Sep 2006

PNN Quarterly File—Third Quarter 2006

PNN Pharmacotherapy Line
July 5, 2006 Vol. 13, No. 127
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
July 5 issue of JAMA (www.jama.com; 2006; 296).
Varenicline for Smoking Cessation: In a study of 1,025 generally healthy smokers, varenicline was significantly more effective for smoking cessation than placebo at all time points and sustained-release bupropion at the end of 12 weeks of active therapy and at 24 weeks of follow-up (pp. 47-55). In this Phase III trial, participants received brief counseling and varenicline titrated to 1 mg twice per day, bupropion SR titrated to 150 mg twice per day, or placebo orally for 12 weeks, with 40 weeks of nondrug follow-up. The investigators report these results: “For weeks 9 through 12, the 4-week continuous abstinence rates were 44.0% for varenicline vs 17.7% for placebo (odds ratio [OR], 3.85; 95% confidence interval [CI], 2.70–5.50; P < .001) and vs 29.5% for bupropion SR (OR, 1.93; 95% CI, 1.40–2.68; P < .001). Bupropion SR was also significantly more efficacious than placebo (OR, 2.00; 95% CI, 1.38–2.89; P < .001). For weeks 9 through 52, the continuous abstinence rates were 21.9% for varenicline vs 8.4% for placebo (OR, 3.09; 95% CI, 1.95-4.91; P<.001) and vs 16.1% for bupropion SR (OR, 1.46; 95% CI, 0.99–2.17; P = .057). Varenicline reduced craving and withdrawal and, for those who smoked while receiving study drug, smoking satisfaction. No sex differences in efficacy for varenicline were observed. Varenicline was safe and generally well tolerated, with study drug discontinuation rates similar to those for placebo. The most common adverse events for participants receiving active-drug treatment were nausea (98 participants receiving varenicline [28.1%]) and insomnia (72 receiving bupropion SR [21.9%]).” (D. Gonzales, Oregon Health & Science U., Portland; gonzales@ohsu.edu)
Commenting on this and two other studies of varenicline in this issue (pp. 56-63, D. E. Jorenby,
dej@ctri.medicine.wisc.edu; pp. 64-71, S. Tonstad, Ullevål U. Hosp., Oslo, Norway, serena.tonstad@uus.no), an editorialist writes (pp. 94-5): “Clearly, quitting smoking, even with pharmacological and behavioral assistance, is extremely difficult. Patients currently cannot and probably never will simply be able to ‘take a pill’ that will make them stop smoking. Smokers must want to stop smoking and must be willing to work hard to achieve the goal of smoking abstinence.
“Although much research needs to be conducted to establish the effectiveness of varenicline, stop smoking researchers and clinicians, as well as smokers wanting to quit smoking, now have another product available that appears to help increase the probability of smoking cessation.” (R. C. Klesges,
bob.klesges@stjude.org)
ALT Elevations with Acetaminophen: In 147 healthy adults, initiation of acetaminophen 4 grams daily was frequently associated with elevations of serum ALT levels to 3 times the upper limit of normal (pp. 87-93). The data come from a study of novel combinations of hydromorphone and acetaminophen in which participants received for 14 days either acetaminophen alone, one of three combinations of acetaminophen plus hydromorphone, or placebo. Results showed: “None of the 39 participants assigned to placebo had a maximum ALT of more than 3 times the upper limit of normal. In contrast, the incidence of maximum ALT of more than 3 times the upper limits of normal was 31% to 44% in the 4 treatment groups receiving acetaminophen, including those participants treated with acetaminophen alone. Compared with placebo, treatment with acetaminophen was associated with a markedly higher median maximum ALT (ratio of medians, 2.78; 95% confidence interval, 1.47–4.09; P < .001). Trough acetaminophen concentrations did not exceed therapeutic limits in any participant and, after active treatment was discontinued, often decreased to undetectable levels before ALT elevations resolved.” (P. B. Watkins, pbwatkins@med.unc.edu)

>>>PNN JournalWatch
* Clinical Factors and ABCB1 Polymorphisms in Prediction of Antiepileptic Drug Response: A Prospective Cohort Study, in Lancet, 2006; 368: doi: 10.1016/S1474-4422(06)70500-2. Reprints: www.thelancet.com; M. R. Johnson, Imperial College, London; m.johnson@imperial.ac.uk
* Psychological Interventions to Improve Glycaemic Control in Patients with Type 1 Diabetes: Systematic Review and Meta-analysis of Randomised Controlled Trials, in
BMJ, 2006; 333: doi:10.1136/bmj.38874.652569.55. Reprints: www.bmj.org; K. Ismail, King’s College, London; khalida.ismail@iop.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
July 6, 2006 Vol. 13, No. 128
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
July 6 issue of the New England Journal of Medicine (content.nejm.org; 2006; 355).
Chemotherapy for Gastroesophageal Cancer: A perioperative regimen of epirubicin, cisplatin, and infused fluorouracil decreased tumor size and stage and significantly improved progression-free and overall survival among 503 patients with resectable adenocarcinoma of the stomach, esophagogastric junction, or lower esophagus (pp. 11-20). Comparing surgery alone with surgery plus three preoperative and three postoperative cycles of intravenous epirubicin (50 mg/sq m) and cisplatin (60 mg/sq m) on day 1, and a continuous intravenous infusion of fluorouracil (200 mg/sq m/day) for 21 days, the investigators report, “ECF-related adverse effects were similar to those previously reported among patients with advanced gastric cancer. Rates of postoperative complications were similar in the perioperative-chemotherapy group and the surgery group (46 percent and 45 percent, respectively), as were the numbers of deaths within 30 days after surgery. The resected tumors were significantly smaller and less advanced in the perioperative-chemotherapy group. With a median follow-up of four years, 149 patients in the perioperative-chemotherapy group and 170 in the surgery group had died. As compared with the surgery group, the perioperative-chemotherapy group had a higher likelihood of overall survival (hazard ratio for death, 0.75; 95 percent confidence interval, 0.60 to 0.93; P = 0.009; five-year survival rate, 36 percent vs. 23 percent) and of progression-free survival (hazard ratio for progression, 0.66; 95 percent confidence interval, 0.53 to 0.81; P < 0.001).” (D. Cunningham, Royal Marsden Hosp., Sutton, Surrey, U.K.; david.cunningham@rmh.nhs.uk)
Influenza Burden in Children: Influenza among young children is underdiagnosed yet the cause of many outpatient visits, according to authors who studied children younger than 5 years of age in three U.S. counties (pp. 31-40). “The average annual rate of hospitalization associated with influenza was 0.9 per 1,000 children,” the investigators report of their epidemiologic data collected from parental surveys and chart reviews. “The estimated burden of outpatient visits associated with influenza was 50 clinic visits and 6 emergency department visits per 1000 children during the 2002–2003 season and 95 clinic visits and 27 emergency department visits per 1,000 children during the 2003–2004 season. Few children who had laboratory-confirmed influenza were given a diagnosis of influenza by the treating physician in the inpatient (28 percent) or outpatient (17 percent) settings.” (K. A. Poehling, Vanderbilt U., Nashville)
An editorialist describes the consequences of failure to recognize influenza in young children and intervene with available medications (pp. 79-81): “[The] lack of recognition represents a missed opportunity to intervene to reduce both the risk of complications and the spread of the virus to contacts. Young children excrete greater concentrations of virus for longer periods of time than do older patients. Treatment of these younger patients even three to four days after the onset of infection may at least reduce the spread of infection to contacts. Identification of infection in the index child is also an opportunity to treat or extend prophylaxis against influenza to family contacts. Antiviral medications are likely to be a central defense against the first wave of the next pandemic. Surveillance networks such as the [CDC’s New Vaccine Surveillance Network] group, coupled with effective treatment of patients and their contacts, will contribute to the control of seasonal influenza and may provide a valuable rehearsal for the next pandemic.” (W. P. Glezen, Baylor College of Medicine, Houston)

>>>PNN NewsWatch
* The supply of influenza vaccine for the upcoming season should not be affected by a recent warning letter issued to Sanofi Pasteur about good manufacturing practice deficiencies with respect to the sterility of Fluzone. In a Q&A posted on the FDA Web site, the agency explained that some monovalent concentrates will be lost as a result of the quality assurance concerns but that the overall impact “is not expected to be significant.”

PNN Pharmacotherapy Line is published via e-mail each business day except 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
July 7, 2006 Vol. 13, No. 129
Providing news and information about medications and their proper use

>>>Ranibizumab OK’d for AMD
Following a 6-month priority review, FDA last week approved ranibizumab injection (Lucentis, Genentech) for treatment of patients with neovascular (wet) age-related macular degeneration (AMD). Ranibizumab is the first treatment that, when dosed monthly, can maintain the vision of more than 90% of patients with this type of AMD. Lucentis will also be the first FDA-approved product to provide prescription information in the new format for prescription drug package inserts.
AMD, a retinal disease causing severe and irreversible vision loss, is a major cause of blindness in individuals older than 55 years. Untreated, the majority of eyes affected with wet AMD may become functionally impaired. Wet AMD, which accounts for 10% of all AMD, is responsible for 80% of the associated vision loss.
The vision loss in wet AMD is caused by the growth of abnormal leaky blood vessels that eventually damage the area of the eye responsible for central vision. Ranibizumab blocks new blood vessel growth and leakiness, which ultimately lead to disease progression and such vision loss.
This recombinant humanized IgG1 kappa isotype therapeutic antibody fragment is administered by injection into the eye. Its efficacy and safety were established in three multicenter randomized studies of patients representative of the population usually affected by AMD. In clinical trials, nearly 95% of the participants who received a monthly injection maintained their vision at 12 months, compared with approximately 60% of patients who received the control treatment.
Approximately one-third of patients in these trials had improved vision at 12 months. In a single study carried out for 24 months, these findings were maintained with continued monthly dosing. The most commonly reported adverse events of ranibizumab included conjunctival hemorrhage, eye pain, floaters, increased eye pressure and inflammation of the eye. Serious adverse events were rare and often related to the injection procedure, including endophthalmitis (severe inflammation of the interior of the eye), intraocular inflammation, retinal detachment, retinal tear, increased eye pressure, and traumatic cataract.

>>>PNN NewsWatch
* A black-box warning has been added to the product labeling of tipranavir (Aptivus, Boehringer Ingelheim) cautioning of fatal and nonfatal hemorrhage associated with use of the antiretroviral drug. In a letter to pharmacists and other health professionals, the company noted that in clinical trials, 14 ICH events occurred in 13 of 6,840 HIV-infected patients, with 8 related fatalities. Median time to onset of these events was 525 days, and many of the affected patients had other medical conditions (CNS lesions, head trauma, recent neurosurgery, coagulopathy, hypertension, alcohol abuse) or were taking other medications (anticoagulants and antiplatelet agents) that could have contributed to the ICH event. Because no pattern of changes in laboratory values has been associated with development of ICH, monitoring of coagulation parameters is not currently indicated in those taking this drug.
* In a statement published jointly in
Diabetes Care (http://care.diabetesjournals.org/cgi/content/full/29/7/1697; 2006; 29: 1697–9) and Circulation, the American Diabetes Association and the American Heart Association focus on the obesity epidemic in a joint call for action in preventing cardiovascular disease and diabetes. “It must be remembered that obesity is far more than an unattractive appearance but can be prevented,” the groups conclude. “Moreover, it is often a visible marker of other underlying risk factors that can be addressed. Thus, the overweight or obese patient deserves major clinical attention. The growing prevalence of this condition threatens to undermine all of our recent gains to prevent and control chronic disease.” AHA also issued a 2006 revision to its diet and lifestyle recommendations in this week’s Circulation (http://circ.ahajournals.org/cgi/content/full/114/1/82; 2006; 114: 82–96).
* A point/counterpoint in
Diabetes Care debates the existence of metabolic syndrome (care.diabetesjournals.org/current.shtml; 2006; 29: 1689–92; 1693–6).

PNN Pharmacotherapy Line is published via e-mail each business day except 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
July 10, 2006 Vol. 13, No. 130
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from BMJ (www.bmj.org; 2006; 333).
Whooping Cough in School-Age Children: Even in those immunized against pertussis, a diagnosis of whooping cough should be considered when school-age children have coughs that persist for 2 weeks or more, based on the results of a prospective cohort study conducted in general practices in Oxfordshire, England, from Oct. 2001 to Mar. 2005 (doi: 10.1136/bmj.38870.655405.AE). The researchers report these blood-test results for 172 children aged 5 to 16 years with coughs lasting more than 14 days: “64 (37.2%, 95% confidence interval 30.0% to 44.4%) children had serological evidence of a recent Bordetella pertussis infection; 55 (85.9%) of these children had been fully immunised. At presentation, children with whooping cough were more likely than others to have whooping (odds ratio 2.85, 95% confidence interval 1.39 to 5.82), vomiting (4.35, 2.04 to 9.25), and sputum production (2.39, 1.14 to 5.02). Children with whooping cough were also more likely to still be coughing two months after the start of their illness (85% v 48%; P = 0.001), continue to have more than five coughing episodes a day (P = 0.049), and cause sleep disturbance for their parents (P = 0.003).” (A. Harden, U. Oxford, Oxford, U.K.; anthony.harnden@dphpc.ox.ac.uk)
Antipsychotics After First Hospitalization: In a nationwide study conducted in Finland, risk of rehospitalization was lowest with community treatment of patients with depot perphenazine, clozapine, or olanzapine following their first hospitalizations for schizophrenia or schizoaffective disorder (doi: 10.1136/bmj.38881.382755.2F). For 2,230 consecutive adults hospitalized in Jan. 1995 through Dec. 2001, rates of drug discontinuation, rehospitalization, and mortality were as follows: “Initial use of clozapine (adjusted relative risk 0.17, 95% confidence interval 0.10 to 0.29), perphenazine depot (0.24, 0.13 to 0.47), and olanzapine (0.35, 0.18 to 0.71) were associated with the lowest rates of discontinuation for any reason when compared with oral haloperidol. During an average follow-up of 3.6 years, 4,640 cases of rehospitalisation were recorded. Current use of perphenazine depot (0.32, 0.22 to 0.49), olanzapine (0.54, 0.41 to 0.71), and clozapine (0.64, 0.48 to 0.85) were associated with the lowest risk of rehospitalisation. Use of haloperidol was associated with a poor outcome among women. Mortality was markedly raised in patients not taking antipsychotics (12.3, 6.0 to 24.1) and the risk of suicide was high (37.4, 5.1 to 276).” (J. Tiihonen, U. Kuopio, Kuopio, Finland; jari.tiihonen@niuva.fi)

>>>PNN JournalWatch
* Assessment of Asthma Severity and Asthma Control in Children, in Pediatrics, 2006; 118: 322-9. Reprints: http://pediatrics.aappublications.org/cgi/content/abstract/118/1/322; B. P. Yawn, Olmsted Med. Ctr., Rochester, Minn.
* Reflections on the Relationship Between Psychiatric Genetics and Psychiatric Nosology, in
American Journal of Psychiatry, 2006; 163: 1138-46. Reprints: http://ajp.psychiatryonline.org/cgi/content/abstract/163/7/1138; K. S. Kendler.
* A Systematic Review of Interventions to Improve Diabetes Care in Socially Disadvantaged Populations, in
Diabetes Care, 2006; 29: 1675-88. Reprints: http://care.diabetesjournals.org/cgi/content/abstract/29/7/1675; R. H. Glazier, St. Michael’s Hosp., Toronto; richard.glazier@utoronto.ca
* Combination Therapy with an Angiotensin Receptor Blocker and an ACE Inhibitor in Proteinuric Renal Disease: A Systematic Review of the Efficacy and Safety Data, in
American Journal of Kidney Diseases, 2006; 48: 8-20. Reprints: http://www.ajkd.org/article/PIIS0272638606007694/abstract; M. MacKinnon, Saint John Regional Hosp., Saint John, New Brunswick, Canada; mmackinnon2545@rogers.com
* Pharmacologic Management of Constipation in the Critically Ill Patient, in
Pharmacotherapy, 2006; 26: 896-902. Reprints: www.pharmacotherapy.org; B. L. Erstad, erstad@pharmacy.arizona.edu
* Dalbavancin: A Novel Lipoglycopeptide Antibacterial, in
Pharmacotherapy, 2006; 26: 908-18. Reprints: www.pharmacotherapy.org; S. D. Pope, Carolinas Med. Ctr., Charlotte, N.C.; scott.pope@carolinas.org
* Cardiovascular Risks of Cyclooxygenase Inhibition, in
Pharmacotherapy, 2006; 26: 919-38. Reprints: www.pharmacotherapy.org; Z. A. Stacy, zstacy@stlcop.edu
* Key Articles, Guidelines, and Consensus Papers Relative to the Treatment of Dyslipidemias—2005, in
Pharmacotherapy, 2006; 26: 939-1010. Reprints: www.pharmacotherapy.org; M. K. Ito, Oregon State U., Portland; itom@ohsu.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
July 11, 2006 Vol. 13, No. 131
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
July 10 issue of Archives of Internal Medicine (www.archinternmed.com; 2006; 166).
Marijuana Smoking and Lung Cancer: Observational studies of the association between marijuana smoking and lung cancer are inconclusive, but the widespread use of the herb combined with the biological plausibility of a link create sufficient concern for physicians to warn patients of potential adverse effects (pp. 1359-67). This conclusion comes from a systematic review of 19 studies that found the following: “Studies that examined lung cancer risk factors or premalignant changes in the lung found an association of marijuana smoking with increased tar exposure, alveolar macrophage tumoricidal dysfunction, increased oxidative stress, and bronchial mucosal histopathologic abnormalities compared with tobacco smokers or nonsmoking controls. Observational studies of subjects with marijuana exposure failed to demonstrate significant associations between marijuana smoking and lung cancer after adjusting for tobacco use. The primary methodologic deficiencies noted include selection bias, small sample size, limited generalizability, overall young participant age precluding sufficient lag time for lung cancer outcome identification, and lack of adjustment for tobacco smoking.”
Based on their findings, the authors conclude: “Although observational studies have not shown a substantive marijuana smoking–lung cancer association, these studies are fraught with serious methodologic limitations. Therefore, the combination of the widespread use of marijuana, potential marijuana-related health implications outlined in this review, and studies evaluating lung premalignant alterations supporting a biologically plausible association between marijuana smoking–lung cancer association, in addition to compelling in vitro data not included in this review, provide support for physician advice regarding the potential adverse effects, including the potential for premalignant lung changes, to their patients that use marijuana.” (R. Mehra, Case Western Reserve U., Cleveland, Ohio;
mehrar@ameritech.net)
Novel CVD Risk Markers: Use of any of 19 emerging risk markers for coronary heart disease is not warranted, conclude Atherosclerosis Risk in Communities (ARIC) Study investigators (pp. 1368-73). Looking at risk markers such as C-reactive protein in a series of case–cohort studies, the authors found: “The basic risk factor model, which included traditional risk factors (age, race, sex, total and high-density lipoprotein cholesterol levels, systolic blood pressure, antihypertensive medication use, smoking status, and diabetes), predicted CHD well, as evidenced by an AUC of approximately 0.8. The C-reactive protein level did not add significantly to the AUC (increase in AUC of 0.003), and neither did most other novel risk factors. Of the 19 markers studied, lipoprotein-associated phospholipase A2, vitamin B6, interleukin 6, and soluble thrombomodulin added the most to the AUC (range, 0.006–0.011).” (A. R. Folsom, folsom@epi.umn.edu)
Editorialists add that the problem in practice is treatment to goal, not recognition of CHD risk (pp. 1342-4): “The established risk factors provide remarkably good ability to discriminate those at risk for CHD and should remain the focus of CHD risk estimation and prevention for now. Routine measurement of any of these 19 novel risk markers for the entire population cannot be recommended based on the currently available data from ARIC or any other study. However, we do not rule out the possibility that some markers could be used to better discriminate certain subpopulations, especially those patients near the boundary of high risk based on levels of traditional risk factors. We need to ensure that the tools we currently have for risk prediction are applied more broadly and routinely throughout clinical practice. We must also address the enormous gaps between the promise of CVD prevention and its reality. We have improved our recognition of those with an elevated blood pressure or cholesterol level, but fewer than 1 of 3 Americans with adverse levels of these factors are controlled to goal levels. These issues must be addressed and improved urgently.” (D. M. Lloyd-Jones,
dlj@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
July 12, 2006 Vol. 13, No. 132
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
July 12 issue of JAMA (www.jama.com; 2006; 296).
Women & Lung Cancer: Women smokers are more susceptible to tobacco carcinogens than are men, but they have a lower mortality rate from the disease, according to a nonexperimental, etiologic study of 7,498 women and 9,427 men (pp. 180-4). Based on a 1.9 (95% CI, 1.5–2.5) prevalence odds ratios for lung cancer and a 0.48 (95% CI, 0.25–0.89) hazard ratio for fatal outcomes from lung cancer, the International Early Lung Cancer Action Program Investigators conclude: “It is well-established by the evidence accumulated over the past 20 years that women with lung cancer survive the disease better than men, and that this difference is more pronounced when the cancer is diagnosed at an early stage. Cancer stage at diagnosis, cell type, or treatment do not appear to be entirely explanatory of this difference. As 85% (229/269) of the cases considered here were clinical stage I at diagnosis, the fatality hazard ratio in favor of women, conditional for pack-years of smoking, disease stage, tumor cell type, and resection was more pronounced than those reported by others. Despite the conditionality, it is not clear whether this survival difference is because lung cancer in women tends to be more commonly curable or less malignant. If lung cancer is more commonly curable in women, then the need to screen women at a lower threshold than men is warranted. If lung cancer is less malignant in women, there may be less need to screen women at a lower threshold.” (C. I. Henschke, chensch@med.cornell.edu)
Noting the irony of gender equality in this context, editorialists write (pp. 218-9): ““The reasons women live with lung cancer longer than men are unclear. Do women fare better because of their body size, better health behaviors, hormonal and reproductive factors, different cigarette smoking histories or patterns, or other factors? Women’s stage-for-stage advantage in survival appears to be a host effect and applies to all the major histological types of lung cancer....
“The prototypical male smoker, the now infamous ‘Marlboro Man,’ no longer represents the cigarette smoking population. In any event, he presumably died of lung cancer. The once prevalent adage, ‘You’ve come a long way, Baby!’ geared to female smokers, unfortunately now applies to increased smoking prevalence and lung cancer risk among women. To prevent gender equality in lung cancer from becoming a reality, it’s now time for women to turn back.” (A. I. Neugut,
ain1@columbia.edu)
Weight Change & Breast Cancer: Weight change during adulthood and especially after menopause is associated with an increased risk of breast cancer among postmenopausal women, according to a prospective cohort portion of the Nurses’ Health Study (pp. 193-201). Weight change since age 18 was determined for 87,143 women who were initially aged 30 to 55 years and 49,514 women were assessed for weight change since menopause. Results showed; “Overall, 4,393 cases of invasive breast cancer were documented. Compared with those who maintained weight, women who gained 25.0 kg or more since age 18 years were at an increased risk of breast cancer (relative risk [RR], 1.45; 95% confidence interval [CI], 1.27–1.66; P < .001 for trend), with a stronger association among women who have never taken postmenopausal hormones (RR, 1.98; 95% CI, 1.55–2.53). Compared with weight maintenance, women who gained 10.0 kg or more since menopause were at an increased risk of breast cancer (RR, 1.18; 95% CI, 1.03–1.35; P = .002 for trend). Women who had never used postmenopausal hormones, lost 10.0 kg or more since menopause, and kept the weight off were at a lower risk than those who maintained weight (RR, 0.43; 95% CI, 0.21–0.86; P = .01 for weight loss trend). Overall, 15.0% (95% CI, 12.8%–17.4%) of breast cancer cases in this population may be attributable to weight gain of 2.0 kg or more since age 18 years and 4.4% (95% CI, 3.6%–5.5%) attributable to weight gain of 2.0 kg or more since menopause. Among those who did not use postmenopausal hormones, the population attributable risks are 24.2% (95% CI, 19.8%–29.1%) for a weight gain since age 18 years and 7.6% (95% CI, 5.9%–9.7%) for weight gain since menopause. (A. H. Eliassen, heather.eliassen@channing.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
July 13, 2006 Vol. 13, No. 133
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
July 13 issue of the New England Journal of Medicine (content.nejm.org; 2006; 355).
Raloxifene in Postmenopausal Women: Among 10,101 postmenopausal women with coronary heart disease or multiple risk factors for CHD, raloxifene had no significant impact on the risk of CHD but did reduce the risk of invasive breast cancer (pp. 125-37). Concluding that the benefits of the SERM need to balanced against an increased risk of venous thromboembolism and fatal stroke, the investigators note these results about the study participants, who averaged 67.5 years in age and were followed for a median of 5.6 years: “As compared with placebo, raloxifene had no significant effect on the risk of primary coronary events (533 vs. 553 events; hazard ratio, 0.95; 95 percent confidence interval, 0.84 to 1.07), and it reduced the risk of invasive breast cancer (40 vs. 70 events; hazard ratio, 0.56; 95 percent confidence interval, 0.38 to 0.83; absolute risk reduction, 1.2 invasive breast cancers per 1,000 women treated for one year); the benefit was primarily due to a reduced risk of estrogen-receptor–positive invasive breast cancers. There was no significant difference in the rates of death from any cause or total stroke according to group assignment, but raloxifene was associated with an increased risk of fatal stroke (59 vs. 39 events; hazard ratio, 1.49; 95 percent confidence interval, 1.00 to 2.24; absolute risk increase, 0.7 per 1000 woman–years) and venous thromboembolism (103 vs. 71 events; hazard ratio, 1.44; 95 percent confidence interval, 1.06 to 1.95; absolute risk increase, 1.2 per 1000 woman–years). Raloxifene reduced the risk of clinical vertebral fractures (64 vs. 97 events; hazard ratio, 0.65; 95 percent confidence interval, 0.47 to 0.89; absolute risk reduction, 1.3 per 1000).” (E. Barrett-Connor, ebarrettconnor@ucsd.edu)
An editorialist observes that raloxifene fails the test as a “magic bullet” (pp. 190-2): “[This] report ... highlights the need to consider the risk of breast cancer as well as other risks and coexisting conditions in determining whether and when raloxifene or another SERM is warranted for an individual woman. For now, there is no magic bullet that can reduce the risks of major health problems related to estrogens and aging without introducing other potentially serious health concerns.” (M. L. Stefanick, Stanford U., Stanford, Calif.)
Doxycycline After Tick Bites: For preventing tick-borne relapsing fever, doxycycline proved a safe and effective prophylactic medication in a trial of 93 healthy subjects with suspected tick exposure (pp. 148-55). Doses of 200 mg on day 1 and 100 mg for 4 days produced these results: “All 10 cases of TBRF identified by a positive blood smear were in the placebo group of subjects with signs of a tick bite (P < 0.001). These findings suggested a 100 percent efficacy of preemptive treatment (95 percent confidence interval, 46 to 100 percent). [Polymerase chain reaction] for the borrelia glpQ gene was negative at baseline for all subjects and subsequently positive in all subjects with fever and a positive blood smear. Seroconversion was detected in eight of nine cases of TBRF. PCR and serum samples were negative for all of the other subjects tested. No major treatment-associated adverse effects were identified.” (T. Hasin, Israel Defense Force, Jerusalem, Israel; hasintal@zahav.net.il)

>>>PNN NewsWatch
* FDA has approved Atripla Tablets, a fixed-dose combination of three widely used antiretroviral drugs, in a single tablet taken once a day, alone or in combination with other antiretroviral products for the treatment of HIV-1 infection in adults. Atripla combines efavirenz (Sustiva), emtricitabine (Emtriva), and tenofovir disoproxil fumarate (Viread). Bristol-Myers Squibb and Gilead Sciences have formed a joint venture to commercialize Atripla in the United States. In certain territories, Merck holds the rights to efavirenz. All three companies will work together to ensure the product is available.
*
FDA is warning consumers not to purchase or consume Zimaxx, Libidus, Neophase, Nasutra, Vigor-25, Actra-Rx, or 4EVERON. These products are promoted and sold on web sites as “dietary supplements” for treating erectile dysfunction and enhancing sexual performance, but they are in fact illegal drugs that contain potentially harmful undeclared ingredients.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
July 14, 2006 Vol. 13, No. 134
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
July issue of Pharmacotherapy (www.pharmacotherapy.org; 2006; 26).
Hypertension Treatments in Blacks: Amlodipine and valsartan produced similar decrements in blood pressure among 20 patients with uncomplicated hypertension (pp. 889-95) Seeking to explore the relative efficacy of angiotensin II receptor blockers in a population of patients known to be less responsive to ACE inhibitors, the investigators treated 12 men and 8 women for 8–10 weeks, with these results from ambulatory blood pressure monitoring (ABPM): “Mean ± SD baseline blood pressure before the two ABPM periods were 155 ± 12/100 ± 8 mm Hg and 156 ± 11/101 ± 9 mm Hg, respectively. Fifteen (75%) patients achieved goal blood pressure with amlodipine and 14 (70%) with valsartan (p = 0.62). Final daily dosages were as follows: amlodipine 5 mg in nine patients, 10 mg in five patients, and 10 mg plus hydrochlorothiazide in six patients; valsartan 80 mg in nine patients, 160 mg in four patients, and 160 mg plus hydrochlorothiazide in seven patients. Ambulatory blood pressure monitoring was not completed in three patients due to adverse effects: headache and dizziness (one patient each, amlodipine and valsartan) and hyperkalemia (one patient, valsartan). Four patients (20%) in each treatment group had drug-related adverse effects. Results of ABPM including averages for 24-hour, daytime, nighttime, first 4 hours, and last 8 hours, and trough:peak ratios were not significantly different between the amlodipine- and valsartan-based treatments. (D. E. Hilleman, hilleman@creighton.edu)
Constipation in Critically Ill Patients: Opioid therapy is an important risk factor for an observed high frequency of constipation among critically ill patients, according to results of a retrospective review of 50 patients in a medical intensive care unit in 2004 (pp. 896-902). Concluding that stimulant or osmotic laxatives should be considered for this population, the authors report: “Of the 50 patients, 25 did not have a bowel movement during the first 96 hours of MICU admission. Patients given a stimulant laxative (senna, bisacodyl) and/or an osmotic laxative (lactulose, milk of magnesia) were more likely to have a bowel movement (odds ratio [OR] 26.6, 95% confidence interval [CI] 3.2–221, p = 0.002). Opioid intake, expressed as logarithmic morphine equivalents, was negatively associated with occurrence of a bowel movement (OR 0.76, 95% CI 0.59–0.97, p = 0.027). Disease severity, as determined by APACHE II score, was also negatively associated with a bowel movement (OR 0.84, 95% CI 0.7–0.99, p = 0.04).” (B. L. Erstad, erstad@pharmacy.arizona.edu)

>>>Diabetes Highlights
Source:
July Diabetes Care (care.diabetesjournals.org; 2006; 29).
Atorvastatin In Type 2 DM: In the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus (ASPEN), treatment with 10-mg doses of this statin failed to lower incidence of a composite risk factor consisting of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, recanalization, coronary artery bypass surgery, resuscitated cardiac arrest, and worsening or unstable angina requiring hospitalization (pp. 1478-85). Among the 2,410 participants, mean LDL cholesterol reduction in the atorvastatin group over 4 years was 29% versus placebo (P < 0.0001), but the composite end point rates were statistically similar (13.7% and 15.0% with atorvastatin and placebo, respectively). However, the group adds, these results “do not detract from the imperative that the majority of diabetic patients are at risk of coronary heart disease and deserve LDL cholesterol lowering to the currently recommended targets.” (R. H. Knopp, rhknopp@u.washington.edu)

>>>PNN NewsWatch
* A single manufacturing lot of Roxane’s azathioprine tablets, 50 mg (lot 558470A, expires March 2009) is being recalled nationwide because of concerns that bottles from this lot, labeled as azathioprine, may contain methotrexate 2.5 mg tablets. Pharmacists who may have dispensed azathioprine tablets from manufacturing lot 558470A should contact affected patients to assure they did not inadvertently receive methotrexate tablets.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
July 17, 2006 Vol. 13, No. 135
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from BMJ (www.bmj.org; 2006; 333).
Spironolactone & GI Events: Gastroduodenal ulcers and upper gastrointestinal bleeding were more common among patients taking spironolactone, compared with control patients in a population-based study from the Netherlands (doi: 10.1136/bmj.38883.479549.2F). Using a primary care information database for the 1996–2003 time period, the investigators found: “Within the source population of 306,645 patients, 523 cases of gastric or duodenal ulcer or upper gastrointestinal bleeding were identified and matched to 5,230 controls. Current use of spironolactone was associated with a 2.7-fold (95% confidence interval 1.2 to 6.0) increased risk of a gastrointestinal event.” (K. Verhamme, Erasmus Med. Ctr., Rotterdam, the Netherlands; k.verhamme@erasmusmc.nl)
Managing Acute Conjunctivitis: In an open, randomimzed, controlled trial conducted in 30 southern England general practices, delayed antibiotic prescribing proved to be the most appropriate strategy for managing acute conjunctivitis (doi: 10.1136/bmj.38891.551088.7C). Noting that the delayed chloramphenicol eye drops approach “reduces antibiotic use, shows no evidence of medicalisation, provides similar duration and severity of symptoms to immediate prescribing, and reduces reattendance for eye infections,” the researchers reported these results: “Prescribing strategies did not affect the severity of symptoms but duration of moderate symptoms was less with antibiotics: no antibiotics (controls) 4.8 days, immediate antibiotics 3.3 days (risk ratio 0.7, 95% confidence interval 0.6 to 0.8), delayed antibiotics 3.9 days (0.8, 0.7 to 0.9). Compared with no initial offer of antibiotics, antibiotic use was higher in the immediate antibiotic group: controls 30%, immediate antibiotics 99% (odds ratio 185.4, 23.9 to 1439.2), delayed antibiotics 53% (2.9, 1.4 to 5.7), as was belief in the effectiveness of antibiotics: controls 47%, immediate antibiotics 67% (odds ratio 2.4, 1.1 to 5.0), delayed antibiotics 55% (1.4, 0.7 to 3.0), and intention to reattend for eye infections: controls 40%, immediate antibiotics 68% (3.2, 1.6 to 6.4), delayed antibiotics 41% (1.0, 0.5 to 2.0). A patient information leaflet or eye swab had no effect on the main outcomes. Reattendance within two weeks was less in the delayed compared with immediate antibiotic group: 0.3 (0.1 to 1.0) v 0.7 (0.3 to 1.6).” (H. A. Everitt, U. Southampton, Southampton, U.K.; hae1@soton.ac.uk)

>>>Lancet Highlights
Source:
Early-release articles from Lancet (www.thelancet.com; 2006; 368).
Gender, Smoking, & Mortality: Virtually all of the excess mortality observed among men during the 1990s in several countries can be attributed to the effects of smoking, conclude authors who analyzed data from England, Wales, Canada, U.S., and Poland (doi: 10.1016/S0140-6736(06)68975-7). Based on differences in smoking rates among social strata, the researchers report: “In each country, there was about a two-fold difference between the highest and the lowest social strata in overall risks of dying among men aged 35–69 years (England and Wales 21% vs 43%, USA 20% vs 37%, Canada 21% vs 34%, Poland 26% vs 50%: four-country mean 22% vs 41%, four-country mean absolute difference 19%). More than half of this difference in mortality between the top and bottom social strata involved differences in risks of being killed at age 35–69 years by smoking (England and Wales 4% vs 19%, USA 4% vs 15%, Canada 6% vs 13%, Poland 5% vs 22%: four-country mean 5% vs 17%, four-country mean absolute difference 12%).” (P. Jha, prabhat.jha@utoronto.ca)

>>>PNN NewsWatch
* Disetronic Medical Systems Inc. and FDA have announced a voluntary nationwide recall of the Disetronic D-TRONplus Power Packs that power the D-TRONplus Insulin Pump. The power packs could shut down the D-TRONplus Insulin Pump without any warning, interrupting insulin delivery.

>>>PNN JournalWatch
* Environmental Tobacco Smoke and Mortality in Chinese Women Who Have Never Smoked: Prospective Cohort Study, in BMJ, 2006; doi: 10.1136/bmj.38834.522894.2F. Reprints: www.bmj.org; W. Wen, wanqing.wen@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
July 18, 2006 Vol. 13, No. 136
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
July 18 issue of the Annals of Internal Medicine (www.annals.org; 2006; 145).
Teenage Obesity, Drug Treatment, & Mortality: Two research articles and an editorial explore treatment options and consequences of obesity during adolescence.
Among 498 adolescents with body mass indexes at least 2 units more than the U.S. weighted mean of the 95th percentile for age and sex, sibutramine produced significant weight losses in a 1-year trial, compared with placebo (pp. 81-90). All participants received behavioral therapy specific to the 33 outpatient clinics where they received care. Those also receiving sibutramine lost a mean of 14 pounds during the study (from a baseline mean of 215 pounds), compared with an increase of 4 pounds among patients on placebo. “The sibutramine group had greater improvements in triglyceride levels, high-density lipoprotein cholesterol levels, insulin levels, and insulin sensitivity (P ≤ 0.001 for all),” the investigators add. “The rate of tachycardia was greater with sibutramine vs. placebo (12.5% vs. 6.2%; difference, 6.3 percentage points [CI, 1.0 to 11.7 percentage points]) but did not lead to increased withdrawal (2.4% vs. 1.5%; difference, 0.9 percentage point [CI, –1.7 to 3.5 percentage points]).” (R. I. Berkowitz, Children’s Hosp., Philadelphia;
berkowitz@email.chop.edu)
Premature deaths occur more frequently among younger and middle-aged women when they had moderately higher adiposity at age 18, concludes an analysis of data from the Nurses’ Health Study II (pp. 91-7). Current weight and height and recalled weight at age 18 were recorded in 1989 for 102,400 women aged 25–44 years and free of cancer, and these events were then recorded: “During 12 years of follow-up, 710 participants died. Compared with a BMI of 18.5 to 21.9 kg/m
2 at age 18 years, the hazard ratio for premature death was 0.98 (95% CI, 0.78 to 1.23) for a BMI less than 18.5 kg/m2, 1.18 (CI, 0.97 to 1.43) for a BMI of 22.0 to 24.9 kg/m2, 1.66 (CI, 1.31 to 2.10) for a BMI of 25.0 to 29.9 kg/m2, and 2.79 (CI, 2.04 to 3.81) for a BMI of 30 kg/m2 or greater. Among participants who never smoked, a BMI of 22.0 to 24.9 kg/m2 at age 18 years was also associated with increased premature death (hazard ratio, 1.50 [CI, 1.16 to 1.94]). Associations between BMI at age 18 years and death could only partly be explained by adult BMI measured in 1989.” (R. M. van Dam, rvandam@hsph.harvard.edu)
Commenting on these studies, an editorialist writes (pp. 145-6): “Implementing weight control strategies requires efforts across several settings. Parents should limit access to calorically dense foods and control television-watching time. Clinicians should promote breastfeeding, reduced soft drink intake, reduced television time, and increased physical activity. Schools can restore physical education and provide nutritionally sound choices. Communities should increase access to recreational facilities. These multisectoral and multicomponent strategies to prevent weight gain in children and adolescents may also help to sustain the weight losses that Berkowitz and colleagues worked so hard to achieve in obese adolescents.” (W. H. Dietz,
wcd4@cdc.gov)
Statins & Albuminuria: Statins may have a beneficial effect on pathologic albuminuria, concludes a meta-analysis of 15 studies involving 1,384 patients followed an average of 24 weeks, but “the validity of this finding, and whether this effect translates into reduction of cardiovascular or end-stage renal disease, requires larger studies” (pp. 117-24). The researchers write: “Meta-analysis of the proportional reduction in proteinuria showed that statins reduced albuminuria (11 studies) and proteinuria (4 studies) in 13 of 15 studies. The reduction in excretion was greater among studies with greater baseline albuminuria or proteinuria: change of 2% (95% CI, –32% to 35%) for those with excretion less than 30 mg/d, –48% (CI, –71% to –25%) for those with excretion of 30 to 300 mg/d, and –47% (CI, –67% to –26%) for those with excretion more than 300 mg/d. Statistical heterogeneity was evident only in the group with excretion greater than 300 mg/d (excretion < 30 mg/d, I2 = 23% [P = 0.27]; excretion of 30 to 299 mg/d, I2 = 0% [P = 0.64]; excretion 300 mg/d, I2 = 63% [P = 0.020]).” (K. Douglas, Walter Reed Army Med.Ctr., Washington, D.C.)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 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
July 19, 2006 Vol. 13, No. 137
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
July 19 issue of JAMA (www.jama.com; 2006; 296).
HAART in Children: The impact of combination highly active antiretroviral therapy in children with HIV infection is quantified in a cohort study (pp. 292-300). Comparing 2,767 pediatric patients enrolled in 2001–04 with 3,331 children enrolled in 1988–98, the investigators observe: “Seventy-five percent of the children were enrolled in 2000 and 2001, 90% acquired HIV perinatally, 52% were girls, and 59% were black. The median age was 8.2 years (range, 6–13 years). The median duration of follow-up was 3.4 years. Overall, 553 first episodes of a specific infection occurred among 395 (14%) of the study participants. The number of events for the 4 most common first-time infections and their incidence rates (IRs) per 100 person–years were 123 bacterial pneumonia (IR, 2.15; 95% confidence interval [CI], 1.79–2.56), 77 herpes zoster (IR, 1.11; 95% CI, 0.88–1.39), 57 dermatophyte infections (IR, 0.88; 0.67–1.14), and 52 oral candidiasis (IR, 0.93; 95% CI, 0.70–1.22). Incidence rates of first bacteremia, Pneumocystis jeroveci pneumonia, disseminated Mycobacterium avium complex, lymphoid interstitial pneumonitis, systemic fungal infection, cytomegalovirus retinitis, and tuberculosis were all less than 0.50 per 100 person–years. There were no statistically significant linear trends in incidence for any of the 29 infections over the 4 calendar years. However, infection rates were significantly lower than those reported in the PACTG in the pre-HAART era. The pre-HAART IRs were as follows: for bacterial pneumonia, IR, 11.1; 95% CI, 10.3–12.0; bacteremia, IR, 3.3; 95% CI, 2.9–3.8; herpes zoster, IR, 2.9; 95% CI, 2.6–3.3; disseminated M avium complex, IR, 1.8; 95% CI, 1.5–2.1; P jeroveci, IR, 1.3; 95% CI, 1.1–1.6; oral candidiasis, IR, 1.2; 95% CI, 1.0–1.5; cytomegalovirus retinitis, IR, 0.5; 95% CI, 0.3–0.6; and tuberculosis, IR, 0.2; 95% CI, 0.1–0.4.” (P. Gona, Boston U., Boston; philgona@math.bu.edu)
Editorialists discuss the “substantial benefit but limited access” to HAART (pp. 330-1): “Until now, concerns about providing antiretroviral medications in settings in which the disease is highly prevalent have focused on the costs associated with these programs. Another way to reframe the issue is to consider the costs associated with not providing effective care. In a study from Malawi, 89% of children not receiving treatment for HIV disease were dead by age 3 years. The real economic and moral costs associated with the preventable deaths of large numbers of children and young adults must be considered in the equation. In the past 5 years, the debate has begun to shift from whether these treatments can be provided in developing countries to how these treatments can be provided. Through programs such as the Global Fund for AIDS, TB, and Malaria; the President’s Emergency Plan for AIDS Relief; and the Clinton Foundation HIV/AIDS Initiative, the issues of ‘how’ to provide treatment are gradually being addressed, but these efforts need to be increased substantially. For 2.3 million children living with HIV infection worldwide, the question is not whether or how but when they will receive (and, like their counterparts in the study by Gona et al, benefit from) the therapy that will allow them to reach adulthood.” (J. I. Harwell, MD, Brown Med. Sch., Providence, R.I.;
jharwell@lifespan.org)
Migraine & CVD Risk: Active migraine with aura is associated with increased risk of major cardiovascular disease and related events, concludes a prospective cohort analysis of 27,840 women aged 45 years or older in the Women’s Health Study (pp. 283-91): “During a mean of 10 years of follow-up, 580 major CVD events occurred. Compared with women with no migraine history, women who reported active migraine with aura had multivariable-adjusted hazard ratios of 2.15 (95% confidence interval [CI], 1.58–2.92; P < .001) for major CVD, 1.91 (95% CI, 1.17–3.10; P = .01) for ischemic stroke, 2.08 (95% CI, 1.30–3.31; P = .002) for myocardial infarction, 1.74 (95% CI, 1.23–2.46; P = .002) for coronary revascularization, 1.71 (95% CI, 1.16–2.53; P = .007) for angina, and 2.33 (95% CI, 1.21–4.51; P = .01) for ischemic CVD death. After adjusting for age, there were 18 additional major CVD events attributable to migraine with aura per 10,000 women per year.” (T. Kurth, tkurth@rics.bwh.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
July 20, 2006 Vol. 13, No. 138
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
July 20 issue of the New England Journal of Medicine (content.nejm.org; 2006; 355).
Genetic Predisposition for Diabetes: Common polymorphisms of the transcription factor 7–like 2 gene TCF7L2 were associated with an increased risk of diabetes among 3,548 patients with impaired glucose tolerance who were enrolled in the Diabetes Prevention Program (pp. 241-50). Genotyping and measures of insulin secretion and sensitivity showed the following: “Over an average period of three years, participants with the risk-conferring TT genotype at rs7903146 were more likely to have progression from impaired glucose tolerance to diabetes than were CC homozygotes (hazard ratio, 1.55; 95 percent confidence interval, 1.20 to 2.01; P < 0.001). The effect of genotype was stronger in the placebo group (hazard ratio, 1.81; 95 percent confidence interval, 1.21 to 2.70; P = 0.004) than in the metformin and lifestyle-intervention groups (hazard ratios, 1.62 and 1.15, respectively; P for the interaction between genotype and intervention not significant). The TT genotype was associated with decreased insulin secretion but not increased insulin resistance at baseline. Similar results were obtained for rs12255372.” (J. C. Florez, George Washington U., Rockville, Md.; dppmail@biostat.bsc.gwu.edu)
Editorialists note that this polymorphism may or may not lead to drug development (pp. 306-8): “Does this new genetic information have any practical health implications? At first glance,
TCF7L2 is not the most attractive of drug targets, since it is closely involved in fundamental developmental processes. The main effect of the high-risk single-nucleotide polymorphisms in relation to diabetes may be developmental and may not be amenable to therapeutic manipulation in the adult patient. Nevertheless, the pharmaceutical industry will be looking carefully at agents that modulate the signaling pathways of TCF7L2. Perhaps a more immediate use of this information, in combination with other genetic and nongenetic information, will be in refining a risk profile for diabetes in order to determine the need for and the intensity of follow-up or to influence decisions about staged implementation of preventive interventions with behavioral or drug therapy.” (S. O’Rahilly, U. Cambridge, Cambridge, U.K.)
Gender Gap in Publishing: Women have closed much of the gender gap in authorship of articles in six prominent medical journals, but they remain a minority of first and senior authors, reports a study that assessed authorship in 1970, 1980, 1990, 2000, and 2004 (pp. 281-7). Of 7,249 authors with MD degrees, “The proportion of first authors who were women increased from 5.9 percent in 1970 to 29.3 percent in 2004 (P < 0.001), and the proportion of senior authors who were women increased from 3.7 percent to 19.3 percent (P < 0.001) during the same period,” the authors wrote. “The proportion of authors who were women increased most sharply in Obstet Gynecol (from 6.7 percent of first authors and 6.8 percent of senior authors in 1970 to 40.7 percent of first authors and 28.0 percent of senior authors in 2004) and J Pediatr (from 15.0 percent of first authors and 4.3 percent of senior authors in 1970 to 38.9 percent of first authors and 38.0 percent of senior authors in 2004) and remained low in Ann Surg (from 2.3 percent of first authors and 0.7 percent of senior authors in 1970 to 16.7 percent of first authors and 6.7 percent of senior authors in 2004). In 2004, 11.4 percent of the authors of guest editorials in NEJM and 18.8 percent of the authors of guest editorials in JAMA were women.” (R. Jagsi, reshma_jagsi@post.harvard.edu)

>>>PNN NewsWatch
* The potentially fatal serotonin syndrome can result when triptans for migraine are used with either selective serotonin reuptake inhibitors or selective serotonin/norepinephrine reuptake inhibitors, FDA warned yesterday. Separately, FDA described the treatment challenges when antidepressants are needed during pregnancy in an advisory that incorporates evidence about antidepressant use in pregnancy published in early February (see PNN, Feb. 1, 9).

PNN Pharmacotherapy Line is published via e-mail each business day except 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
July 21, 2006 Vol. 13, No. 139
Providing news and information about medications and their proper use

>>>IOM: Much Can Be Done To Avoid Med Errors
In a follow-up to its well-known 1999 report, “To Err Is Human: Building a Safer Health System,” the Institute of Medicine yesterday released “Preventing Medication Errors.” A part of IOM’s ongoing “Quality Chasm” series, the report updates data on the frequency and severity of medication errors and provides a list of actions that can minimize the chances of being involved in a drug-related mistake.
Cochair of the committee that wrote the report, J. Lyle Bootman of the U. Arizona noted during a news conference, “The American people expect and deserve safe and effective medication care. Our committee has developed an ambitious agenda for making the use of medications safer and ensuring that patients experience the desired clinical results. This agenda requires that all stakeholders—patients, health care providers, payers, industry, and government—commit to working together to prevent medication errors. Given that a large proportion of injurious drug events are preventable, this proposed agenda should deliver early and measurable benefits.”
A paradigm shift is needed in the patient–provider relationship, the committee explained. “One of the most effective ways to reduce medication errors ... is to move toward a model of health care where there is more of a partnership between the patients and the health care providers,” IOM noted in a report summary. “Patients should understand more about their medications and take more responsibility for monitoring those medications, while providers should take steps to educate, consult with, and listen to the patients.” In a fact sheet for patients, the IOM committee advised patients and guardians to do several things: Make sure they know the name of the drug and directions as provided by both the prescriber and pharmacy, know that they can review their list of medications with their pharmacist, know that they have the right to counseling by their pharmacist, and ask for written information about their medications.
The committee also called for greater use of information technologies that can reduce medication errors, including universal use of e-prescriptions by 2010. FDA was also targeted in committee recommendations that called for better labeling and packaging of medications along with attention to look-alike, sound-alike drug names.
Copies of “Preventing Medication Errors” are available from the National Academies Press, 500 Fifth Street, NW, Lockbox 285, Washington, DC 20055; 800/624-6242 or 202/334-3313;
www.nap.edu. The full text of the report can be downloaded for a fee at www.nap.edu.

>>>Allergy Highlights
Source:
July issue of Journal of Allergy and Clinical Immunology (www.jacionline.org; 2006; 118).
Lack of Efficacy of Phenylephrine 10 mg: In a letter, the effectiveness of currently marketed doses of phenylephrine is questioned (pp. 279-80). In 1976, FDA deemed a 10-mg oral dose of phenylephrine safe and effective at relieving congestion, making it possible for companies to use the ingredient without conducting studies. But letter authors write that phenylephrine does not effectively relieve nasal stuffiness at this dose, primarily because the first-pass effect prevents 62% of an absorbed dose from reaching the general circulation. They say FDA cited four tests demonstrating efficacy at the 10-mg dose, two of which were unpublished and sponsored by drug manufacturers. In contrast, FDA cited six tests demonstrating no significant difference between phenylephrine and placebo. The authors provide these therapeutic recommendations to prescribers in their letter: “Healthcare providers can recommend that patients obtain pseudoephedrine from a pharmacist if they require an oral decongestant for sinusitis or eustachian tube dysfunction. For patients with nasal stuffiness from a common cold, they can recommend a topical nasal decongestant, which is more effective than oral decongestants. However, a topical decongestant should be avoided by patients with allergic rhinitis because of the risk of rhinitis medicamentosa. For these patients, an intranasal corticosteroid is likely to provide the greatest relief with low risk of systemic effects.” (L. Hendeles, U. Fla., Gainesville)

PNN Pharmacotherapy Line is published via e-mail each business day except 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
July 24, 2006 Vol. 13, No. 140
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from BMJ (www.bmj.org; 2006; 333).
Postoperative Nausea & Vomiting: Addition of metoclopramide 50 mg to dexamethasone 8 mg is “an effective, safe, and cheap way to prevent postoperative nausea and vomiting,” write investigators who studied 3,140 patients (doi: 10.1136/bmj.38903.419549.80). At four clinics of a university hospital and four district hospitals in Germany, the researchers observed: “Cumulative incidences (95% confidence intervals) of postoperative nausea and vomiting were 23.1% (20.2% to 26.0%), 20.6% (17.8% to 23.4%), 17.2% (14.6% to 19.8%), and 14.5% (12.0% to 17.0%) for 0 mg, 10 mg, 25 mg, and 50 mg metoclopramide. In the secondary analysis, 25 mg and 50 mg metoclopramide were equally effective at preventing early nausea (0-12 hours), but only 50 mg reduced late nausea and vomiting (>12 hours). The most frequent adverse drug reactions were hypotension and tachycardia, with cumulative incidences of 8.8% (6.8% to 10.8%), 11.2% (9.0% to 13.4%), 12.9% (10.5% to 15.3%), and 17.9% (15.2% to 20.6%) for 0 mg, 10 mg, 25 mg, and 50 mg metoclopramide.” (G. Gelbrich , U. Leipzig, Leipzig, Germany; goetz.gelbrich@kksl.uni-leipzig.de)
Furosemide in ARF: Furosemide is of no benefit in the prevention or treatment of acute renal failure, according to results of a meta-analysis of nine randomized trials that included 849 patients (doi: 10.1136/bmj.38902.605347.7C). “Outcome measures not significantly different after [furosemide] treatment were in-hospital mortality (relative risk 1.11, 95% confidence interval 0.92 to 1.33), risk for requiring renal replacement therapy or dialysis (0.99, 0.80 to 1.22), number of dialysis sessions required (weight mean difference -0.48 sessions, –1.45 to 0.50), and proportion of patients with persistent oliguria (urine output <500 ml/day: 0.54, 0.18 to 1.61). Stratifying studies that used [furosemide] to prevent or treat acute renal failure did not change the results on mortality (relative risk ratio 2.10, 95% confidence interval 0.67 to 6.63) and the risk for requiring dialysis (4.12, 0.46 to 37.2). Evidence suggested an increased risk of temporary deafness and tinnitus in patients treated with high doses of [furosemide] (relative risk 3.97, 95% confidence interval 1.00 to 15.78).” (K. M. Ho, Royal Perth Hosp., Perth, Western Australia; kwok.ho@health.wa.gov.au)

>>>PNN NewsWatch
* FDA is warning consumers and health care providers not to use a product called “bismacine,” also known as chromacine. The agency said it is investigating one report of a death and several reports of injury related to the administration of this agent. Bismacine is an injectable product that has been used to treat Lyme disease. But bismacine is not approved for anything, including Lyme disease, FDA cautioned. Bismacine is not a pharmaceutical and is mixed individually by pharmacists. It is prescribed or administered by doctors of “alternative health” or by people claiming to be medical doctors, and it contains high amounts of the heavy metal bismuth, an agent used orally in approved products but not approved for injection.

>>>PNN JournalWatch
* Virological and Immunological Outcomes at 3 Years After Starting Antiretroviral Therapy with Regimens Containing Non-Nucleoside Reverse Transcriptase Inhibitor, Protease Inhibitor, or Both In Initio: Open-Label Randomised Trial, in Lancet, 2006; 368: 287-8. Reprints: www.thelancet.com/journals/lancet/article/PIIS0140673606690740/abstract; A. G. Babiker, Clinical Trials Unit, London; a.babiker@ctu.mrc.ac.uk
* Believability of Relative Risks and Odds Ratios in Abstracts: Cross Sectional Study, in
BMJ, 2006; doi:10.1136/bmj.38895.410451.79. Reprints: http://bmj.bmjjournals.com/cgi/content/abstract/bmj.38895.410451.79v1; P. C. Gøtzsche, Nordic Cochrane Ctr., Copenhagen, Denmark.
* Improving How We Evaluate the Toxicity of Approved Drugs [commentary], in
Clinical Pharmacology & Therapeutics, 2006; 80: 1-6. Reprints: www.sciencedirect.com; M. M. Reidenberg, Cornell U., New York.
* The Prevalence of Weight Concerns in a Smoking Abstinence Clinical Trial, in
Addictive Behaviors, 2006; 31: 1144-52. Reprints: www.sciencedirect.com; M. M. Clark; Clark.matthew@mayo.edu

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 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
July 25, 2006 Vol. 13, No. 141
Providing news and information about medications and their proper use

>>>Idursulfase, Ecamsule Approved by FDA
FDA yesterday announced approval of idursulfase (Elaprase—Shire Human Genetic Therapies) for treatment of Hunter syndrome and of a sunscreen product, Anthelios SX (L’Oreal), that includes a new molecular entity, ecamsule, to provide a sun protection factor (SPF) of 15.
Hunter syndrome (mucopolysaccharidosis II, or MPS II), usually first apparent in children 1–3 years of age, is a disease in which the person’s body is defective in producing iduronate-2-sulfatase, needed to adequately breakdown complex sugars. Symptoms include growth delay, joint stiffness, and coarsening of facial features. In severe cases, patients experience respiratory and cardiac problems, enlargement of the liver and spleen, neurologic deficits, and death.
Idursulfase, an orphan drug, was approved after a randomized, double-blind, placebo-controlled study of 96 patients with Hunter syndrome showed that the treated participants had an improved capacity to walk. At the end of the 53-week trial, patients who received idursulfase infusions experienced on average a 38-yard greater increase in the distance walked in 6 minutes compared with patients on placebo.
The most serious adverse events reported during the trial were potentially life-threatening hypersensitivity reactions to idursulfase. Other frequent but less serious adverse events included fever, headache, and joint pain.
Anthelios SX contains ecamsule, avobenzone, and octocrylene. The latter two ingredients are generally recognized as safe and effective under the current OTC monograph for sunscreens.
The safety and efficacy data for Anthelios SX included information from 28 studies in more than 2,500 patients, ranging in age from 6 months to older than 65 years. Adverse effects reported during clinical studies were infrequent and nonserious, most commonly acne, dermatitis, dry skin, eczema, abnormal redness, itching, skin discomfort, and sunburn.

>>>Internal Medicine Report
Source:
July 24 issue of Archives of Internal Medicine (www.archinternmed.com; 2006; 166).
CAM for Menopause: No complementary and alternative therapy has been consistently effective for treating the symptoms of menopause, concludes a systematic review of 70 randomized controlled trials, but several CAM approaches deserve further study (pp. 1453-65). The authors report that 48 studies of “phytoestrogens and other biologically based agents showed mixed results,” and “smaller numbers of studies using mind–body, energy, manipulative, and body-based therapies and whole medical systems showed little benefit in treating menopausal symptoms.” The group concludes: “Future research should focus on large, rigorously designed trials that ensure reliable comparisons between studies, distinguishing cause and phase of menopause and ethnic differences. Lifestyle modification and mind–body techniques may have high safety profiles and result in additional health benefits. Many alternative therapies used by menopausal women, such as massage, aromatherapy, yoga, and ayurvedic therapy, need to be studied in randomized, controlled trials. It is imperative that future research be directed toward safety and efficacy of the common modalities used by women to treat their menopausal symptoms.” (A. Nedrow, Oregon Health and Science U., Portland; nedrowa@ohsu.edu)
Neuromuscular Disorders Unmasked by Statins: “Latent neuromuscular disorders can be disclosed by statin therapy in presymptomatic patients,” conclude authors who present four cases (pp. 1519-24). “The present case series illustrates that statins may act as unmasking agents in asymptomatic patients with a latent neuromuscular disorder,” the group writes. “Thus, it may be postulated that statin intake may be a sufficient insult to precipitate neuromuscular symptoms and substantially increase muscle enzymes in presymptomatic patients with an abnormal neuromuscular substrate. In conclusion, muscular symptoms or increased serum [creatine kinase] levels persisting after statin treatment discontinuation should alert the clinician to pursue further diagnostic evaluations for the detection of potential underlying neuromuscular diseases.” (K. Spengos, Athens, Greece; spengos@hol.gr)

PNN Pharmacotherapy Line is published via e-mail each business day except 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
July 26, 2006 Vol. 13, No. 142
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
July 26 issue of JAMA (www.jama.com; 2006; 296).
Improving Diabetes Care: Use of nurse specialists or pharmacists as case managers—especially when they are empowered to adjust medications without waiting for physician approval—improves glycemic control among patients with diabetes, according to a meta-regression analysis of 50 randomized controlled trials, 3 quasi-randomized trials, and 13 controlled before–after trials (pp. 427-40). “Across these 66 trials, interventions reduced HbA1c values by a mean of 0.42% (95% confidence interval [CI], 0.29%–0.54%) over a median of 13 months of follow-up,” the investigators report. “Trials with fewer patients than the median for all included trials reported significantly greater effects than did larger trials (0.61% vs 0.27%, P = .004), strongly suggesting publication bias. Trials with mean baseline HbA1c values of 8.0% or greater also reported significantly larger effects (0.54% vs 0.20%, P = .005). Adjusting for these effects, 2 of the 11 categories of [quality improvement] strategies were associated with reductions in HbA1c values of at least 0.50%: team changes (0.67%; 95% CI, 0.43%–0.91%; n = 26 trials) and case management (0.52%; 95% CI, 0.31%–0.73%; n = 26 trials); these also represented the only 2 strategies conferring significant incremental reductions in HbA1c values. Interventions involving team changes reduced values by 0.33% more (95% CI, 0.12%–0.54%; P = .004) than those without this strategy, and those involving case management reduced values by 0.22% more (95% CI, 0.00%–0.44%; P = .04) than those without case management. Interventions in which nurse or pharmacist case managers could make medication adjustments without awaiting physician authorization reduced values by 0.80% (95% CI, 0.51%–1.10%), vs only 0.32% (95% CI, 0.14%–0.49%) for all other interventions (P = .002).” (K. G. Shojania, Ottawa Hosp., Ottawa, Ont., Canada; kshojania@ohri.ca)
Determining Risk Among Patients with VTE: Measurement of thrombin generation can assist in categorizing patients with venous thromboembolism as low or high risk for recurrent VTE, thus avoiding the need for anticoagulation among lower-risk patients (pp. 397-402). In a prospective cohort study of 914 patients with first spontaneous VTE, these results were observed during a mean of 47 months of follow-up after discontinuation of vitamin K antagonist therapy: “Venous thromboembolism recurred in 100 patients (11%). Patients without recurrent VTE had lower thrombin generation than patients with recurrence (mean [SD], 349.2 [108.0] nM vs 419.5 [110.5] nM, respectively; P < .001). Compared with patients who had thrombin generation greater than 400 nM, the relative risk (RR) of recurrence was 0.42 (95% confidence interval [CI], 0.26–0.67; P < .001) in patients with values between 400 nM and 300 nM; for patients with lower values, the RR was 0.37 (95% CI, 0.21–0.66; P = .001). After 4 years, the probability of recurrence was 6.5% (95% CI, 4.0%–8.9%) among patients with thrombin generation less than 400 nM compared with 20.0% (95% CI, 14.9%–25.1%) among patients with higher values (P < .001). Patients with thrombin generation less than 400 nM, representing two thirds of patients, had a 60% lower RR of recurrence than those with greater values (RR, 0.40; 95% CI, 0.27–0.60; P < .001).” (P. A. Kyrle, Med. U., Vienna; paul.kyrle@meduniwien.ac.at)
Early-Onset DM: Onset of type 2 diabetes mellitus during youth is associated with significantly increased risk of death before age 55, concludes a study conducted in Pima Indians in Arizona (pp. 421-6). Among 1,856 participants with diabetes, 96 individuals with youth-onset cases had 15.4 deaths per 1,000 person–years between 25 and 55 years of age, compared with 7.3 deaths per 1,000 person–years in those with later onset. “Compared with nondiabetic participants, the death rate was 3.0 times as high in individuals with youth-onset diabetes mellitus (95% CI, 1.1–8.0) and 1.4 times as high in individuals with older-onset diabetes mellitus (95% CI, 1.1–1.8),” the researchers write. “The longer duration of diabetes by middle age in those diagnosed at younger than 20 years is largely responsible for the higher incidence of ESRD.” (M. E. Pavkov, mpavkov@phx.niddk.nih.gov)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 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
July 27, 2006 Vol. 13, No. 143
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
July 27 issue of the New England Journal of Medicine (content.nejm.org; 2006; 355).
Counseling & Opioid Dependence: Strategies to improve adherence to buprenorphine–naloxone therapy for opioid dependence are needed, conclude authors who found no added benefit from extended weekly counseling and three-times-weekly dispensing of the replacement medications (pp. 365-74). For 166 patients over a 24-week trial, one of three treatments was provided randomly: standard medical management (brief, manual-guided, medically focused counseling) and either once-weekly or thrice-weekly medication dispensing or enhanced medical management (similar to medical management but with extended sessions) and thrice-weekly medication dispensing. Investigators report these results: “The three treatments had similar efficacies with respect to the mean percentage of opioid-negative urine specimens (standard medical management and once-weekly medication dispensing, 44 percent; standard medical management and thrice-weekly medication dispensing, 40 percent; and enhanced medical management and thrice-weekly medication dispensing, 40 percent; P = 0.82) and the maximum number of consecutive weeks during which patients were abstinent from illicit opioids. All three treatments were associated with significant reductions from baseline in the frequency of illicit opioid use, but there were no significant differences among the treatments. The proportion of patients remaining in the study at 24 weeks did not differ significantly among the patients receiving standard medical management and once-weekly medication dispensing (48 percent) or thrice-weekly medication dispensing (43 percent) or enhanced medical management and thrice-weekly medication dispensing (39 percent) (P = 0.64). Adherence to buprenorphine–naloxone treatment varied; increased adherence was associated with improved treatment outcomes.” (D. A. Fiellin, david.fiellin@yale.edu)
Inhaled Nitric Oxide in Preterm Infants: Two research articles and an editorial explore use of nitric oxide in preterm infants.
At 21 centers, infants with birth weights of 1,250 grams or less who required ventilatory support between 7 and 21 days of age were randomly assigned to receive either inhaled nitric oxide or placebo (pp. 343-55). Pulmonary outcomes were better for those receiving nitric oxide, including greater survival rates at 36 weeks of postmenstrual age (43.9% versus 36.8%, P = 0.042), faster discharge (P = 0.04), and shorter time periods during which supplemental oxygen was needed (P = 0.006). No short-term safety concerns were identified. (R. A. Ballard, Children’s Hosp., Philadelphia;
ballard@email.chop.edu)
In a second multicenter, randomized trial, 793 neonates with gestational ages of 34 weeks or less who had respiratory failure requiring mechanical ventilation received either inhaled nitric oxide or placebo (pp. 354-64). While no significant differences were observed in mortality or frequency of bronchopulmonary dysplasia, the investigators found these subgroup improvements: “For infants with a birth weight between 1000 and 1250 g, as compared with placebo, inhaled nitric oxide therapy reduced the incidence of bronchopulmonary dysplasia (29.8 percent vs. 59.6 percent); for the cohort overall, such treatment reduced the combined end point of intracranial hemorrhage, periventricular leukomalacia, or ventriculomegaly (17.5 percent vs. 23.9 percent, P = 0.03) and of periventricular leukomalacia alone (5.2 percent vs. 9.0 percent, P = 0.048). Inhaled nitric oxide therapy did not increase the incidence of pulmonary hemorrhage or other adverse events.” (J. P. Kinsella, Children’s Hosp., Denver;
john.kinsella@uchsc.edu)
An editorialist argues against nitric oxide use (pp. 404-6): “In the most critically ill infants with extremely low birth weights, inhaled nitric oxide does not appear to improve survival or bronchopulmonary dysplasia, and since such treatment may be associated with brain injury or increased mortality in some groups, it cannot be recommended. The two reports in this issue of the
Journal suggest the possibility of benefit in less critically ill infants, but questions remain. The most effective dose, duration, and time of initiation and the selection of infants most likely to benefit remain uncertain.” (A. R. Stark, Tex. Children’s Hosp., Houston)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 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
July 28, 2006 Vol. 13, No. 144
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Aug. issue of Diabetes Care (care.diabetesjournal.org; 2006; 29).
Consensus Statements: A call for action for better glycemic control among inpatients with diabetes (pp. 1955-62; A. J. Garber, Baylor College Of Med., Houston; agarber@bcm.tmc.edu) and management of hyperglycemia in type 2 diabetes (pp. 1963-72; D. M. Nathan, dnathan@partners.org) are topics of two consensus statements from the American Diabetes Association and related organizations.
Continuous Monitoring of Intensive Insulin Therapy in ICUs: A 48-hour continuous glucose monitoring device, GlucoDay, showed that normoglycemia was achieved just 22% of the time among 50 adults receiving intensive insulin therapy in a medical intensive care unit (pp. 1750-6). The patients, 20 of whom were diabetic, were treated with intravenous or subcutaneous insulin, with doses determined through discontinuous glucose monitoring. Continuous subcutaneous monitoring with GlucoDay revealed the following: “During 48-h CGM, glycemia reached target (80–110 mg/dl) in only 22 ± 18%, was >140 mg/dl in 39 ± 27%, and was <60 mg/dl in 5 ± 10% of the time. Patients on subcutaneous versus intravenous insulin had more glycemia readings >110 mg/dl (P = 0.016). Glycemia was higher in diabetic patients (170 ± 77 vs. 129 ± 35 mg/dl, P = 0.013). [Body mass index] was an independent determinant for bad glycemic control (beta = 0.73, P < 0.0001). Diabetic state (beta = 0.47, P < 0.0001), septic shock (beta = 0.22, P = 0.045), sequential organ failure assessment score (beta = 0.40, P = 0.001), and use of corticoids (beta = 0.28, P = 0.014) and inotropics (beta = –0.24, P = 0.035) were independent determinants of insulin dose. GlucoDay values and arterial glycemia correlated well (r = 0.85, P < 0.0001, n = 555 after six-point calibration), with 97% of data falling in regions A and B of error grid analysis. There were no adverse events using GlucoDay.” (C. De Block, Antwerp U. Hosp., Edegem, Belgium; christophe.deblock@ua.ac.be)
Influenza Vaccination: No differences in influenza vaccine effectiveness were found among those with diabetes in the Prevention of Influenza, Surveillance and Management (PRISMA) study of 75,235 patients (pp. 1771-6). Comparing 9,238 adult patients with diabetes with the rest of the participants, the authors report these benefits of influenza vaccination: “Vaccination was associated with a 56% reduction in any complication (95% CI 36–70%), a 54% reduction in hospitalizations (26–71%), and 58% reduction in deaths (13–80%). Among study subjects aged 18–64 years, we observed somewhat higher reductions in the occurrence of any complication than among those aged >65 years (72 vs. 39%). In first-time vaccinated subjects, the primary end point was reduced by 47% (0.2–72%), and in those who received vaccination in the year before, the reduction was 58% (4–81%).” (E. Hak, U. Med. Ctr., Utrecht, the Netherlands; e.hak@umcutrecht.nl)
Chromium Supplements: Chromium supplementation improved insulin sensitivity and glucose control and attenuated weight gain among a group of patients with type 2 diabetes being treated with sulfonylureas (pp. 1826-32). Study participants received glipizide via a gastrointestinal therapeutic system 5 mg/day plus either placebo (n = 12) or chromium picolinate 1,000 mcg/day (n = 17) for 6 months, with these results: “Subjects randomized to sulfonylurea/placebo, as opposed to those randomized to sulfonylurea/CrPic, had a significant increase in body weight (2.2 kg, P < 0.001 vs. 0.9 kg, P = 0.11), percent body fat (1.17%, P < 0.001 vs. 0.12%, P = 0.7), and total abdominal fat (32.5 cm2, P < 0.05 vs. 12.2 cm2, P < 0.10) from baseline. Subjects randomized to sulfonylurea/CrPic had significant improvements in insulin sensitivity corrected for fat-free mass (28.8, P < 0.05 vs. 15.9, P = 0.4), GHb (–1.16%, P < 0.005 vs. –0.4%, P = 0.3), and free fatty acids (–0.2 mmol/l, P < 0.001 vs. –0.12 mmol/l, P < 0.03) as opposed to sulfonylurea/placebo.” (W. T. Cefalu, Pennington Biomedical Res, Ctr., Baton Rouge, La.; cefaluwt@pbrc.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
July 31, 2006 Vol. 13, No. 145
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from BMJ (www.bmj.org; 2006; 333).
Anaphylactic Reactions Due to Iodinated Contrast Media: Life-threatening anaphylactic reactions to iodinated contrast media are rare, conclude authors of a systematic review (doi. 10.1136/bmj.38905.634132.AE). Further, physicians cannot rely on premedication with H1 and/or H2 antihistamines or corticosteroids to prevent serious reactions, even among patients with histories of problematic allergies, the group adds, reporting these results for nine trials that included 10,011 adults with or without allergies: “No reports on death, cardiopulmonary resuscitation, irreversible neurological deficit, or prolonged hospital stays were found. In two trials, 3/778 (0.4%) patients who received oral methylprednisolone 2 x 32 mg or intravenous prednisolone 250 mg had laryngeal oedema compared with 11/769 (1.4%) controls (odds ratio 0.31, 95% confidence interval 0.11 to 0.88). In two trials, 7/3093 (0.2%) patients who received oral methylprednisolone 2 x 32 mg had a composite outcome (including shock, bronchospasm, and laryngospasm) compared with 20/2178 (0.9%) controls (odds ratio 0.28, 0.13 to 0.60). In one trial, 1/196 (0.5%) patients who received intravenous clemastine 0.03 mg/kg and cimetidine 2–5 mg/kg had angio-oedema compared with 8/194 (4.1%) controls (odds ratio 0.20, 0.05 to 0.76).” (M. R. Tramèr, Geneva U. Hosp., Geneva, Switzerland; martin.tramer@hcuge.ch)
Food v. Touch in Growth-Retarded Children: Psychostimulation provided sustained psychological benefits, compared with dietary supplementation, among 129 children with growth retardation at 9–24 months. (doi: 10.1136/bmj.38897.555208.2F). Weekly play sessions with mother and child and weekly supplementation with 1 kg of milk for 2 years were compared, with these results: “Primary analysis indicated that participants who received stimulation had significantly different overall scores from those who did not (F = 2.047, P = 0.049). Supplementation had no significant effect (F = 1.505, P = 0.17). Participants who received stimulation reported less anxiety (mean difference –2.81, 95% confidence interval –5.02 to –0.61), less depression (–0.43, –0.78 to –0.07), and higher self esteem (1.55, 0.08 to 3.02) and parents reported fewer attention problems (–3.34, –6.48 to –0.19). These differences are equivalent to effect sizes of 0.40–0.49 standard deviation.” (S. P. Walker, U. West Indies, Kingston, Jamaica; susan.walker@uwimona.edu.jm)

>>>Lancet Highlights
Source:
July 29 issue of Lancet (www.thelancet.com; 2006; 368).
Gender Differences in Recurrent VTE Risk: After anticoagulation is stopped, men have a 50% higher risk of recurrent venous thromboembolism than do women, according to a meta-analysis of nine randomized controlled trials and six prospective observational studies (pp. 371-8). All 2,729 men and 2,687 women in the studies had objectively diagnosed VTE that had been treated for at least 1 month. Follow-up for recurrence after anticoagulation was stopped showed the following: “The pooled estimate of the relative risk (RR) of recurrent venous thromboembolism for men compared with for women was 1.6 (95% CI 1.2–2.0). Significant heterogeneity was shown among individual study findings; however, the higher risk of recurrent venous thromboembolism in men than in women was consistent across predefined subgroups. The relative risk for recurrence in men from randomised trials (RR 1.3; 95% CI 1.0–1.8) was lower than that from observational studies (2.1; 1.5–2.9). The lower risk of recurrent venous thromboembolism in women did not seem to be accounted for by a reduced rate of recurrence after venous thromboembolism associated with oestrogen treatment or pregnancy.” (S. McRae, Queen Elizabeth Hosp., Woodville, Australia; Simon.Mcrae@imvs.sa.gov.au)

>>>PNN JournalWatch
* Clinical Benefits and Risks Associated with Epoetin and Darbepoetin in Patients with Chemotherapy-Induced Anemia: A Systematic Review of the Literature, in Clinical Therapeutics, 2006; 28: 801-31. Reprints: www.sciencedirect.com; S. D. Ross, MetaWorks, Medford, Mass.; SDR@MetaWorksinc.com
* Tigecycline: First of a New Class of Antimicrobial Agents, in
Pharmacotherapy, 2006; 26: 1099-110. Reprints: www.pharmacotherapy.org; M. J. Rybak, m.rybak@wayne.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
Aug. 1, 2006 Vol. 13, No. 146
Providing news and information about medications and their proper use

>>>Psychiatry Highlights
Source:
Aug. issue of the American Journal of Psychiatry (ajp.psychiatryonline.org; 2006; 163).
Early EPS, Later TD: While concluding that “drug regimens and disease processes that increase extrapyramidal symptoms are likely to result in increased risk of tardive dyskinesia,” researchers were unable to definitively link early antipsychotic-induced EPS with development of TD a year later (pp. 1438-40). Among 9,298 patients in the European Schizophrenia Outpatient Health Outcomes (SOHO) study, researchers noted: “Baseline extrapyramidal symptoms predicted later onset of tardive dyskinesia (broad risk set: hazard ratio = 2.0, narrow risk set: hazard ratio = 1.6). In analyses adjusted for age, gender, and medication exposure, this effect size was not reduced. About half of patients who developed tardive dyskinesia had earlier extrapyramidal symptoms.” (D. E. Tenback)
An editorialist advises clinicians on the use of older and atypical antipsychotic agents (pp. 1316-8): “Although the balance of the data suggest a substantial reduction in the risk of tardive dyskinesia with the second-generation medications, there remain unanswered questions about the differences in relative risk, the role of dose, and comparisons with a variety of different conventional agents. At the same time, the risk of tardive dyskinesia continues to exist and it is important that clinicians maintain appropriate awareness and vigilance for emerging cases regardless of what medication(s) the patient is receiving. In addition, the use of long-term antipsychotic treatment should be well justified with appropriate consideration of alternative treatments. Lowering the dose, discontinuing the implicated agent, or switching to another agent with potentially lower risk should be considered when early signs of abnormal involuntary movements occur. Another important point is that undoubtedly there are individual patient characteristics that contribute to vulnerability, and it is hoped that further progress in pharmacogenetics might ultimately help in reducing existing risk even further.) (J. M. Kane, Hillside Hosp., Glen Oaks, N.Y.;
psychiatry@lij.edu)

>>>Internal Medicine Report
Source:
Early-release articles from the Annals of Internal Medicine (www.annals.org; 2006; 145).
Vitamin/Mineral Supplements: The NIH state-of-the-science conference statement on use of multivitamin/mineral supplements for chronic disease prevention (see PNN, May 18) is published early on the Annals Web site with a systematic review that presents evidence considered at the conference. Authors of the review write: “In a poorly nourished Chinese population, combined supplementation with beta-carotene, alpha-tocopherol, and selenium reduced the incidence of and mortality rate from gastric cancer and the overall mortality rate from cancer by 13% to 21%. In a French trial, combined supplementation with vitamin C, vitamin E, beta-carotene, selenium, and zinc reduced the rate of cancer by 31% in men but not in women. Multivitamin and mineral supplements had no significant effect on cardiovascular disease or cataracts, except that combined beta-carotene, selenium, alpha-tocopherol, retinol, and zinc supplementation reduced the mortality rate from stroke by 29% in the Linxian study and that a combination of 7 vitamins and minerals stabilized visual acuity loss in a small trial. Combined zinc and antioxidants slowed the progression of advanced age-related macular degeneration in high-risk persons.” (H-Y Huang, Johns Hopkins U., Baltimore; hyhuang@jhsph.edu)

>>>PNN NewsWatch
* On the eve of Acting FDA Commissioner Andrew von Eschenbach’s confirmation hearings on Capitol Hill, FDA reversed itself by announcing an apparent intent to approve the emergency contraceptive Plan B for nonprescription sales to women aged 18 years and older. If FDA reaches an acceptable agreement with Barr subsidiary Duramed, the levonorgestrel product would have a unique status, being a prescription product for those younger than 18 and an OTC item with different packaging for older patients. Pharmacists would likely be required to keep the nonprescription product behind the prescription department counter to ensure that younger patients do not obtain Plan B.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Aug. 2, 2006 Vol. 13, No. 147
Providing news and information about medications and their proper use

>>>Pediatrics Highlights
Source:
Aug. issue of Pediatrics (www.pediatrics.org; 2006; 118).
Adverse Drug Reactions Among Hospitalized Children: Measures are needed “to improve detection and reporting of adverse drug reactions by all health care professionals,” conclude authors who assessed reactions among children in a community-based, tertiary care, children’s teaching hospital (pp. 555-62). The 10-year retrospective cohort study showed the following: “A total of 1,087 adverse drug reactions were reported; the overall incidence was 1.6%. The severity of most adverse drug reactions was low (levels 1–3: 89%; high levels 4–6: 11%). Adverse drug reactions with low severity were significantly more common in both the general pediatric unit and the [neonatal intensive care unit]. Adverse reactions resulting from use of antibiotics (particularly penicillins, cephalosporins, and vancomycin) were usually mild. In contrast, adverse drug reactions rated high in severity were significantly more common among reactions that led to hospital admission or occurred during surgery and among certain drug classes, including anticonvulsants and antineoplastic agents. Adverse drug reactions were reported by pharmacists (89%), nurses (10%), and physicians (<1%). Although documentation of physician notification occurred for 93% of adverse drug reactions, only 29% of cases were documented in the patient’s medical chart, 13% included follow-up education for individuals involved, and 10% were updated in the allergy profile of the hospital computer system.” (J. Le, Western U., Pomona, Calif.)
Metoclopramide for GERD in Infants: Evidence in favor of or opposing the use of metoclopramide for gastroesophageal reflux disease in infants is lacking, according to a systematic review of 12 trials (pp. 746-52). Noting that the patient populations in the studies were too varied to permit meta-analysis, the authors report these findings: “Study size ranged from 6 to 77 patients. Eight studies showed patient improvement with metoclopramide in at least 1 measured outcome; 1 study showed worsening symptoms with metoclopramide. Of the 5 randomized, blinded trials, 2 showed no effect of metoclopramide on any outcome, and 2 showed a significant placebo effect. Four studies commented on adverse effects of therapy, with irritability being the most frequently reported potential adverse effect of therapy. Other reported adverse effects included dystonic reactions, drowsiness, oculogyric crisis, emesis, and apnea.... We both agreed on a US Preventive Service Task Force rating of ‘poor’ for the level of evidence, leading to an ‘inconclusive’ recommendation for the safety and efficacy of metoclopramide in infants.” (A. M. Hibbs, Children’s Hosp., Philadelphia)

>>>PNN NewsWatch
* Today’s JAMA (www.jama.com) is a special theme issue on violence and human rights. It includes articles on neuropsychological problems among U.S. Army personnel who have served in Iraq; approaches to screening for intimate partner violence in health care settings; mental health problems among survivors of the tsunami in southern Thailand; and psychological disorders in Kurds who were exposed to chemical warfare during the Iran–Iraq War of the 1980s.
* Similar to a June recall of Triaminic Vapor Patches (see PNN, June 20),
Mentholatum and FDA yesterday announced a nationwide recall of WellPatch Cough & Cold Soothing Vapor Pads because of the possibility that children may remove and chew the patches. This product contains camphor, eucalyptus oil, and menthol. Possible adverse events associated with chewing or ingesting products containing camphor or eucalyptus oils can vary from minor symptoms, such as burning sensation in the mouth, headache, nausea and vomiting, to more severe reactions, such as seizures. Consumers should immediately discontinue use of this product and return it to their point of purchase for a full refund or discard it. The Mentholatum Company Customer Service Department can be contacted at 877/636-2677 or visit www.wellpatch.com. Adverse reactions associated with use of the product should be reported to FDA’s MedWatch program at 800/FDA-1088 or www.fda.gov/MedWatch/report.htm.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Aug. 3, 2006 Vol. 13, No. 148
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Aug. 3 issue of the New England Journal of Medicine (content.nejm.org; 2006; 355)
Measles Outbreak in Indiana: An outbreak of measles among largely home-schooled students who had not been vaccinated is traced to an unvaccinated 17-year-old girl who was incubating measles when she returned from a trip to Romania, report authors of a case-series investigation (pp. 447-55). While measles has been declared eliminated from the U.S., it remains endemic worldwide, the group notes, adding these findings about the largest measles outbreak in this country since 1996: “Approximately 500 persons attended a gathering with the index patient one day after her return home. Approximately 50 lacked evidence of measles immunity, of whom 16 (32 percent) acquired measles at the gathering. During the six weeks after the gathering, a total of 34 cases of measles were confirmed. Of the patients with confirmed measles, 94 percent were unvaccinated, 88 percent were less than 20 years of age, and 9 percent were hospitalized. Of the 28 patients who were 5 to 19 years of age, 71 percent were home-schooled. Vaccine failure occurred in two persons. The virus strain was genotype D4, which is endemic in Romania. Although containment measures began after 20 persons were already infectious, measles remained confined mostly to children whose parents had refused to have them vaccinated, primarily out of concern for adverse events from the vaccine. Seventy-one percent of patients were from four households. Levels of measles-vaccination coverage in Indiana were 92 percent for preschoolers and 98 percent for sixth graders. Estimated costs of containing the disease were at least $167,685, including $113,647 at a hospital with an infected employee.” (A. A. Parker, CDC, Atlanta)
Pharmacogenetic Differences & Antidiabetic Drugs: Among 49 consecutive patients with diabetes caused by Kir6.2 mutations and diagnosed in the first 4 months of life, sulfonylurea therapy proved safe in the short term and possibly more effective than insulin (pp. 467-77). Noting that these patients had KCNJ11 mutations, which impair insulin secretion by causing a failure of the beta-cell KATP channel to close in response to increased intracellular ATP, the authors explain: “This pharmacogenetic response to sulfonylureas may result from the closing of mutant KATP channels, thereby increasing insulin secretion in response to incretins and glucose metabolism.” Results of the study showed the following: “A total of 44 patients (90 percent) successfully discontinued insulin after receiving sulfonylureas. The extent of the tolbutamide blockade of KATP channels in vitro reflected the response seen in patients. Glycated hemoglobin levels improved in all patients who switched to sulfonylurea therapy (from 8.1 percent before treatment to 6.4 percent after 12 weeks of treatment, P<0.001). Improved glycemic control was sustained at one year. Sulfonylurea treatment increased insulin secretion, which was more highly stimulated by oral glucose or a mixed meal than by intravenous glucose. Exogenous glucagon increased insulin secretion only in the presence of sulfonylureas.” (A. T. Hattersley, Peninsula Med. Sch., Exeter, U.K.; andrew.hattersley@pms.ac.uk)
An editorialist describes the possibility of extending this research into other patient groups (pp. 507-10): “It is ... intriguing to consider the role of these mutations in adults with diabetes mellitus. One mutation affecting Kir6.2 has been identified as a cause of transient neonatal diabetes mellitus, childhood diabetes, and the later onset of classic type 2 diabetes mellitus.1 Mutations affecting Kir6.2 and SUR1 have been identified in familial forms of diabetes mellitus; milder mutations may contribute to the clinical appearance of type 2 diabetes mellitus when insulin resistance develops. Hence, genotyping of a large number of patients with type 2 diabetes mellitus may prove rewarding by determining the extent to which patients with Kir6.2 mutations or polymorphisms might benefit from sulfonylurea therapy.” (M. A. Sperling, Children’s Hosp., U. Pittsburgh, Pittsburgh)

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Aug. 4, 2006 Vol. 13, No. 149
Providing news and information about medications and their proper use

>>>Pharmacotherapy Update
Source:
Aug. issue of Pharmacotherapy (www.pharmacotherapy.org; 2006; 26).
Midazolam as Phenotypic Probe: Oral midazolam proved not to be a useful probe for determining cytochrome P450 phenotype and thereby predicting saquinavir or indinavir exposure in a group of 36 healthy volunteers (pp. 1051-9). Using single oral doses of midazolam 8 mg followed by successive administration of the protease inhibitors, the researchers determined: “No correlations between phenotype results for midazolam and any pharmacokinetic parameter for indinavir or saquinavir were identified (r2 = 0.00002–0.073). When the results were analyzed based on race, significant correlations were identified in five African- American subjects, including correlations between 4-hour midazolam levels and apparent oral clearance of saquinavir (r2 = 0.734, p = 0.064), area under the plasma concentration–time curve from 0–8 hours (r2 = 0.914, p = 0.011), minimum concentration (r2 = 0.857, p = 0.024), and maximum concentration (r2= 0.969, p = 0.002). These findings for African-American subjects were not seen with indinavir. No correlation was found between indinavir and saquinavir pharmacokinetic parameters (r2 = 0.017–0.261)....
“Reasons for the lack of correlation likely included differences between midazolam and protease inhibitor P-glycoprotein specificity, differences in the relative contribution of CYP3A5-mediated metabolism, and/or variation in intestinal and hepatic CYP3A specificity. The strong correlation between midazolam phenotype and pharmacokinetic parameters for saquinavir in African-American subjects indicated a racial difference in one or more of these confounding variables.” (S. M. Robertson,
robertsonsa@cc.nih.gov)
Food, Ranitidine, & Saquinavir Kinetics: Although coadministration of saquinavir with food plus ranitidine produced significantly higher plasma concentrations of the antiretroviral agent, the increases were not related to a higher gastric pH, leading authors of a study of 12 healthy men volunteers to conclude that the effect of food on saquinavir bioavailability is not mediated through that mechanism (pp. 1060-8). Of treatments A (ranitidine without food), B (ranitidine plus food), and C (food alone), the authors write: “The highest mean maximum plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC) for saquinavir occurred with treatment B; the lowest Cmax and AUC occurred with treatment A. Compared with treatment C (control), saquinavir’s bioavailability was 15.9% (90% confidence interval [CI] 10–25%) after treatment A and 167% (90% CI 106–265%) after treatment B. Interindividual variability in both Cmax and AUC was slightly greater after treatments A and B than after treatment C. No correlation was found between pharmacokinetic parameters (Cmax and AUC) and gastric pH parameters, including maximum pH and pH at the time of drug delivery.” (T. N. Kakuda, Tibotec, Inc., Yardley, Pa.; TKakuda@tibus.jnj.com)
Review of Antiretroviral Therapy: “The CD4 count and viral load are the most important surrogate markers used to determine if treatment is indicated,” notes an author of a review of antiretroviral therapy (pp. 1111-3). “Current guidelines suggest starting treatment in patients who are symptomatic with an acquired immunodeficiency syndrome–defining illness regardless of CD4 count or viral load, as well as in asymptomatic patients with a CD4 count of 350 cells/mm3 or below.... Within the last 8 years, newer antiretroviral agents have focused on ways to improve adherence, such as convenient dosing (fewer pills), pharmacokinetic and formulation changes to reduce dosing frequency or pill burden, and coformulated dosage forms that contain two or three drugs in one convenient pill. Other improvements include increased potency of newer agents, agents sensitive to a highly resistant virus, improved adverse-effect profile (e.g., less gastrointestinal effects, improved lipid profiles), as well as protease inhibitor boosting with ritonavir, which takes advantage of the potent cytochrome P450 inhibitory action of ritonavir.” (F. J. Piacenti, Lincoln Med. Ctr., Bronx, N.Y.; frank1966@optonline.net)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 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
Aug. 7, 2006 Vol. 13, No. 150
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Aug. 5 issue of Lancet (www.thelancet.com; 2006; 368).
HIV Treatment Interruptions: Results were promising with scheduled interruptions of HIV treatment, yielding lower costs, fewer adverse effects, and no evidence of resistance in a study of 430 patients with HIV-1 infection (pp. 459-65). One of numerous HIV studies in this issue or published online in advance of next week’s International AIDS Society meeting in Toronto, this trial randomized participants to continued therapy (n = 146) or scheduled treatment interruptions (n = 284) for a median of 21.9 months (range 16.4–25.3), with these results: “Drug savings in the scheduled treatment interruption group, compared with continuous treatment, amounted to 61.5%. 257 of 284 (90.5%) patients in the scheduled treatment interruption group reached a viral load less than 50 copies per mL, compared with 134 of 146 (91.8%) in the continued treatment group (difference 1.3%, 95% CI–4.3 to 6.9, p = 0.90). No AIDS-defining events occurred. Diarrhoea and neuropathy were more frequent with continuous treatment; candidiasis was more frequent with scheduled treatment interruption. Ten patients (2.3%) had resistance mutations, with no significant differences between groups.” (B. Hirschel, Geneva U. Hosp., Geneva, Switzerland; bernard.hirschel@hcuge.ch)
First Decade of HAART: Virological response after beginning highly active antiretroviral therapy has improved over the years but without any effect on mortality, conclude investigators who analyzed data on 22,217 treatment-naive, HIV-infected adults who participated in any of 12 cohort studies (pp. 451-8). “The proportion of heterosexually infected patients increased from 20% in 1995–96 to 47% in 2002–03, and the proportion of women from 16% to 32%,” writes the Antiretroviral Therapy (ART) Cohort Collaboration. “The median CD4 cell count when starting HAART increased from 170 cells per µL in 1995–96 to 269 cells per µL in 1998 but then decreased to around 200 cells per µL. In 1995–96, 58% achieved HIV-1 RNA of 500 copies per mL or less by 6 months compared with 83% in 2002–03. Compared with 1998, adjusted hazard ratios for AIDS were 1.07 (95% CI 0.84–1.36) in 1995–96 and 1.35 (1.06–1.71) in 2002–03. Corresponding figures for death were 0.87 (0.56–1.36) and 0.96 (0.61–1.51).” (M. T. May, U. Bristol, Bristol, U.K.; m.t.may@bristol.ac.uk)

>>>BMJ Highlights
Source:
Early-release articles from BMJ (www.bmj.org; 2006; 333).
Ibuprofen After Hip Surgery: Use of NSAIDs as a means of prophylaxis against ectopic bone formation in patients undergoing total hip replacement or revision surgery is not supported by results of a study of 902 patients at 20 centers in Australia and New Zealand (doi: 10.1136/bmj.38925.471146.4F). Compared with placebo, 14 days of ibuprofen 1,200 mg daily showed these results: “There were no significant differences between the groups for improvements in hip pain (mean difference –0.1, 95% confidence interval –0.4 to 0.2, P = 0.6) or physical function (–0.1, –0.4 to 0.2, P = 0.5), despite a decreased risk of ectopic bone formation (relative risk 0.69, 0.56 to 0.83) associated with ibuprofen. There was a significantly increased risk of major bleeding complications in the ibuprofen group during the admission period (2.09, 1.00 to 4.39).” (M. Fransen, George Inst. for Intl. Health, U. Sydney, mfransen@george.org.au)

>>>PNN JournalWatch
* Recent Progress in the Biology of Airway Dendritic Cells and Implications for Understanding the Regulation of Asthmatic Inflammation, in Journal of Allergy and Clinical Immunology, 2006; 118: 331-6. Reprints: www.jacionline.org/article/PIIS0091674906008542/abstract; H. Hammad, Erasmus U., Rotterdam, the Netherlands.
* Idiopathic Pain Disorders–Pathways of Vulnerability, in
Pain, 2006; 123: 226-30. Reprints: www.sciencedirect.com; W. Maixner, bill_maixner@dentistry.unc.edu
* A Multidisciplinary Program for Delivering Primary Care to the Underserved Urban Homebound: Looking Back, Moving Forward, in
Journal of the American Geriatrics Society, 2006; 54: 1283 ff. Reprints: www.blackwell-synergy.com/doi/abs/10.1111/j.1532-5415.2006.00835.x; J. Boal, Mount Sinai Sch. of Med., New York; jeremy.boal@mssm.edu

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 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
Aug. 8, 2006 Vol. 13, No. 151
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
Aug. 1 issue of the Journal of the American College of Cardiology (content.onlinejacc.org; 2006; 48).
Intensive v. Moderate Statin Therapy: Among patients with either stable coronary heart disease or acute coronary syndromes, intensive lipid lowering with high-dose statin therapy provides significant benefits over standard-dose therapy, according to a meta-analysis of the TNT, IDEAL, PROVE IT–TIMI-22, and A-to-Z trials (pp. 438-45). “A total of 27,548 patients were enrolled in the 4 large trials,” the authors write. “The combined analysis yielded a significant 16% odds reduction in coronary death or myocardial infarction (p < 0.00001), as well as a significant 16% odds reduction of coronary death or any cardiovascular event (p < 0.00001). No difference was observed in total or non-cardiovascular mortality, but a trend toward decreased cardiovascular mortality (odds reduction 12%, p = 0.054) was observed.” (C. P. Cannon, cpcannon@partners.org)
Dietary Fish & ECG Changes: Higher dietary fish intake is associated with beneficial changes in cardiac electrophysiology, including heart rate, atrioventricular conduction, and ventricular repolarization (pp. 478-84). Noting that these changes have implications for arrhythmic risk, the researchers report their findings in 5,096 men and women: “Consumption of tuna or other broiled or baked fish (comparing the highest to the lowest category of intake) was associated with lower heart rate (–3.2 beats/min, 95% confidence interval [CI] = 1.3 to 5.1; p trend < 0.001), slower atrioventricular conduction (PR interval +7.2 ms, 95% CI = 1.4 to 12.9; p trend = 0.03), and substantially lower likelihood of prolonged QT (relative risk = 0.50, 95% CI = 0.27 to 0.95; p trend = 0.03). Tuna/other fish intake was not associated with ventricular conduction (p = 0.60). Findings were similar for estimated intake of marine n-3 fatty acids: a 1 g/day higher intake was associated with 2.3 beats/min lower heart rate (95% CI = 0.9 to 3.7), 7.6 ms longer PR interval (95% CI = 3.3 to 11.9), and 46% lower likelihood of prolonged QT (relative risk = 0.54, 95% CI = 0.33 to 0.88).” (D. Mozaffarian, dmozaffa@hsph.harvard.edu)
Ranolazine Added to Amlodipine Antianginal Therapy: The frequency of angina and nitroglycerin consumption were significantly reduced by adjunctive ranolazine in patients who were having three or more anginal attacks per week despite maximum (10 mg) doses of amlodipine (pp. 566-75). In the 6-week study, addition of ranolazine 1,000 mg twice a day produced these results: “A total of 565 patients were randomized: 281 patients to ranolazine and 284 patients to placebo. Baseline characteristics were similar between treatment groups. At baseline, angina frequency averaged 5.63 ± 0.18 episodes/week, and nitroglycerin consumption averaged 4.72 ± 0.21 tablets/week. Compared with placebo, ranolazine significantly reduced frequency of angina episodes (2.88 ± 0.19 on ranolazine vs. 3.31 ± 0.22 on placebo; p = 0.028) and nitroglycerin consumption (2.03 ± 0.20 on ranolazine vs. 2.68 ± 0.22; p = 0.014), with treatment effect that appeared consistent across subgroups. The median angina weekly episode rate at baseline was 4.5 per week. Subgroup analysis showed statistically significant reductions of angina frequency, nitroglycerin use, and [Seattle Angina Questionnaire] angina frequency for patients with a baseline frequency >4.5 per week but only of angina frequency for those with baseline frequency 4.5 per week. Patients with more frequent angina appeared to have a more pronounced treatment effect. No hemodynamic changes were observed. Ranolazine was well tolerated.” (P. H. Stone, pstone@partners.org)
Valvular Heart Disease Guidelines: A 2006 revision to the 1998 ACC/American Heart Assoc. practice guidelines for management of patients with valvular heart disease in adolescents and adults is published (pp. 598-675; e1-e148). Detection, medical and invasive therapies, and prevention of valvular heart disease are covered, including the importance of prophylaxis against rheumatic fever, treatment of patients with atrial fibrillation, and prevention of systemic embolization. The document is also available in the Aug. 1 issue of Circulation. (www.acc.org; www.americanheart.org; S. C. Smith, Jr.)

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Aug. 9, 2006 Vol. 13, No. 152
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Aug. 9 issue of JAMA (www.jama.com; 2006; 296).
Hib Vaccine in Kenya: Within 3 years of the 2001 introduction of Haemophilus influenzae type b (Hib) conjugate vaccine in Kenya, the incidence of Hib disease had been reduced to 12% of its baseline level, according to a surveillance study (pp. 671-8). The vaccine was incorporated into routine childhood immunizations in Nov. 2001, and the researchers found these subsequent trends in culture-documented Hib disease among 38,000 children younger than 5: “Prior to vaccine introduction, the median age of children with Hib was 8 months; case fatality was 23%. Among children younger than 5 years, the annual incidence of invasive Hib disease 1 year before and 1 and 3 years after vaccine introduction was 66, 47, and 7.6 per 100,000, respectively. For children younger than 2 years, incidence was 119, 82, and 16 per 100,000, respectively. In 2004–2005, vaccine effectiveness was 88% (95% confidence interval, 73%–96%) among children younger than 5 years and 87% (95% confidence interval, 66%–6%) among children younger than 2 years. Of 53 children with Hib admitted during 2002–2005, 29 (55%) were age-ineligible to have received vaccine, 12 (23%) had not been vaccinated despite being eligible, and 12 (23%) had received 2 or more doses of vaccine (2 were HIV positive).” (J. A. G. Scott, U. Oxford, Headington, Oxford, U.K.; ascott@ikilifi.net)
HAART Adherence: Self-reports of adherence to highly active antiretroviral therapy shows better results in sub-Saharan Africa than in resource-rich North America (pp. 679-90). Compiling data from published studies and examining them using meta-analysis, the investigators report: “Thirty-one studies from North America (28 full-text articles and 3 abstracts) and 27 studies (9 full-text articles and 18 abstracts) from sub-Saharan Africa were included. African studies represented 12 sub-Saharan countries. Of the North American studies, 71% used patient self-report to assess adherence; this was true of 66% of the African assessments. Studies reported similar thresholds for adherence monitoring (eg, 100%, >95%, >90%, >80%). A pooled analysis of the North American studies (17,573 patients total) indicated a pooled estimate of 55% (95% confidence interval, 49%–62%; I2, 98.6%) of the populations achieving adequate levels of adherence. Our pooled analysis of African studies (12,116 patients total) indicated a pooled estimate of 77% (95% confidence interval, 68%–85%; I2, 98.4%). Study continent, adherence thresholds, and study quality were significant predictors of heterogeneity. Bayesian analysis was used as an alternative statistical method for combining adherence rates and provided similar findings.” (E. J. Mills, Ctr. for Intl. Health and Human Rights Studies, North York, Ontario, Canada; emills@cihhrs.org)
Tracking Progress in Patient Safety: To answer the question “are patients safer now” than when the Institute of Medicine’s medical errors report was released in 1999, a model for measurement of error is needed and several barriers to its implementation must be overcome, write authors of a commentary (pp. 696-9). The model uses two easily captured measures (how often are patients harmed, how often do clinicians provide appropriate interventions) and two measures that “cannot be presented as rates” (have clinicians learned from system defects, how successful are clinicians and health care systems in creating a culture of safety). Five barriers to implementation are described by the writers: Hospitals need staff who understand measurement and epidemiology to collect measures, a problem that might solved through creation of hospital-based departments of epidemiology; payers must determine the costs and benefits of measuring additional patient injuries and both commit the resources and coordinate their efforts with individual health care institutions and clinicians; few valid safety-related process and structural measures currently exist; the science for measuring safety must advance; and the lack of an existing mechanism for data collection and poor performance feedback to front-line caregivers must be addressed. (P. J. Pronovost, Johns Hopkins U., Baltimore; ppronovo@jhmi.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 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
Aug. 10, 2006 Vol. 13, No. 153
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Aug. 10 issue of the New England Journal of Medicine (content.nejm.org; 2006; 355).
High-Dose Atorvastatin Following Stroke or TIA: The overall incidences of strokes and of cardiovascular events were reduced by high-dose atorvastatin among 4,731 patients with recent stroke or transient ischemic attack (pp. 549-59). The patients, whose thromboembolic events had occurred from 1 to 6 months before study entry, had no coronary heart disease, but had LDL cholesterol levels of 100–190 mg/dL. They received either atorvastatin 80 mg daily or placebo.
Despite a small increase in the incidence of hemorrhagic stroke, the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) investigators reported these benefits of statin therapy: “The mean LDL cholesterol level during the trial was 73 mg per deciliter (1.9 mmol per liter) among patients receiving atorvastatin and 129 mg per deciliter (3.3 mmol per liter) among patients receiving placebo. During a median follow-up of 4.9 years, 265 patients (11.2 percent) receiving atorvastatin and 311 patients (13.1 percent) receiving placebo had a fatal or nonfatal stroke (5-year absolute reduction in risk, 2.2 percent; adjusted hazard ratio, 0.84; 95 percent confidence interval, 0.71 to 0.99; P = 0.03; unadjusted P = 0.05). The atorvastatin group had 218 ischemic strokes and 55 hemorrhagic strokes, whereas the placebo group had 274 ischemic strokes and 33 hemorrhagic strokes. The five-year absolute reduction in the risk of major cardiovascular events was 3.5 percent (hazard ratio, 0.80; 95 percent confidence interval, 0.69 to 0.92; P = 0.002). The overall mortality rate was similar, with 216 deaths in the atorvastatin group and 211 deaths in the placebo group (P = 0.98), as were the rates of serious adverse events. Elevated liver enzyme values were more common in patients taking atorvastatin.” (K. M. A. Welch, Rosalind Franklin U. of Med. and Sci., North Chicago, Ill.;
michael.welch@rosalindfranklin.edu)
Writing that stroke provides “an equal opportunity for the initiation of statin therapy,” an editorialist notes (pp. 613-5): “The SPARCL trial is likely to add to the gathering momentum favoring the promotion of ischemic stroke to a ‘coronary heart disease risk equivalent,’ the adoption of statin therapy into guidelines for treatment of ischemic stroke, the enforcement of statin therapy on discharge after a stroke as a ‘quality indicator,’ and the inclusion of statins in preprinted stroke orders to improve adherence by physicians. Those who might object to this collective-treatment approach to such a heterogeneous disease should be reminded of our abysmal performance as individual doctors taking care of individual patients. In one recent study, even among patients who were eligible for statin therapy according to the ATP II guidelines, only one third had discharge medications that included statins. This finding is especially egregious given the evidence that, as with acute myocardial infarction, hospitalization for stroke provides an excellent opportunity to initiate preventive therapy, and leads to rates of adherence higher than those observed when this therapy is initiated during follow-up. Although we can all agree with the calls for careful science, and although we await the various SPARCL substudies to help clarify some controversies, it does not take recursive subgroup analyses to show that the greatest current risk to patients with ischemic stroke vis-à-vis statins remains gross undertreatment.” (D. M. Kent, Tufts–New England Med. Ctr., Boston)
Radical Changes in the Drug-Approval Process: “Economic Darwinism” should be used to improve the drug-approval process in the U.S., writes an author (pp. 618-23). Problems inherent in the current system—including no long-term safety data, no head-to-head comparative studies, Phase 4 studies not fulfilled, uncertainty about conversion of surrogate markers into hard clinical end points, no incentives for drug development with high commercial risk, and no encouragement to make a paradigm shift rather than replicative strategies—can be solved by granting of extended periods of exclusivity for generating new and better types of data and limiting approval periods contingent on meeting research obligations. (A. J. J. Wood, Vanderbilt U., Nashville)

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Aug. 11, 2006 Vol. 13, No. 154
Providing news and information about medications and their proper use

>>>Rheumatology Highlights
Source:
Aug. issue of Arthritis & Rheumatism (www3.interscience.wiley.com; 2006; 54).
Gout & MI: Hyperuricemia and gouty arthritis increase men’s risk of acute myocardial infarction, but not through well-known links such as renal function, metabolic syndrome, diuretic use, and traditional cardiovascular risk factors, according to data from MRFIT, the Multiple Risk Factor Intervention Trial (pp. 2688-96). “Overall, there were 12,866 men in the MRFIT who were followed up for a mean of 6.5 years,” investigators write. “There were 118 events of acute MI in the group with gout (10.5%) and 990 events in the group without gout (8.43%; P = 0.018). Hyperuricemia was an independent risk factor for acute MI in the multivariable regression models, with an odds ratio (OR) of 1.11 (95% confidence interval [95% CI] 1.08–1.15, P < 0.001). In multivariable regressions in which the above risk factors were used as covariates, gout was found to be associated with a higher risk of acute MI (OR 1.26 [95% CI 1.14–1.40], P < 0.001). Subgroup analyses showed that a relationship between gout and the risk of acute MI was present among nonusers of alcohol, diuretics, or aspirin and among those who did not have metabolic syndrome, diabetes mellitus, or obesity. In separate analyses, a relationship between gout and the risk of acute MI was evident among those with and without those hyperuricemia.” (E. Krishnan, U. Pittsburgh, Pittsburgh; Arthritis.MD@gmail.com)
Mortality Rates with SLE: Mortality rates among patients with systemic lupus erythematosus remain elevated, especially among women, younger patients, those shorter SLE duration, and blacks (pp. 2550-7). But deaths from causes primarily related to lupus activity (such as renal disease) have modulated over the years, while deaths from circulatory disease remain just as common, researchers report. From the largest cohort of patients with SLE ever assembled—totaling 9,547 patients at 23 international centers—these standardized mortality ratio data were generated: “The overall SMR was 2.4 (95% confidence interval 2.3–2.5). Particularly high mortality was seen for circulatory disease, infections, renal disease, non-Hodgkin’s lymphoma, and lung cancer. The highest SMR estimates were seen in patient groups characterized by female sex, younger age, SLE duration <1 year, or black/African American race. There was a dramatic decrease in total SMR estimates across calendar-year periods, which was demonstrable for specific causes including death due to infections and death due to renal disorders. However, the SMR due to circulatory diseases tended to increase slightly from the 1970s to the year 2001.” (S. Bernatsky, Montreal General Hosp. Res. Inst., Montreal)
Estradiol & Knee Osteoarthritis: Low levels of endogenous estrogens and estrogen metabolites were associated with development of osteoarthritis of the knee among 842 middle-aged women (pp. 2481-7). The patients, from the Southeast Michigan Arthritis Cohort and with a mean age of 42.3 years and mean body mass index of 28.5 kg/m2, showed these trends: “Women who developed knee OA also had greater odds of having baseline urinary concentrations of 2-hydroxyestrone in the lowest tertile (OR 2.9, 95% CI 1.49–5.68) compared with women with 2-hydroxyestrone concentrations in the middle tertile), after adjustment for covariates. Women who developed knee OA were more likely to have a ratio of 16-alpha-hydroxyestrone to 2-hydroxyestrone in the highest tertile (>0.86; OR 1.86, 95% CI 1.01–3.44 compared with women with ratios in the 0.54–0.86 range), after adjustment for other covariates.” (M. R. Sowers, U. Michigan, Ann Arbor; mfsowers@umich.edu)

>>>PNN NewsWatch
* FDA yesterday said it had sent warning letters to three pharmacies— RoTech Healthcare, Inc., CCS Medical, and Reliant Pharmacy Services—demanding that they stop production of “compounded, unapproved inhalation drugs” and distributing them nationwide. FDA said that millions of doses annually were being made by the firms and that the compounded products were often copies of “FDA-approved, commercially available drugs.”

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Aug. 14, 2006 Vol. 13, No. 155
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release article from BMJ (www.bmj.org; 2006; 333).
Infertility Treatments & Congenital Malformations: While hormonal means of treating infertility may be associated with malformations of newborns’ genitals, a longitudinal study from Denmark indicates that the “underlying infertility or its determinants” are also involved (doi: 10.1136/bmj.38919.495718.AE). Analyzing children born to fertile couples (50,897 singletons and 1,366 twins), infertile couples (defined as those requiring more than 12 months to conceive) who conceived naturally (5,764 singletons and 100 twins), and infertile couples who conceived after infertility treatments (4,588 singletons and 1,690 twins), the researchers report, “Compared with singletons born of fertile couples, singletons born of infertile couples who conceived naturally or after treatment had a higher prevalence of congenital malformations—hazard ratios 1.20 (95% confidence interval 1.07 to 1.35) and 1.39 (1.23 to 1.57). The overall prevalence of congenital malformations increased with increasing time to pregnancy. When the analysis was restricted to singletons born of infertile couples, babies born after treatment had an increased prevalence of genital organ malformations (hazard ratio 2.32, 1.24 to 4.35) compared with babies conceived naturally. No significant differences existed in the overall prevalence of congenital malformations among twins.” (J. L. Zhu, U. Aarhus, Aarhus, Denmark; zjl@soci.au.dk)

>>>AIDS 2006 NewsWatch
* At AIDS 2006 in Toronto (www.aids2006.org), researchers reported that use of tenofovir was safe when used as an HIV preventive among 400 women in Ghana. Efficacy results emerging from the trial showed that 2 women in the tenofovir developed HIV infections during the first 6 months of the study, compared with 6 women in the placebo group. While not statistically significant and not the main focus of this safety study, this lower number of HIV infections with tenofovir is sparking excitement among attendees that an HIV-preventive strategy might be feasible. The CDC also has prevention studies underway (www.cdc.gov/hiv/resources/qa/SafeguardServices.htm).
* Reviewing experiences in nine
tenofovir pre-exposure prophylaxis trials, Y. Halima of the International AIDS Society in London noted that four trials were closed “prematurely,” two because of activist protests (Cambodia, Cameroon), one in Nigeria because of inadequate conditions for research, and one because of concerns related to “implementation of intervention” (Malawi). Halima reported these lessons learned in the trials: “Improved understanding of the complex and sometimes divergent responsibilities of the stakeholder communities including community advocates; considerations and response to gaps in international ethical guidance; and defining progressive models of research that incorporate improved scientific and ethical criteria to ensure that future trials are better equipped, located, and designed.”
* Opening the AIDS 2006 conference, Microsoft’s
Bill Gates told attendees that stopping AIDS is his charitable foundation’s top priority. He also noted the importance of developing a means for women to protect themselves from the AIDS virus, using vaccines, creams, gels, or drugs.
*
MK-0518, an integrase inhibitor under development by Merck, performed well as early treatment of 160 patients with HIV. Given with other antiretroviral agents, MK-0518 produced 85% to 95% virologic response rates after 24 weeks, compared with 92% with efavirenz. MK-0518 blocks HIV DNA integration into human DNA through a >1000-fold selectivity for the HIV integrase enzyme, reported M. Miller of Merck Research Laboratories and colleagues.

>>>PNN JournalWatch
* Advanced Glycation End Products: Sparking the Development of Diabetic Vascular Injury, in Circulation, 2006; 114: 597-605. Reprints: http://circ.ahajournals.org/cgi/content/abstract/114/6/597; M. A. Creager, mcreager@partners.org
* A Multidisciplinary Program for Delivering Primary Care to the Underserved Urban Homebound: Looking Back, Moving Forward, in
Journal of the American Geriatrics Society, 2006; 54: 1283 ff. Reprints: www.blackwell-synergy.com/doi/abs/10.1111/j.1532-5415.2006.00835.x; J. Boal, Mount Sinai Sch. of Med., New York; jeremy.boal@mssm.edu

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 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
Aug. 15, 2006 Vol. 13, No. 156
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Aug. 14/28 issue of the Archives of Internal Medicine (www.archinternmed.com; 2006; 166).
Smoking Cessation with Varenicline: Two research articles and an editorial detail clinical use of varenicline for smoking cessation.
Treatment with this selective nicotinic receptor partial agonist proved at least equivalent to bupropion for smoking cessation in both short- and long-term analyses (pp. 1561-8). These results emerged from this Phase 2 study of 638 healthy adult smokers: “During the treatment phase, the continuous quit rates for any 4 weeks were significantly higher for varenicline tartrate, 1.0 mg twice daily (48.0%; P < .001) and 1.0 mg once daily (37.3%; P < .001), than for placebo (17.1%). The bupropion rate was 33.3% (P = .002 vs placebo). The carbon monoxide–confirmed continuous quit rates from week 4 to week 52 were significantly higher in the varenicline tartrate, 1.0 mg twice daily, group compared with the placebo group (14.4% vs 4.9%; P = .002). The bupropion rate was 6.3% (P = .60 vs placebo). Discontinuation owing to treatment-emergent adverse events was 15.9% for bupropion, 11.2% to 14.3% for varenicline, and 9.8% for placebo. No dose-related increases occurred in adverse events for varenicline.” (M. Nides, Los Angeles Clinical Trials, Los Angeles;
mnides@laclinicaltrials.com)
The second trial, also conducted by the Varenicline Study Group, concluded that the drug is effective for smoking cessation in doses of 0.5 and 1 mg twice daily (pp. 1571-7). Among 647 healthy adult smokers, titrated and nontitrated varenicline doses yielded these results: “Weeks 9 through 12 continuous quit rates were greater in the 1.0-mg group (49.4%) and the 0.5-mg group (44.0%) vs placebo (11.6%; P < .001 vs both doses). Weeks 9 through 52 abstinence rates were greater in the 1.0-mg group (22.4%; P < .001) and the 0.5-mg group (18.5%; P < .001) vs placebo (3.9%). Varenicline was generally well tolerated, with nausea occurring in 16% to 42% of varenicline-treated subjects. Reports of nausea were lower for the titrated vs nontitrated dosing and infrequently led to medication discontinuation.” (C. Oncken, U. Connecticut Health Ctr., Farmington;
ncken@nso2.uchc.edu">oncken@nso2.uchc.edu)
An editorialist writes that the availability of this “new weapon to curb smoking” means there are “no more excuses to delay treatment” (pp. 1547-50): “Pharmacological and immunological studies are opening up new vistas for safe, efficacious, and potent treatments for nicotine dependence. Molecular genetic studies also are investigating how to identify those individuals vulnerable to becoming nicotine dependent and, once they are dependent, the treatments that might work best for them. All these advances will deliver real aid to curbing smoking. Now, a smoker who wants help to quit no longer has a legitimate excuse to delay seeking treatment.” (B. A. Johnson,
bankolejohnson@virginia.edu
Cytisine for Smoking Cessation: Used for 40 years in Eastern Europe, cytisine may be effective for smoking cessation, concludes a literature review and meta-analysis (pp. 1553-9). “Ten studies reported the effects of cytisine on smoking cessation, including 4 controlled studies (3 placebo controlled). Nine studies used the Bulgarian drug Tabex, containing 1.5 mg of cytisine per tablet, and one Russian study used buccal films containing either 1.5 mg of cytisine or 0.75 mg of cytisine plus 0.75 mg of anabasine. All studies were published between 1967 and 2005 in Bulgaria, Germany, Poland, and Russia. There were 4,404 smokers treated with cytisine and 3,518 in control conditions. The pooled odds ratio after 3 to 8 weeks in the 3 placebo-controlled trials (2 were double blind and 1 was randomized) was 1.93 (95% confidence interval, 1.21–3.06). For the 2 placebo-controlled double-blind trials with a longer follow-up, the pooled odds ratio after 3 to 6 months was 1.83 (95% confidence interval, 1.12–2.99). One placebo-controlled double-blind trial had follow-up after 2 years (odds ratio, 1.77; 95% confidence interval, 1.29–2.43). Some adverse effects were reported. Most trials were, however, of poor quality.” (J-F Etter, PhD, U. Geneva, Geneva, Switzerland; jean-francois.etter@imsp.unige.ch)

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Aug. 16, 2006 Vol. 13, No. 157
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Aug. 16 issue of JAMA (www.jama.com; 2006; 296).
Initial HIV Treatment: Addition of abacavir to a three-drug regimen of highly active antiretroviral therapy provided no additional benefit among 765 treatment-naive, HIV-1–infected patients with initial HIV-1 RNA levels of 400 copies/mL or more (pp. 769-81). Comparing zidovudine/lamivudine plus efavirenz with a four-drug regimen consisting of those agents plus abacavir, the AIDS Clinical Trials Group found in its A5095 study: “After a median 3-year follow-up, 99 (26%) of 382 and 94 (25%) of 383 patients receiving the 3-drug and 4-drug regimens, respectively, reached protocol-defined virologic failure; time to virologic failure was not significantly different (hazard ratio, 0.95; 97.5% confidence interval, 0.69–1.33; P = .73). In planned subgroup analyses, increased risk for virologic failure was seen in non–Hispanic black patients (adjusted hazard ratio, 1.66; 95% confidence interval, 1.18–2.34; P = .003). At 3 years, the HIV-1 RNA level was less than 200 copies/mL in 152 (90%) of 169 and 143 (92%) of 156 patients receiving the 3-drug and 4-drug regimens, respectively (P = .59), and less than 50 copies/mL in 144 (85%) of 169 and 137 (88%) of 156 patients (P = .39). CD4 cell count increases and grade 3 or 4 adverse events were not significantly different.” (R. M. Gulick, rgulick@med.cornell.edu)
2006 Adult HIV Treatment Recommendations: The International AIDS Society–USA panel reviews its 2006 treatment recommendations for adult HIV infection in a Clinician’s Corner article (pp. 827-43). In the 25th year since the first report of what would become known as acquired immunodeficiency syndrome, the panel emphasizes adherence to medication therapy as a “crucial” element in successful treatment: “Antiretroviral therapy in adults continues to evolve rapidly, making delivery of state-of-the-art care challenging. Initiation of therapy continues to be recommended in all symptomatic persons and in asymptomatic persons after the CD4 cell count falls below 350/µL and before it declines to 200/µL. A nonnucleoside reverse transcriptase inhibitor or a protease inhibitor boosted with low-dose ritonavir each combined with 2 nucleoside (or nucleotide) reverse transcriptase inhibitors is recommended with choice being based on the individual patient profile. Therapy should be changed when toxicity or intolerance mandate it or when treatment failure is documented. The virologic target for patients with treatment failure is now a plasma HIV-1 RNA level below 50 copies/mL. Adherence to antiretroviral therapy in the short-term and the long-term is crucial for treatment success and must be continually reinforced.” (S. M. Hammer, smh48@columbia.edu)
HIV Regimen Simplification: A preliminary study provides justification for exploring in larger, randomized trials the simplification of maintenance therapy with atazanavir–ritonavir in carefully selected patients with HIV infection (pp. 806-14). In a single-group, open-label, multicenter, 24-week pilot study of 36 HIV-infected adults with virologic suppression for 48 weeks or longer receiving their first protease inhibitor (PI)–based regimen, researchers found: “Thirty-four patients were included in the analysis of the primary end point after 24 weeks: 1 withdrew voluntarily, and 33 continued the regimen. Virologic success (absence of failure) through 24 weeks of simplified therapy occurred in 91% (31 of 34 patients; lower 90% confidence interval limit = 85%). Three participants experienced virologic failure 12, 14, and 20 weeks after simplification, with plasma HIV-1 RNA levels of 4,730, 1,285, and 28,397 copies/mL, respectively. Resistance testing at failure did not identify PI resistance mutations. Plasma atazanavir concentrations at failure were low or below detection in 2 of 3 participants experiencing failure. There were no treatment discontinuations for adverse events after simplification; no significant changes in CD4 cell counts or plasma lipid levels; and no detectable HIV-1 RNA in seminal plasma from all 8 participants tested.” (S. Swindells, U. Nebraska Med. Ctr., Omaha; sswindells@unmc.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
Aug. 17, 2006 Vol. 13, No. 158
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Early-release article and Aug. 17 issue of the New England Journal of Medicine (content.nejm.org; 2006; 355).
Cytokine Storm with Monoclonal Antibody: Following a single intravenous dose of TGN1412 in a Phase 1 trial, six healthy young male volunteers who received developed a systemic inflammatory response that required intensive cardiopulmonary support, high-dose methylprednisolone, and an anti-interleukin-2 receptor antagonist antibody (DOI: 10.1056/NEJMoa063842). Symptoms began within 90 minutes of the dose, with a rapid induction of proinflammatory cytokines and accompanied by headache, myalgias, nausea, diarrhea, erythema, vasodilatation, and hypotension. The study participants were critically ill within 12–16 hours (pulmonary infiltrates and lung injury, renal failure, and disseminated intravascular coagulation), and “severe and unexpected depletion of lymphocytes and monocytes occurred within 24 hours after infusion,” the treating physicians report. While all six men survived, two of them required intensive organ support for 8 and 16 days. TGN1412 is described in the article as “a novel superagonist anti-CD28 monoclonal antibody that directly stimulates T cells.” Two volunteers who received placebo infusions were not affected. (N. Panoskaltsis, Northwick Park and St. Mark’s Hosp., London; n.panoskaltsis@imperial.ac.uk)
Staph. aureus Therapies: Two articles and an editorial analyze options for treating infections caused by Staphylococcus aureus.
For
S. aureus bacteremia and right-sided endocarditis, daptomycin proved not inferior to standard therapy with initial low-dose gentamicin plus either an antistaphylococcal penicillin or vancomycin (pp. 653-65). At 42 days after the end of treatment, the authors found the following: “A successful outcome was documented for 53 of 120 patients who received daptomycin as compared with 48 of 115 patients who received standard therapy (44.2 percent vs. 41.7 percent; absolute difference, 2.4 percent; 95 percent confidence interval, –10.2 to 15.1 percent).... As compared with daptomycin therapy, standard therapy was associated with a nonsignificantly higher rate of adverse events that led to treatment failure due to the discontinuation of therapy (17 vs. 8, P = 0.06). Clinically significant renal dysfunction occurred in 11.0 percent of patients who received daptomycin and in 26.3 percent of patients who received standard therapy (P = 0.004).” (V. G. Fowler, vance.fowler@duke.edu)
At emergency departments in 11 U.S. cities, methicillin-resistant
S. aureus was “the most common identifiable cause of skin and soft-tissue infections,” investigators report, adding, “When antimicrobial therapy is indicated for the treatment of skin and soft-tissue infections, clinicians should consider obtaining cultures and modifying empirical therapy to provide MRSA coverage” (pp. 666-74). Susceptibilites of MRSA isolates ranged from 6% with erythromycin to 100% with rifampin. (G. J. Moran, idnet@ucla.edu)
A decline in the development of new antibiotics, recognition that partial vancomycin resistance may result in some treatment failures among patients with MRSA infections, and emergence of new community-associated MRSA strains are among the problems identified by an editorialist (pp. 724-7). The author maintains that treatment needs to return to a triangle that includes wound culture and narrow-spectrum antibiotics but is weighted in favor of surgical drainage as “the priority intervention” (M. L. Grayson, U. Melbourne, Melbourne, Australia)
Preventing Glucocorticoid-Induced Osteoporosis: Alendronate proved more effective than an active vitamin D3 analogue, alfacalcidol, for prevention of osteoporosis among 201 patients with rheumatic disease who were beginning glucorticoid therapy (pp. 675-84). At 18 months, patients taking alendronate had a significantly greater bone mineral density in the lumbar spine, with the mean difference of 4.0% compared with those taking alfacalcidol. New vertebral deformities occurred in three patients taking alendronate and eight of those on alfacalcidol, and three of the latter patients had symptomatic vertebral fractures. (R. N. J. de Nijs, U. Med. Ctr., Utrecht, the Netherlands; r.denijs@mmc.nl)

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Aug. 18, 2006 Vol. 13, No. 159
Providing news and information about medications and their proper use

>>>JAPhA Highlights
Source:
July/August issue of the Journal of the American Pharmacists Association (www.japha.org, japha.metapress.com; 2006; 46).
Financial Analysis of Wellness Center: In an independent community pharmacy, revenues exceeded expenses for a wellness center providing one or more of nine services (blood pressure [BP], blood glucose, body fat [BF], glycosylated hemoglobin [A1C], bone density [BD], total cholesterol/blood glucose, total lipid panel [TLP], total cholesterol/ high-density lipoprotein, alanine aminotransferase) during a 2-year period (pp. 447-52). From the pharmacy’s perspectives, this economic picture emerged: “A total of 1,181 pharmacy records for the selected services were reviewed for the specified time period. A net financial gain for the wellness center was achieved when the services were performed by a pharmacist, a pharmacy resident, or a pharmacist/pharmacy resident combination, respectively. Three of the individual services (BG, BF and TLP) and assays performed using the Cholestech LDX Analyzer had a net financial gain for each sensitivity analysis. Two of the services (BP and A1C) had a net financial gain only when a resident provided the service. One of the services (BD) had a net financial loss for all of analyses.” (W. R. Doucette, william-doucette@uiowa.edu)
ADHD Medication Interactions with Dextromethorphan: In vivo interactions involving dextromethorphan and atomoxetine are possible, but the cough suppressant does not appear likely to interact with methylphenidate, based on in vitro and ex vivo analysis using a CYP 2D6 probe (pp. 472-8). The investigators report: “Atomoxetine and paroxetine inhibited the formation of dextrorphan by about 50% in human liver microsomes and by more than 80% in recombinant microsomes; the profiles of atomoxetine and the known 2D6 inhibitor paroxetine were similar. High concentrations of dextromethorphan reversed the inhibition of its metabolism, indicating a competitive mechanism of the interaction. Conversely, dextromethorphan and dextrorphan only modestly inhibited atomoxetine and paroxetine metabolism. dl-Methylphenidate did not inhibit dextrorphan formation in either microsome preparation, and dl-methylphenidate metabolism was unaffected by dextromethorphan or dextrorphan.” (P. E. Ciccone, McNeil Pediatrics, Fort Washington, Pa.; pciccon@mccus.jnj.com)
Statin Safety: When prescribing statins for patients who are at elevated risk for adverse effects, including the elderly and those on multiple medications, “clinicians should consider the use of statins that are least likely to interact with other medications,” concludes the author of a review article (pp. 479-90). “The number of patients requiring intensive therapy with statins to achieve lipid goals is climbing, and as the number grows, so does the potential for adverse effects with these agents. The most detrimental adverse effects of statins are hepatotoxicity and myopathy. Liver dysfunction induced by statins is rare and usually mild, with asymptomatic transaminase elevation or acute cholecystitis. Progression to liver failure is exceedingly rare, and transaminase elevations is usually reversible with dose reduction. Statin-associated myopathy is generally a concern when patients have more than one risk factor for muscle syndromes, such as an elderly patient with poor renal function. Drug interactions represent an additional concern, especially for atorvastatin, lovastatin, and simvastatin, all of which are metabolized by the important 3A4 isoenzyme of the cytochrome P450 system of the liver.” (R. L. Talbert, Talbert@uthscsa.edu)
Cardiovascular Risk with Antipsychotic Switches: When patients need to be switched from one second-generation antipsychotic agent to another, the cardiovascular risk varies depending on the specific agents involved (pp. 491-501). The review authors explain: “Depending upon the type of SGA switch, the risk of an adverse cardiovascular event may be lower, as when olanzapine is switched to risperidone, or may increase by as much as 33%, as when risperidone is switched to olanzapine or clozapine.” (L. D. Ried, ried@cop.ufl.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 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
Aug. 21, 2006 Vol. 13, No. 160
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release article from BMJ (www.bmj.org; 2006; 333).
Pharmacist Counseling for Poor Adherence in Polypharmacy: Among 502 patients receiving five or more medications for chronic disease who were not adhering to therapy, telephone counseling by pharmacists improved medication-taking patterns and reduced mortality (doi: 10.1136/bmj.38905.447118.2F). Patients were those among a group of 1,102 patients receiving polypharmacy who did not take 80% to 120% of prescribed daily doses of every drug every day. Results showed the following: “60 of the 502 eligible patients defaulted and only 442 patients were randomised. After two years, 31 (52%) of the defaulters had died, 38 (17%) of the control group had died, and 25 (11%) of the intervention group had died. After adjustment for confounders, telephone counselling was associated with a 41% reduction in the risk of death (relative risk 0.59, 95% confidence interval 0.35 to 0.97; P = 0.039). The number needed to treat to prevent one death at two years was 16. Other predictors included old age, living alone, rate of admission to hospital, compliance score, number of drugs for chronic disease, and non-treatment with lipid lowering drugs at screening visit. In the cohort of 1011 patients, the adjusted relative risk for death was 1.61 (1.05 to 2.48; P = 0.029) and 2.87 (1.80 to 2.57; P < 0.001) in patients with compliance scores of 34–66% and 0–33%, respectively, compared with those who had a compliance score of 67% or more.” (J. C. N. Chan, Chinese U. Hong Kong, Prince of Wales Hosp., Shatin, Hong Kong; jchan@cuhk.edu.hk)

Lancet Highlights
Source:
Aug. 19 issue of Lancet (www.thelancet.com; 2006; 368).
Tobacco Use & MI: Especially in men, tobacco use is “one of the most important causes of [acute myocardial infarction] globally,” conclude authors of a case–control study of 27,089 participants in 52 countries (pp. 647-58). Concluding that “all forms of tobacco use, including different types of smoking and chewing tobacco and inhalation of [second-hand smoke], should be discouraged to prevent cardiovascular diseases,” the INTERHEART study investigators provide these details about their 12,461 cases and 14,637 controls: “Current smoking was associated with a greater risk of non-fatal AMI (odds ratio [OR] 2.95, 95% CI 2.77–3.14, p < 0.0001) compared with never smoking; risk increased by 5.6% for every additional cigarette smoked. The OR associated with former smoking fell to 1.87 (95% CI 1.55–2.24) within 3 years of quitting. A residual excess risk remained 20 or more years after quitting (1.22, 1.09–1.37). Exclusion of individuals exposed to SHS in the never smoker reference group raised the risk in former smokers by about 10%. Smoking beedies alone (indigenous to South Asia) was associated with increased risk (2.89, 2.11–3.96) similar to that associated with cigarette smoking. Chewing tobacco alone was associated with OR 2.23 (1.41–3.52), and smokers who also chewed tobacco had the highest increase in risk (4.09, 2.98–5.61). SHS was associated with a graded increase in risk related to exposure; OR was 1.24 (1.17–1.32) in individuals who were least exposed (1–7 h per week) and 1.62 (1.45–1.81) in people who were most exposed (>21 h per week). Young male current smokers had the highest population attributable risk (58.3%; 95% CI 55.0–61.6) and older women the lowest (6.2%, 4.1–9.2). Population attributable risk for exposure to SHS for more than 1 h per week in never smokers was 15.4% (12.1–19.3).” (S. Yosuf, yusufs@mcmaster.ca)

>>>PNN JournalWatch
* Highly Active Antiretroviral Therapy Interruption: Predictors and Virological and Immunologic Consequences., in Journal of Acquired Immune Deficiency Syndromes, 2006; 42: 554-61. Reprints: www.jaids.com/pt/re/jaids/abstract.00126334-200608150-00005.htm; T. Giota.
* Inappropriate Drug Use and Risk of Transition to Nursing Homes Among Community-Dwelling Older Adults, in
Medical Care, 2006; 44: 722-30. Reprints: www.lww-medicalcare.com/pt/re/medcare/abstract.00005650-200608000-00004.htm; I. H. Zuckerman.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Aug. 22, 2006 Vol. 13, No. 161
Providing news and information about medications and their proper use

>>>Dermatology Highlights
Source:
Aug. issue of the Archives of Dermatology (www.archdermatol.com; 2006; 142).
Low- Versus High-Dose Acitretin: For treating severe psoriasis requiring systemic therapy, low-dose acitretin therapy—using a mean dosage of 25 mg/day—is an effective strategy for reducing adverse effects of this oral retinoid, conclude authors who pooled data from two large pivotal trials (pp. 1000-4). Comparing study participants who received an average of 50 mg/day of acitretin, those on lower doses had fewer adverse effects in the 8- and 16-week trials: “Common adverse effects (dry skin, alopecia, rhinitis, etc) were 2 to 3 times more frequent in subjects receiving 50-mg/d acitretin than in those receiving 25 mg/d. Increases in hepatic enzymes and triglycerides in subjects receiving low-dose therapy were minimal compared with levels in those receiving high-dose therapy.” (S R. Feldman, Wake Forest U, Winston-Salem, N.C.; sfeldman@wfubmc.edu).
Laboratory Abnormalities with Isotretinoin: “The incidence of abnormally high serum lipid levels during isotretinoin treatment may be greater than previously estimated,” conclude authors of a case–control trial of 13,772 patients (pp. 1016-22). Using 1995–2002 records from a northern California managed care plan, the investigators note: “Substantial increases in the cumulative incidence of abnormalities were seen in serum lipid and transaminase levels, but not in hematologic parameters, during isotretinoin treatment compared with the baseline period. The cumulative incidence of new abnormalities in patients with normal values at baseline was 44% for triglyceride level, 31% for total cholesterol level, and 11% for transaminase level. Moderate to severe abnormalities in lipid and transaminase levels were generally transient and reversible. New abnormalities in hematological test results were uncommon.” Based on these findings, the researchers recommend: “Routine monitoring of white blood cell count, hemoglobin level, and platelet count during isotretinoin therapy may be of little utility without clinical suspicion of an abnormality. The clinical significance of laboratory abnormalities during isotretinoin therapy remains to be determined.” (L. T. Zane, ZaneL@derm.ucsf.edu).
Azelaic Acid & Rosacea: Azelaic acid in a 20% cream or 15% gel appears to be effective in treatment of papulopustular rosacea, with efficacy equivalent to if not better than topical metronidazole, according to a systematic review of randomized controlled trials of topical treatments (pp. 1047-52). Meta-analysis could not be performed because standard deviation data were not available for four of five studies, but the authors report these summary findings: “Azelaic acid has been shown to be effective in the treatment of acne vulgaris. In recent years, it has emerged as a potentially effective medication for treating the papulopustular form of rosacea.... The results of our review demonstrate that patients with papulopustular rosacea appear to derive substantial benefit with regard to decreased mean inflammatory lesion count when treated with azelaic acid cream or gel....” (E. R. Farmer, Va. Commonwealth U., Norfolk, Va.; farmerer@cox.net).

>>>PNN NewsWatch
* FDA and GlaxoSmithKline have notified health care professionals of changes to the product labeling for Dexedrine (dextroamphetamine sulfate), approved for the treatment of attention-deficit hyperactivity disorder and narcolepsy. New warnings describe reports of sudden death in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems.
* A special report in
Circulation challenges a recent recommendation of the U.S. Preventive Services Task Force regarding the lack of benefit associated with screening for peripheral arterial disease. Noting that most patients with PAD “have neither classic symptoms of leg claudication nor threatened limbs but have an extraordinarily high rate of adverse cardiovascular events,” authors encourage USPSTF “to reevaluate the extant data, add vascular specialty expertise to its review group, and reconsider its recommendation” (2006; 114:861-6; J. A. Beckman, jbeckman@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
Aug. 23, 2006 Vol. 13, No. 162
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Aug. 23/30 issue of JAMA (www.jama.com; 2006; 296).
Heparin v. LMWHs for VTE Treatment: Fixed-dose subcutaneous unfractionated heparin proved as safe and effective as low molecular weight heparin in 708 patients with acute venous thromboembolism (pp. 935-42). Concluding that heparin “is suitable for outpatient treatment,” the investigators report these results with heparin 333 units/kg initially followed by 250 units/kg every 12 hours and dalteparin or enoxaparin 100 IU/kg every 12 hours: “Recurrent venous thromboembolism occurred in 13 patients in the unfractionated heparin group (3.8%) compared with 12 patients in the low-molecular-weight heparin group (3.4%; absolute difference, 0.4%; 95% confidence interval, –2.6% to 3.3%). Major bleeding during the first 10 days of treatment occurred in 4 patients in the unfractionated heparin group (1.1%) compared with 5 patients in the low-molecular-weight heparin group (1.4%; absolute difference, –0.3%; 95% confidence interval, –2.3% to 1.7%). Treatment was administered entirely out of hospital in 72% of the unfractionated heparin group and 68% of the low-molecular-weight heparin group.” (C. Kearon, kearonc@mcmaster.ca)
An editorialist discusses relative cost of VTE treatments in light of the lack of need for heparin monitoring demonstrated in this study (pp. 991-3): “The question that physicians must now answer is whether this evidence is strong enough to change practice. Specifically, should patients with venous thromboembolism be treated with fixed-dose weight-based subcutaneous unfractionated heparin instead of low-molecular-weight heparin to save money? This approach is appealing because prior trials have demonstrated that unfractionated heparin given by subcutaneous injection is at least as effective and safe as when given by intravenous infusion. Since the study by Kearon et al is the first trial to demonstrate that monitoring of aPTT is not required, the results must be replicated using an adequately powered, double-blind trial design (in which neither physicians or patients know which anticoagulant the patient is receiving) before this approach can be adopted widely in clinical practice. If the patient can be observed very closely, this treatment regimen might be used very cautiously in carefully selected patients who prefer outpatient treatment of venous thromboembolism and cannot afford the expense of low-molecular-weight heparin. However, more than 1 study that demonstrates efficacy of this new treatment regimen is necessary before changing the management strategy for this potentially lethal disease.” (J. L. Carson,
carson@umdnj.edu)
Fusarium Keratitis: The outbreak of cases of Fusarium keratitis in the U.S. that occurred earlier this year (see PNN, May 16) was associated with use of ReNu with MoistureLoc contact lens solution, according to results of an epidemiological investigation (pp. 953-63). Researchers report: “As of June 30, 2006, we identified 164 confirmed case patients in 33 states and 1 US territory. Median age was 41 years (range, 12–83 years). Corneal transplantation was required or planned in 55 (34%). One hundred fifty-four (94%) of the confirmed case patients wore soft contact lenses. Forty-five case patients and 78 controls were included in the case–control study. Case patients were significantly more likely than controls to report using a specific contact lens solution, ReNu with MoistureLoc (69% vs 15%; odds ratio, 13.3; 95% confidence interval, 3.1-119.5). The prevalence of reported use of ReNu MultiPlus solution was similar between case patients and controls (18% vs 20%; odds ratio, 0.7; 95% confidence interval, 0.2-2.8). Fusarium was not recovered from the factory, warehouse, solution filtrate, or unopened solution bottles; production of implicated lots was not clustered in time. Among 39 isolates tested, at least 10 different Fusarium species were identified, comprising 19 unique multilocus genotypes.” Based on the apparent contamination of the product after it left the factory, the authors recommend that users of soft contact lens use optimal hygiene practices (washing and drying hands before handling lenses, storing lenses in new solution after each use, and carefully following directions). (D. C. Chang, Chang@cdc.gov">DChang@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
Aug. 24, 2006 Vol. 13, No. 163
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Aug. 24 issue of the New England Journal of Medicine (content.nejm.org; 2006; 355).
Heparin-Induced Thrombocytopenia: Needed diagnostic studies and treatment are detailed for a 63-year-old man suspected of having heparin-induced thrombocytopenia (pp. 809-17). Presenting with dyspnea following recent bypass surgery for coronary artery disease, physical examination and chest X-ray films were unremarkable. But his platelet count had dropped to 86,000 per mm3, compared with 225,000 per mm3 at discharge 9 days earlier, and CT scan revealed a pulmonary embolism. Serologic assays for detecting HIT rely on detection of circulating IgG, IgA, and IgM antibodies; their negative predictive value is high (greater than 95%), but their positive predictive value varies from 10% to 93%, depending on the population, because the assays detect PF4–heparin antibodies in patients who do not have HIT. No treatment is recommended for patients with positive results but lacking any other disease manifestations, especially thrombocytopenia or thrombosis, the authors note.
The writers recommend, “We would treat this patient with a direct thrombin inhibitor until his platelet counts recover, followed by overlap with the initiation of warfarin therapy. Although data are lacking to guide the optimal duration of treatment for thrombosis related to heparin-induced thrombocytopenia, oral anticoagulant therapy should be continued for three to six months. Documentation of heparin-induced thrombocytopenia should be included in the patient’s medical record, and future exposure to heparin should generally be avoided.” (T. L. Ortel,
thomas.ortel@duke.edu)
Adiposity & Mortality Risk: Two articles and a Perspectives article explore the relationship between overweight and mortality.
An NIH–AARP analysis shows an increased risk of death for those with excess body weight during midlife (pp. 763-78). During 10 years of follow-up for 42,173 men and 19,144 women who were aged 50 to 71 years at enrollment in 1995–96, these results were noted: “In analyses of BMI during midlife (age of 50 years) among those who had never smoked, the associations became stronger, with the risk of death increasing by 20 to 40 percent among overweight persons and by two to at least three times among obese persons.” An overall association between the lowest categories of BMI and increased mortality was attenuated in smokers were excluded from the analysis. (K. F. Adams,
adamske@mail.nih.gov)
A 12-year prospective study of 1.2 million Koreans aged 30 to 95 years found that ideal body weights were in fact best with regard to mortality risk (pp. 779-87): “In both sexes, the average baseline BMI was 23.2, and the rate of death from any cause had a J-shaped association with the BMI, regardless of cigarette-smoking history. The risk of death from any cause was lowest among patients with a BMI of 23.0 to 24.9. In all groups, the risk of death from respiratory causes was higher among subjects with a lower BMI, and the risk of death from atherosclerotic cardiovascular disease or cancer was higher among subjects with a higher BMI. The relative risk of death associated with BMI declined with increasing age.” (S. H. J. Jee, Yonsei U., Seoul, Korea;
jsunha@yumc.yonsei.ac.kr)
A Perspectives article says that baby steps may be enough for many baby boomers, pointing to actions such as cutting out powdered doughnuts and taking the stairs instead of the elevator (pp. 758-60): “As we baby boomers move past 50, we will have to address the reality that excess adiposity substantially increases with advancing age. Fortunately, evidence points to a substantial health benefit from even small changes in weight trajectory, so the achievement of an ideal body weight need not be the primary goal. There are many ways that physicians can help patients to make the critical first step of stopping weight gain. Small steps toward weight control, such as short bursts of activity and discrete changes in eating habits, need not require major lifestyle modification.” (T. Byers, U. Colorado, Denver)

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Aug. 25, 2006 Vol. 13, No. 164
Providing news and information about medications and their proper use

>>>Plan B Creates History With Dual-Status Product
FDA yesterday approved Plan B, the levonorgestrel emergency contraceptive marketed in the U.S. by Barr Laboratories’ subsidiary Duramed, for over-the-counter sales to women aged 18 years and older. However, in a historic decision by FDA, the product will be available to those younger than 18 only by prescription, and Barr has committed to restricting distribution of the product to licensed clinics and pharmacies. APhA applauded FDA’s decision—which adds to a growing number of products that stocked “behind the counter” in U.S. pharmacies, including nicotine and pseudoephedrine products—noting that “pharmacists are uniquely positioned to help manage access to emergency contraception under this unique approach.”
Pharmacists can expect the new dual-label package to become available later this year. It will allow for a prescription label to be adhered to the package when dispensed to women age 17 and younger. Because Plan B will still remain a prescription product for women 17 and younger, it will be sold in community pharmacies from behind the counter. As part of the Plan B OTC approval, Barr reached an agreement with FDA on its CARE (Convenient Access, Responsible Education) program that supports efforts to ensure that Plan B is used responsibly and appropriately. In addition to limited distribution of Plan B, the CARE program will educate health care professionals and consumers within the target age groups regarding the availability and responsible use of Plan B, and the company monitor the effectiveness of the program. In addition, the company intends to work closely with community pharmacies and drug wholesalers to ensure that they understand and follow the FDA’s prescription age requirement for the dispensing of the product.
The age of 18 was reached by FDA based on a number of considerations, not all of them scientific. Since nicotine patches can be purchased without a prescription only by those 18 and older, pharmacy groups argued that this age would be easy to implement. In addition, FDA noted, 18 is the age of majority, and use of emergency contraceptives by minors should be carried out with medical supervision.
In a statement released to the media, APhA referred to the need to respect pharmacists’ individual beliefs on the sensitive subject of emergency contraception: “During the implementation phase of Plan B’s change to OTC status, it will be important for employers to work with pharmacists to develop systems that support a pharmacist’s ability to opt out of working with emergency contraception, while providing a timely alternative for consumers.”

>>>Infectious Diseases Report
Source:
Sept. 15 of Clinical Infectious Diseases (www.journals.uchicago.edu; 2006; 43).
Antirheumatic Drugs & Tuberculosis: Increased risk of tuberculosis was identified among patients with rheumatoid arthritis who were taking biological and/or traditional disease-modifying antirheumatic drugs (pp. 717-22). Using a nested case–control design to evaluate records from 1998 to 2003, the researchers estimated rate ratios of TB with DMARD use in the prior year: “The cohort consisted of 112,300 patients with RA. A total of 386 cases of TB were identified, which resulted in an overall rate of 2.19 cases per 1,000 person–years. The adjusted RR of TB for biological DMARD use is 1.5 (95% CI, 1.1–1.9). Use of traditional DMARDs was also independently associated with TB (RR, 1.2; 95% CI, 1.0–1.5). RRs of developing TB disease with the use of biological or traditional DMARD were lower among current users of corticosteroids than among noncurrent users of corticosteroids.” (P. Brassard, McGill U., Montreal)
Antimicrobe.org: Antimicrobe.org a Web-based version of the textbook Antimicrobial Therapy and Vaccines, volumes I and II, “would be of great benefit to physicians who treat infections on a routine basis,” concludes an invited “Surfing the Web” article (pp. 765-9). The site covers most infectious diseases encountered in practice, is frequently updated, and can be searched using specific questions. (S. D. Burdette, Wright State U., Dayton, Ohio; steve.burdette@wright.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
Aug. 28, 2006 Vol. 13, No. 165
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Aug. 26 issue of Lancet (www.thelancet.com; 2006; 368).
Asthma as Symptom, Not Disease: As part of a theme issue on asthma, Lancet editors surmise that this condition may one day be recognized as a symptom of several other true diseases and that perhaps the best course of action is to eliminate use of the term altogether (p. 705): “The general consensus now emerging is that, even in adults, asthma is unlikely to be a single disease entity. Sally Wenzel describes an approach to distinguish different phenotypes and subphenotypes. Whether these various and overlapping phenotypes simply represent different time points in a single underlying pathological process—airway inflammation—in people with different predispositions who are susceptible to different triggers driven by specific cellular and molecular responses, is unknown. Or perhaps, asthma as a symptom is really only the clinical manifestation of several distinct diseases. As Martinez explains, until the 19th century fever was regarded as a disease and maybe in 20, 30, or 50 years’ time we will look back at asthma in the same way.
“So why wait? Rather than confusing scientists, doctors, and patients even further, is it not time to step out of the straightjacket of a seemingly unifying name that has outlived its usefulness? The conclusion should surely be that it is best to abolish the term asthma altogether.”
Relief from Asthma Exacerbations: Testing the relative contributions of as-needed inhaled corticosteroids and long-acting beta-2 agonists, researchers find that both components contribute to relief from severe exacerbations of asthma (pp. 744-53). In a 12-month trial of 3,394 patients in 20 countries, all of whom were using inhaled corticosteroids at study entry and symptomatic on budesonide–formoterol, investigators randomly assigned patients to receive terbutaline 0.4 mg, formoterol 4.5 mcg, or budesonide 160 mcg plus formoterol 4.5 mcg as relief therapy. With budesonide–formoterol continuing as maintenance therapy, patients had these outcomes: “Time to first severe exacerbation was longer with as-needed budesonide-formoterol versus formoterol (p = 0.0048; log-rank test) and with as-needed formoterol versus terbutaline (p = 0.0051). The rate of severe exacerbations was 37, 29, and 19 per 100 patients per year with as-needed terbutaline, formoterol, and budesonide-formoterol, respectively (rate ratios budesonide-formoterol versus formoterol 0.67 [95% CI 0.56–0.80; p < 0.0001]; budesonide-formoterol versus terbutaline 0.52 [0.44–0.62; p < 0.0001]; formoterol versus terbutaline 0.78 [0.67–0.91; p = 0.0012]). Asthma control days increased to a similar extent in all treatment groups. As-needed formoterol did not significantly improve symptoms compared with as-needed terbutaline. All treatments were well tolerated.” (K. F. Rabe, Leiden U. Med. Ctr., Leiden, the Netherlands; K.F.Rabe@lumc.nl)

>>>PNN JournalWatch
* Telephone Administered Cognitive Behaviour Therapy for Treatment of Obsessive Compulsive Disorder: Randomised Controlled Non-Inferiority Trial, in BMJ, 2006; doi: 10.1136/bmj.38940.355602.80. Reprints: http://bmj.bmjjournals.com/cgi/content/abstract/bmj.38940.355602.80v1; K. Lovell, U. Manchester, Manchester. U.K.; Karina.Lovell@manchester.ac.uk
* Obsessive-Compulsive Disorder, in
BMJ, 2006; 333: 424-9. Reprints: http://bmj.bmjjournals.com/cgi/content/extract/333/7565/424; I Heyman, Inst. of Psychiatry, London; i.heyman@iop.kcl.ac.uk
* Lower Baseline Glycemia Reduces Apparent Oral Agent Glucose-Lowering Efficacy: A Meta-regression Analysis, in
Diabetes Care, 2006; 29: 2137-9. Reprints: http://care.diabetesjournals.org/cgi/content/extract/29/9/2137; Z. T. Bloomgarden, Mount Sinai Sch. of Med., New York; zbloomgard@aol.com
* Nutrition Recommendations and Interventions for Diabetes–2006. A Position Statement of the American Diabetes Association, in
Diabetes Care, 2006; 29: 2140-57. Reprints: http://care.diabetesjournals.org/cgi/content/extract/29/9/2140; American Diabetes Assoc.
* Angiotensin Receptor Blockers May Increase Risk of Myocardial Infarction: Unraveling the ARB-MI Paradox; Angiotensin Receptor Blockers Do Not Increase Risk of Myocardial Infarction [point–counterpoint], in
Circulation, 2006; 114: 838-54; 855-60. Reprints: http://circ.ahajournals.org/current.shtml - CONTROVERSIES_IN_CARDIOVASCULAR_MEDICINE; M. H. Strauss; R. T. Tsuyuki.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Aug. 29, 2006 Vol. 13, No. 166
Providing news and information about medications and their proper use

>>>Circulation Highlights
Source:
Early-release articles and the Aug. 29 issue of Circulation (circ.ahajournals.org; 2006; 114).
Ventricular Arrhythmias & Sudden Death: Guidelines for management of patients with ventricular arrhythmias and prevention of sudden cardiac death are updated (doi: 10.1161/CIRCULATIONAHA.106.178104). Developed by the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines, the guidelines cover all aspects of clinical presentation, diagnosis, and management, including special considerations when antiarrhythmic drugs may be indicated, acute management of specific arrhythmias, ventricular arrhythmias and sudden death, heart failure, and ventricular arrhythmias and sudden death in special populations such as athletes, pregnant women, elderly patients, pediatric patients, patients with implantable cardioverter defibrillators, and patients with digitalis toxicity, drug-induced long QT syndrome, sodium channel blocker–related toxicity, tricyclic antidepressant overdose, and other drug-induced toxicities. (www.acc.org; www.americanheart.org, www.escardio.org)
Angiotensin Blockade & Salt-Dependent Hypertension: Whether hypertension develops as a result of salt or independently of sodium intake may be critical is assessing the need for angiotensin receptor blockade, according to data from a Dahl salt-sensitive model of hypertension (pp. 905-11). Noting that “angiotensin type 1 blockade reduces injury in the L-nitroarginine methyl ester model but increases tissue injury in the salt-sensitive model,” the researcher report these findings with respect to effective and ineffective doses of candesartan cilexetil: “Both low- and high-dose candesartan cilexetil significantly reduced cardiac and renal damage in the nitric oxide synthase inhibitor model of hypertension (P < 0.05 versus untreated); however, high-dose candesartan caused a significant increase in renal damage in the Dahl salt-sensitive model of hypertension (P < 0.05 versus untreated). Interestingly, the beneficial end-organ effects of candesartan in the nitric oxide synthase inhibition model were independent of sustained antihypertensive actions of candesartan, whereas the exacerbation of renal injury with candesartan in the Dahl salt-sensitive model was inversely related to its blood pressure–lowering effect.” (M. A. Pointer, North Carolina Central U. Durham, N.C.; mpointer@nccu.edu)
New Cholesterol Cutpoints for Teens: A new classification system for defining high-risk lipoprotein levels in adolescents is proposed in a study of National Health and Nutrition Examination Survey data (doi: 10.1161/CIRCULATIONAHA.106.620864). Comparing findings with National Cholesterol Education Program cutpoints, the authors report: “A series of growth curves and tables are presented that can be used to diagnose high-risk lipoprotein levels in the clinical and research settings. For example, in 1-year increments for males starting at age 12 and extending to age 19 years, the high-risk thresholds for total cholesterol were 6.03, 5.83, 5.70, 5.70, 5.77, 5.88, 6.02, and 6.16 mmol/L. The corresponding high-risk threshold for adults (20 years) is 6.22 mmol/L.” (I. Janssen, Queen’s U., Kingston, Ontario, Canada; janssen@post.queensu.ca)

>>>PNN NewsWatch
* Alaris Signature Edition Gold infusion pumps, model numbers 7130, 7131, 7230, and 7231, were seized on Friday by U.S. marshalls at FDA’s request at a San Diego manufacturing facility. The seized infusion pumps have a “key bounce” design defect that may cause overinfusion of medications, FDA said. Key bounce occurs when a number pressed on the pump registers twice although the operator only pressed the key once. If a key bounce occurs and is not detected during programming verification, infusion rates may be erroneously increased by at least 10 fold. No products were seized from health care facilities or individual users, and there are no plans to do so, as Alaris has provided interim recommendations to pump users on steps they can take to minimize key entry errors until the problem can be corrected (maintain proper stance, listen for number of beeps, verify screen displays, have unit double checked by another professional, and look at drip rate in tubing.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Aug. 30, 2006 Vol. 13, No. 167
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Sept. issue of Diabetes Care (care.diabetesjournals.org; 2006; 29).
Adherence to Preventive Medications in Prediabetes: Adhering to preventive medications is associated with a reduction in risk of developing diabetes, according to an analysis from the Diabetes Prevention Program (pp. 1997-2002). Focusing on 2,155 adults with impaired glucose tolerance, researchers found these results when adherence to metformin or placebo was assessed: “Older age-groups were more adherent than the youngest group (P = 0.01) in the metformin group. The most frequently reported barrier to adherence was ‘forgetting’ (22%). Women reported more adverse effects of metformin (15 vs. 10%, P = 0.002) in the metformin group. Odds of nonadherence increased as participants reported more than one barrier (odds ratio 19.1, P < 0.001). Odds of adherence increased as participants reported multiple strategies to take medication (2.69, P < 0.0001). There was a 38.2% risk reduction for developing diabetes for those adherent to metformin compared with those adherent to placebo (P < 0.0003).” (E. A. Walker, George Washington U., Rockville, Md.; dppmail@biostat.bsc.gwu.edu)
Targeting Weight Reduction: Intensive lifestyle interventions in patients with type 2 should focus on weight reduction, according to a study of 1,079 Diabetes Prevention Program participants (pp. 2102-7). Beginning with a mean age of 50.6 years and BMI of 33.9 kg/m2, participants showed these results over 3.2 years of follow-up: “Weight loss was the dominant predictor of reduced diabetes incidence (hazard ratio per 5-kg weight loss 0.42 [95% CI 0.35–0.51]; P < 0.0001). For every kilogram of weight loss, there was a 16% reduction in risk, adjusted for changes in diet and activity. Lower percent of calories from fat and increased physical activity predicted weight loss. Increased physical activity was important to help sustain weight loss. Among 495 participants not meeting the weight loss goal at year 1, those who achieved the physical activity goal had 44% lower diabetes incidence.” (R. F. Hamman, George Washington U., Rockville, Md.; dppmail@biostat.bsc.gwu.edu)
Benfotiamine & Vascular Effects of Type 2 Diabetes: A study of 13 people with type 2 diabetes confirms the microvascular and macrovascular damage wrought by a meal high in advanced glycation end (AGE) products and shows that benfotiamine is potential candidate for preventing the endothelial dysfunction caused by increased oxidative stress (pp. 2064-71). Study participants ate a heat-processed test meal with a high AGE content (HAGE; 15.100 AGE kU, 580 kcal, 54 g protein, 17 g lipids, and 48 g carbohydrates) before and after a 3-day therapy with benfotiamine (1,050 mg/day). Results showed the following: “The HAGE induced a maximum reactive hyperemia decrease of –60.0% after 2 h and a maximum [macrovascular flow-mediated dilatation (FMD)] impairment of –35.1% after 4 h, without affecting endothelium-independent vasodilatation. The effects of HAGE on both FMD and reactive hyperemia were completely prevented by benfotiamine. Serum markers of endothelial dysfunction and oxidative stress, as well as AGE, increased after HAGE. These effects were significantly reduced by benfotiamine.” (D. Tschoepe, Heart and Diabetes Center NRW, Bad Oeynhausen, Germany; dtschoepe@hdz-nrw.de)

>>>PNN NewsWatch
* An FDA panel yesterday recommended approval of 17-alpha-hydroxyprogesterone caproate (Gestiva—Adeza Biomedical Corp.), a long-acting progestin used for preventing preterm labor. This morning’s Wall Street Journal reports that FDA granted Gestiva priority review, meaning that a decision will be due on Oct. 20.
*
FDA yesterday approved several Abbreviated New Drug Applications (ANDAs) for generic injectable formulations of ciprofloxacin, AP-rated as bioequivalent to Bayer Corporation Pharmaceutical Division’s Cipro I.V. Ciprofloxacin Injection USP, 10 mg/ mL, indicated for treatment of a variety of infections, is packaged in 20- and 40-mL vials and a 120 mL pharmacy bulk package. These products are manufactured by several generic companies, including Abraxis, Bedford, Hospira, and Sicor.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Aug. 31, 2006 Vol. 13, No. 168
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Aug. 31 issue of the New England Journal of Medicine (content.nejm.org; 2006: 355).
Celecoxib for Preventing Colorectal Adenomas: Two research studies and an editorial explore the utility of celecoxib for prevention of colorectal adenomas in patients at high risk.
While celecoxib is effective for prevention of colorectal adenomas among patients with familial adenomatous polyposis, its use cannot be recommended because of an increase in risk for cardiovascular events. That conclusion was reached in a study of 2,035 patients who received placebo or celecoxib 200 mg or 400 mg twice daily. Colonoscopies at years 1 and 3 showed the following: “The estimated cumulative incidence of the detection of one or more adenomas by year 3 was 60.7 percent for patients receiving placebo, as compared with 43.2 percent for those receiving 200 mg of celecoxib twice a day (risk ratio, 0.67; 95 percent confidence interval, 0.59 to 0.77; P < 0.001) and 37.5 percent for those receiving 400 mg of celecoxib twice a day (risk ratio, 0.55; 95 percent confidence interval, 0.48 to 0.64; P < 0.001). Serious adverse events occurred in 18.8 percent of patients in the placebo group, as compared with 20.4 percent of those in the low-dose celecoxib group (risk ratio, 1.1; 95 percent confidence interval, 0.9 to 1.3; P = 0.5) and 23.0 percent of those in the high-dose group (risk ratio, 1.2; 95 percent confidence interval, 1.0 to 1.5; P = 0.06). As compared with placebo, celecoxib was associated with an increased risk of cardiovascular events (risk ratio for the low dose, 2.6; 95 percent confidence interval, 1.1 to 6.1; and risk ratio for the high dose, 3.4; 95 percent confidence interval, 1.5 to 7.9).” (pp. 873-84). (M. M. Bertagnolli,
mbertagnolli@partners.org)
In the Prevention of Colorectal Sporadic Adenomatous Polyps trial, celecoxib 400 mg once daily significantly reduced the occurrence of colorectal adenomas within 3 years after polypectomy (pp. 885-95). Among 1,561 participants who randomly received celecoxib 400 mg daily (n = 933) or placebo (n = 628) for 3 years after removal of adenomas, researchers observed: “Colonoscopies were performed at year 1 on 88.7 percent of the subjects who had undergone randomization and at year 3 on 79.2 percent. Of the 557 subjects in the placebo group and the 840 subjects in the celecoxib group who were included in the efficacy analysis, 264 and 270, respectively, were found to have at least one adenoma at year 1, at year 3, or both. The cumulative rate of adenomas detected through year 3 was 33.6 percent in the celecoxib group and 49.3 percent in the placebo group (relative risk, 0.64; 95 percent confidence interval, 0.56 to 0.75; P < 0.001). The cumulative rate of advanced adenomas detected through year 3 was 5.3 percent in the celecoxib group and 10.4 percent in the placebo group (relative risk, 0.49; 95 percent confidence interval, 0.33 to 0.73; P < 0.001). Adjudicated serious cardiovascular events occurred in 2.5 percent of subjects in the celecoxib group and 1.9 percent of those in the placebo group (relative risk, 1.30; 95 percent confidence interval, 0.65 to 2.62).” (B. Levin, U. Texas M.D. Anderson Cancer Ctr., Houston)
The increased rate of cardiovascular events associated with use of celecoxib precludes its use for prevention of adenomas and adenomatous polyps, writes a pair of editorialists (pp. 950-2): “These two trials provide strong evidence that among patients with colonic adenomas, the use of celecoxib for up to three years reduces the risk of metachronous adenoma. These placebo-controlled trials were too small to evaluate the role of celecoxib in preventing colorectal cancer. Nevertheless, in these same studies, significant cardiovascular risks were demonstrated. In patients with adenomas who undergo repeated colonoscopies, the increase in cardiovascular events caused by celecoxib outweighs what may be an optimistic projection of its potential benefit in decreasing colorectal-cancer events. It is reasonable to conclude that celecoxib has no role as a chemopreventive agent either in patients with nonfamilial colonic adenomas or in the general population.” (B. M. Psaty, U. Washington, Seattle)

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Sept. 1, 2006 Vol. 13, No. 169
Providing news and information about medications and their proper use

>>>Psychiatry Highlights
Source:
Sept. issue of the American Journal of Psychiatry (ajp.psychiatryonline.org; 2006; 163).
Lithium, Thyronine Supplementation for Depression: For patients not responsive to several trials of antidepressants, triiodothyronine supplementation may provide a better therapeutic option than lithium, report researchers from the STAR*D trial (pp. 1519-30). For 142 adult outpatients with major depressive disorder who had not achieved remission with two optimally delivered trials of antidepressants, researchers provided either lithium in doses of up to 900 mg/day or T3 in doses of up to 50 mcg/day. Results showed the following: “After a mean of 9.6 weeks (SD = 5.2) of treatment, remission rates were 15.9% with lithium augmentation and 24.7% with T3 augmentation, although the difference between treatments was not statistically significant. Lithium was more frequently associated with side effects (p = 0.045), and more participants in the lithium group left treatment because of side effects (23.2% versus 9.6%; p = 0.027).” (A. A. Nierenberg for the STAR*D Study Team)
Quoting President Theodore Roosevelt (“keep your eyes on the stars, and your feet on the ground&rdquoWinking, an editorialist writes that psychiatrists need to “keep [their] eyes on STAR*D” by noting its results but also considering whether study methods make findings applicable to individual patients (pp. 1484-6): “Even the narrow conclusion that T
3 is superior to lithium after two failed trials may be problematic, given the manner in which lithium was administered in the study. Lithium doses were capped at 900 mg/day, and blood levels were not routinely tested. Among tested patients, only half had levels ≥0.6 meq/liter. While low lithium doses have been used in some augmentation studies, a meta-analysis indicates that higher doses are associated with greater efficacy. Lithium is also one of the few drugs with evidence for a specific antisuicide effect, an important consideration when treating patients with major depressive disorder.” (M. Valenstein; marciav@med.umich.edu)
Psychotherapy v. Pharmacotherapy for Later-Life Depression: In a meta-analysis of 89 controlled studies of acute major depression and other depressive disorders in older adults, psychotherapy and pharmacotherapy showed no “strong differences in effect sizes,” leading researchers to conclude that “treatment choice should be based on other criteria, such as contraindications, treatment access, or patient preferences” (pp. 1493-501). Warning that “comparisons of psychotherapy and pharmacotherapy must be interpreted with caution, in part because medication studies are more likely to use a credible active placebo, which may lead to smaller adjusted effect sizes in medication studies,” the authors report these results for the 5,328 study participants: “Clinician-rated depression scores improved, on average, by 0.80 standard deviation (SD) units; self-rated depression scores improved by 0.76 SD units. Clinician-rated depression improved by 0.69 SD units in pharmacotherapeutic studies and by 1.09 SD units in psychotherapeutic studies. Self-rated depression improved by 0.62 SD units and 0.83 SD units, respectively. An interesting finding was the stronger improvements in clinician-rated depression among control subjects participating in medication studies, compared to those in psychotherapeutic studies.” (M. Pinquart)

>>>PNN NewsWatch
* Generic sales of clopidogrel have been stopped as a result of a preliminary injunction issued yesterday against Apotex Corp. Sanofi Aventis and Bristol-Myers Squibb had asked a federal district court to also order a recall of generic forms of Plavix that have already been shipped, but the judge refused.
* Another Sanofi Aventis drug,
dronedarone (Multaq), was not approved by FDA for treatment of atrial fibrillation. Clinical trials of the drug had been halted at one point in 2003 when patients in a treatment arm appeared to have a higher mortality rate than the placebo group, and the Wall Street Journal reports this morning that the agency has now issued a nonapprovable letter for the new chemical entity.
*
PNN will not be published on Mon., Sept. 4, Labor Day.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 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
Sept. 5, 2006 Vol. 13, No. 170
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Early-release articles from and Sept. 2 issue of Lancet (www.thelancet.com; 2006; 368).
High-Dose Statins in Metabolic Syndrome: Patients with coronary heart disease and metabolic syndrome benefit from high-dose atorvastatin therapy, regardless of whether they also have diabetes, according to a new analysis from the Treating to New Targets (TNT) study (DOI: 10.1016/S0140-6736(06)69292-1). All 10,001 patients in TNT had clinically evident CHD; they were 35–75 years in age and were followed a median of 4.9 years. Analyzed in this report were 5,584 patients who met ATP III criteria for metabolic syndrome.
Comparing atorvastatin 80 mg/day with placebo, the investigators found these results based on a primary outcome of time to first major cardiovascular event, defined as death from coronary heart disease, nonfatal nonprocedure-related myocardial infarction, resuscitated cardiac arrest, or fatal or nonfatal stroke: “Mean on-treatment low-density lipoprotein cholesterol concentrations at 3 months were 2.6 mmol/L (99.3 mg/dL) with atorvastatin 10 mg, and 1.9 mmol/L (72.6 mg/dL) with atorvastatin 80 mg. At a median follow-up of 4.9 years, major cardiovascular events occurred in 367 (13%) patients receiving atorvastatin 10 mg, compared with 262 (9.5%) receiving atorvastatin 80 mg (hazard ratio 0.71; 95% CI 0.61–0.·84; p < 0.0001). Irrespective of treatment assignment, significantly more patients with metabolic syndrome (11.3%) had a major cardiovascular event at a median of 4.9 years than those without metabolic syndrome (8.0%; hazard ratio 1.44; 95% CI 1.26–1.64; p < 0.0001). This increased risk was significantly reduced by intensive therapy with atorvastatin 80 mg beyond that achieved with atorvastatin 10 mg.” (P. Deedwania,
pdeedwania@fresno.ucsf.edu)
Chaperonin 10 for Rheumatoid Arthritis: Chaperonin 10, a heat shock protein (XToll) that inhibits Toll-like receptor signalling pathways, was well tolerated and effective for treating symptoms of rheumatoid arthritis in a small, short-term study (pp. 855-63). A total of 23 patients with moderate to severe active rheumatoid arthritis receiving disease-modifying antirheumatic drugs randomly received intravenous chaperonin 10 twice weekly for 12 weeks at doses of 5, 7.5, or 10 mg, with these changes in disease activity scores (DAS28) and core disease measures: “Primary endpoint measures improved from day 14 in all groups and continued to improve to day 84. By end of study, a 20% improvement of core disease measures was seen in six (86%, 95% CI 43–100), a 50% improvement in four (57%, 14–86), and a 70% improvement in two (29%, 0–57) patients given the highest dose of chaperonin 10. Clinical remission (as defined by a DAS28 <2.6) was achieved in three (13%) of 23 patients. Three individuals dropped out during the study: one in the 5 mg group (rheumatoid arthritis not controlled), one in the 7.5 mg group (adverse event), and one in the 10 mg group (lost to follow-up). The most common adverse events were exacerbation of rheumatoid arthritis (both during and after the study) and upper respiratory tract infection. Only one adverse event was judged to be of severe intensity.” (D. Feeney, CBio, Ltd., Queensland, Australia; dennis.feeney@cbio.com.au)

>>>PNN JournalWatch
* Meta-Analysis: Convalescent Blood Products for Spanish Influenza Pneumonia: A Future H5N1 Treatment?, in Annals of Internal Medicine, 2006; 145 (early release). Reprints: www.annals.org/cgi/content/full/0000605-200610170-00139v1; S. L. Hoffman, Protein Potential LLC, Rockville, Md.; slhoffman@protpot.com
* Churg-Strauss Syndrome in Children: A Clinical and Pathologic Review, in
Pediatrics, 2006; 118: e914-20. Reprints: http://pediatrics.aappublications.org/cgi/content/abstract/118/3/e914; D. Boyer, Children’s Hosp., Boston.
* Intravenous Injection of Pharmaceutical Tablets Presenting as Multiple Pulmonary Nodules and Declining Pulmonary Function in an Adolescent with Cystic Fibrosis, in
Pediatrics, 2006; 118: e924-8-. Reprints: http://pediatrics.aappublications.org/cgi/content/abstract/118/3/e924; K. J. Smith, Tex. Children’s Hosp., Houston.
* Cardiovascular Biomarkers in CKD: Pathophysiology and Implications for Clinical Management of Cardiac Disease, in
American Journal of Kidney Diseases, 2006; 48: 341-60. Reprints: www.ajkd.org/article/PIIS0272638606010717/abstract; F. L. Ierino, Austin Health, Heidelberg, Victoria, Australia; frank.ierino@austin.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
Sept. 6, 2006 Vol. 13, No. 171
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Sept. 6 issue of JAMA, a theme issue on medical education (www.jama.com; 2006; 296).
ADR Reporting by Physicians: Among 6,451 physicians practicing in northern Portugal, 1-hour educational outreach visits improved high-quality reporting of adverse drug events (pp. 1086-93). Comparing four spatial clusters in the intervention group with 11 clusters in the control group, the investigators report: “At baseline, ADR reporting rates (per 1,000 physician–years) did not differ significantly between the intervention groups and the control groups in reporting ADRs overall (7.6 vs 11.3), nor did they differ significantly by category: serious, 4.3 vs 6.0; high-causality, 5.4 vs 7.6; unexpected, 1.6 vs 3.5; and new-drug-related ADRs, 3.7 vs 3.8. (P > .05 for all comparisons). The control group had no significant increase in ADR reports during follow-up. The adjusted increase in ADR reporting rates attributable to intervention was 90.19 for total ADRs (95% confidence interval [CI], 54.51–125.87; relative risk [RR], 10.23; 95% CI, 3.81–27.51), 30.16 for serious ADRs (95% CI, 18.84–41.47; RR, 6.32; 95% CI, 2.09–19.16), 64.90 for high-causality ADRs (95% CI, 38.38-91.42; RR, 8.75; 95% CI, 3.05–25.07), 28.04 for unexpected ADRs (95% CI, 16.25–39.83; RR, 30.21; 95% CI, 4.54–200.84), and 42.17 for new-drug-related ADRs (95% CI, 21.58–62.76; RR, 8.05; 95% CI, 2.10–30.83). The greatest difference occurred during the first 4 months after intervention, but differences remained statistically significant for 12 months.” (A. Figueiras, Facultad de Medicina, Santiago de Compostela (A Coruña), Spain; adolfo.figueiras@usc.es)

>>>Internal Medicine Report
Source:
Early-release articles from and Sept. 5 issue of Annals of Internal Medicine (www.annals.org; 2006; 145).
Smoking Cessation: Community-based interventions and efforts initiated systematically in health systems are among the smoking-cessation approaches reviewed in an NIH State-of-the-Science conference statement on tobacco use (early release). Other topics addressed by the panel include effective strategies for increasing consumer demand for and use of proven, individually oriented cessation treatments, including among diverse populations; effective strategies for increasing the implementation of proven, population-level, tobacco-use cessation strategies, particularly by health care systems and communities; effect of smokeless tobacco product marketing and use on population harm from tobacco use; effectiveness of prevention and of cessation interventions in populations with co-occurring morbidities and risk behaviors; and research needed for making the most progress and greatest public health gains nationally and internationally. (www.consensus.nih.gov; 888-644-2667)
Cost-Effectiveness of Shingles Vaccine: Uncertainties about the average quality-of-life effects of acute zoster and the duration of vaccine efficacy must be resolved to better determine the cost-effectiveness of zoster vaccination in older adults, according to an analysis based on a decision theoretical model (pp. 317-25). Taking a societal perspective and a lifetime horizon, the researchers compare varicella-zoster virus vaccination versus no vaccination this way: “By reducing incidence and severity of herpes zoster, vaccination can increase quality-adjusted survival by 0.6 day compared with no vaccination. One scenario in which vaccination costs less than $100,000 per QALY gained is when 1) the unit cost of vaccination is less than $200, 2) the age at vaccination is less than 70 years, and 3) the duration of vaccine efficacy is more than 30 years.” Sensitivity analysis showed: “Vaccination would be more cost-effective in ‘younger’ older adults (age 60 to 64 years) than in ‘older’ older adults (age 80 years). Longer life expectancy and a higher level of vaccine efficacy offset a lower risk for herpes zoster in the younger group. Other factors influencing cost-effectiveness include quality-of-life adjustments for acute zoster, unit cost of the vaccine, risk for herpes zoster, and duration of vaccine efficacy.” (J. Hornberger, Acumen LLC, Burlingame, Calif.; jhornberger@acumen-llc.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
Sept. 7, 2006 Vol. 13, No. 172
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Sept. 7 issue of the New England Journal of Medicine (content.nejm.org; 2006; 355).
Cisplatin Resistance in NSCLC: Among patients with completely resected non–small-cell lung cancer, those with tumors negative for the excision repair cross-complementation group 1 (ERCC1) protein responded to adjuvant cisplatin-based therapy, but those with ERCC1-positive tumors did not, according to International Adjuvant Lung Cancer Trial data (pp. 983-91). “Among 761 tumors, ERCC1 expression was positive in 335 (44%) and negative in 426 (56%). A benefit from cisplatin-based adjuvant chemotherapy was associated with the absence of ERCC1 (test for interaction, P = 0.009). Adjuvant chemotherapy, as compared with observation, significantly prolonged survival among patients with ERCC1-negative tumors (adjusted hazard ratio for death, 0.65; 95% confidence interval [CI], 0.50 to 0.86; P = 0.002) but not among patients with ERCC1-positive tumors (adjusted hazard ratio for death, 1.14; 95% CI, 0.84 to 1.55; P = 0.40). Among patients who did not receive adjuvant chemotherapy, those with ERCC1-positive tumors survived longer than those with ERCC1-negative tumors (adjusted hazard ratio for death, 0.66; 95% CI, 0.49 to 0.90; P = 0.009).” (J-C Soria, Institut Gustave Roussy, Villejuif, France; soria@igr.fr)
An editorialist comments on the implications of these findings on therapy (pp. 1054-5): “The results of the IALT Bio study do not imply that ERCC1 is a marker for resistance to all types of chemotherapy. Nor should these results be taken to imply that ERCC1 is the only marker that is appropriate for cisplatin resistance. However, this study does confirm the findings of many other smaller studies that suggest that ERCC1 expression (RNA or protein) is the most useful marker of resistance to cisplatin and its analogues. Now the question is whether this information can be used prospectively.” (E. Reed, CDC, Atlanta)
Anticoagulation During Elective PCI: A single dose of enoxaparin provided better anticoagulation among 3,528 patients undergoing elective percutaneous intervention than did standard therapy with unfractionated heparin (pp. 1006-17). In this open-label, randomized trial, results lower rates of bleeding and more predictable anticoagulation levels with the glycoprotein IIb/IIIa inhibitor: “Enoxaparin at a dose of 0.5 mg per kilogram was associated with a significant reduction in the rate of non–CABG-related bleeding in the first 48 hours, as compared with unfractionated heparin (5.9% vs. 8.5%; absolute difference, –2.6; 95% confidence interval [CI], –4.7 to –0.6; P = 0.01), but the higher enoxaparin dose was not (6.5% vs. 8.5%; absolute difference, –2.0; 95% CI, –4.0 to 0.0; P = 0.051). The incidence of major bleeding was significantly reduced in both enoxaparin groups, as compared with the unfractionated heparin group. Target anticoagulation levels were reached in significantly more patients who received enoxaparin (0.5-mg-per-kilogram dose, 79%; 0.75-mg-per-kilogram dose, 92%) than who received unfractionated heparin (20%, P < 0.001).” (G. Montalescot, Centre Hospitalier Universitaire Pitié–Salpêtrière, Paris; gilles.montalescot@psl.aphp.fr)
“On balance, the 0.75-mg dose of enoxaparin appears to be a safe alternative to weight-adjusted unfractionated heparin for elective PCI,” concludes an editorialist (pp. 1058-60). “Before the 0.5-mg dose of enoxaparin can be considered safe and effective, much larger numbers of patients need to be studied. Industry, investigators, and the Food and Drug Administration could cooperate to systematically collect outcome data on a large number of patients from well-designed registries. In the future, to make a safe procedure even safer, comparisons of unfractionated heparin with bivalirudin, fondaparinux, or even no antithrombin therapy should continue to focus on reducing the risk of bleeding during PCI.” (W. W. O’Neill, U. Miami, Miami)
Social Anxiety Disorder: The use of SSRIs and benzodiazepines in treatment of social anxiety disorder is reviewed in a Clinical Practice article (pp. 1029-36; F. R. Schneier, frs1@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
Sept. 8, 2006 Vol. 13, No. 173
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Sept. issue of Pharmacotherapy (www.pharmacotherapy.org; 2006; 26).
ID Issues in International Adoptions: American families preparing to adopt a child from abroad should pay special attention to the infectious diseases they may encounter and to the precautions they should take on returning home, warn authors of a review of infectious disease issues in adopting children from other parts of the world (pp. 1207-20). “International adoptions have become increasingly common in the United States. Children awaiting international adoption and families traveling to adopt these children can be exposed to a variety of infectious diseases. Compared with the United States, foreign countries often have different immunization practices and methods of diagnosing, treating, and monitoring disease. Reporting of medical conditions can also differ from that of the United States. The prevalence of infectious diseases varies from country to country and may or may not be common among adopted children. The transmission of tuberculosis, hepatitis B, and measles from adopted children to family members has been documented. Furthermore, infectious organisms (e.g., intestinal parasites), bacterial pathogens (e.g., Bordetella pertussis and Treponema pallidum), and viruses (e.g., human immunodeficiency virus and hepatitis viruses) may cause clinically significant morbidity and mortality among infected children. Diseases such as severe acute respiratory syndrome or avian influenza have not been reported among international adoptees, but transmission is possible if infection is present. Family members may be infected by others during travel or by their adopted child after returning home.” (D. D. Staat, danastaat@ferris.edu)
Lepirudin v. Heparin for Central Venous Flushes: Using conservative doses of lepirudin, researchers found this agent no more effective than heparin for flushing central venous access devices (pp. 1262-7). While higher doses of lepirudin might prove more effective, their use would present unacceptable risks of systemic anticoagulation, the authors add, noting these results among 49 patients undergoing bone marrow transplantation for hematologic or solid cancers: “Efficacy was assessed by the frequency with which the patients were treated with alteplase instillations for withdrawal occlusion of their central venous access devices during the first 4 months of catheterization. Three (12.5%) patients treated with heparin alone and five (20%) treated initially with lepirudin required alteplase instillations for an estimated relative risk with lepirudin versus heparin of 1.6 (95% confidence interval [CI] 0.40–13.86, p = 0.70). (M. K. Horne, III, mhorne@mail.cc.nih.gov)
Hallucinogen Content of Salvia divinorum Products: Salvia divinorum products sold in “head shops” contain the psychoactive compound salvinorin A, and because of reports of teenage suicide possibly related to ingestion of these products, health professionals need to become familiar with signs and symptoms of salvia use (pp. 1268-72). That conclusion comes from an analysis of five products purchased on the Internet or in local drug paraphernalia shops, which showed salvinorin A in all five products but at much lower concentrations than stated on product labels, vitamin E in two samples, and caffeine in one sample. The authors add: “Any discrepancy between the advertised salvinorin A concentration and their actual concentration may pose a potential risk of both misuse and overdose.” (W. R. Wolowich, Nova Southeastern U., Fort Lauderdale, Fla.)
Review Articles: Topics reviewed in this issue of Pharmacotherapy include treatment options for nausea and vomiting during pregnancy (pp. 1273-87; J. A. Smith, jasmith@mdanderson.org); clinical implications and molecular mechanisms of statin withdrawal (pp. 1288-96; L. X. Cubeddu, lcubeddu@nova.edu); effects of ACE inhibitor and ARB use on rates of new-onset diabetes mellitus (pp. 1297-306; K. L. McCall, ken.mccall@ttuhsc.edu); interaction between SSRIs and NSAIDs (pp. 1307-13; J. R. Mort, South Dakota State U., Brookings); and interaction between warfarin and cranberry juice (pp. 1314-9; N. L. Shapiro, nlasack@uic.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
Sept. 11, 2006 Vol. 13, No. 174
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Early-release articles from Lancet (www.thelancet.com; 2006; 368).
Bird-Flu Vaccine: Two doses of an inactivated whole-virion influenza A (H5N1) vaccine met European regulatory requirements for licensing of a seasonal influenza vaccine in a Phase I trial of 120 adult volunteers aged 18–60 years (doi: 10.1016/S0140-6736(06)69294-5). On days 0 and 28, participants received placebo or vaccine 1.25, 2.5, 5, or 10 mcg hemagglutinin per dose with aluminum hydroxide adjuvant, and serum samples taken on days 0, 14, 28, 42, and 56 showed these responses: “All four formulations of vaccines were well tolerated. No serious adverse event was reported and most local and systemic reactions were mild and transient. All formulations induced antibody responses after the first dose; the highest immune response of 78% seropositivity was seen in the 10 mcg group after two vaccine doses. Two individuals dropped out: one in the 1.25 mcg group (withdrew consent) and one in the 10 mcg group (discontinued); one individual was also excluded from the final analysis.”
In the case of a bird-flu pandemic, the authors predicted that this whole-virion vaccine could be used more effectively than split-virion products: “Lower doses of this vaccine could achieve immune responses equivalent to those elicited by adjuvanted or non-adjuvanted split-virion vaccines. The use of a whole virion vaccine could be more adaptable to the antigen-sparing strategy recommended by WHO for protection against an influenza pandemic.” (W. Yin, Sinovac Biotech Co., Beijing;
yinwd@sinovac.com)

>>>BMJ Highlights
Source:
Early-release articles from BMJ (www.bmj.org; 2006; 333).
Postinfective Fatigue Syndrome: Following clinical infection with several viral and nonviral pathogens, a sizable proportion of patients have “a relatively uniform post-infective fatigue syndrome ... for six months or more,” according to an analysis of 253 patients who had Epstein–Barr virus (glandular fever), Coxiella burnetii (Q fever), or Ross River virus (epidemic polyarthritis) infections (doi:10.1136/bmj.38933.585764.AE). Researchers found these symptoms among patients during 12 months of monitoring by self-report, structured interviews, and clinical assessments: “Prolonged illness characterised by disabling fatigue, musculoskeletal pain, neurocognitive difficulties, and mood disturbance was evident in 29 (12%) of 253 participants at six months, of whom 28 (11%) met the diagnostic criteria for chronic fatigue syndrome. This post-infective fatigue syndrome phenotype was stereotyped and occurred at a similar incidence after each infection. The syndrome was predicted largely by the severity of the acute illness rather than by demographic, psychological, or microbiological factors.” This postinfective fatigue syndrome is “a valid illness model for investigating one pathophysiological pathway to chronic fatigue syndrome,” the group concludes. (A. Lloyd, U. New South Wales, Sydney; a.lloyd@unsw.edu.au)

>>>PNN NewsWatch
* FDA on Friday issued information to patients and professionals about the possible interaction between ibuprofen and low-dose aspirin that can interfere with the antiplatelet effects of aspirin.

>>>PNN JournalWatch
* SSRI-Associated Sexual Dysfunction, in American Journal of Psychiatry, 2006; 163: 1504-9. Reprints: http://ajp.psychiatryonline.org/cgi/content/full/163/9/1504; R. Balon.
* Protease-Activated Receptors in Cardiovascular Diseases, in
Circulation, 2006; 114: 1070-7. Reprints: http://circ.ahajournals.org/cgi/content/abstract/114/10/1070; A. Kuliopulos, athan.kuliopulos@tufts.edu
* Mortality in Patients Hospitalized for Asthma Exacerbations in the United States, in
American Journal of Respiratory and Critical Care Medicine, 2006; 174: 633-8. Reprints: http://ajrccm.atsjournals.org/cgi/content/abstract/174/6/633; J. A. Krishnan, U.Chicago, Chicago; jerry.krishnan@gmail.com
* Update in Infectious Diseases, in
Annals of Internal Medicine, 2006; 145: 354-60. Reprints: www.annals.org/cgi/content/full/145/5/354; B. Lorber, bennett.lorber@temple.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
Sept. 12, 2006 Vol. 13, No. 175
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
Sept. 5 issue of the Journal of the American College of Cardiology (content.onlinejacc.org; 2006; 48).
High Clopidogrel Doses in Non-ST–Elevation ACS: Clopidogrel loading doses of 600 mg and especially 900 mg provide a faster onset of action, a higher inhibition of platelet aggregation (IPA) plateau, and greater reductions in platelet activation during the first 24 hours of treatment of patients with non–ST-elevation acute coronary syndromes, compared with LDs of 300 mg (pp. 931-8). In addition to aspirin and other standard therapies, 103 study patients received clopidogrel loading doses of 300, 600, or 900 mg, with these results: “Compared with the 300-mg LD, greater doses were associated with significantly greater platelet inhibition, with dose-effect relationships observed for onset of action, maximal plateau, 24-h areas under the curves of IPA, and rates of low IPA (<10% at 6 h), using 20 µmol/l major adverse cardiac events. A significant dose-response was also observed for the vasodilator-stimulated phosphoprotein index, a measure of P2Y12 receptor inhibition. Similar but nonsignificant trends were observed for troponin release and major adverse cardiac events. Bleeding rates were similar in each group.” (G. Montalescot, Pitié-Salpêtrière Hosp., Paris; gilles.montalescot@psl.aphp.fr)
Metformin in Nondiabetic Women: In 33 nondiabetic women with chest pain and angiographically normal coronary arteries, metformin improved vascular function and myocardial ischemia (pp. 956-63). For 8 weeks, participants received either placebo or metformin 500 mg twice a day. Testing microvascular function using laser Doppler imaging combined with iontophoresis, the researchers found: “In comparison with placebo (n = 17), metformin recipients (n = 16) showed significant reductions in weight and in homeostatic model assessment for insulin resistance (p < 0.05, intention to treat). Endothelium-dependent microvascular responses improved significantly with metformin (2-way repeated analysis of variance, p = 0.0003), but responses with placebo were unchanged (p = 0.50). A comparison of change in acetylcholine responses between metformin and placebo recipients was significant, whether analyzed by a 2-way analysis of variance (p < 0.0001) or change in area under curves (mean change +392 perfusion units, 95% confidence interval [CI] 20 to 764). Endothelium-independent responses were not altered. Maximal ST-segment depression (–0.84 mm, 95% CI –1.49 to –0.20, p = 0.013), Duke score (6.1 U, 95% CI 1.8 to 10.5, p = 0.008), and chest pain incidence (–0.11 episodes/day, 95% CI –0.22 to 0.00, p = 0.056) improved in metformin relative to placebo recipients.” (N. Sattar, U. Glasgow, Glasgow, Scotland; nsattar@clinmed.gla.ac.uk)
Trimetazidine for HF: Long-term treatment with the partial free fatty acid oxidation inhibitor trimetazidine (marketed in Europe as Vastarel MR [Servier] with indications for long-term treatment of angina pectoris) improved functional class and left ventricular function in 55 patients with heart failure, as evidenced by more favorable New York Heart Association and ejection fraction results, compared with standard HF therapy alone (pp. 992-8). Comparing open-label conventional therapy and trimetazidine 20 mg three times daily, the investigators report: “In the trimetazidine group, NYHA functional class significantly improved compared with the conventional therapy group (p < 0.0001). Treatment with trimetazidine significantly decreased left ventricular end-systolic volume (from 98 ± 36 ml to 81 ± 27 ml, p = 0.04) and increased EF from 36 ± 7% to 43 ± 10% (p = 0.002). On the contrary, in the conventional therapy group, both left ventricular end-diastolic and -systolic volumes increased from 142 ± 43 ml to 156 ± 63 ml, p = 0.2, and from 86 ± 34 ml to 104 ± 52 ml, p = 0.1, respectively; accordingly, EF significantly decreased from 38 ± 7% to 34 ± 7% (p = 0.02).” (G. Fragasso, Istituto Scientifico-Universita Vita/Salute San Raffaele, Milan, Italy; gabriele.fragasso@hsr.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
Sept. 13, 2006 Vol. 13, No. 176
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Early-release articles and the Sept. 13 issue of JAMA (www.jama.com; 2006; 296).
Renal, Cardiovascular Problems with COX-2 Inhibitors: Two articles and an editorial discuss renal and cardiovascular events with COX-2 inhibitors.
Rofecoxib was associated with increased renal and arrhythmia risks, but no COX-2 inhibitor class effect was evident in a meta-analysis of 114 randomized trials that included 116,094 participants (doi: 10.1001/jama.296.13.jrv60015). “A total of 6,394 composite renal events (2,670 peripheral edema, 3,489 hypertension, 235 renal dysfunction) and 286 arrhythmia events” were reported in this analysis of data on rofecoxib, celecoxib, valdecoxib plus parecoxib, etoricoxib, and lumiracoxib. “Results indicated significant heterogeneity of renal effects across agents (P for interaction = .02), indicating no class effect. Compared with controls, rofecoxib was associated with increased risk of arrhythmia (relative risk [RR], 2.90; 95% confidence interval [CI], 1.07–7.88) and composite renal events (RR, 1.53; 95% CI, 1.33–1.76); adverse renal effects increased with greater dose and duration (both P ≤ .05). For all individual renal end points, rofecoxib was associated with increased risk of peripheral edema (RR, 1.43; 95% CI, 1.23–1.66), hypertension (RR, 1.55; 95% CI, 1.29–1.85), and renal dysfunction (RR, 2.31; 95% CI, 1.05–5.07). In contrast, celecoxib was associated with lower risk of both renal dysfunction (RR, 0.61; 95% CI, 0.40–0.94) and hypertension (RR, 0.83; 95% CI, 0.71–0.97) compared with controls. Other agents were not significantly associated with risk. Time-cumulative analyses indicated that for rofecoxib the adverse risks for peripheral edema and hypertension were evident by the end of year 2000 and for risk of arrhythmia by 2004.” (E. L. Ding, Harvard School of Public Health, Boston;
eding@jhu.edu)
A systematic review of observational studies of selective and nonselective COX-2 inhibitors “confirms the findings from randomized trials regarding the risk of cardiovascular events with rofecoxib and suggests that celecoxib in commonly used doses may not increase the risk, contradicts claims of a protective effect of naproxen, and raises serious questions about the safety of diclofenac, an older drug” (doi: 10.1001/jama.296.13.jrv60011). “A dose-related risk was evident with rofecoxib, summary relative risk with 25 mg/d or less, 1.33 (95% confidence interval [CI], 1.00–1.79) and 2.19 (95% CI, 1.64–2.91) with more than 25 mg/d,” the authors write. “The risk was elevated during the first month of treatment. Celecoxib was not associated with an elevated risk of vascular occlusion, summary relative risk 1.06 (95% CI, 0.91–1.23). Among older nonselective drugs, diclofenac had the highest risk with a summary relative risk of 1.40 (95% CI, 1.16–1.70). The other drugs had summary relative risks close to 1: naproxen, 0.97 (95% CI, 0.87–1.07); piroxicam, 1.06 (95% CI, 0.70–1.59); and ibuprofen, 1.07 (95% CI, 0.97–1.18).” (D. Henry, Newcastle Mater Hosp., Waratah, New South Wales, Australia;
david.henry@newcastle.edu.au)
An editorialist writes that the days of angst over COX-2 inhibitors are not finished (doi: 10.1001/jama.296.13.jed60058): “With the recent announcement by Merck that it will press for US approval of its COX-2 inhibitor NSAID etoricoxib, the FDA, academia, and the medical research enterprise are once again faced with the opportunity to forsake common sense by willfully accepting misdirection and disinformation presented in the guise of science....
“From a business perspective, were etoricoxib to be exposed as another ‘naked emperor,’ its US approval might be difficult, even by the FDA’s apparently industry-friendly standards. If the lessons of recent history have been learned, the FDA’s concerns will now be squarely focused on patient safety rather than corporate profitability, and, ultimately, common sense will prevail.” (D. J. Graham,
david.graham1@fda.hhs.gov)
Wait-and-See Approach with Otitis Media: Providing parents with wait-and-see prescriptions when their children have acute otitis media reduces antibiotic usage and produces equivalent outcomes in terms of subsequent fever, otalgia, and unscheduled visits for medical care, according to a study of 283 patients (pp. 1235-41; D. M. Spiro, Oregon Health and Science U., Portland; spirod@ohsu.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
Sept. 14, 2006 Vol. 13, No. 177
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Sept. 14 issue of the New England Journal of Medicine (content.nejm.org; 2006; 355).
Chemotherapy with Preoperative Radiotherapy in Rectal Cancer: Adding fluorouracil-based chemotherapy preoperatively or postoperatively had no significant effect on survival among 1,011 patients with clinical stage T3 or T4 resectable rectal cancer, but local control of the tumor was evident when patients received the medications either before or after surgery (pp. 1114-23). Chemotherapy consisted of fluorouracil 350 mg/sq m/day and leucovorin 20 mg/sq m/day given for 5 days, and these were combined with various combinations of radiotherapy administered before and after resection. Results showed the following: “There was no significant difference in overall survival between the groups that received chemotherapy preoperatively (P = 0.84) and those that received it postoperatively (P = 0.12). The combined 5-year overall survival rate for all four groups was 65.2%. The 5-year cumulative incidence rates for local recurrences were 8.7%, 9.6%, and 7.6% in the groups that received chemotherapy preoperatively, postoperatively, or both, respectively, and 17.1% in the group that did not receive chemotherapy (P = 0.002). The rate of adherence to preoperative chemotherapy was 82.0%, and to postoperative chemotherapy was 42.9%.” (J-F Bosset, Besançon U. Hosp., Besançon, France; jean-francois.bosset@ufc-chu.univ-fcomte.fr)
Fingolimod for MS: In a proof-of-concept study, a new oral immunomodulating agent, fingolimod (FTY720), reduced the number of lesions detected on MRI and clinical disease activity in 281 patients with relapsing multiple sclerosis (pp. 1124-40). “The median total number of gadolinium-enhanced lesions on MRI was lower with 1.25 mg of fingolimod (1 lesion, P < 0.001) and 5.0 mg of fingolimod (3 lesions, P = 0.006) than with placebo (5 lesions)” the group reports. “The annualized relapse rate was 0.77 in the placebo group, as compared with 0.35 in the group given 1.25 mg of fingolimod (P = 0.009) and 0.36 in the group given 5.0 mg of fingolimod (P = 0.01). For the 227 patients who completed the extension study, the number of gadolinium-enhanced lesions and relapse rates remained low in the groups that received continuous fingolimod, and both measures decreased in patients who switched from placebo to fingolimod. Adverse events included nasopharyngitis, dyspnea, headache, diarrhea, and nausea. Clinically asymptomatic elevations of alanine aminotransferase levels were more frequent with fingolimod (10 to 12%, vs. 1% in the placebo group). One case of the posterior reversible encephalopathy syndrome occurred in the 5.0-mg group. Fingolimod was also associated with an initial reduction in the heart rate and a modest decrease in the forced expiratory volume in 1 second.” (L. Kappos, U. Hosp., Basel, Switzerland; kappos@uhbs.ch)
Cost-Effectiveness of HIV Treatment in Resource-Poor Settings: The combination of trimethoprim–sulfamethoxazole prophylaxis and criteria-guided antiretroviral therapy is an “economically attractive health investment in settings with limited resources,” conclude authors of a cost-effectiveness analysis conducted from a modified societal perspective (pp. 1141-53). Using computer simulation for a cohort of adults in the Côte d’Ivoire, the investigators report: “Undiscounted gains in life expectancy ranged from 10.7 months with antiretroviral therapy and prophylaxis initiated on the basis of clinical criteria to 45.9 months with antiretroviral therapy and prophylaxis initiated on the basis of CD4 testing and clinical criteria, as compared with trimethoprim–sulfamethoxazole prophylaxis alone. The incremental cost per year of life gained was $240 (in 2002 U.S. dollars) for prophylaxis alone, $620 for antiretroviral therapy and prophylaxis without CD4 testing, and $1,180 for antiretroviral therapy and prophylaxis with CD4 testing, each compared with the next least expensive strategy. None of the strategies that used antiretroviral therapy alone were as cost-effective as those that also used trimethoprim–sulfamethoxazole prophylaxis. Life expectancy was increased by 30% with use of a second line of antiretroviral therapy after failure of the first-line regimen.” (S. J. Goldie, sue_goldie@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
Sept. 15, 2006 Vol. 13, No. 178
Providing news and information about medications and their proper use

>>>Diabetes Meeting Highlights
A number of important articles are being presented this week at the 42nd annual meeting of the European Association for the Study of Diabetes (EASD) in Copenhagen, Denmark, and Malmoe, Sweden. Medication-related presentations included these findings:
* Results of the DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) study plenary presentation will be webcast live this morning at 11 am EDT at
www.dream-results.tv. The 21-country trial included 5,269 patients who had prediabetes, and the effects of ramipril and rosiglitazone were tested over a 5-year period. An estimated 41 million Americans have one of the prediabetic conditions (impaired glucose tolerance and/or impaired fasting glucose).
* Several studies addressed use of Exubera (insulin human [rDNA origin]) Inhalation Powder, which arrived on U.S. pharmacy shelves this month following its Jan. 2006 FDA approval. Adult patients with diabetes using inhaled insulin were able to safely maintain blood glucose control even if they developed a respiratory infection or were exposed to passive (second-hand) cigarette smoke, reported Philippe Camus, U. Med. Ctr., Dijon, France. Another new study found that while passive smoke exposure could result in decreased absorption, Exubera could be used by patients who were exposed to a smoky environment. Nick Freemantle, of the U. Birmingham in the U.K., analyzing data from a previously reported study, reported that Exubera has the potential to encourage twice as many people with uncontrolled type 2 diabetes to try insulin (44% choosing insulin when Exubera was a choice versus 17% with only injectable routes). This held true even in countries where insulin pens are commonly used to administer insulin. Priscilla Hollander, lead investigator from Baylor U. Med. Ctr. in Dallas, analyzed results from five clinical trials and found that people with either type 1 or type 2 diabetes who used inhaled insulin gained less weight than those using injectable insulin. Weight gain was more than cut in half with Exubera in type 2 patients (0.7 kg vs. 1.6 kg), and an even greater difference was noted for type 1 patients (0.2 kg with Exubera vs. 1.1 kg with injected insulin).
* Glycosylated hemoglobin levels dropped by 2.1 percentage points among patients receiving metformin 1,000 mg and sitagliptin phosphate 50 mg twice daily. Sitagliptin (Januvia, Merck) is the first in a class of dipeptidyl peptidase-4 (DPP-4) inhibitors, and an FDA decision regarding its marketing is expected during October. In the study, patients had moderate baseline A1c levels (mean, 8.8%), and two thirds of those treated with metformin plus sitagliptin achieved goal A1c levels of less than 7%, compared with 38% of those treated with metformin alone. Adverse effects of combination therapy with the DPP-4 inhibitor included diarrhea (9% vs. 10% with metformin alone), nausea (6% vs. 8%, respectively), abdominal pain/discomfort (3% vs. 5%, respectively) and vomiting (3% vs. 1%, respectively). Adverse effects reported with sitagliptin that occurred in at least 3% of patients and at greater frequencies than with placebo were stuffy or runny nose and sore throat; headache; diarrhea; upper respiratory infection; joint pain; and urinary tract infection.
* Liraglutide, an investigational glucagon-like peptide-1 (GLP-1) analogue under development by Novo Nordisk for treatment of type 2 diabetes, increased the maximum capacity of pancreatic beta cells to secrete insulin in a 14-week trial reported by S. Madbad of Hvidovre U. Hosp., Hvidovre, Denmark, and colleagues. Insulin secretion was particularly increased during the first-phase insulin response, which is typically diminished in patients with type 2 diabetes. The data come from a larger double-blind, placebo-controlled, randomized trial. It showed that, compared with placebo, liraglutide reduced levels of A1C and produced significantly more weight loss at its highest dose. In the trial of 165 patients, 43% to 50% of those taking liraglutide achieved A1C levels of 7% or lower, compared with 8% of those on placebo. Patients taking the highest liraglutide dose lost a mean of 2.99 kg, significantly more than the 1.21-kg loss in the placebo group.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Sept. 18, 2006 Vol. 13, No. 179
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from and Sept. 16 issue of BMJ (www.bmj.org; 2006; 333).
Calcium Supplements in Children: In a meta-analysis of 29 studies of 2,859 children, calcium supplementation that lasted at least 3 months had little effect on bone mineral density and was deemed by the authors to be unlikely to reduce fracture risks in childhood or later in life (doi: 10.1136/bmj.38950.561400.55). Included studies were randomized controlled trials in healthy children that had at least 6 months of follow-up. The authors report: “Calcium supplementation had no effect on bone mineral density at the femoral neck or lumbar spine. There was a small effect on total body bone mineral content (standardised mean difference 0.14, 95% confidence interval 0.01 to 0.27) and upper limb bone mineral density (0.14, 0.04 to 0.24). This effect persisted after the end of supplementation only at the upper limb (0.14, 0.01 to 0.28). There was no evidence that sex, baseline calcium intake, pubertal stage, ethnicity, or level of physical activity modified the effect.” (T. Winzenberg, Menzies Res. Inst., Hobart, Tas, Australia; tania.winzenberg@utas.edu.au)
Needle Characteristics & Vaccine Effects: Long needles (25 mm) proved preferable to 16-mm needles in a study demonstrating equivalent immunogenicity but lower rates of reactions with deeper injections of vaccines (pp. 571 ff). Combined diphtheria, tetanus, whole cell pertussis, and Haemophilus influenzae type b vaccine and a serogroup C meningococcal glycoconjugate vaccine were administered using either a wide, long needle (23 gauge/0.6 mm diameter, 25 mm), a narrow, short needle (25 gauge/0.5 mm diameter, 16 mm), or a narrow, long needle (25 gauge, 25 mm). Among 696 study infants, the researchers found: “Local reactions to diphtheria, tetanus, whole cell pertussis, H influenzae type b vaccinations decreased significantly with wide, long needles compared with narrow, short needles. At all three doses one less infant experienced local reactions at days 1, 2, or 3 for every six to eight vaccinated. Significantly fewer infants vaccinated with the long needle experienced severe local reactions. Non-inferiority of the immune response was shown using a wide, long needle rather than a narrow, short needle for serogroup C meningococcal glycoconjugate vaccine and for diphtheria but not for H influenzae type b or tetanus, although no evidence was found of a decrease. Little difference was found between needles of the same length but different gauges in local reaction or immune response.” (L. Diggle. U. Oxford, Oxford, U.K.; linda.diggle@paediatrics.ox.ac.uk)

>>>Lancet Highlights
Source:
Sept. 16 issue of Lancet (www.thelancet.com; 2006; 368).
Invasive Management of NSTEMI: Early invasive management of non–ST-elevation acute coronary syndrome provides sustained benefit over a noninvasive, primarily medical, strategy, conclude the Fast Revascularisation during InStability in Coronary artery disease (FRISC-II) investigators (pp. 998-1004). Among 2,457 patients at moderate to high risk who were randomized to early invasive care (coronary angiography and if needed revascularization) or medical treatment, the researchers found significant advantages with invasive care after 5 years for a primary composite endpoint of death, myocardial infarction, or both (invasive 217, 19.9 %; noninvasive 270, 24.5 %; risk ratio 0.81; 95% CI 0.69–0.95; P = 0.009). (L. Wallentin, U. Hosp., Uppsala, Sweden; lars.wallentin@ucr.uu.se)

>>>PNN JournalWatch
* Biomaterials for the Treatment of Myocardial Infarction, in Journal of the American College of Cardiology, 2006; 48: 907-13. Reprints: www.cardiosource.com; R. J. Lee, lee@medicine.ucsf.edu
* Homocysteine Hypothesis for Atherothrombotic Cardiovascular Disease: Not Validated, in
Journal of the American College of Cardiology, 2006; 48: 914-23. Reprints: www.cardiosource.com; S. Kaul.Cedars-Sinai Med. Ctr., Los Angeles; kaul@cshs.org
* Erectile Dysfunction in Heart Failure Patients, in
Journal of the American College of Cardiology, 2006; 48: 1111-9. Reprints: www.cardiosource.com; E. R. Schwarz, Cedars-Sinai Med. Ctr., Los Angeles; ernst.schwarz@cshs.org
* Diagnosis and Management of Ankylosing Spondylitis, in
BMJ, 2006; 333: 581. Reprints: http://bmj.bmjjournals.com/cgi/content/extract/333/7568/581; A. P. Cairns, Musgrave Park Hosp., Belfast, U.K.; andrew.cairns@greenpark.n-i.nhs.uk

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 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
Sept. 19, 2006 Vol. 13, No. 180
Providing news and information about medications and their proper use

>>>Posaconazole Approved for Immunocompromised Patients
FDA has approved posaconazole oral suspension (Noxafil, Schering) for prevention of fungal infections in adolescents (age 13 and older) and adults who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant recipients with graft-versus-host disease or those with hematologic malignancies with prolonged neutropenia from chemotherapy. Posaconazole is the first antifungal agent approved for prevention of invasive fungal infections caused by Aspergillus species, Schering noted in a news release.
The safety and efficacy of posaconazole were evaluated in trials of 1,844 patients between 13 and 82 years of age. In two randomized controlled studies of patients who had compromised immunity and were at high risk for invasive fungal infections, those patients who received posaconazole had comparable or lower rates of invasive
Aspergillus and Candida infections than those patients who received other antifungal medications.
The most common adverse effects with posaconazole were nausea, vomiting, diarrhea, rash, a decrease in serum potassium concentrations and platelet counts, and abnormalities in liver function tests. Rare adverse events possibly related to the drug include QTc prolongation and liver function impairment. Liver-function tests should be monitored at the start of and during the course of therapy.
Posaconazole must be taken with a full meal or nutritional supplement to allow adequate drug absorption. Coadministration with the CYP 3A4 substrates terfenadine, astemizole, cisapride, pimozide, halofantrine, or quinidine is contraindicated since this may result in increased plasma concentrations of these medications, leading to QTc prolongation and rare occurrences of torsades de pointes. Coadministration with ergot alkaloids is also contraindicated.

>>>Internal Medicine Report
Source:
Sept. 19 Annals of Internal Medicine (www.annals.org; 2006; 145).
Med Errors After Bar-Code Implementation: Scanning of every dose is critical when hospital pharmacies implement bar-code technology, according to a study of dispensing errors and potential adverse drug events in a 735-bed tertiary medical center (pp. 426-34). A bar code–assisted dispensing system was implemented in three configurations, two of which required scanning of all doses and one in which only one dose was scanned if several doses of the same medication were being dispensed. Comparing before-and-after rates of errors and potential ADEs detected through direct observation, the investigators report: “The rates of target potential ADEs and all potential ADEs decreased by 74% and 63%, respectively. Of the 3 configurations of bar code technology studied, the 2 configurations that required staff to scan all doses had a 93% to 96% relative reduction in the incidence of target dispensing errors (P < 0.001) and 86% to 97% relative reduction in the incidence of potential ADEs (P < 0.001). However, the configuration that did not require scanning of every dose had only a 60% relative reduction in the incidence of target dispensing errors (P < 0.001) and an increased (by 2.4-fold) incidence of target potential ADEs (P = 0.014). There were several potentially life-threatening ADEs involving intravenous dopamine and intravenous heparin in that configuration.” (E. G. Poon, epoon@partners.org)
USP & Medicare Part D: A narrative review describes development and annual updating of the USP Model Guidelines and Formulary Key Drug Types, which are used by the Centers for Medicare and Medicaid Services in provision of the Part D drug benefit (pp. 448-53). “Approximately 75% of the plans applying to CMS to offer the Part D benefit used the Model Guidelines, and the entire CMS evaluative process seemed to advance smoothly based on the CMS Guidelines, which included the Formulary Key Drug Types,” the authors explain. “Implementation of the benefit is now in progress, and a better understanding of the CMS’s evaluative process regarding the USP categories and classes is expected. The USP believes that the categories and classes will benefit from access to sound, up-to-date drug information.” (S. Schuber, sps@usp.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
Sept. 20, 2006 Vol. 13, No. 181
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Sept. 18 issue of the Archives of Internal Medicine (www.archinternmed.com; 2006; 166), a theme issue on sleep disorders.
Sildenafil for Sleep Apnea: Administered at bedtime, a single dose of sildenafil 50 mg significantly worsens respiratory and desaturation events among patients with severe obstructive sleep apnea, investigators report (pp. 1763-7). OSA is “a major contributing factor in the development of erectile dysfunction,” the authors note, adding that this problems is undiagnosed in 80% of men with OSA. Among 14 men with severe OSA, single bedtime doses of sildenafil or placebo produced these results in this crossover study: “In comparison to placebo, a single 50-mg dose of sildenafil significantly increased the percentage of total sleep time with an arterial oxygen saturation of less than 90% (mean ± SD, 14.2% ± 9.1% vs 8.5% ± 3.2%, P < .01), without a difference in the nadir of oxygen desaturation. The mean arterial oxygen saturation also decreased (92.1% ± 1.91% vs 93.8% ± 1.3%, P = .02), and the desaturation index increased (30.3 ± 18.1 events per hour vs 18.5 ± 14.6 events per hour, P < .001). There was an increase in apnea-hypopnea index (42.4 ± 25.5 events per hour vs 34.6 ± 24.1 events per hour, P = .01), involving mostly obstructive events. (S. Roizenblatt, Federal U. São Paulo, Sao Paulo, Brazil; suelyroi@psicobio.epm.br)
CAM Use for Insomnia: A national survey shows that use of complementary and alternative medicine for sleep disorders is common among Americans (pp. 1775-82). Extrapolating data from the 2002 National Health Interview Survey, the researchers estimate that 1.6 million civilian, noninstitutionalized U.S. citizens use either herbal agents or mind–body approaches such as meditation or relaxation techniques. “The 12-month prevalence rate of insomnia or trouble sleeping was 17.4%,” write the researchers. “There was a strong positive association between adults who reported having insomnia or trouble sleeping and adults who reported 4 of 5 common conditions: obesity (adjusted odds ratio [OR], 1.15; 99% confidence interval [CI], 1.01–1.31), hypertension (OR, 1.32; 99% CI, 1.16–1.51), congestive heart failure (OR, 2.24; 99% CI, 1.60–3.14), and anxiety or depression (OR, 5.64; 99% CI, 5.07–6.29). Of those with insomnia or trouble sleeping, 4.5% used some form of CAM therapy to treat their condition.”
Of respondents who used herbal medicines, 49% indicated that the agents were effective, as did 48% of those who used relaxation therapy. “Although the question asking whether the CAM therapy helped provides useful information on the public’s perception of effectiveness of CAM therapies for insomnia or trouble sleeping, it does not directly address the efficacy of the CAM therapy,” the authors wrote. “A positive answer to this question could be due to a placebo effect, the natural history of the condition or other unidentified influences rather than efficacy of the CAM treatment.” (N. J. Pearson, PhD,
pearsonn@mail.nih.gov)
Diabetes & Sleep: Sleep duration and quality were significant predictors of A1c levels in patients with type 2 diabetes, suggesting that optimizing sleep duration and quality should be tested as an intervention to improve glucose control in patients with type 2 diabetes (pp. 1768-74). Based on a cross-sectional study of 161 volunteers with type 2 diabetes, the authors report: “The mean ± SD sleep duration was 6.0 ± 1.6 hours, and 71% of the participants were classified as having poor quality sleep (PSQI score >5). We excluded patients with sleep frequently disrupted by pain (n = 39). In patients without diabetic complications, glycemic control was associated with perceived sleep debt but not PSQI score. The predicted increase in HbA1c level for a perceived sleep debt of 3 hours per night was 1.1% above the median. In patients with at least 1 complication, HbA1c level was associated with PSQI score but not perceived sleep debt. The predicted increase in HbA1c level for a 5-point increase in PSQI was 1.9% above the median.” (E. Van Cauter, evcauter@medicine.bsd.uchicago.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
Sept. 21, 2006 Vol. 13, No. 182
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Sept. 21 issue of the New England Journal of Medicine (content.nejm.org; 2006; 355).
Eculizumab in Paroxysmal Nocturnal Hemoglobinuria: In a Phase III trial, eculizumab proved an effective therapy for paroxysmal nocturnal hemoglobinuria (pp. 1233-43). Patients intravenously received either placebo or eculizumab 600 mg weekly for 4 weeks, followed 1 week later by a 900-mg dose and then 900 mg every other week through week 26. Based on responses of 87 patient as gauged by two primary end points (stabilization of hemoglobin levels and number of units of packed red cells transfused), the investigators report: “Stabilization of hemoglobin levels in the absence of transfusions was achieved in 49% (21 of 43) of the patients assigned to eculizumab and none (0 of 44) of those assigned to placebo (P < 0.001). During the study, a median of 0 units of packed red cells was administered in the eculizumab group, as compared with 10 units in the placebo group (P < 0.001). Eculizumab reduced intravascular hemolysis, as shown by the 85.8% lower median area under the curve for lactate dehydrogenase plotted against time (in days) in the eculizumab group, as compared with the placebo group (58,587 vs. 411,822 U per liter; P < 0.001). Clinically significant improvements were also found in the quality of life, as measured by scores on the Functional Assessment of Chronic Illness Therapy-Fatigue instrument (P < 0.001) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire. Of the 87 patients, 4 in the eculizumab group and 9 in the placebo group had serious adverse events, none of which were considered to be treatment-related; all these patients recovered without sequelae.” (P. Hillmen, Leeds General Infirmary, Leeds, U.K.; peter.hillmen@nhs.net)
Cardiac Cell Therapy: Several articles in this issue pertain to stem-cell research and its applicability in treating acute myocardial infarction (research studies on pp. 1199-209; 1210-21; 1222-32; and a Perspectives article on pp. 1189-91). Commenting on the research trials, an editorialist notes the challenges faced in sorting out the benefits of cardiac cell therapy for a serious condition that must be treated simultaneously with highly effective interventions and medications (pp. 1274-7): “It may be challenging to achieve significant improvements in [left ventricular ejection fraction] in small cohorts of patients who have relatively preserved ventricular function and who are already receiving state-of-the-art therapy. Even some early trials of reperfusion in patients with acute myocardial infarction demonstrated either no improvement in LVEF or a modest improvement. Ultimately, the validation of cardiac cell therapy will require demonstration of benefit with regard to clinical outcomes—as was the case with reperfusion. Studies performed to date have not been designed or powered to evaluate clinical outcomes. Nevertheless, it is encouraging that the REPAIR-AMI investigators found the rate of adverse clinical events to be significantly lower at 1 year among patients receiving [bone marrow cells] than among those receiving placebo. Given the relatively small number of events, this result will require replication in larger cohorts. However, it reinforces the message that BMC infusion is not only feasible but also safe, and it raises the possibility that clinical benefits may exceed the modest improvement seen in ventricular function. Data on ventricular function at 1 year are not available.” (A. Rosenzweig, Beth Israel Deaconess Med. Ctr., Boston)

>>>PNN NewsWatch
* FDA yesterday announced an update to product labeling for Ortho Evra (ethinyl estradiol–norelgestromin; Ortho-McNeil) stating an increased risk of venous thromboembolism associated with use of the patch, compared with similar oral contraceptives. Two epidemiologic studies using electronic claims data were performed, and while one should no increased VTE risk, the other indicated that women on the patch had a twofold increase in thromboembolic events.
* The
foodborne outbreak of Escherichia coli 0157:H7 spread to two more states yesterday, and an additional company recalled its fresh spinach products. In all, 146 cases of illness have been reported, with 23 cases of hemolytic uremic syndrome, 76 hospitalizations, and 1 death.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Sept. 22, 2006 Vol. 13, No. 183
Providing news and information about medications and their proper use

>>>Allergy/Immunology Report
Source:
Sept. Journal of Allergy and Clinical Immunology (www.jacionline.org; 2006; 118).
Natural History of Asthma: A review article provides this perspective on the onset, incidence, and natural history of asthma (pp. 543-8): “Asthma begins most often in infants as wheezing with respiratory infections. If these episodes are mild and infrequent, asthma does not usually persist into the school years. However, if they are more frequent and severe, the asthma is likely to persist. After infancy, incidence falls and continues at about 100/100,000 for the rest of the lifespan. Allergic asthma develops most often in the second decade of life and frequently persists into adult years, but young patients with allergic asthma often enjoy a transient or even a permanent remission. More severe disease and continued allergen exposure cause persistence. Some patients with occupational asthma continue to have asthma long after exposure ceases. Asthma beginning after the fourth decade is usually intrinsic and may include the aspirin triad. Its severity tends to increase with time. Many middle-aged and elderly adults have a persistent decline in lung function that is retarded but not completely prevented by aerosol glucocorticoids. This loss of lung function is often the result of coexisting lung diseases, particularly bronchiectasis and COPD. Patients with asthma have the same overall rate and age of death as the general population, but are more likely to die of lung diseases, including cancer.” (C. E. Reed, Mayo Med. Sch., Boulder Junction, Wis.)
Modes of Action of Unconventional Meds: Do herbal agents and mind–body approaches to treatment of disease work through the same mechanisms of action as pharmacologic substances? That question is posed in the Rostrum article in this issue, and the authors conclude that conventional and complementary approaches might merge on a common scientific platform (pp. 569-73): “Conventional and effective unconventional medicine might both work by means of pharmacology (eg, substances in medical herbs), including pharmacologic interactions between the 2 treatment options (eg, herbs and drugs with coagulation effects). Both conventional and unconventional treatments involve a considerable risk of side effects, which are sometimes even severe. In general, the pattern of side effects of alternative treatments is similar to that observed with the use of conventional medicine. The placebo effect and suggestive aspects are also apparent in both treatments. Furthermore, mind–body medicine (eg, use of relaxation techniques) might be explained by pathophysiologic mechanisms. Overall, many aspects seem to contribute to the mosaic of joint modes of action involved in both conventional and unconventional medicine. This might demystify the aura of some of the complementary and alternative approaches and might help to bring both conventional and unconventional approaches together on a scientific basis.” (B. Niggemann, Children’s Hospital Charité, Humboldt U., Berlin)

>>>PNN NewsWatch
* A new Web site at the University of California, San Diego School of Medicine–www.statineffects.com–will enable people from around the world to self-report adverse effects of statins or other cholesterol drugs. The site is being launched to support the UCSD Statin Study, headed by Beatrice A. Golomb, MD, PhD. She and the research team at UCSD are currently completing an NIH-funded study of 1,000 subjects to evaluate the effects of statin drugs on cognition, behavior, and serotonin biochemistry. According to Golomb, among people who have contacted the UCSD Statin Study to report adverse effects, nearly 60% of patients reported muscle weakness or fatigue, and about half reported cognitive problems.
* The Sept/Oct issue of the
Journal of the American Pharmacists Association (www.japha.org) includes the 2006 Remington and Prescott lectures by Californians Robert D. Gibson and Michael J. Negrete, respectively; an article on a stepwise approach to developing point-of-care testing in community and ambulatory pharmacy settings (J. L. Rodis and R. Ahrens Thomas); and an analysis of medication errors in community pharmacies following implementation of automated dispensing systems (E. A. Flynn and K. N. Barker).

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Sept. 25, 2006 Vol. 13, No. 184
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Sept. 23 issue of Lancet (www.thelancet.com; 2006; 368).
Rosiglitazone in Prediabetes: The incidence of type 2 diabetes was reduced significantly among 5,269 patients with prediabetes when they were treated with rosiglitazone 8 mg daily for 3 years, according to results from the DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) trial (pp. 1096–105). The likelihood of regression to normoglycemia was also increased among adults with impaired fasting glucose or impaired glucose tolerance, the investigators conclude, adding these details about DREAM results: “306 (11.6%) individuals given rosiglitazone and 686 (26.0%) given placebo developed the composite primary outcome [of incident diabetes or death] (hazard ratio 0.40, 95% CI 0.35–0.46; p < 0.0001); 1,330 (50.5%) individuals in the rosiglitazone group and 798 (30.3%) in the placebo group became normoglycaemic (1.71, 1.57–1.87; p < 0.0001). Cardiovascular event rates were much the same in both groups, although 14 (0.5%) participants in the rosiglitazone group and two (0.1%) in the placebo group developed heart failure (p = 0.01).” (DREAM Project Office, Population Health Res. Inst., Hamilton, Ont., Canada; dream@cardio.on.ca)
Results from the ramipril arm of the DREAM study are being published separately in the
New England Journal of Medicine. A GlaxoSmithKline news release states that ramipril increased regression to normoglycemia but did not reduce the risk of diabetes or death.

>>>BMJ Highlights
Source:
Early-release article from BMJ (www.bmj.org; 2006; 333).
Upper GI Bleeding & Antithrombotic Therapy: Combined antithrombotic therapy, an increasingly common intervention, is associated with a high incidence gastrointestinal bleeding, according to a population-based case–control study from Funen County, Denmark (doi: 10.1136/bmj.38947.697558.AE). Among 470,000 residents, 1,443 cases of serious upper gastrointestinal bleeds were identified during 2000–04, and these patients were compared with 57,720 age- and gender-matched control patients: “Adjusted odds ratios associating drug use with upper gastrointestinal bleeding were 1.8 (95% confidence interval 1.5 to 2.1) for low dose aspirin, 1.1 (0.6 to 2.1) for clopidogrel, 1.9 (1.3 to 2.8) for dipyridamole, and 1.8 (1.3 to 2.4) for vitamin K antagonists. Corresponding figures for combined use were 7.4 (3.5 to 15) for clopidogrel and aspirin, 5.3 (2.9 to 9.5) for vitamin K antagonists and aspirin, and 2.3 (1.7 to 3.3) for dipyridamole and aspirin. Other combinations were used too infrequently to allow estimation. The number of treatment years needed to produce one excess case varied from 124 for the clopidogrel–aspirin combination to 8,800 for clopidogrel alone. During the study period, exposure to combined antithrombotic regimens increased by 425% in the background population.” (J. Hallas, Syddansk U., Odense, Denmark; jhallas@health.sdu.dk)

>>>PNN JournalWatch
* Oral Malodour (Halitosis), in BMJ, 2006; 333: 632–5. Reprints: http://bmj.bmjjournals.com/cgi/content/extract/333/7569/632; S. R. Porter, UCL Eastman Dental Inst., London; S.Porter@eastman.ucl.ac.uk
* Effect of the Global Alliance for Vaccines and Immunisation on Diphtheria, Tetanus, and Pertussis Vaccine Coverage: An Independent Assessment, in
Lancet, 2006; 368: 1088–95. Reprints: www.thelancet.com/journals/lancet/article/PIIS0140673606693379/abstract; C. J. L. Murray, christopher_murray@harvard.edu
* Mechanisms Underlying Development of Spatially Distributed Chronic Pain (Fibromyalgia), in
Pain, 2006; 124: 242–63. Reprints: www.sciencedirect.com/science; C. J. Vierck, Jr., vierck@mbi.ufl.edu
* Mild Cognitive Impairment: An Opportunity To Identify Patients at High Risk for Progression to Alzheimer’s Disease, in
Clinical Therapeutics, 2006; 28: 991–1001. Reprints: www.sciencedirect.com/science; A. Levey, allan.levey@emory.edu
* The $64,000 Question—What Is a Quality-Adjusted Life-Year Worth [editorial]?, in
Clinical Therapeutics, 2006; 28: 1042–3. Reprints: www.sciencedirect.com/science; K. Rascati, U. Texas, Austin.
* Is It Appropriate To Make Statins Available Over The Counter [point–counterpoint]?—Over-The-Counter Statins Are Worth Considering in Primary Prevention of Cardiovascular Disease, and The Argument Against the Appropriateness of Over-the-Counter Statins, in
Circulation, 2006; 114: 1310–4 and 1315–20. Reprints: http://circ.ahajournals.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
Sept. 26, 2006 Vol. 13, No. 185
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Sept. 25 issue of Archives of Internal Medicine (www.archinternmed.com; 2006; 166).
Cost-Related Medication Nonadherence: High rates of cost-related medication nonadherence (CRN) are identified among elderly and disabled Medicare beneficiaries in a national survey conducted in fall 2004, a year before the implementation of Medicare Part D (pp. 1829-35). The authors conclude that CRN was exacerbated by poor health, multiple morbidities, and limited drug coverage, and they note that the high cost sharing under Part D makes it “important to closely monitor CRN in high-risk subgroups.” They offer these specific results: “In a national sample of 13,835 noninstitutionalized Medicare enrollees, 29% of the disabled and 13% of the elderly beneficiaries reported CRN; those in fair to poor health with multiple comorbidities and without coverage were most at risk. Among the disabled enrollees with 4 or more morbidities, 52% (95% confidence interval [CI], 43.3%–60.3%) without drug coverage skipped prescriptions or doses compared with 26% (95% CI, 17.7%–34.8%) with Medicaid drug coverage. Those with partial drug coverage through Medigap policies or Medicare health maintenance organizations reported intermediate rates of CRN. The adjusted odds ratio of CRN among disabled enrollees in poor (vs good) health was 3.9 (95% CI, 1.7–9.2), whereas for those with 4 or more (vs <4) comorbidities, the odds ratio of CRN was 2.7 (95% CI, 1.7–4.1).” (S. B. Soumerai, ssoumerai@hms.harvard.edu)
An editorialist lists eight challenges to improving medication adherence, starting with the observation that “patient” nonadherence is often not the fault of the patient but rather the result of physician behaviors and economic factors, according to this and other research (pp. 1802-4). The writer concludes: “Medication nonadherence is very expensive, sometimes lethal, and depressingly common. Recent reports suggest new and creative ways to address medication nonadherence—strategies that focus on not only patients but also physicians, insurance products, and policy makers. A common theme that unifies many of the challenges we face is the need to use medications judiciously, to systematically attempt to keep the number of medications and daily doses to a minimum, and to improve communication between health care providers and patients at care transitions. Efforts to use financial incentives to improve adherence to especially beneficial medications and coaching patients on the relative importance of their drugs may help. Finally, increased availability of sophisticated information and decision support systems will eventually open up exciting and more effective ways to compare and communicate medication risks and benefits when designing personalized treatment regimens.” (P. J. O’Connor, HealthPartners Research Foundation, Minneapolis;
Patrick.J.OConnor@healthpartners.com)
Medication Nonadherence: Two reports from a research group demonstrate the detrimental effects of medication nonadherence in patients with diabetes and medication discontinuance following hospitalization for myocardial infarction.
In a retrospective cohort study of 11,532 patients with diabetes in a managed care organization, nonadherent patients had higher glycosylated hemoglobin, systolic and diastolic blood pressure, and LDL cholesterol levels and significantly higher rates of all-cause hospitalization (23.2% versus 19.2% among adherent patients) and all-cause mortality (5.9% vs. 4.0%) (pp. 1836-41). Nonadherent patients tended to be younger and have fewer comorbidities than those who took their medications as prescribed.
Medication discontinuation was common after hospital discharge for MI, and mortality rates were higher among those stopping evidence-based medications, according to a prospective cohort study of patients in the Prospective Registry Evaluating Myocardial Infarction: Event and Recovery study (pp. 1842-7). “Patients who discontinued use of all medications at 1 month had lower 1-year survival (88.5% vs 97.7%; log-rank P < .001) compared with patients who continued to take 1 or more medication(s),” the authors write, adding that improved transition of care from the hospital to outpatient setting is needed. (P. M. Ho, VA Med. Ctr., Denver;
michael.ho@uchsc.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
Sept. 27, 2006 Vol. 13, No. 186
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Sept. 27 issue of JAMA (www.jama.com; 2006; 296)
Antibiotics for Trachoma & Reinfection: Use of azithromycin to treat trachoma in Vietnam resulted in an increase in the risk of reinfections, according to a study of three communes of 3,186 individuals from Nov. 2000 through Nov. 2003 (pp. 1488-97). In 1996, the WHO designed the SAFE (Surgery for trachomatous trichiasis; Antibiotics for Chlamydia trachomatis; Facial cleanliness; and Environmental improvement) strategy with the goal of elimination of blinding trachoma by 2020. In the current report, azithromycin was given to children from 5 through 15 years of age with active trachoma and their household members in SAFE and SA communes at baseline and 12 months over 2 consecutive years with follow-up for 2 years beyond the last treatment. The researchers found that reinfection rates increased significantly between 12 and 36 months for SAFE (from 1.6 to 29.3 per 1,000) and SA (5.1 to 25.3 per 1,000) communes but not for the S-only commune (13.4 to 6.7 per 1,000) after 24 months. Compared with the S-only commune, analysis showed that re-infection risk was about four times higher for SAFE and SA communes at 36 months. (D. Dean, Children’s Hosp. Oakland Res. Inst., Oakland, Calif.; ddean@chori.org)
Anniversary for Cancer Chemotherapy: The origins of cancer chemotherapy lie in wartime research into poison gases, an author recounts in marking the 60th anniversary of cancer chemotherapy (pp. 1518-20): “There seems to be no end to this sad story of chemical warfare. The abundance of plagues, diseases, and epidemics ranging over time from history books to today’s newspaper make a grim story, but few memories are worse than that of poison gas. Fortunately, physicians, such as Krumbhaar in World War I and Goodman in World War II, had the keen awareness and clinical investigative bent enabling them to extract useful data from the horror and secrecy of chemical warfare and to disseminate their findings. The inquisitive minds of physician-investigators had sifted through the horror and extracted a gem—something potentially useful for the abatement of human disease. And so with the greatest respect for bedside, patient-oriented research, happy 60th anniversary to cancer chemotherapy and the molecular biology that it has inaugurated, which may lead to effective cures for neoplastic disease.” (J. Hirsch, hirsch@mail.rockefeller.edu)

>>>PNN NewsWatch
* In The Future of Drug Safety: Action Steps for Congress, the Institute of Medicine outlines a series of major steps that could be taken to correct problems at FDA and enhance the safety of medications available in the U.S. The report’s 25 recommendations fall into eight categories, including these: (1) Clarify FDA’s regulatory authority through Congressional empowerment of the agency to act rapidly and decisively “when necessary and appropriate”; (2) requiring a special symbol that would alert consumers to new products and those requiring heightened regulatory attention; (3) establish performance goals for safety by restoring “appropriate balance between the FDA’s dual goals of speeding access to innovative drugs and ensuring drug safety over the product’s lifecycle”; (4) hold industry and researchers accountable for making drug safety study results public; and (5) ensuring adequate resources for drug safety.
* Genentech and
FDA have notified health professionals about revisions to the warnings and adverse reactions sections of the product labeling of bevacizumab (Avastin) to include two rare, new adverse effects: cases of a rare brain-capillary leak syndrome, reversible posterior leukoencephalopathy syndrome (RPLS), and nasal septum perforation. RPLS is a neurologic disorder associated with hypertension, fluid retention, and cytotoxic effects of immunosuppressive drugs on the vascular endothelium. The syndrome can present with headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances. Mild to severe hypertension may be present, but is not necessary for diagnosis.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Sept. 28, 2006 Vol. 13, No. 187
Providing news and information about medications and their proper use

>>>Panitumumab Approved for Metastatic Colon Cancer
FDA has approved panitumumab (Vectibix—Amgen) for treatment of patients with colorectal cancer that has metastasized following standard chemotherapy. Panitumumab, a monoclonal antibody that binds to epidermal growth factor receptor (EGFR) on some cancer cells, received an accelerated approval after showing effectiveness in slowing tumor growth and, in some cases, reducing the size of the tumor.
FDA said that it approved panitumumab on the basis of the results of a randomized controlled clinical trial of 463 patients with metastatic cancer of the colon and the rectum after undergoing treatment with chemotherapy drugs, including fluoropyrimidine, oxaliplatin, and irinotecan. The mean time to disease progression or death in patients receiving panitumumab was 96 days versus 60 days in patients receiving the best standard supportive care. In addition, 8% of the patients on panitumumab experienced a tumor shrinkage that in some cases exceeded 50% of the pretreatment size of the tumor. Both study groups showed similar overall survival.
As a condition of the accelerated approval, Amgen committed to conduct a postmarketing trial to show whether panitumumab improves patients’ survival in patients with fewer prior chemotherapies.
The most serious adverse events in the studies of panitumumab included pulmonary fibrosis, severe skin rash complicated by infections, infusion reactions, abdominal pain, nausea, vomiting, and constipation. The most common adverse events associated with the drug included skin rash, fatigue, abdominal pain, nausea, and diarrhea.

>>>NEJM Highlights
Source:
Sept. 28 issue of the New England Journal of Medicine (content.nejm.org; 2006; 355).
Islet Transplantation for Diabetes: In 36 patients with type 1 diabetes with refractory hypoglycemia, islet transplantation restored long-term endogenous insulin production and glycemic stability but failed to provide sustainable insulin independence (pp. 1318-30). However, even without insulin independence, patients had fewer episodes of severe hypoglycemia and improved A1c levels, the authors note, adding these details: “Of the 36 subjects, 16 (44%) met the primary end point, 10 (28%) had partial function, and 10 (28%) had complete graft loss 1 year after the final transplantation. A total of 21 subjects (58%) attained insulin independence with good glycemic control at any point throughout the trial. Of these subjects, 16 (76%) required insulin again at 2 years; 5 of the 16 subjects who reached the primary end point (31%) remained insulin-independent at 2 years.” (A. M. J. Shapiro, U. Alberta, Edmonton; shapiro@islet.ca)
Wondering whether the glass is half full, editorialists paint this picture of the current state of research into this intervention for patients with diabetes (pp. 1372-4): “Islet transplantation is at a crossroads. It is clear that poor long-term results, high costs, and the relatively high incidence of major and minor serious adverse events make it difficult to argue for expansion of islet transplantation to the general population. Nonetheless, the dramatic discoveries and successful dissemination of information in a relatively short period encourage us to believe these advances will continue apace. Additional research investments are likely to be high yield and to have a positive effect on many patients in the not-too-distant future.” (J. S. Bromberg, Mount Sinai Sch. of Med., New York)
Generic Competition: The high-stakes but murky world of brand-name patents and generic substitutes is explored through the events surrounding this summer’s brief marketing of generic clopidogrel (pp. 1297-300). During the few days that Apotex’s product was marketed, one customer placed an order for $75 million. Courts have differed on the legality of major pharmaceutical companies paying generic firms to keep substitutes off the U.S. market, the author notes, and Congressional action is likely needed to stop this usurpation of the patent laws and provisions of the Hatch–Waxman Act. (M. Shuchman, U. Buffalo, Buffalo, N.Y.)

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Sept. 29, 2006 Vol. 13, No. 188
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Oct. issue of Diabetes Care (care.diabetesjournals.org; 2006; 29).
Pramlintide in Intensive Insulin Therapy: Addition of pramlintide to intensive insulin therapy enabled lower mealtime insulin doses along with fewer glucose excursions and decreased weight, according to a 29-week study of 296 patients with type 1 diabetes (pp. 2189-95). Pramlintide doses were escalated during the trial from 15 to 60 mcg/meal, and mealtime insulin doses were reduced proactively by 30% to 50%. Glycosylated hemoglobin improvements were similar with or without pramlintide, but results showed these benefits of treatment: “Pramlintide treatment significantly reduced postprandial glucose excursions (incremental area under the curve [AUC]0–3h: pramlintide –175 ± 40, placebo –64 ± 38 mg/h/dl; P < 0.0005) and weight (pramlintide –1.3 ± 0.30, placebo +1.2 ± 0.30 kg; P < 0.0001). At week 29, insulin dose decreased by 28 and 4% in pramlintide- and placebo-treated groups, respectively. Nausea, reported by 63% and 36% of patients in pramlintide and placebo groups (P < 0.01), respectively, was predominately mild to moderate in intensity. Severe hypoglycemia rates were low in both groups (pramlintide 0.57 ± 0.09, placebo 0.30 ± 0.06 event rate/patient-year; P < 0.05), with increased rates observed in patients remaining at 30 µg pramlintide.” (O. Kolterman, kolterman@amylin.com">okolterman@amylin.com)
Teaching Patients About Flexible Intensive Insulin Therapy: Patients with type 1 diabetes who are at high risk of severe hypoglycemia or severe ketoacidosis may benefit from a diabetes treatment and teaching program (DTTP), report investigators who studied 9,583 routine-care patients between 1992 and 2004 (pp. 2196-9). “A total of 341 participants had three or more episodes of severe hypoglycemia the year before a DTTP,” the group notes. “Mean baseline [A1C] was 7.4% vs. 7.2% after the DTTP, incidence of severe hypoglycemia was 6.1 vs. 1.4 events/patient/ year, and hospitalization was 8.6 vs. 3.9 days/patient/year. In mixed-effects models taking effects of centers and diabetes duration into account, mean difference was –0.3% (95% CI –0.5 to –0.1%; P = 0.0006) for [A1C] and –4.7 events/patient/year (–5.4 to –4; P < 0.0001) for severe hypoglycemia. A total of 95 patients had two or more episodes of severe ketoacidosis. [A1C] was 9.4% at baseline versus 8.7% after DTTP; incidence of severe ketoacidosis was 3.3 vs. 0.6 events/patient/year, and hospitalization was 19.4 vs. 10.2 days/patient/year. In linear models with diabetes duration as the fixed effect, the adjusted mean difference was –2.7 events/patient/year (95% CI –3.3 to –2.1; P < 0.0001) for severe ketoacidosis and –8.1 days (–12.9 to –3.2; P = 0.0014) for hospitalization.” (A. Sämann, Friedrich-Schiller-Universität, Jena, Germany; alexander.saemann@med.uni-jena.de)
Adolescent Adherence: Two measures of diabetes regimen adherence tested well, with good psychometric properties and criterion validity, in a study of 146 adolescents with type 1 diabetes (pp. 2263-7): “Both measures had good evidence of internal consistency (for the DSMP: parent 0.75 and youth 0.70; for the DBRS: parent 0.84 and youth 0.84). Scores on the DSMP and the DBRS were significantly related (r = 0.72 for parents and 0.74 for youth). There was moderate agreement between parent and youth (DSMP, r = 0.51; DBRS, r = 0.48). The measures were correlated with HbA1c for both parent (DSMP, r = –0.35; DBRS, r = –0.35) and youth (DSMP, r = –0.36; DBRS, r = –0.34) reports.” However, the Diabetes Self-Management Profile, a widely used, structured interview, and the Diabetes Behavior Rating Scale, a self-administered, fixed-choice survey, differed in terms of respondent and interviewer burden. (R. J. Iannotti, iannottr@mail.nih.gov)

>>>PNN NewsWatch
* An FDA decision on approval of paliperidone (Johnson & Johnson) is expected today, according to this morning’s Wall Street Journal. Paliperidone is the active metabolite of the company’s top-selling risperidone (Risperdal), a product that could encounter generic competition by 2007 or 2008, the paper notes. Paliperidone does not yet have a trade name. The formulation under review would be dosed once daily.

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