatrinaHealth.org was honored. This consortium of agencies and companies, including SureScripts and Informed Decisions LLC, responded in the wake of Hurricane Katrina to set up computer systems that enabled clinicians and pharmacists to access patients’ medication histories so that the correct prescription medications could be continued in those displaced by the storm.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, 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, 2006 Vol. 13, No. 115
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
June 15 issue of the New England Journal of Medicine (content.nejm.org; 2006; 354).
Circumventing Kinase-Inhibitor Resistance in Leukemias: Two articles and an editorial present new information and ideas on treatment of imatinib-resistant Philadelphia chromosome–positive leukemias and imatinib-resistant chronic myelogenous leukemia.
Dasatinib, an ABL tyrosine kinase inhibitor being developed by Bristol-Myers Squibb, induced hematologic and cytogenetic responses in patients with CML or Ph-positive ALL who could not tolerate or were resistant to imatinib, report authors who conducted a Phase I dose-escalation study (pp. 2531-41). Using oral doses of 15 to 240 mg/day in 4-week treatment cycles of dasatinib, the investigators found: “A complete hematologic response was achieved in 37 of 40 patients with chronic-phase CML, and major hematologic responses were seen in 31 of 44 patients with accelerated-phase CML, CML with blast crisis, or Ph-positive ALL. In these two phases, the rates of major cytogenetic response were 45 percent and 25 percent, respectively. Responses were maintained in 95 percent of patients with chronic-phase disease and in 82 percent of patients with accelerated-phase disease, with a median follow-up more than 12 months and 5 months, respectively. Nearly all patients with lymphoid blast crisis and Ph-positive ALL had a relapse within six months. Responses occurred among all BCR-ABL genotypes, with the exception of the T315I mutation, which confers resistance to both dasatinib and imatinib in vitro. Myelosuppression was common but not dose-limiting.” (C. L. Sawyers,
csawyers@mednet.ucla.edu)
A BCR-ABL tyrosine kinase inhibitor, nilotinib (AMN107, Novartis), showed activity and was safe in a Phase I dose-escalation study of 119 patients with imatinib-resistant CML or ALL (pp. 2542-51). Drug doses of 50–1,200 mg once daily or 400 or 600 mg twice daily produced these results: “Common adverse events were myelosuppression, transient indirect hyperbilirubinemia, and rashes. Of 33 patients with the blastic phase of disease, 13 had a hematologic response and 9 had a cytogenetic response; of 46 patients with the accelerated phase, 33 had a hematologic response and 22 had a cytogenetic response; 11 of 12 patients with the chronic phase had a complete hematologic remission.” (H. Kantarjian,
hkantarj@mdanderson.org)
Noting that treatment of CML “has set precedents for cancer research and therapy,” an editorialist writes about the impact of these two studies on ways of circumventing resistance to kinase-inhibitor therapy (pp. 2594-6): “It would be logical to ask why two large pharmaceutical companies would have an interest in a disease that affects fewer than 5,000 patients per year in the United States—and one in which drug resistance is relatively uncommon. One reason is that imatinib had gross sales of $2.1 billion in 2004. Although this volume of sales is not entirely attributable to its use in CML, it does mean that CML therapy is an attractive market. An encouraging thought is that some large pharmaceutical companies recognize the power of genomic medicine. They have an interest in testing a drug in a small, molecularly defined population, such as patients with imatinib-resistant CML. By limiting testing to a population with a high probability of having a response to therapy, the company reduces the risk of drug failure, and the number of patients who are required to demonstrate clinical activity of the drug can be relatively small. These two factors minimize the costs of drug development, could lead to rapid approval by the Food and Drug Administration, and might result in decreased drug costs.” (B. J. Druker, Oregon Health and Sci. U. Cancer Inst., Portland)
Insulin Resistance: The role of the adipocyte product retinol-binding protein 4 is explored in a research article (pp. 2552-63; B. B. Kahn, bkahn@bidmc.harvard.edu), and an editorialist responds (pp. 2596-8): “[This] study ... should prompt investigations to ... define the biologic action of RBP4 in relation to insulin resistance and diabetes. Whatever the outcome of these investigations, it will take new approaches such as those used by Graham et al. to identify unanticipated mechanisms underlying type 2 diabetes and to identify better treatments for this disease.” (K. S. Polonsky, Washington U., St. Louis)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, 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 16, 2006 Vol. 13, No. 116
Providing news and information about medications and their proper use

>>>Rheumatology Update
Source:
June issue of Arthritis & Rheumatism (www3.interscience.wiley.com/cgi-bin/jhome/76509746; 2006; 54).
IV Ibandronate for Osteoporosis: Intravenous doses of ibandronate 2 mg every 2 months or 3 mg every 3 months proved at least as effective as daily oral doses of 2.5 mg, according to a 1- year study of bone mineral density in 1,395 women who were at least 5 years postmenopausal (pp. 1838-46). All participants had lumbar spine BMDs of less than –2.5, and all took daily calcium 500 mg and vitamin D 400 IU. Results showed: “At 1 year, mean lumbar spine BMD increases were as follows: 5.1% among 353 patients receiving 2 mg of ibandronate every 2 months, 4.8% among 365 patients receiving 3 mg of ibandronate every 3 months, and 3.8% among 377 patients receiving 2.5 mg of oral ibandronate daily. Both of the intravenous regimens not only were noninferior, but also were superior (P < 0.001) to the oral regimen. Hip BMD increases (at all sites) were also greater in the groups receiving medication intravenously than in the group receiving ibandronate orally. Robust decreases in the serum CTX level were observed in all arms of the study. Both of the intravenous regimens were well tolerated and did not compromise renal function.” (P. D. Delmas, Hôpital Edouard Herriot, Lyon, France; delmas@lyon.inserm.fr)
Fentanyl for Osteoarthritic Pain: Transdermal fentanyl reduced pain and improved function among a group of 399 patients with radiographically confirmed osteoarthritis of the hip or knee, 199 of whom completed this study (pp. 1829-37). Following a 1-week pretreatment run-in phase, participants received either TDF or placebo for 6 weeks. Prescribed NSAIDs and nonopioid analgesics were continued, and investigators observed these results: “TDF provided significantly better pain relief than placebo, as demonstrated by the primary outcome measure (area under the curve for VAS scores –20 in the TDF group versus –14.6 in the placebo group; P = 0.007). TDF was also associated with significantly better overall WOMAC scores and pain scores. The most common adverse events were nausea, vomiting, and somnolence, and these occurred more often in the TDF group.” (U. Richarz, Janssen-Cilag, Baar, Switzerland; urichar1@jacch.jnj.com)

>>>PNN NewsWatch
* FDA and the Institute for Safe Medication Practices have launched a national educational campaign focused on eliminating the use of potentially confusing abbreviations by health care professionals, medical students, medical writers, the pharmaceutical industry, and FDA staff. The campaign will address the use of mistake-prone abbreviations in all forms of medical communication, including written medication orders, computer-generated labels, medication administration records, pharmacy or prescriber computer order entry screens and commercial medication labeling, packaging, and advertising. ISMP’s list of problematic abbreviations, symbols, and dose designations can be accessed at www.ismp.org/PDF/ErrorProne.pdf.
* The combination of
topotecan (Hycamtin, GlaxoSmithKline) and cisplatin has been approved by FDA for use in women with Stage IVB (incurable), recurrent, or persistent metastatic cancer of the cervix that is not likely to respond to treatment with surgery or radiation. at surgery or radiation therapy are unlikely to be effective. The approval, which followed a 6-month priority review at FDA, was based on a randomized multicenter trial that showed a survival advantage of the combination over cisplatin alone. Median survival for topotecan plus cisplatin was 9.4 months, compared with 6.5 months for cisplatin alone. The most common dose-limiting toxicity of the combination was myelosuppression. Major hematologic adverse events (Grade 3 and 4) were more frequent in the combination arm than in the single-agent arm and included neutropenia (74% versus 2%), thrombocytopenia (33% versus 3%), Infection-febrile neutropenia (19% versus 8%), respectively. The most common nonhematologic adverse events reported were constitutional (fatigue, fever, rigors, chills, sweating, weight gain or loss), gastrointestinal, pain and metabolic toxicities.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, 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, 2006 Vol. 13, No. 117
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release article from BMJ (www.bmj.org; 2006; 332).
Metformin in Polycystic Ovary Syndrome: In a trial of 228 women with polycystic ovary syndrome conducted at 20 Dutch hospitals, addition of metformin to clomiphene citrate therapy failed to improve the induction of ovulation (doi: 10.1136/bmj.38867.631551.55). “111 women were allocated to clomifene citrate plus metformin (metformin group) and 114 women were allocated to clomifene citrate plus placebo (placebo group),” the authors report. “The ovulation rate in the metformin group was 64% compared with 72% in the placebo group, a non-significant difference (risk difference –8%, 95% confidence interval –20% to 4%). There were no significant differences in either rate of ongoing pregnancy (40% v 46%; –6%, –20% to 7%) or rate of spontaneous abortion (12% v 11%; 1%, –7% to 10%). A significantly larger proportion of women in the metformin group discontinued treatment because of side effects (16% v 5%; 11%, 5% to 16%).” (E. Moll, Academic Med. Ctr., Amsterdam; e.moll@amc.uva.nl)

>>>Lancet Highlights
Source:
Early-release articles from Lancet (www.thelancet.com; 2006; 367).
Nitazoxanide for Rotavirus Diarrhea: A 3-day course of the broad-spectrum anti-infective agent nitazoxanide significantly reduced the duration of severe rotavirus diarrhea among 38 children hospitalized at the Cairo U. Children’s Hosp. (doi: 10.1016/S0140-6736(06)68852-1). Study participants, with a median age of 11 months, randomly received either nitazoxanide 7.5 mg/kg as an oral suspension or placebo twice daily for 3 days and remained hospitalized for 7 days after treatment began. Results showed: “Survival analysis showed that the median time to resolution of illness was 31 h ([interquartile range] 22–73) for the nitazoxanide-treated group compared with 75 h (51–124) for the placebo group (p = 0·0137). No significant adverse events were reported.” (J-F Rossignol, Romark Inst. for Medical Res., Tampa, Fla.; jrossignol@romark.com)
Rotavirus Vaccine: Prospects for new rotavirus vaccines “to achieve their full effect” in preventing deaths of children in developing countries are reviewed (doi: 10.1016/S0140-6736(06)68815-6): “A new generation of rotavirus vaccines will soon be licensed in many countries and available for more widespread use. Early introduction into the private markets of these countries could lead to appreciable reductions in health-care costs and burden of disease within 2–4 years. Identifying the full value of these vaccines to prevent mortality from rotavirus in developing countries is still several years away and each of the vaccines must first show its effectiveness in poor populations in Africa and Asia. Further studies are also needed to prove the cost-effectiveness of rotavirus vaccination in prevention of overall childhood mortality compared with other health interventions. Although many hurdles remain to ascertain the effectiveness of these vaccines in key target populations and their affordability, and to remove lingering concerns about safety from intussusception, the presence of two candidate vaccines provides an important new instrument to decrease the morbidity and mortality associated with rotavirus diarrhoea.” (R. I. Glass, Rglass@cdc.gov)

>>>PNN JournalWatch
* Gene Therapy for Arthritis: What Next? in Arthritis & Rheumatism, 2006; 54: 1714-29. Reprints: www3.interscience.wiley.com/cgi-bin/abstract/112636775/ABSTRACT; C. H. Evans, Ctr. for Molecular Orthopaedics, Boston; cevans@rics.bwh.harvard.edu
* ACC/AHA 2006 Guideline Update on Perioperative Cardiovascular Evaluation for Noncardiac Surgery: Focused Update on Perioperative Beta-Blocker Therapy in
Journal of the American College of Cardiology, 2006; 47: 2343-55. Reprints: http://content.onlinejacc.org/cgi/content/full/47/11/2343; American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
* Single-Gene Mutations and Increased Left Ventricular Wall Thickness in the Community: The Framingham Heart Study, in
Circulation, 2006; 113: 2697-705. Reprints: http://circ.ahajournals.org/cgi/content/abstract/113/23/2697; J. Seidman, seidman@genetics.med.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 © 2006, 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, 2006 Vol. 13, No. 118
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
June 20 issue of the Annals of Internal Medicine (www.annals.org; 2006; 144).
Abatacept for RA: Once-monthly infusion of abatacept 10 mg/kg was a useful addition to therapy in 652 patients with methotrexate-refractory rheumatoid arthritis, according to researchers who conducted a 1-year study (pp. 865-76). In the Abatacept in Inadequate Responders to Methotrexate (AIM) trial, co-primary end points were a 20% improvement in American College of Rheumatology (ACR) response criteria at 6 months, clinically meaningful improvements in physical function, and change from baseline in joint erosion score at 1 year. The authors report: “In a modified intention-to-treat analysis, 6-month ACR 20, ACR 50, and ACR 70 responses were 67.9% for abatacept versus 39.7% for placebo (difference, 28.2 percentage points [95% CI, 19.8 to 36.7 percentage points]), 39.9% for abatacept versus 16.8% for placebo (difference, 23.0 percentage points [CI, 15.0 to 31.1 percentage points]), and 19.8% for abatacept versus 6.5% for placebo (difference, 13.3 percentage points [CI, 7.0 to 19.5 percentage points]), respectively. At 1 year, the responses increased to 73.1% for abatacept versus 39.7% for placebo (difference, 33.4 percentage points [CI, 25.1 to 41.7 percentage points]), 48.3% for abatacept versus 18.2% for placebo (difference, 30.1 percentage points [CI, 21.8 to 38.5 percentage points]), and 28.8% for abatacept versus 6.1% for placebo (difference, 22.7 percentage points [CI, 15.6 to 29.8 percentage points]), respectively (P < 0.001 for all). Physical function significantly improved in 63.7% versus 39.3% of patients (P < 0.001). At 1 year, abatacept statistically significantly slowed the progression of structural joint damage compared with placebo. Abatacept-treated patients had a similar incidence of adverse events (87.3% vs. 84.0%; difference, 3.3 percentage points [CI, –2.5 to 9.1 percentage points]) and a higher incidence of prespecified serious infections (2.5% vs. 0.9%; difference, 1.6 percentage points [CI, –0.3 to 3.6 percentage points]) and infusion reactions (acute, 8.8% vs. 4.1%; difference, 4.7 percentage points [CI, 0.9 to 8.4 percentage points]; peri-infusional, 24.5% vs. 16.9%; difference, 7.6 percentage points [CI, 1.2 to 14.0 percentage points]) compared with placebo recipients.” (J. M. Kremer, Ctr. for Rheumatology, Albany, N.Y.; jkremer@joint-docs.com)
An editorialist notes that the bottom line on this study “is a mixed message” (pp. 933-5): “Abatacept has intrinsic activity in patients with RA whose methotrexate and TNF inhibitor therapies have failed. This result is important because we have too few effective antirheumatic drugs. However, we don’t know how well abatacept will do in practice compared with other alternatives, such as combinations of traditional disease-modifying antirheumatic drugs that include glucocorticoids.” (M. Boers, VU University Med. Ctr., Amsterdam, the Netherlands)

>>>PNN NewsWatch
* Triaminic Vapor Patch products are being recalled by Novartis Consumer Health because of serious adverse events associated with accidental ingestion by children. The products—which contain camphor, eucalyptus oil, and menthol and are indicated for cough suppression in children older than 2 years of age—can produce symptoms ranging from minor (burning in the mouth, headache, nausea, vomiting) to severe or life-threatening (seizures) when chewed.
* A total of 2.4 million Americans aged 12 or older initiated
nonmedical use of prescription analgesics within the year before a 2004 survey, the Substance Abuse & Mental Health Services Administration announced yesterday. About 615,000 persons began nonmedical use of OxyContin, and 99.1% of them had used other drugs illicitly before beginning nonmedical use of Rx analgesics, SAMHSA noted. The most popular drugs for nonmedical use were Vicodin, Lortab, or Lorcet, which were used by 48% of those initiating nonmedical use; 34.3% had used Darvocet, Darvon, or Tylenol with codeine nonmedically; and 20.0% had used Percocet, Percodan, or Tylox nonmedically.
*
Correction: In the bold-face lead-in to the ibandronate item in Friday’s PNN, osteoarthritis should have been osteoporosis.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, 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, 2006 Vol. 13, No. 119
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
June 21 issue of JAMA (www.jama.com; 2006; 295).
Statins & Cataracts: Patients in an observational, longitudinal, population-based study who were using statins had lower risks of nuclear cataracts, the most common type of these age-related lens problems (pp. 2752-8). Attributing this benefit of statins to their putative antioxidant properties, investigators in the Beaver Dam (Wis.) Eye Study noted these results for the 1,299 study participants who were deemed at risk for cataract development: “A total of 210 persons developed incident nuclear cataract in the interval from 1998–2000 to 2003–2005. Five-year incidence of nuclear cataract was 12.2% in statin users compared with 17.2% in nonusers (odds ratio [OR], 0.55; 95% confidence interval [CI], 0.36–0.84), controlling for age. When only never smokers without diabetes were assessed, the age-, lipid level–, and sex-adjusted OR was 0.40 (95% CI, 0.18–0.90). Five-year incidence of cortical cataract was 9.9% in statin users and 7.5% in nonusers (OR, 1.28; 95% CI, 0.79–2.08); posterior subcapsular cataract occurred in 3.0% of statin users and 3.4% of nonusers (OR, 0.82; 95% CI, 0.39–1.71).” (B. E. K. Klein, kleinb@epi.ophth.wisc.edu)
SERMs & Breast Cancer Risk: Results from the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) trial, released early by JAMA (see PNN, June 7, Apr. 18), are published in two articles (pp. 2727-41, V. G. Vogel, U. Pittsburgh, Pittsburgh, vvogel@magee.edu; pp. 2742-51, S. R. Land, land@pitt.edu) in this issue along with an accompanying editorial (pp. 2784-6, W. J. Gradishar, w-gradishar@northwestern.edu).
Prophylaxis for Contrast-Induced Nephropathy: Poor understanding of the pathophysiology and the clinical significance of contrast-induced nephropathy has limited development of an effective prophylactic strategy, conclude authors of a Clinician’s Corner review article (pp. 2765-79). Adding that “future research should focus on correctly identifying higher-risk patients and testing therapies in the setting of large well-powered clinical trials,” the writers provide this evidence from the literature: “Important patient-related risk factors for contrast-induced nephropathy include chronic kidney disease, diabetes mellitus, heart failure, older age, anemia, and left ventricular systolic dysfunction. Non–patient-related risk factors include high-osmolar contrast, ionic contrast, contrast viscosity, and contrast volume. Practice guidelines recommend obtaining preprocedural serum creatinine levels among patients with renal disease, diabetes, proteinuria, hypertension, gout, or congestive heart failure. Available evidence, largely based on small- to medium-sized trials, supports the use of hydration, bicarbonate, and low volumes of iso- or low-osmolar contrast in patients at risk. N-acetylcysteine or ascorbic acid may be of value in very high-risk patients.” (N. Pannu, npannu@ualberta.ca)
Clinical Trial Participation & Physician Prescribing Patterns: Physicians who participate in clinical trials sponsored by pharmaceutical companies continue to adhere to international treatment guidelines but also prescribe more of the trial sponsor’s drugs, according to an observational cohort study conducted in Funen County, Denmark (pp. 2759-64). Comparing prescribing for 5,439 patients seen at 10 participating practices with 59,574 at 165 uninvolved practices, the investigators report these results: “The baseline proportion of asthma patients using inhaled corticosteroids was 68.5% in trial-conducting and 69.1% in control practices. Conducting the trial did not influence guideline adherence (odds ratio [OR] after 2 years, 1.00; 95% confidence interval [CI], 0.84–1.19). In trial-conducting practices, the sponsoring company’s share of the total prescribed volume of asthma drugs increased compared with control practices (6.7%; 95% CI, 3.0%–11.7%). This could be attributed to a significantly higher preference for the company’s inhaled corticosteroids (OR, 1.26; 95% CI, 1.04–1.54) and trends toward increased prescribing of the company’s other asthma drugs.” (M. Andersen, U. Southern Denmark, Odense, Denmark; mandersen@health.sdu.dk)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, 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, 2006 Vol. 13, No. 120
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
June 22 issue of the New England Journal of Medicine (content.nejm.org; 2006; 354).
Condom Use & HPV Infection: During a mean follow-up period of 33.9 months, transmission of human papillomavirus was significantly lowered by consistent condom use among a group of 82 university women (pp. 2645-54).These students had their first vaginal intercourse with a male partner during the study or shortly before enrollment, and the researchers report the following based on electronic diaries and analysis of cervical and vulvovaginal samples: “The incidence of genital HPV infection was 37.8 per 100 patient-years at risk among women whose partners used condoms for all instances of intercourse during the eight months before testing, as compared with 89.3 per 100 patient-years at risk in women whose partners used condoms less than 5 percent of the time (adjusted hazard ratio, 0.3; 95 percent confidence interval, 0.1 to 0.6, adjusted for the number of new partners and the number of previous partners of the male partner). Similar associations were observed when the analysis was restricted to high-risk and low-risk types of HPV and HPV types 6, 11, 16, and 18. In women reporting 100 percent condom use by their partners, no cervical squamous intraepithelial lesions were detected in 32 patient-years at risk, whereas 14 incident lesions were detected during 97 patient-years at risk among women whose partners did not use condoms or used them less consistently.” (R. L. Winer, rlw@u.washington.edu)
Cyclophosphamide for Scleroderma Lung Disease: Among patients with symptomatic scleroderma-related interstitial lung disease, treatment with oral cyclophosphamide 2 mg/kg/day (or less) for 1 year significantly but modestly improved lung function and other symptoms of the disease (pp. 2655-66). Adding that the improvements in symptoms continued during an additional year of monitoring, the researchers report these results for the cyclophosphamide and placebo groups: “Of 158 patients, 145 completed at least six months of treatment and were included in the analysis. The mean absolute difference in adjusted 12-month FVC percent predicted between the cyclophosphamide and placebo groups was 2.53 percent (95 percent confidence interval, 0.28 to 4.79 percent), favoring cyclophosphamide (P < 0.03). There were also treatment-related differences in physiological and symptom outcomes, and the difference in FVC was maintained at 24 months. There was a greater frequency of adverse events in the cyclophosphamide group, but the difference between the two groups in the number of serious adverse events was not significant.” (D. P. Tashkin, dtashkin@mednet.ucla.edu)
Editorialists write that this is an important study but cyclophosphamide is not for everyone with scleroderma (pp. 2707-9): “This well-designed trial will be regarded as a sentinel study confirming a beneficial response to cyclophosphamide in highly selected patients with scleroderma-related interstitial lung disease. In the absence of long-term follow-up data on mortality and the development of malignant diseases, however, the modest therapeutic response and the potential for significant toxic effects do not, in our opinion, support the conclusion that one year of daily cyclophosphamide should be considered routine therapy for all such patients. Additional analyses based on the current data set could offer further guidance regarding patients who are most likely to benefit from this drug. Future studies will be required to provide additional information and build on the encouraging, albeit preliminary, results reported by Tashkin and colleagues.” (F. J. Martinez, U. Mich., Ann Arbor)
Omalizumab for Asthma: Clinical Therapeutics is a new series of review articles that begins in this issue of NEJM. It will focus on specific therapies—including medications but also devices or procedures—for a given clinical problem (see editorial, pp. 2706-7; J. A. Jarcho). The first installment details treatment of asthma with the humanized IgG1 monoclonal anti-IgE antibody omalizumab (pp. 2689-95). For the case presented in the article, the expense of omalizumab caused the authors to recommend improvements in adherence with current therapies before this agent might be added to the patient’s drug regimen. (R. C. Strunk, Washington U., St. Louis)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, 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 23, 2006 Vol. 13, No. 121
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; 2006; 54).
Cognitive Function & Chemotherapy: Among 28 elderly women with breast cancer, adjuvant chemotherapy was associated with a decline in cognitive function during the 6 months after chemotherapy (pp. 925-31). “Participants had a mean age of 71 (range 65–84): 39% Stage I, 50% Stage II, and 11% Stage III,” the investigators reported based on neuropsychological and functional status testing. “The number of scores 2 standard deviations (SDs) below the norm were calculated for each patient before and 6 months after chemotherapy; 14 (50%) had no change, 11 (39%) worsened, and three (11%) improved (P = .05). Seven patients (25%) experienced a decline in cognitive function, defined as a 1-SD decline from pre- to posttesting in two or more neuropsychological domains. Exploratory analyses revealed no significant difference between functional status, comorbidity, and depression scale scores and change in overall quality-of-life scores before and after chemotherapy.” (A. Hurria, Memorial Sloan-Kettering Cancer Ctr., New York; hurriaa@mskcc.org)
Antidepressant Prescribing & Provider Characteristics: A longitudinal analysis of prescribing patterns from five counties in the Piedmont area of North Carolina shows that antidepressant use has increased over time, but the characteristics of those prescribing the drugs has not changed much (pp. 942-9). Study participants included 2,261 blacks and 1,875 whites who were community-dwelling elderly residents ranging in age from 65 to 105. Analysis of information provided by participants and matched to prescriber databases showed the following for the 1986-87, 1989-90, 1992-93, and 1996-97 time periods: “The characteristics of the usual medical care providers remained stable over the decade, although prevalence of antidepressant use increased. Two provider characteristics—race and area of practice (but not the interaction between them)—were significantly associated with patients’ use of antidepressants. Patients of white physicians and of physicians with urban practices were more likely to use antidepressants.” (G. G. Fillenbaum, ggf@geri.duke.edu)
CPOE & Inappropriate Prescribing: Implementation of age-specific alerts as part of a computerized prescriber order entry system reduced potentially inappropriate prescribing as well as the alert burden in 15 clinics of a staff-model health-maintenance organization (pp. 963-8). Alerts targeted potentially problematic drugs such as tertiary tricyclic amine antidepressants and long-acting benzodiazepines, supplementing drug-specific suggestions of alternatives at the point of prescribing. At seven clinics, academic detailing was provided in addition to the alerts. The authors report: “Age-specific alerts resulted in a continuation of the effects of the drug-specific alerts without measurable additional effect (P = .75 for level change), but the age-specific alerts led to fewer false-positive alerts for clinicians. Group academic detailing did not enhance the effect of the alerts.” (S. R. Simon, steven_simon@hms.harvard.edu)

>>>PNN NewsWatch
* Changes are on the horizon at FDA, with agency officials and Congressional overseers looking at ways to modernize the agency’s approval and monitoring functions. The Wall Street Journal reported earlier this week that clinical research organizations are a major focus for FDA as it reviews the procedures involved in drugs gaining initial approval for marketing. Most current rules, written in the early 1980s, focus on the pharmaceutical company sponsoring the new drug application and the clinical researchers performing Phase I, II, and III trials, but in the intervening years clinical research organizations have become middlemen in this process. Rules under development would address what information sponsors must share with FDA about these CROs, including instances of research fraud and adverse events encountered. Safety of medications and postmarketing surveillance is a major focus of Senate and House members who are drafting a bill for introduction in the coming weeks. Industry user fees will be tapped to fund new efforts, the Wall Street Journal reported.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, 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, 2006 Vol. 13, No. 122
Providing news and information about medications and their proper use

>>>HIV Drug, Darunavir, Approved by FDA
FDA on Friday approved a new HIV protease inhibitor, darunavir (Prezista—Tibotec), for treatment of refractory HIV infection in combination with a low dose of ritonavir and other active anti-HIV agents. Ritonavir decreases the metabolism of darunavir, thereby increasing its serum concentration.
This accelerated approval was based on evidence from two randomized controlled studies comparing the safety and effectiveness of a darunavir–ritonavir combination with other ritonavir-boosted protease inhibitor combinations. Patients in both arms of these trials also used other anti-HIV agents (nucleoside reverse transcriptase inhibitors) with or without the fusion inhibitor enfuvirtide. In these studies, patients on a darunavir–ritonavir combination experienced higher rates of reduction of their HIV viral load than patients on other ritonavir-boosted protease inhibitor combinations. Among treatment-experienced patients, 70% achieved a virologic response with darunavir–ritonavir, compared with 21% in a control group at week 24.
The most common adverse effects reported by patients on the darunavir–ritonavir regimen included diarrhea, nausea, and headache. About 7% of patients on this combination therapy experienced skin rashes ranging from mild to serious.
The risks and benefits of darunavir have not been established for adults who have not been previously treated for HIV or for children.
As a condition of the accelerated approval, the manufacturer is required to conduct postmarketing trials to verify and describe the clinical benefits of darunavir. The manufacturer has also committed to conduct studies in pediatric populations, evaluations that will better define certain drug–drug interactions, and trials to evaluate the drug in patients with varying degrees of liver impairment to identify appropriate dosing for this patient population.
Patients should take darunavir and ritonavir with food and not use the combination therapy with St. John’s wort or various other drugs, including certain anticonvulsants, antihistamines, sedatives, and some protease inhibitors.

>>>BMJ Highlights
Source:
Early-release article from BMJ (www.bmj.org; 2006).
“Healthy Adherers”: People who take their medications—even sugar pills—as prescribed live longer, at least as long as they are on the right drugs (doi: 10.1136/bmj.38875.675486.55). That conclusion comes from a meta-analysis of observational studies that provides these results: “Data were available from 21 studies (46,847 participants), including eight studies with placebo arms (19,633 participants). Compared with poor adherence, good adherence was associated with lower mortality (odds ratio 0.56, 95% confidence interval 0.50 to 0.63). Good adherence to placebo was associated with lower mortality (0.56, 0.43 to 0.74), as was good adherence to beneficial drug therapy (0.55, 0.49 to 0.62). Good adherence to harmful drug therapy was associated with increased mortality (2.90, 1.04 to 8.11).” The authors surmise that the beneficial effects of adherence “may be a surrogate marker for overall healthy behaviour.” (S. H. Simpson, ssimpson@pharmacy.ualberta.ca)

>>>Lancet Highlights
Source:
Early-release article from Lancet (www.thelancet.com; 2006).
Staph. aureus as Threat: A review article warns of the widespread prevalence (25–30% of healthy people) and virulence of methicillin-resistant Staphylococcus aureus (doi: 10.1016/S0140-6736(06)68853-3): “Of all the resistance traits S aureus has acquired since the introduction of antimicrobial chemotherapy in the 1930s, meticillin resistance is clinically the most important, since a single genetic element confers resistance to the most commonly prescribed class of antimicrobials—the beta-lactam antibiotics, which include penicillins, cephalosporins, and carbapenems.” (H. Grundmann, Natl. Inst. for Public Health and the Environment, Bilthoven, the Netherlands)

>>>PNN JournalWatch
* Mortality After Staphylococcus Aureus Bacteraemia in Two Hospitals in Oxfordshire, 1997–2003: Cohort Study, in BMJ, 2006; doi: 10.1136/bmj.38834.421713.2F. Reprints: D. H. Wyllie, U. Oxford, Oxford, U.K.; david.wyllie@ndcls.ox.ac.uk

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, 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, 2006 Vol. 13, No. 123
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
June 26 issue of the Archives of Internal Medicine (www.archinternmed.com; 2006; 166).
Vitamin K & Fractures: Patients at risk of fractures should be encouraged to consume a diet rich in vitamin K, focusing on green leafy vegetables and selected vegetable oils, recommend authors of a review article (pp. 1256-61). The studies included in the systematic review and meta-analysis used supplements of oral vitamin K, including phytonadione and menaquinone, but the authors concluded that the evidence does not yet support routine use of supplements to enhance dietary intake of vitamin K. Evidence supporting decreased fractures was especially strong for Japanese patients, the investigators write: “Thirteen trials were identified with data on bone loss, and 7 reported fracture data. All studies but 1 showed an advantage of phytonadione and menaquinone in reducing bone loss. All 7 trials that reported fracture effects were Japanese and used menaquinone. Pooling the 7 trials with fracture data in a meta-analysis, we found an odds ratio (OR) favoring menaquinone of 0.40 (95% confidence interval [CI], 0.25–0.65) for vertebral fractures, an OR of 0.23 (95% CI, 0.12–0.47) for hip fractures, and an OR of 0.19 (95% CI, 0.11–0.35) for all nonvertebral fractures.” (D. J. Torgerson, U. York, York, U.K.; djt6@york.ac.uk)
Long QT Syndrome in Methadone Users: Injection drug users on maintenance methadone therapy often have prolonged QT intervals during hospitalizations, according to a systematic, retrospective study (pp. 1280-7). Over a 5-year period at a tertiary-care hospital, 167 active or former injection drug users receiving methadone were compared with a control group of 80 injection drug users not receiving methadone. The prevalence of prolonged QT interval was 16.2% among those on methadone, compared with 0% in the control group. Regression analysis showed that 31.8% of QTc variability was explained by methadone dose, cytochrome P450 3A4 drug–drug interactions, hypokalemia, and altered liver function. The most commonly encountered CYP inhibitors among patients with prolonged QTc intervals were fluoxetine, clarithromycin, fluconazole, and valproate. Based on these findings, the authors conclude: “Effective and safe treatment of methadone-induced long QT syndrome exists with the use of opioid rotation. Electrocardiographic control in patients at risk could thus be beneficial as a simple means of screening for QT interval prolongation, especially after introducing a CYP3A4 inhibitor and increasing the methadone dose and in the presence of hypokalemia or diminished liver function.” (J. A. Desmeules, Geneva U. Hosp., Geneva, Switzerland; jules.desmeules@hcuge.ch)
Treatable Conditions Associated with Nursing Home Aggression: Treatment of depression, delusions, hallucinations, and constipation may help reduce physical aggression among nursing home residents, conclude authors of a cross-sectional study conducted in five states (pp. 1295-300). Using 2002 Minimum Data Sets, the researchers report: “A total of 103,344 residents met study criteria, of whom 7,120 (6.9%) had been physically aggressive in the week before their annual Minimum Data Set assessment. After adjustment for potential confounders, including age, sex, severity of cognitive impairment, and dependence in activities of daily living, physical aggression was associated with depressive symptoms (adjusted odds ratio [AOR], 3.3; 99% confidence interval [CI], 3.0–3.6), delusions (AOR, 2.0; 99% CI, 1.7–2.4), hallucinations (AOR, 1.4; 99% CI, 1.1–1.8), and constipation (AOR, 1.3; 99% CI, 1.2–1.5). Urinary tract infections, respiratory tract infections, fevers, reported pain, and participation in recreational activities were not significantly associated with physical aggression in multivariate analyses (P > .01 for all). Except for constipation, the correlates of verbal aggression were similar to those of physical aggression.” (R. Leonard, St. Louis Park, Minn.)
Pertussis Vaccination: To prevent outbreaks such as one in Jackson County, Ore., in 2003, universal vaccination against pertussis is needed for adolescents and adults (pp. 1317-21). Jail inmates and workers and school students and employees were among clusters of affected people. (S. Schafer, Oregon State Public Health, Portland; sean.schafer@state.or.us)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, 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, 2006 Vol. 13, No. 124
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
June 28 issue of JAMA (www.jama.com; 2006; 295).
Fusarium Keratitis Associated with Contact Lens Wear: Identification of the epidemic of Fusarium keratitis among contact lens wearers in Singapore is described (see PNN, Apr. 14 and May 16), and possible explanations are discussed (pp. 2867-73). Writing about a nationwide, hospital-based case series of patients seen from March 2005 to May 2006, the researchers note: “66 patients (68 affected eyes) were diagnosed with Fusarium keratitis associated with contact lens wear; the estimated annual national incidence is 2.35 cases per 10,000 contact lens wearers (95% confidence interval, 0.62–7.22). Patients ranged in age from 13 to 44 years (mean [SD], 27.1 [8.4] years), of which 32 (48.5%) were men. The vast majority (65 patients; 98.5%) wore soft, disposable contact lenses; 62 patients (93.9%) reported using 1 brand of contact lens cleaning solution (ReNu, Bausch & Lomb, Rochester, NY), including 42 patients (63.6%) who recalled using ReNu with MoistureLoc. Most patients (81.8%) reported poor contact lens hygiene practices, including overnight use of daily wear contact lenses (19.7%), and use of contact lenses past the replacement date (43.9%). The final best-corrected visual acuity ranged from 20/20 to 20/80. Five patients (5 eyes; 7.4%) required emergency therapeutic or tectonic corneal transplantation.” In discussing their findings, these authors note that Bausch & Lomb has pointed to the possible involvement of a disinfecting agent in the MoistureLoc formulation: “While the company noted that alexidine was safe and effective, it acknowledged that under certain extreme conditions (eg, when the solution is allowed to evaporate, the solution is not regularly replaced in the lens case, when the bottle is kept open in between uses, or when the case is not cleaned properly or changed regularly) ‘the concentration of polymers included in the formula to enhance comfort may make the solution more likely to be contaminated with Fusarium in the environment.’” (D. T. H. Tan, Singapore Eye Res. Inst., Singapore; snecdt@pacific.net.sg)
CBT for Chronic Insomnia: Cognitive behavioral therapy proved superior to drug treatment among 46 older patients with chronic insomnia in a 6-month study (pp. 2851-8). Comparing CBT (sleep hygiene, sleep restriction, stimulus control, cognitive therapy, and relaxation) with zopiclone 7.5 mg every night and placebo for 6 weeks and the two active treatments for up to 6 months, the investigators report: “CBT resulted in improved short- and long-term outcomes compared with zopiclone on 3 out of 4 outcome measures. For most outcomes, zopiclone did not differ from placebo. Participants receiving CBT improved their sleep efficiency from 81.4% at pretreatment to 90.1% at 6-month follow-up compared with a decrease from 82.3% to 81.9% in the zopiclone group. Participants in the CBT group spent much more time in slow-wave sleep (stages 3 and 4) compared with those in other groups, and spent less time awake during the night. Total sleep time was similar in all 3 groups; at 6 months, patients receiving CBT had better sleep efficiency using polysomnography than those taking zopiclone.” (B. Sivertsen, U. Bergen, Bergen, Norway; borge.sivertsen@psykp.uib.no)

>>>PNN NewsWatch
* Rivastigmine tartrate (Exelon, Novartis) has been approved by FDA for treatment of mild to moderate dementia associated with Parkinson’s disease. The agent, previously indicated for treatment of mild to moderate Alzheimer’s disease, becomes the first medication approved for treating PD-related dementia. In a news release, Novartis noted that the National Parkinson Foundation estimates that 40% of the 1.5 million Americans with PD also develop dementia. The risk for developing dementia among patients with PD is approximately 4–6 times higher than among elderly people without this disease. According to a clinical study reported in the New England Journal of Medicine (see PNN, Dec. 9, 2004), rivastigmine improved a number of primary and secondary measures of dementia among 410 patients with PD. Common adverse effects of the drug included nausea (29.0%), vomiting (16.6%), and tremor (10.2%).

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, 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, 2006 Vol. 13, No. 125
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
June 29 issue of the New England Journal of Medicine (content.nejm.org; 2006; 354).
Homocysteine Lowering & Cognitive Performance: Daily supplements of vitamins B6 10 mg and B12 500 mcg combined with folate 1,000 mcg do not improve cognitive performance, according to a 2-year study of 276 healthy participants aged 65 years or older (pp. 2764-72). Testing the hypothesis that lowering of plasma homocysteine concentrations would benefit the study participants mentally, the investigators report these results from baseline and after 1 and 2 years of treatment: “On average, during the course of the study, the plasma homocysteine concentration was 4.36 µmol per liter (95 percent confidence interval, 3.81 to 4.91 µmol per liter) lower in the vitamin group than in the placebo group (P < 0.001). Overall, there were no significant differences between the vitamin and placebo groups in the scores on tests of cognition.” (C. M. Skeaff, U. Otago, Dunedin, New Zealand; murray.skeaff@stonebow.otago.ac.nz)
An editorialist considers the cardiovascular benefits of homocysteine lowering in providing this perspective on vitamin B
12 and folate supplements (pp. 2817-9): “The Scientific Advisory Committee on Nutrition in the United Kingdom recognized that vitamin B12 deficiency is an important public health issue for older people and that a management strategy should be assessed, regardless of whether mandatory folic acid fortification is introduced. However, none of the large homocysteine-lowering trials for the prevention of cardiovascular events can distinguish the independent effects of vitamin B12 from those of folic acid. To address the treatment of the elderly population with biochemical evidence of vitamin B12 deficiency in the absence of symptoms, additional randomized evidence should be sought for the effects of daily oral dietary supplementation with 1,000 mcg of vitamin B12 in persons 70 years of age or older in the absence of previous vascular disease, anemia, or cognitive impairment. In addition to testing the relevance of vitamin B12 for the maintenance of cognitive function in a high-risk older population, trials adopting a factorial design could simultaneously assess the efficacy of other practicable treatments for the prevention of dementia and inform strategies for healthy aging.” (R. Clarke, U. Oxford, Oxford, U.K.)
N-Acetylcysteine and Contrast-Induced Nephropathy: Among 354 patients undergoing primary angioplasty, intravenous and oral doses of N-acetylcysteine helped to prevent contrast-medium–induced nephropathy (pp. 2773-82). Participants received either standard or double doses of N-acetylcysteine before the procedure intravenously and twice daily orally for 48 hours thereafter, with these results: “The serum creatinine concentration increased 25 percent or more from baseline after primary angioplasty in 39 of the control patients (33 percent), 17 of the patients receiving standard-dose N-acetylcysteine (15 percent), and 10 patients receiving high-dose N-acetylcysteine (8 percent, P < 0.001). Overall in-hospital mortality was higher in patients with contrast-medium–induced nephropathy than in those without such nephropathy (26 percent vs. 1 percent, P < 0.001). Thirteen patients (11 percent) in the control group died, as did five (4 percent) in the standard-dose N-acetylcysteine group and three (3 percent) in the high-dose N-acetylcysteine group (P = 0.02). The rate for the composite end point of death, acute renal failure requiring temporary renal-replacement therapy, or the need for mechanical ventilation was 21 (18 percent), 8 (7 percent), and 6 (5 percent) in the three groups, respectively (P = 0.002).” (G. Marenzi, Centro Cardiologico Monzino, Milan, Italy; giancarlo.marenzi@ccfm.it)
Rofecoxib Correction: Posted on the journal’s Web site in advance of publication in the July 13 issue of NEJM, a correction notice, three letters, and a Perspective article discuss new analyses of the data from the APPROVe trial of rofecoxib prevention of polyps. The correction removes most references to the increase in cardiovascular events after 18 months with rofecoxib, making the statements more general, as in, ““In our randomized, placebo-controlled trial, we found an increased risk of confirmed thrombotic events associated with the use of rofecoxib.”

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, 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 30, 2006 Vol. 13, No. 126
Providing news and information about medications and their proper use

>>>Dasatinib Approved by FDA
FDA yesterday granted accelerated approval for dasatinib (Sprycel, Bristol-Myers Squibb), a new oral treatment for patients with chronic myeloid leukemia (CML). In addition, the FDA gave regular approval to dasatinib for use in the treatment of adults who have Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), a more serious form of leukemia. Both approvals are for second-line treatment of patients who have experienced resistance or intolerance to prior therapy, and because of the small numbers of patients with these conditions, the drug has orphan status for both indications.
Dasatinib is intended for patients with CML who are no longer responding to or who can no longer tolerate therapy with imatinib (Gleevec, Novartis), approved in 2001 for CML. Dasatinib reduces the activity of multiple tyrosine kinases, thought to be responsible for the uncontrolled growth of the leukemia cells. Dasatinib treatment reduces and in some cases eliminates detectable leukemia cells in the blood and bone marrow of patients with CML. As provided for under FDA accelerated approval regulations, studies are underway to demonstrate that these improved white blood cell counts also result in clinical benefit such as improved survival or improvement in leukemia-related symptoms.
The approval of dasatinib is based on evidence from four single-arm studies in more than 400 patients who were no longer responsive to or tolerant of treatment with imatinib. The efficacy of dasatinib was determined by the response rate, defined as the percentage of patients in whom treatment resulted in the elimination of detectable leukemia cells or a significant reduction in the number of leukemia cells. Responses were measured primarily in the bone marrow for those patients with the earliest stage of disease, and in the blood for those patients with later stage disease. For patients with the earliest stage of CML (chronic phase), treatment with dasatinib resulted in response in 45% of patients. Response rates for patients with advanced phases of CML and for Ph+ ALL ranged from 31% to 59%. Responses to dasatinib were maintained for 6 months in most of those responding to the drug.
Adverse effects reported in these trials included fluid retention, bleeding, diarrhea, skin rash, infections, headache, fatigue and nausea. Dasatinib also frequently causes anemia, neutropenia, and thrombocytopenia.

PNN NewsWatch
* FDA announced yesterday that Baxter Healthcare Corp. and two of its top corporate executives have signed a consent decree of condemnation and permanent injunction for certain infusion pumps made by the firm. FDA explained in a news release that the signees had agreed to stop manufacturing and distributing within the U.S. all models of the Colleague Volumetric Infusion Pump (Colleague) and the Syndeo Patient Controlled Analgesic Syringe Pump (Syndeo) until they correct manufacturing deficiencies and until the devices are made in compliance with FDA’s current good manufacturing practice (CGMP) requirements and the Quality System (QS) regulation for devices (see PNN, July 22, 2005). Under the terms of the consent decree, signed by Baxter’s chairman/CEO and the corporate vice president/president of medication delivery services, the company has agreed to take necessary measures to ensure compliance with CGMP and QS requirements by all of its facilities that manufacture, process, pack, label, hold, or distribute the Colleague and Syndeo Pumps. Baxter will also retain an independent expert consultant to conduct inspections of its infusion pump facilities and certify to FDA that corrections have been made, and the agency will monitor progress through continued inspections.
*
FDA is requiring addition of bold-face warnings to product labeling cautioning about hepatotoxicity with telithromycin (Ketek—Sanofi Aventis). The first FDA-approved antibiotic of the ketolide class, telithromycin has been associated with rare cases of serious liver injury and liver failure with four reported deaths and one liver transplant after the administration of the drug (see PNN, Jan. 23, Mar. 21).
*
PNN will not be published on Mon. and Tues., July 3–4, Independence Day.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, 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.