Dec 2006

PNN Quarterly File—Fourth Quarter 2006

PNN Pharmacotherapy Line
Oct. 2, 2006 Vol. 13, No. 189
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Early-release articles from and Sept. 30 issue of Lancet (www.thelancet.com; 2006; 368).
Oral Renin Inhibitors: Development of oral renin inhibitors is reviewed, and information is presented on their pharmacokinetic and pharmacodynamic properties, with a focus on aliskiren (doi: 10.1016/S0140-6736(06)69442-7). “Use of drugs that inhibit the renin-angiotensin system is an effective way to intervene in the pathogenesis of cardiovascular and renal disorders,” the authors write. “The idea of blocking the renin system at its origin by inhibition of renin has existed for more than 30 years. Renin inhibition suppresses the generation of the active peptide angiotensin II. The first generation of orally active renin inhibitors were never used clinically because of low bioavailability and weak blood-pressure-lowering activity. At present, aliskiren is the first non-peptide orally active renin inhibitor to progress to phase-III clinical trials. It might become the first renin inhibitor with indications for the treatment of hypertension and cardiovascular and renal disorders. Novel compounds with improved oral bioavailability, specificity, and efficacy are now in preclinical development.” (J. A. Staessen, U. Leuven, Leuven, Belgium; jan.staessen@med.kuleuven.be)
Lower-Dose Pravastatin: In the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) study, treatment with a low dose of pravastatin reduced risks of coronary heart disease by amounts similar to higher doses in European and American studies (pp. 1155-63). An open-label, double-blinded trial, MEGA compared diet only with diet plus pravastatin 10–20 mg/day, with these results: “3,966 patients were randomly assigned to the diet group and 3,866 to the diet plus pravastatin group. Mean follow-up was 5.3 years. At the end of study, 471 and 522 patients had withdrawn, died, or been lost to follow-up in the diet and diet plus pravastatin groups, respectively. Mean total cholesterol was reduced by 2.1% (from 6.27 mmol/L to 6.13 mmol/L) and 11.5% (from 6.27 mmol/L to 5.55 mmol/L) and mean LDL cholesterol by 3.2% (from 4.05 mmol/L to 3.90 mmol/L) and 18.0% (from 4.05 mmol/L to 3.31 mmol/L) in the diet and the diet plus pravastatin groups, respectively. Coronary heart disease was significantly lower in the diet plus pravastatin group than in the diet alone group (66 events vs 101 events; HR 0.67, 95% CI 0.49–0.91; p = 0.01). There was no difference in the incidence of malignant neoplasms or other serious adverse events between the two groups.” (H. Nakamura, Mitsukoshi Health and Welfare Foundation, Tokyo; nakamura@mhwf.or.jp)
Medical Treatment of Urinary Stones: Treatment with calcium-channel blockers or alpha-adrenergic blockers is a reasonable option for patients with urinary stones, conclude authors of a meta-analysis of nine trials of 693 patients (pp. 1171-9). “Patients given calcium-channel blockers or alpha-blockers had a 65% (absolute risk reduction = 0.31 95% CI 0.25–0.38) greater likelihood of stone passage than those not given such treatment (pooled risk ratio 1.65; 95% CI 1.45–1.88),” report the investigators. “The pooled risk ratio for alpha-blockers was 1.54 (1.29–1.85) and for calcium-channel blockers with steroids was 1.90 (1.51–2.40). The proportion of heterogeneity not explained by chance alone was 28%. The number needed to treat was 4.” (B. K. Hollenbeck, bhollen@umich.edu)

>>>PNN JournalWatch
* Gut Hormones and Related Concepts, in Diabetes Care, 2006; 29: 2319–24. Reprints: Z. T. Bloomgarden, New York; http://care.diabetesjournals.org/cgi/content/extract/29/10/2319
* Medication-Induced Weight Gain and Dyslipidemia in Patients with Schizophrenia, in
American Journal of Psychiatry, 2006; 163: 1697–704. Reprints: http://ajp.psychiatryonline.org/cgi/content/full/163/10/1697
* The Nature of Genetic Influences on Behavior: Lessons from “Simpler” Organisms, in
American Journal of Psychiatry, 2006; 163: 1683–94. Reprints: K. S. Kendler. http://ajp.psychiatryonline.org/cgi/content/abstract/163/10/1683

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Oct. 3, 2006 Vol. 13, No. 190
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Oct. 3 issue of the Annals of Internal Medicine (www.annals.org; 2006; 145).
Tadalafil, Dexamethasone for High-Altitude Pulmonary Edema: Among 29 patients with a history of high-altitude pulmonary edema, both dexamethasone and tadalafil decreased systolic pulmonary artery pressure and reduced the incidence of HAPE, and dexamethasone prophylaxis also reduced the incidence of acute mountain sickness (pp. 497-506). In this study, participants ascended from 490 to 4,559 meters over 24 hours and stayed there for two nights. Prophylactic doses of tadalafil 10 mg, dexamethasone 8 mg, or placebo twice daily during the ascent and stay produced these results: “Two participants who received tadalafil developed severe AMS on arrival at 4,559 m and withdrew from the study; they did not have HAPE at that time. High-altitude pulmonary edema developed in 7 of 9 participants receiving placebo and 1 of the remaining 8 participants receiving tadalafil but in none of the 10 participants receiving dexamethasone (P = 0.007 for tadalafil vs. placebo; P < 0.001 for dexamethasone vs. placebo). Eight of 9 participants receiving placebo, 7 of 10 receiving tadalafil, and 3 of 10 receiving dexamethasone had AMS (P = 1.0 for tadalafil vs. placebo; P = 0.020 for dexamethasone vs. placebo). At high altitude, systolic pulmonary artery pressure increased less in participants receiving dexamethasone (16 mm Hg [95% CI, 9 to 23 mm Hg]) and tadalafil (13 mm Hg [CI, 6 to 20 mm Hg]) than in those receiving placebo (28 mm Hg [CI, 20 to 36 mm Hg]) (P = 0.005 for tadalafil vs. placebo; P = 0.012 for dexamethasone vs. placebo). No statistically significant difference between groups was found in change in nasal potentials and expression of leukocyte sodium transport protein messenger RNA.” (M. Maggiorini, U. Hosp., Zürich, Switzerland; klinmax@usz.unizh.ch)
Geriatrics Update: A review article provides an update in geriatrics based on a review of some 30 journals published during 2005 (pp. 538-43). The author recommends that geriatricians consider advising patients concerned about future cognitive function to eat diets high in folate and vitamins B6 and B12, prescribing low-dose haloperidol to prevent postoperative delirium in high-risk older patients, prescribing antiarrhythmics in those with atrial fibrillation and activity-limiting symptoms, and prescribing ACE inhibitors before other antihypertensive medications in frail elders and those at risk for weight loss. (W. J. Hall, william_hall@urmc.rochester.edu)

>>>PNN NewsWatch
* Preliminary findings from a Bayer-conducted safety study shows that aprotinin injection (Trasylol, Bayer) can increase patients’ risk of death, serious kidney damage, congestive heart failure, and strokes. In an advisory posted on its Web site last Friday, FDA said that it was not aware of these new data when one of its advisory committees met the previous week to discuss the drug’s safety. The agency said it is actively evaluating these new data and their implications for appropriate use of the drug. While these new data are evaluated, FDA suggested that health professionals limit use of the drug to situations where the benefit of reducing blood loss “is essential to medical management of the patient and outweighs the potential risks” and report adverse drug events to the agency’s MedWatch program or Bayer.
* Preliminary data from the North American Antiepileptic Drug Pregnancy Registry suggest a possible association between exposure to
lamotrigine (Lamictal, GlaxoSmithKline) monotherapy during the first trimester of pregnancy and cleft lip and/or cleft palate. The oral clefts reported were few and not part of a syndrome that included other birth defects, and other pregnancy registries of similar size have not identified this problem. Thus, the validity of this possible association is of uncertain relevance, but clinicians should weigh the possibility against benefits of the drug in reaching a decision to use lamotrigine early in pregnancy. Lamotrigine is used for epilepsy and bipolar disorder, and these have their own substantial risks if not controlled during pregnancy, and alternative agents such as phenobarbital and valproate are known teratogens.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Oct. 4, 2006 Vol. 13, No. 191
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Oct. 4 issue of JAMA (www.jama.com; 2006; 296).
Renal, Cardiovascular Problems with COX-2 Inhibitors: Two articles and an editorial that were released previously discuss renal and cardiovascular events with COX-2 inhibitors (see PNN, Sept. 13).
Pharmacogenetics of Antidepressants: If confirmed in larger studies, preliminary results of 241 patients could lead to pharmacogenetic selection of antidepressant treatment (pp. 1609-18). Researchers looked at polymorphisms in the serotonin transporter gene (5-HTT), which influences response to SSRIs, and the norepinephrine transporter (NET), involved in response to norepinephrine reuptake inhibitors (NRIs). Based on genotyping for s/l polymorphisms in 5-HTT promoter region (5-HTTLPR), 5-HTT intron 2 s/l variation, and NET G1287A variation of exon 9, the researchers determined the following: “NRI response was associated with the NET G1287A polymorphism (odds ratio [OR], 7.54; 95% confidence interval [CI], 2.53–22.49; P < .001). An SSRI response was associated with the 5-HTT intron 2 s/l variation (OR, 20.11; 95% CI, 4.27–94.74; P < .001). The 5-HTTLPR was also associated with an SSRI response (OR, 3.34; 95% CI, 1.41–7.91; P = .006). In contrast to studies in white patients, the favorable allele for SSRI response was S 5-HTTLPR. The S 5-HTTLPR was associated also with NRI response (OR, 3.73; 95% CI, 1.32–10.53; P = .01). The NET polymorphism was not associated with an SSRI response. The NET G1287A GG genotype (56% of the population) was associated with better response to the NRI (83.3% [35/42]) than to SSRI (58.7% [44/75]) (OR, 3.52; 95% CI, 1.39–8.95; P = .006). Some genotype combinations were associated with high rates of antidepressant response and others with low rates of response.” (D. K. Kim, Samsung Med. Ctr., Seoul, Korea; paulkim@smc.samsung.co.kr)

>>>Infectious Diseases Report
Source:
Oct. 15 issue of Clinical Infectious Diseases (www.journals.uchicago.edu/CID; 2006; 43).
Pyomyositis, Myositis in MRSA Era: Community-acquired methicillin-resistant Staphylococcus aureus is an increasingly common cause of infective pyomyositis and myositis, report authors of a retrospective analysis (pp. 953-60). Delving through medical records of patients with these skeletal muscle abscesses for the 2000 to 2005 period and looking at susceptibility tests indicating the presence of pvl (lukS-PV and lukF-PV), the group finds: “Forty-five previously healthy children with bacterial pyomyositis or myositis were analyzed. The causes were S. aureus (in 57.8% of children) and Streptococcus pyogenes (in 2.2%); 40.0% of children had negative culture results. The number of cases increased between 2000 and 2005, primarily as a result of an increase in the prevalence of community-acquired MRSA. The mean patient age was 5.5 years (range, 0.06–15 years). The thigh (40.0% of children) and pelvis (28.9%) were the most commonly affected sites. The mean abscess diameter was 3.5 cm. Eighteen children required at least 1 muscle drainage procedure. Of the 24 available S. aureus isolates (15 community-acquired MRSA isolates and 9 community-acquired, methicillin-susceptible S. aureus [MSSA] isolates), 16 were found to be USA300 by pulsed-field gel electrophoresis, and 17 carried pvl. Patients with community-acquired MRSA, USA300, and/or pvl-positive strains required more drainage procedures than did those with community-acquired MSSA, non-USA300, and/or pvl-negative strains (81% vs. 40% [P = .05], 82% vs. 29% [P = .02], and 81% vs. 38% [P = .07], respectively).” (P. S. Pannaraj, Baylor Coll. of Med., Houston; pannaraj@bcm.tmc.edu)
Pneumococcal Vaccination: Citing cases of nonbacteremic pneumococcal pneumonia among patients vaccinated with the 23-valent pneumococcal capsular polysaccharide vaccine, authors call for “a continued search for a better pneumococcal vaccine” (pp. 1004-8). “PPV conferred a 54% protection rate against bacteremic versus nonbacteremic pneumococcal pneumonia,” the group notes. “There was no apparent protection against nonbacteremic pneumonia compared, for example, with colonized persons or with those who had [acute exacerbation of chronic bronchitis].” (D. M. Musher, VA Med. Ctr., Houston; daniel.musher@med.va.gov)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 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
Oct. 5, 2006 * Vol. 13, No. 192
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Oct. 5 issue of the New England Journal of Medicine (content.nejm.org; 2006; 355).
Ranibizumab for Macular Degeneration: Research studies, perspectives and review articles, and an editorial present information on use of ranibizumab injection (Lucentis, Genentech), approved recently by FDA (see PNN, July 7), for neovascular age-related macular degeneration.
“Intravitreal administration of ranibizumab for 2 years prevented vision loss and improved mean visual acuity, with low rates of serious adverse events, in patients with minimally classic or occult (with no classic lesions) choroidal neovascularization secondary to age-related macular degeneration,” concludes a study of monthly injections of 0.3 or 0.5 mg (pp. 1419-31). For the 716 patients in the study, the authors report: “At 12 months, 94.5% of the group given 0.3 mg of ranibizumab and 94.6% of those given 0.5 mg lost fewer than 15 letters, as compared with 62.2% of patients receiving sham injections (P < 0.001 for both comparisons). Visual acuity improved by 15 or more letters in 24.8% of the 0.3-mg group and 33.8% of the 0.5-mg group, as compared with 5.0% of the sham-injection group (P < 0.001 for both doses). Mean increases in visual acuity were 6.5 letters in the 0.3-mg group and 7.2 letters in the 0.5-mg group, as compared with a decrease of 10.4 letters in the sham-injection group (P < 0.001 for both comparisons). The benefit in visual acuity was maintained at 24 months. During 24 months, presumed endophthalmitis was identified in five patients (1.0%) and serious uveitis in six patients (1.3%) given ranibizumab.” (P. J. Rosenfeld, U. Miami, Miami;
prosenfeld@med.miami.edu)
Compared with verteporfin, ranibizumab was superior as intravitreal treatment of predominantly classic neovascular age-related macular degeneration, with low rates of serious ocular adverse events, reports a 423-patient study (pp. 1432-44). “94.3% of those given 0.3 mg of ranibizumab and 96.4% of those given 0.5 mg lost fewer than 15 letters, as compared with 64.3% of those in the verteporfin group (P < 0.001 for each comparison),” the investigators report. “Visual acuity improved by 15 letters or more in 35.7% of the 0.3-mg group and 40.3% of the 0.5-mg group, as compared with 5.6% of the verteporfin group (P < 0.001 for each comparison). Mean visual acuity increased by 8.5 letters in the 0.3-mg group and 11.3 letters in the 0.5-mg group, as compared with a decrease of 9.5 letters in the verteporfin group (P < 0.001 for each comparison). Among 140 patients treated with 0.5 mg of ranibizumab, presumed endophthalmitis occurred in 2 patients (1.4%) and serious uveitis in 1 (0.7%).” (D. M. Brown, Vitreoretinal Consultants, Houston;
dmbmd@houstonretina.com)
Describing this treatment as very effective for neovascular macular degeneration, an editorialist provides a perspective on ranibizumab and another recently approved agent, bevacizumab (pp. 1493-5): “Anecdotal and retrospective data ... suggest that many patients with choroidal neovascularization could be effectively treated with fewer than the 24 monthly injections evaluated by Rosenfeld et al. For example, a physician might administer three or more injections to gain control of the choroidal neovascularization and then follow the patient with frequent clinical examinations and optical coherence tomography to determine whether and, if so, when additional injections are needed. A prospective clinical trial of such a strategy—using ranibizumab, bevacizumab, or both—would be of great benefit to the medical community.” (E. M. Stone, U. Iowa, Iowa City)
Lenalidomide for 5q-Deletion Myelodysplastic Syndrome: Lenalidomide on a daily or cyclic schedule reduced transfusion requirements and reversed cytologic and cytogenetic abnormalities among 148 patients with myelodysplastic syndrome with 5q31 deletion (pp. 1456-65). Overall, 76% of patients had a reduced need for transfusions, and 67% no longer required transfusions. Moderate-to-severe neutropenia (55%) and thrombocytopenia (44%) were the most common reasons for interrupting treatment or adjusting lenalidomide doses. (A. List, heberten@moffitt.usf.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
Oct. 6, 2006 * Vol. 13, No. 193
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Oct. issue of Pharmacotherapy (www.pharmacotherapy.org; 2006; 26).
Pharmacist-Managed Antiepileptic Drug Therapy: An assessment of 1998 hospital and clinical pharmacy data shows that patients whose antiepileptic drug therapy was managed by pharmacists had significantly better clinical and economic outcomes (pp. 1369-78). Among 9,380 Medicare patients with epilepsy and hospitalized in 794 U.S. hospitals, the investigators found that hospitals without pharmacist-managed AED therapy had 20.61% higher mortality rates (374 excess deaths), 14.68% increase in length of stay (8,069 excess patient–days), 11.19% higher Medicare charges ($14.4 million), laboratory charges that were 32.34% higher ($5.7 million), and aspiration rates that were 54.61% higher, compared with hospitals that had such services. (C. A. Bond, cab.bond@ttuhsc.edu)
Community Pharmacists Managing CVD in Workplaces: Improved blood pressure and LDL cholesterol levels were evident among 56 workers who received cardiovascular case management by community pharmacists in their rural Iowa manufacturing facility (pp. 1511-7). Using a pre–post design in which workers served as their own controls, the investigators found these results in a retrospective analysis of billing data from July 2001 to Oct. 2004: “The number of pharmacist visits/participant ranged from 1–13 (mean ± SD 6.97 ± 3.05).... Statistically significant differences between the first and last visits were achieved for both systolic (124.12 ± 11.07 and 120.36 ± 14.39 mm Hg, respectively, p = 0.016) and diastolic (80.4 ± 9.01 and 77.43 ± 9.14 mm Hg, respectively, p = 0.019) blood pressure. The 19 patients without diabetes showed a statistically significant improvement in diastolic blood pressure (p = 0.039), but the 37 patients with diabetes did not show a significant difference. A nonsignificant increase was seen in the percentage of patients with diabetes achieving low-density lipoprotein cholesterol ... level goal between the first and last visits (p = 0.06).” (K. Farris, karen-farris@uiowa.edu)
MIs & COX Inhibitors:
In a study of nonselective and COX-2–selective NSAIDs, extensive use of rofecoxib, celecoxib, and diclofenac increased patients’ risk of acute myocardial infarction, while similar use of ibuprofen and naproxen did not (pp. 1379-87). Five separate case–control studies, one of each drug, from the United Kingdom General Practice Research Database showed elevated risks of MI when patients had received 10 or more prescriptions for rofecoxib, celecoxib, or diclofenac. (H. Jick, Boston Collaborative Drug Surveillance Program, Lexington, Mass.; hjick@bu.edu)
Hyperglycemia Management in Hospitals: A nurse-managed insulin infusion protocol lowered mortality, time in intensive care, and days of mechanical ventilation among adults in ICUs (pp. 1410-20). Blood glucose was measured every 2 hours with the goal of maintaining a target blood glucose concentration of 91–130 mg/dL through intensive insulin therapy. The target was achieved in 34% of all measurements in 70 protocol patients, compared with 23% of measurements of 143 control patients who received physician-directed usual care. (J. A. Quinn, St. Vincent Hosp., Indianapolis)
A second retrospective study shows the problems associated with use of sliding-scale insulin in hospitalized patients (pp. 1421-32; L. K. Golightly, U. Colorado Hosp., Denver;
larry.golightly@uch.edu)

>>>PNN NewsWatch
* FDA yesterday licensed a fifth influenza vaccine, FluLaval (manufactured by GlaxoSmithKline Biologics subsidiary ID Biomedical Corporation of Quebec; distributed in the U.S. by GlaxoSmithKline), indicated for use in people 18 years of age and older. Reviewed on an accelerated basis by FDA, FluLaval was studied in two safety trials involving about 1,000 adults. Other data from use of the vaccine in Canada since 2001 were also evaluated. After vaccination, the rate and nature of adverse effects were similar to those seen with other licensed seasonal influenza vaccines: pain, redness and swelling at the injection site, headache, fatigue, and cough.
*
PNN will not be published on Mon., Oct. 9, Columbus 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
Oct. 10, 2006 * Vol. 13, No. 194
Providing news and information about medications and their proper use

>>>
Internal Medicine Report
Source:
Oct. 9 issue of Archives of Internal Medicine (www.archinternmed.com; 2006; 166).
FDA Reform: Serious limitations in the way FDA regulates medications are outlined and recommendations for change presented in a special article penned by five influential authors (pp. 1938-42): “We urge Congress, which is ultimately responsible for the FDA’s performance, to implement the following 5 recommendations: (1) give the FDA more direct legal authority to pursue violations, (2) authorize the adoption of a conditional drug approval policy, at least for selected drugs, (3) provide additional financial resources to support the safety operations, (4) mandate a reorganization of the agency with emphasis on strengthening the evaluation and proactive monitoring of drug safety, and (5) require broader representation of safety experts on the FDA’s advisory committees.” (C. D. Furberg, Wake Forest U., Winston-Salem, N.C.; cfurberg@wfubmc.edu)
The above recommendations echo some of those in the recently released Institute of Medicine report (see
PNN, Sept. 27). The New England Journal of Medicine yesterday released an analysis of the IOM report and an editorial by journal editors supporting reform at FDA (content.nejm.org).
Nonvitamin Dietary Supplement Use: In the U.S., 21% of users of prescription medications took a nonvitamin dietary supplement during a 1-year period, but 69% of NVDS users did not share this information with a conventional medical professional, according to an analysis of data from the 2002 National Health Interview Survey (pp. 1968-74). “The most commonly used supplements included echinacea, ginseng, ginkgo, garlic, and glucosamine–chondroitin,” write the authors. “Prescription medication users with menopause and chronic gastrointestinal disorders had the highest rates of NVDS use (33% and 28%, respectively), and prescription medication users with coronary heart disease and history of myocardial infarction had the lowest rates of use (12% each). In the adjusted analysis, factors associated with increased use of NVDSs by prescription medication users included being female, being Hispanic, having more years of education, living in the West, lacking medical insurance, and having chronic conditions. Elderly respondents were less likely to use NVDSs.” (P. Gardiner, paula_gardiner@hms.harvard.edu)

>>>PNN NewsWatch
* FDA has approved vorinostat (Zolinza—Merck) for oral treatment of cutaneous T-cell lymphoma (CTCL) when this type of skin cancer persists, gets worse, or comes back during or after treatment with other medicines. Evidence of vorinostat’s safety and effectiveness was developed in two clinical trials with 107 CTCL patients whose disease had recurred following other treatments. A response, defined by improvements on a scale that scores skin lesions, occurred in 30% of patients who received vorinostat and lasted an average of 168 days. The most common serious adverse events were pulmonary embolism, dehydration, deep-vein thrombosis, and anemia. The most common other adverse events were gastrointestinal symptoms (including diarrhea, nausea, anorexia, vomiting, and constipation), fatigue, chills, and taste disorders. Vorinostat, a histone deacetylase inhibitor, has not been studied in pregnant women, but results of animal studies suggest that the drug may cause fetal harm when administered during pregnancy.

>>>PNN JournalWatch
* Cochrane Reviews Compared with Industry Supported Meta-analyses and Other Meta-analyses of the Same Drugs: Systematic Review, in BMJ, 2006; doi: 10.1136/bmj.38973.444699.0B. Reprints: http://bmj.bmjjournals.com/cgi/content/abstract/bmj.38973.444699.0Bv1; P. C. Gøtzsche, Nordic Cochrane Ctr., Copenhagen, Denmark; pcg@cochrane.dk
* Magnesium Sulphate for Treatment of Severe Tetanus: A Randomised Controlled Trial, in
Lancet, 2006; DOI: 10.1016/S0140-6736(06)69444-0. Reprints: www.thelancet.com/journals/lancet/article/PIIS0140673606694440; C. L. Thwaites, Oxford U. Clinical Research Unit, Hosp. for Tropical Diseases, Ho Chi Minh City, Vietnam; louise.thwaites@btinternet.com
* Annual Influenza Vaccination in Community-Dwelling Elderly Individuals and the Risk of Lower Respiratory Tract Infections or Pneumonia, in
Archives of Internal Medicine, 2006; 166: 1980–5. Reprints: http://archinte.ama-assn.org/cgi/content/abstract/166/18/1980; B. C. G. Voordouw, Medicines Evaluation Board, The Hague, the Netherlands; ac.voordouw@cbg-meb.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
Oct. 11, 2006 * Vol. 13, No. 195
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Oct. 11 issue of JAMA (www.jama.com; 2006; 296).
Pertussis & Personal Exemptions from School Immunizations: Pertussis incidence is higher in states that allow parents to invoke personal exemptions to mandatory school immunizations and that more easily allow such exemptions, according to a study of state-level rates of nonmedical exemptions at school entry in 1991 through 2004 and pertussis incidence data for individuals aged 18 years or younger 1986 through 2004 (pp. 1757-63). As of March 2006, all states permitted medical exemptions to school and day-care immunization requirements; 48 states allowed religious exemptions; and 19 states had a provision for personal belief exemptions, such as religious, philosophical, or unspecified objections.
The authors report: “From 2001 through 2004, states that permitted personal belief exemptions had higher nonmedical exemption rates than states that offered only religious exemptions, and states that easily granted exemptions had higher nonmedical exemption rates in 2002 through 2003 compared with states with medium and difficult exemption processes. The mean exemption rate increased an average of 6% per year, from 0.99% in 1991 to 2.54% in 2004, among states that offered personal belief exemptions. In states that easily granted exemptions, the rate increased 5% per year, from 1.26% in 1991 to 2.51% in 2004. No statistically significant change was seen in states that offered only religious exemptions or that had medium and difficult exemption processes. In multivariate analyses adjusting for demographics, easier granting of exemptions (incidence rate ratio = 1.53; 95% confidence interval, 1.10–2.14) and availability of personal belief exemptions (incidence rate ratio = 1.48; 95% confidence interval, 1.03–2.13) were associated with increased pertussis incidence.” (D. A. Salmon,
das@ehpr.ufl.edu)
Pharmacology, Politics of Plan B: Two members of the FDA advisory committee that voted to approve the emergency contraceptive Plan B in the U.S. review the pharmacology of levonorgestrel when used for postcoital contraception (pp. 1775-8). Right-to-life advocates oppose emergency contraception on the basis that the hormones prevent implantation of a fertilized egg and therefore “is really nothing other than a chemically induced abortion,” the authors note. However, the article recounts, currently available evidence indicates that postcoital levonorgestrel acts by changing the cervical and uterine environments to interfere with sperm migration, prevention of ovulation, and causing released ova to be resistant to fertilization.
“In the absence of absolute proof about Plan B’s mechanisms of action, the right to make personal decisions about whether its use is morally acceptable must be respected and for that reason women should continue to be informed, as they are now in the Plan B labeling, that its use may affect postfertilization events,” conclude the authors. “At the same time, however, all women should be informed that the ability of Plan B to interfere with implantation remains speculative, since virtually no evidence supports that mechanism and some evidence contradicts it. Women should also be informed that the best available evidence indicates that Plan B’s ability to prevent pregnancy can be fully accounted for by mechanisms that do not involve interference with postfertilization events.” (F. Davidoff, Wethersfield, Conn.;
fdavidoff@cox.net)
Bar Workers & Smoking Ban: Bar workers in Scotland showed significant improvements in respiratory symptoms and lung function within 2 months following a ban on smoking in confined public places, notes a study of 77 such employees (pp. 1742-8). A total of 79.2% (n = 61) of the bar workers experienced respiratory or sensory symptoms before the introduction of the smoke-free policy, but 1 month after the ban, 53.2% (n = 41) reported these symptoms, a decline of 26%. At 2 months after introduction of the smoke-free policy, this improvement was maintained, with 46.8% of participants reporting any symptom (a decrease of 32.4% from baseline). Lung function improved, serum cotinine levels fell, and asthmatic bar workers had less airway inflammation and an increase in quality of life scores. (D. Menzies, Ninewells Hosp. and Med. Sch., Dundee, Scotland; d.menzies@dundee.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
Oct. 12, 2006 * Vol. 13, No. 196
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Oct. 12 issue of the New England Journal of Medicine (content.nejm.org; 2006; 355).
Second-Generation Antipsychotic Agents in AD: “Adverse effects offset advantages in the efficacy of atypical antipsychotic drugs for the treatment of psychosis, aggression, or agitation in patients with Alzheimer’s disease,” conclude investigators who studied 421 outpatients in CATIE-AD, the Clinical Antipsychotic Trials of Intervention Effectiveness–Alzheimer’s Disease (pp. 1525-38). Compared with placebo in the 36-week study were individualized doses of the second-generation agents olanzapine (mean dose, 5.5 mg/day), quetiapine (mean dose, 56.5 mg/day), and risperidone (mean dose, 1.0 mg/day).
Results showed: “There were no significant differences among treatments with regard to the time to the discontinuation of treatment for any reason: olanzapine (median, 8.1 weeks), quetiapine (median, 5.3 weeks), risperidone (median, 7.4 weeks), and placebo (median, 8.0 weeks) (P = 0.52). The median time to the discontinuation of treatment due to a lack of efficacy favored olanzapine (22.1 weeks) and risperidone (26.7 weeks) as compared with quetiapine (9.1 weeks) and placebo (9.0 weeks) (P = 0.002). The time to the discontinuation of treatment due to adverse events or intolerability favored placebo. Overall, 24% of patients who received olanzapine, 16% of patients who received quetiapine, 18% of patients who received risperidone, and 5% of patients who received placebo discontinued their assigned treatment owing to intolerability (P = 0.009). No significant differences were noted among the groups with regard to improvement on the [Clinical Global Impression of Change] scale. Improvement was observed in 32% of patients assigned to olanzapine, 26% of patients assigned to quetiapine, 29% of patients assigned to risperidone, and 21% of patients assigned to placebo (P = 0.22).” (L. S. Schneider,
lschneid@usc.edu)
An editorialist supports the adaptive design used in CATIE-AD (pp. 1604-6): “The study by Schneider and colleagues addresses a number of the problems with previous clinical trials of atypical antipsychotic medications. For instance, the designs of previous trials did not reflect clinical practice. Hence, their results could not directly change clinical practice. In contrast, the study by Schneider et al. adhered to the ‘logic of clinical purpose.’ This scientific and ethical model asserts that clinical trials are logically grounded in and ethically justified by the way in which they reflect and contribute to clinical practice.” (J. Karlawish, U. Penn., Philadelphia)
Ramipril in Prediabetes: While normoglycemia was improved, ramipril 15 mg/day for 3 years failed to reduce the incidence of diabetes or mortality among 5,269 participants with impaired fasting glucose levels or impaired glucose tolerance (pp. 1551-62). Adding the ramipril data to the already-reported rosiglitazone arm of the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) study (see PNN, Sept. 25), investigators report: “The incidence of the primary outcome did not differ significantly between the ramipril group (18.1%) and the placebo group (19.5%; hazard ratio for the ramipril group, 0.91; 95% confidence interval [CI], 0.81 to 1.03; P = 0.15). Participants receiving ramipril were more likely to have regression to normoglycemia than those receiving placebo (hazard ratio, 1.16; 95% CI, 1.07 to 1.27; P = 0.001). At the end of the study, the median fasting plasma glucose level was not significantly lower in the ramipril group (102.7 mg per deciliter [5.70 mmol per liter]) than in the placebo group (103.4 mg per deciliter [5.74 mmol per liter], P = 0.07), though plasma glucose levels 2 hours after an oral glucose load were significantly lower in the ramipril group (135.1 mg per deciliter [7.50 mmol per liter] vs. 140.5 mg per deciliter [7.80 mmol per liter], P = 0.01).” (DREAM Project Office, Population Health Res. Inst., Hamilton, Ont., Canada; dream@cardio.on.ca)
Self-Regulated Weight Maintenance: Compared with quarterly newsletters, a self-regulation program of daily weighing was effective for helping successful dieters to maintain their new body weights (pp. 1563-71; R. R. Wing, Weight Control and Diabetes Res. Ctr., Providence, R.I.; rwing@lifespan.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
Oct. 13, 2006 * Vol. 13, No. 197
Providing news and information about medications and their proper use

>>>Geriatrics Highlights
Source:
Oct. Journal of the American Geriatrics Society (www.blackwell-synergy.com; 2006; 54).
SSRIs & Sleep Disturbances: Older women, including those without depression, have increased sleep disturbances when taking SSRIs, according to a 2,853-patient study (pp. 1508-15). Poorer sleep efficiency, longer sleep latency, and sleep fragmentation, manifested by multiple long wake episodes, were evident among the 223 women taking SSRIs alone. Compared with 2,630 nonusers of antidepressants, the SSRI users showed these clinical findings: “After excluding women with evidence of depression and adjusting for multiple potential confounders, women taking SSRIs were more likely to have a sleep duration of 5 hours or less (multivariate odds ratio [MOR] = 2.15, 95% confidence interval [CI] = 1.04–4.47), sleep efficiency less than 70% (MOR = 2.37, 95% CI=1.32–4.25), sleep latency of 1 hour or more (MOR = 3.99, 95% CI = 2.29–6.96) and eight or more long wake episodes (MOR = 1.75, 95% CI = 0.99–3.10).” (K. E. Ensrud, ensru001@.umn.edu)
Polypharmacy, Prescribing Quality in Older People: Both inappropriate use and underuse of medications are evident among 40% of older patients taking five or more medications, report investigators who assessed 196 outpatients at a VA facility (pp. 1516-23). After excluding vitamins and minerals, topical and herbal products, and as-needed medications, the authors used the 2003 update of the Beers’ criteria and subscales of the Medication Appropriateness Index to determine: “Mean age was 74.6, and patients used a mean ± standard deviation of 8.1 ± 2.5 medications (range 5–17). Use of one or more inappropriate medications was documented in 128 patients (65%), including 73 (37%) taking a medication in violation of the Beers drugs-to-avoid criteria and 112 (57%) taking a medication that was ineffective, not indicated, or duplicative. Medication underuse was observed in 125 patients (64%). Together, inappropriate use and underuse were simultaneously present in 82 patients (42%), whereas 25 (13%) had neither inappropriate use nor underuse. When assessed by the total number of medications taken, the frequency of inappropriate medication use rose sharply from a mean of 0.4 inappropriate medications in patients taking five to six drugs, to 1.1 inappropriate medications in patients taking seven to nine drugs, to 1.9 inappropriate medications in patients taking 10 or more drugs (P < .001). In contrast, the frequency of underuse averaged 1.0 underused medications per patient and did not vary with the total number of medications taken (P = .26). Overall, patients using fewer than eight medications were more likely to be missing a potentially beneficial drug than to be taking a medication considered inappropriate.” (M. Steinman, mike.steinman@ucsf.edu)
OTC Product Use in NHs: Over-the-counter medications are commonly used by Medicare beneficiaries in nursing homes, and this occurs without regard to drug coverage (pp. 1543-9). That conclusion comes from an analysis of the 2001 Medicare Current Beneficiary Survey. Based on use of medications by 798 Medicare beneficiaries who had resided in nursing homes 1 month or more, the investigators found: “Study subjects were high users of Rx (98%) and OTC (94%) drugs. The average resident was administered 8.8 unique medications per month (5.9 Rx and 2.9 OTC medications). Twelve therapeutic classes accounted for 93.9% of OTC medication use by residents, but Rx use was also high in some of these same classes. For example, 70.3% of all subjects used nonopioid OTC analgesics, and 19.0% used nonopioid Rx analgesics, and 13.8% used OTC antacids/antiulcer agents, whereas 35.8% used Rx products in this class. The highest overlap was in the category of cough and cold medications, of which 19.3% used OTCs and 20.1% used Rx drugs. Multivariate regression analyses applied to users of drugs in each these three therapeutic classes found no evidence that Rx coverage influenced the choice of OTC versus Rx-only medications.” (L. Simoni-Wastila, LSimoniw@rx.umaryland.edu)

>>>PNN NewsWatch
* FDA has approved first-line use of bevacizumab (Avastin, Genentech) in combination treatment of unresectable, locally advanced, recurrent or metastatic, non-squamous, non-small cell lung cancer.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 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
Oct. 16, 2006 * Vol. 13, No. 198
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Early-release article from and Oct. 14 issue of Lancet (www.thelancet.com; 2006; 368).
Alcohol Abuse Disorders in ICU Patients: About 10% of patients admitted to intensive-care units have alcohol abuse and dependence disorders, and these require recognition and treatment, write authors of a review article (doi: 10.1016/S0140-6736(06)69490-7). “The systemic effects from the excessive use of alcohol increase susceptibility to, or directly cause various important disorders in the critically ill,” the writers note. “Early recognition of alcohol abuse and dependence is necessary and should prompt consideration of several alcohol-specific diagnoses that have important prognostic and therapeutic implications for these patients. We discuss the use of screening tests to improve the identification of alcohol abuse and dependence disorders, the epidemiology and pathogenesis of important alcohol-related disorders, differences in the presentation of several common alcohol-related diagnoses in the ICU, and important alcohol-specific therapies.” (M. Moss, U. Colorado, Denver; Marc.Moss@uchsc.edu)
Sunitinib After Imatinib Failure in GIST: Among 312 patients with unresectable imatinib-resistant gastrointestinal stromal tumor, sunitinib provided significant clinical benefit, including disease control and superior survival, compared with placebo (pp. 1329-38). After imatinib was discontinued because of treatment failure, study participants received either sunitinib 50 mg or placebo orally once daily in 6-week cycles of 4 weeks on and 2 weeks off treatment. The investigators report these results: “Median time to tumour progression was 27.3 weeks (95% CI 16.0–32.1) in patients receiving sunitinib and 6.4 weeks (4.4–10.0) in those on placebo (hazard ratio 0.33; p < 0.0001). Therapy was reasonably well tolerated; the most common treatment-related adverse events were fatigue, diarrhoea, skin discolouration, and nausea.” (G. D. Demetri, gdemetri@partners.org)

>>>BMJ Highlights
Source:
Early-release article from BMJ (www.bmj.org; 2006; 333).
Albumin Resuscitation & Serum Albumin Levels: Analyzing data from the Saline versus Albumin Fluid Evaluation (SAFE) study, researchers found that patients’ baseline serum albumin concentrations fail to predict outcomes with albumin supplementation (doi: 10.1136/bmj.38985.398704.7C). “The odds ratios for death for albumin compared with saline for patients with a baseline serum albumin concentration of 25 g/l or less and more than 25 g/l were 0.87 and 1.09, respectively (ratio of odds ratios 0.80, 95% confidence interval 0.63 to 1.02); P = 0.08 for heterogeneity,” SAFE investigators note. “No significant interaction was found between baseline serum albumin concentration as a continuous variable and the effect of albumin and saline on mortality. No consistent interaction was found between baseline serum albumin concentration and treatment effects on length of stay in the intensive care unit, length of hospital stay, duration of renal replacement therapy, or duration of mechanical ventilation.” The authors conclude that while “albumin does not increase the risk of mortality in patients with hypoalbuminaemia, data do not support its routine use to maintain or increase intravascular volume in critically ill adults.” (S. Finfer, Australian and New Zealand Intensive Care Society Clinical Trials Group, Carlton, Victoria, Australia; sfinfer@george.org.au)

>>>PNN JournalWatch
* Clinical and Pathologic Perspectives on Aspirin Sensitivity and Asthma, in Journal of Allergy and Clinical Immunology, 2006; 118: 773–86. Reprints: www.jacionline.org/article/PIIS0091674906015703/abstract; D. D. Stevenson, Scripps Clinic, La Jolla, Calif.
* Folate Intake,
MTHFR Polymorphisms, and Risk of Esophageal, Gastric, and Pancreatic Cancer: A Meta-analysis, in Gastroenterology, 2006; 131: 1271–83. Reprints: www.gastrojournal.org/article/PIIS0016508506017276/abstract; S. C. Larsson, Karolinska Institutet, Stockholm, Sweden.
* Direct Vascular Effects of Protease-Activated Receptor Type 1 Agonism In Vivo in Humans, in
Circulation, 2006; 114: 1625–32. Reprints: http://circ.ahajournals.org/cgi/content/abstract/114/15/1625; I. J. Gudmundsdóttir, U. Edinburgh, Edinburgh, U.K.; Ingibjorg.Gudmunds@ed.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
Oct. 17, 2006 * Vol. 13, No. 199
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Oct. 17 issue of the Annals of Internal Medicine (www.annals.org; 2006; 145).
Rifaximin for IBS: Symptoms of irritable bowel syndrome were reduced for 10 weeks following a 10-day course of rifaximin 400 mg three time daily, compared with placebo (pp. 557-63). Among 87 patients who met Rome I criteria for IBS, rifaximin significantly improved disease symptoms and lowered bloating scores as measured using a global improvement instrument and weekly symptom diaries. “Improvements were sustained through 10 weeks of follow-up despite cessation of therapy after only 10 days,” the investigators note. “Recent data suggest that the optimal dosage of rifaximin may, in fact, be higher than that used in our study.... This new concept of IBS treatment will warrant future studies that allow for head-to-head comparison of antibiotics to other treatment strategies for IBS, such as prokinetics and probiotics.” (M. Pimentel, Cedars-Sinai Med. Ctr., Los Angeles; pimentelm@cshs.org)
Explaining that rifaximin treats the bacterial overgrowth that is common in patients with IBS, an editorialist provides guidance on patient selection for antibiotic treatments (pp. 626-8): “The clinical challenge is to identify the subset of patients with IBS who are most likely to have bacterial overgrowth that produces symptoms relative to the many other factors (such as abnormal motility, visceral hypersensitivity, and psychosocial distress factors) contributing to patients’ clinical state. Unfortunately, no data are available to help us in this decision, so I suggest the following on the basis of personal experience and limited data. First, determine whether the patient fits the clinical profile of bacterial overgrowth with postprandial abdominal discomfort, bloating, and possibly loose stools. If the clinical features are present, perform a lactulose H
2 breath study if it is available and, if the result is positive, consider a course of a broad-spectrum antibiotic. After this, treat the patient with a probiotic to provide more ‘good’ bacteria and, if the stool normalizes or becomes more constipated, consider adding a prokinetic agent to increase small-bowel transit. If symptoms recur and the previous lactulose test result was positive, repeat the study and retreat with antibiotics only if the lactulose H2 breath test result is again positive. If lactulose testing is not available, the clinician should be conservative and should not repeat treatments unless a clear and sustained benefit is evident for at least several months.” (D. A. Drossman, U. North Carolina, Chapel Hill)
Thyroid Function & Mental Problems: Subclinical thyroid dysfunction was not associated with depression, anxiety, or altered cognition in a study of 5,865 patients aged 65 years or older at primary care practices in England (pp. 573-81). After confounding effects of comorbid conditions and medication use were controlled for, researchers found a statistically significant but clinically irrelevant association between scores on the Hospital Anxiety and Depression Scale and thyroid-stimulating hormone levels and between cognition and TSH and free thyroxine levels. (L. M. Roberts, U. Birmingham, Birmingham, U.K.; l.m.roberts@bham.ac.uk)
Rescreening for STDs: Men and women with Chlamydia trachomatis, Neisseria gonorrhoeae, or Trichomonas vaginalis infections should be rescreened 3 months later because of a high incidence of reinfection, recommend authors of a study of 2,419 patients in an HIV-prevention counseling trial (pp. 564-72). During the study, 25.8% of women and 14.7% of men with these infections were reinfected at 3-month visits with one or more of these sexually transmitted diseases. (T. A. Peterman, tpeterman@cdc.gov)

>>>PNN NewsWatch
* FDA last week approved use of donepezil (Aricept, Eisai) in patients with severe dementia of the Alzheimer’s type. It becomes the first product approved for patients with all three severities of this condition. Today’s Wall Street Journal outlines emerging treatments for Alzheimer’s disease, noting that trials are underway of raloxifene, sage extract, huperzine A, atorvastatin plus a cholinesterase inhibitor, and exercise.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Oct. 18, 2006 * Vol. 13, No. 200
Providing news and information about medications and their proper use

>>>FDA OKs Sitagliptin for Type 2 Diabetes
FDA yesterday approved sitagliptin phosphate (Januvia, Merck), the first dipeptidyl peptidase-4 (DPP-4) inhibitor marketed in the U.S. Sitagliptin, an oral agent, was approved as both monotherapy and add-on therapy to metformin or thiazolidinediones to improve glycemic control in patients with type 2 diabetes when diet and exercise are insufficient. The new agent should not be used in patients with type 1 diabetes or for treatment of diabetic ketoacidosis, as it would not be effective in these settings.
In two double-blind, placebo-controlled studies of 24 weeks (n = 473) and 18 weeks (n = 296) in patients with mild to moderate baseline A1C levels (mean 8.0%; enrollment range 7.0% to 10.0%), sitagliptin 100 mg once daily showed significant mean differences in A1C from placebo of –0.8% and –0.6%, respectively (P < .001), Merck explained in a news release. In a pooled analysis of these two monotherapy studies, a prespecified subgroup analysis showed that when patients were grouped by baseline A1C into those with mildly elevated A1C levels (<8%, n = 411), moderately elevated A1C levels ( >8% to <9%, n = 239) and the highest elevated A1C levels ( >9%, n = 119), mean differences in A1C from placebo after 18 weeks were –0.6%, –0.7%, and –1.4%, respectively (P < .001 for treatment by subgroup interactions).
The recommended dose of sitagliptin is 100 mg once daily, with or without food, for all approved indications. No dosage adjustment is needed for patients with mild to moderate hepatic insufficiency or in patients with mild renal insufficiency (creatinine clearance > 50 mL/min). Lower dosages are recommended in product labeling for patients with moderate and severe renal insufficiency as well as in patients with end-stage renal disease requiring hemodialysis.
Sitagliptin once daily was weight neutral compared with placebo in clinical trials. Mean body weight decreased 0.2 kg (versus a 1.1-kg decrease for placebo) and 0.7 kg (versus 0.6 kg), respectively, in two 24-week trials: one in patients taking sitagliptin as monotherapy (n = 193) and one in combination with metformin (n = 399). The overall incidence of hypoglycemia in patients treated with sitagliptin 100 mg was similar to placebo (1.2% versus 0.9%, respectively) across the clinical program. The incidence of selected gastrointestinal adverse reactions in patients treated with sitagliptin was as follows: abdominal pain (sitagliptin, 2.3%; placebo, 2.1%), nausea (1.4%, 0.6%), and diarrhea (3.0%, 2.3%).

>>>JAMA Highlights
Source:
Oct. 18 issue of JAMA (www.jama.com; 2006; 296).
Medication-Related ED Visits: Particularly in older patients, adverse drug events are an important cause of emergency department visits and related morbidity in the U.S., report investigators who used 2004–05 data from the National Electronic Injury Surveillance System–Cooperative Adverse Drug Event Surveillance project to identify these results (pp. 1858-66): “Over the 2-year study period, 21,298 adverse drug event cases were reported, producing weighted annual estimates of 701,547 individuals (95% confidence interval [CI], 509,642–893,452) or 2.4 individuals per 1,000 population (95% CI, 1.7–3.0) treated in emergency departments. Of these cases, 3,487 individuals required hospitalization (annual estimate, 117,318 [16.7%]; 95% CI, 13.1%–20.3%). Adverse drug events accounted for 2.5% (95% CI, 2.0%–3.1%) of estimated emergency department visits for all unintentional injuries and 6.7% (95% CI, 4.7%–8.7%) of those leading to hospitalization and accounted for 0.6% of estimated emergency department visits for all causes. Individuals aged 65 years or older were more likely than younger individuals to sustain adverse drug events (annual estimate, 4.9 vs 2.0 per 1,000; rate ratio [RR], 2.4; 95% CI, 1.8–3.0) and more likely to require hospitalization (annual estimate, 1.6 vs 0.23 per 1,000; RR, 6.8; 95% CI, 4.3–9.2). Drugs for which regular outpatient monitoring is used to prevent acute toxicity accounted for 41.5% of estimated hospitalizations overall (1,381 cases; 95% CI, 30.9%–52.1%) and 54.4% of estimated hospitalizations among individuals aged 65 years or older (829 cases; 95% CI, 45.0%–63.7%).” (D. S. Budnitz, dbudnitz@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
Oct. 19, 2006 * Vol. 13, No. 201
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Oct. 19 issue of the New England Journal of Medicine (content.nejm.org; 2006; 355).
Hormonal Fountains of Youth: Hormones promoted as antiaging supplements have no physiologically beneficial effects on body composition, physical performance, insulin sensitivity, or quality of life, concludes a 2-year study of 87 elderly men and 57 elderly women (pp. 1647-59). Both men and women participants had low levels of the sulfated form of dehydroepiandrosterone, and the men also had low levels of bioavailable testosterone. Men received DHEA, testosterone, or placebo, while women were given either DHEA or placebo, with these results: “As compared with the change from baseline to 24 months in the placebo group, subjects who received DHEA for 2 years had an increase in plasma levels of sulfated DHEA by a median of 3.4 µg per milliliter (9.2 µmol per liter) in men and by 3.8 µg per milliliter (10.3 µmol per liter) in women. Among men who received testosterone, the level of bioavailable testosterone increased by a median of 30.4 ng per deciliter (1.1 nmol per liter), as compared with the change in the placebo group. A separate analysis of men and women showed no significant effect of DHEA on body-composition measurements. Neither hormone altered the peak volume of oxygen consumed per minute, muscle strength, or insulin sensitivity. Men who received testosterone had a slight increase in fat-free mass, and men in both treatment groups had an increase in [bone mineral density] at the femoral neck. Women who received DHEA had an increase in BMD at the ultradistal radius. Neither treatment improved the quality of life or had major adverse effects.” (K. S. Nair, nair.sree@mayo.edu)
An editorialist calls for FDA to increase its regulation of DHEA (pp. 1724-6): “The search for eternal youth is vibrant in North America. In this search, it is all too easy to ascribe the aging process to endocrines. Although the secretion of growth hormone falls by about 12% per decade after middle age, perhaps the greatest attention has focused on sex steroids, since estrogen secretion falls abruptly in postmenopausal women, and testosterone levels decline with age, though more gradually, in men. Levels of the adrenal sex steroid [DHEA] and its sulfate ester fall progressively after 30 years of age, and after 60 years of age are less than half the levels in youth...
“The search for eternal youth will continue, but the reversal of age-related decreases in the secretion of DHEA and testosterone through ‘physiologic’ replacement regimens offers no answer and should not be attempted. In light of an evidence base for the efficacy of DHEA in patients with adrenal insufficiency, DHEA should no longer be accepted as a food supplement and should instead be treated as a regulated drug. Appropriate regulation would dispel much of the quackery associated with this elusive hormone.” (P. M. Stewart, U. Birmingham, Birmingham, U.K.)
Guidelines & Industry: After reviewing the influence of Xigris (drotrecogin alfa [activated]) manufacturer Lilly on development of guidelines for sepsis treatment, Perspectives authors note (pp. 1640-2): “When properly formulated and applied, practice guidelines and performance standards hold the promise of improving patients’ outcomes. Professional societies and other stakeholders must work together to promote a consistent guideline-development process, a robust rating system for guidelines that is applicable to all subspecialties, and a policy that prohibits the pharmaceutical and medical-device industries from directly or indirectly funding or influencing practice standards. The challenges involved in producing first-rate guidelines and performance standards are only exacerbated by the intrusion of marketing strategies masquerading as evidence-based medicine.” (P. Q. Eichacker, NIH, Bethesda, Md.)
Sepsis management is also reviewed in this issue (pp. 1699-713; J. A. Russell, U. Br. Columbia, Vancouver;
jrussell@mrl.ubc.ca)

>>>PNN NewsWatch
* Variance in the gene for CYP 2D6 can increase women’s risk of recurrence of breast cancer during adjuvant tamoxifen therapy, an FDA panel is advising, adding that this information should be added to product labeling. Media reports indicate FDA may recommend pretherapy testing to identify the 7% to 10% of women with the variant.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Oct. 20, 2006 * Vol. 13, No. 202
Providing news and information about medications and their proper use

>>>Medical Care Highlights
Source:
Oct. issue of Medical Care (www.lww-medicalcare.com; 2006; 44).
Quality of Adult Pharmacotherapy in U.S.: Underuse of appropriate medications is one of several “significant deficits in the quality of pharmacologic care ... for adults in the United States,” according to a assessment that relied on 153 quality-of-care indicators (pp. 936-45). Researchers contacted a random sample of adults in 12 metropolitan areas and asked for consent to obtain copies of medical records. In all, 3,457 participants were eligible for evaluation based on at least one quality indicator, and 10,739 eligible events were assessed for appropriate medication use (underuse), avoidance of unnecessary medication use (overuse), medication monitoring, and medication education and documentation.
The investigators report: “Participants received 61.9% of recommended pharmacologic care overall (95% confidence interval 60.3–63.5%). Performance was lowest in education and documentation (46.2%); medication monitoring (54.7%) and underuse of appropriate medications (62.6%) performance were higher. Performance was best for avoiding inappropriate medications (83.5%). Patient race and health services utilization were associated with modest quality differences, while insurance status was not.” (W. H. Shrank)
HAART Nonadherence: The “typical” adherence seen with highly active antiretroviral therapy is associated with a 12% reduction in quality-adjusted life expectancy, compared with “ideal” adherence as is usually present in clinical trials (pp. 893-9). This deficit makes “interventions to improve adherence appear to be a highly cost-effective use of resources,” the authors conclude, based on these study findings generated using a Markov model: “With typical adherence, patients lose 1.2 quality-adjusted life years (QALYs) that could be gained with ideal adherence. Improving adherence to ideal levels is cost-effective at $29,400/QALY gained. As much as $1,600/y per patient could be spent on an intervention to improve adherence to ideal levels, and the incremental cost-effectiveness would remain less than $50,000/QALY gained. A cost-effectiveness ratio of $50,000/QALY is a commonly accepted minimum standard for cost-effective medical interventions in the United States, although many experts believe this standard has drifted upwards over time.” (J. Munakata)

>>>Cardiology Report
Source:
Oct. 17 issue of the Journal of the American College of Cardiology (content.onlinejacc.org; 2006; 48).
Depression in HF Patients: One in five patients with heart failure also has clinically relevant depression, and these patients have poorer outcomes and significantly higher use of health resources, according to a state-of-the-art paper (pp. 1527-37). “Clinically significant depression was present in 21.5% of HF patients, and varied by the use of questionnaires versus diagnostic interview (33.6% and 19.3%, respectively) and New York Heart Association–defined HF severity (11% in class I vs. 42% in class IV), among other factors,” write the authors. “Combined results suggested higher rates of death and secondary events (risk ratio = 2.1, 95% confidence interval 1.7 to 2.6), trends toward increased health care use, and higher rates of hospitalization and emergency room visits among depressed patients. Treatment studies generally relied on small samples, but also suggested depression symptom reductions from a variety of interventions.” (T. Rutledge, VA, San Diego; Thomas.Rutledge@va.gov)

>>>PNN NewsWatch
* Severe congestive heart failure and left ventricular dysfunction occur occasionally with imatinib treatment, FDA and Novartis are warning. Language is being added to the Gleevec product labeling stating that most affected patients had other comorbidities and risk factors, including advanced age and previous medical history of cardiac disease. Such patients should be monitored carefully and any patients with signs or symptoms consistent with cardiac failure should be evaluated and treated, the warning recommends.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Oct. 23, 2006 * Vol. 13, No. 203
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release article from BMJ (www.bmj.org; 2006; 333).
Physiotherapy, Pharmacy Reviews for Knee Pain: Care of older patients with knee pain by primary care physiotherapists and community pharmacists produced short-term improvements in outcomes in a study of 325 patients at 15 general practices in North Staffordshire (doi: 10.1136/bmj.38977.590752.0B). Using evidence-based criteria, pharmacists reviewed drug therapy for osteoarthritis and knee pain and provided simple self-help messages to patients. A community physiotherapy service promoted self-management and an exercise-based treatment package. Assessing changes in the Western Ontario and McMaster Universities osteoarthritis index (WOMAC) at 3, 6, and 12 months, the researchers observed: “Mean baseline WOMAC pain score was 9.1 (SD 3.7), and mean baseline function score was 29.9 (SD 12.8). At three months, the mean reductions in pain scores were 0.41 (SD 2.8) for control, 1.59 (3.2) for pharmacy, and 1.56 (3.4) for physiotherapy; reductions in function scores were 0.80 (8.5), 2.61 (9.8), and 4.79 (10.8). Compared with control, mean differences in change scores for physiotherapy were 1.15 (95% confidence interval 0.2 to 2.1) for pain and 3.99 (1.2 to 6.8) for function; those for pharmacy were 1.18 (0.3 to 2.1) for pain and 1.80 (–0.8 to 4.5) for function. These differences were not sustained to six or 12 months. Significantly fewer participants in the physiotherapy group reported consulting their general practitioner for knee pain in the follow-up period, and use of non-steroidal anti-inflammatory drugs was lower in the physiotherapy and pharmacy groups than in the control group.” (E. M. Hay, Keele U., Keele, U.K.; e.m.hay@cphc.keele.ac.uk)

>>>Lancet Highlights
Source:
Oct. 21 issue of Lancet (www.thelancet.com; 2006; 368).
Antibiotics for Otitis Media: In children younger than 2 years, antibiotics are most beneficial for those with bilateral acute otitis media and in patients with both acute otitis media and otorrhea, concludes a meta-analysis of six randomized trials (pp. 1429-35). “For most other children with mild disease an observational policy seems justified,” the authors add, providing these details from the literature review and analysis: “Significant effect modifications were noted for otorrhoea, and for age and bilateral acute otitis media. In children younger than 2 years of age with bilateral acute otitis media, 55% of controls and 30% on antibiotics still had pain, fever, or both at 3–7 days, with a rate difference between these groups of −25% (95% CI −36% to −14%), resulting in a number-needed-to-treat (NNT) of four children. We identified no significant differences for age alone. In children with otorrhoea the rate difference and NNT, respectively, were −36% (−53% to −19%) and three, whereas in children without otorrhoea the equivalent values were −14% (−23% to −5%) and eight.” (M. M. Rovers, Julius Ctr. for Health Sci. and Primary Care, Utrecht, the Netherlands; M.Rovers@umcutrecht.nl)

>>>PNN JournalWatch
* Oral Renin Inhibitors, in Lancet, 2006; 368: 1449–56. Reprints: www.thelancet.com/journals/lancet/article/PIIS0140673606694427/abstract; J. A. Staessen, U. Leuven, Leuven, Belgium; jan.staessen@med.kuleuven.be
* Favorable Effects of Inhaled Treprostinil in Severe Pulmonary Hypertension: Results From Randomized Controlled Pilot Studies, in
Journal of the American College of Cardiology, 2006; 48: 1672–81. Reprints: http://content.onlinejacc.org/cgi/content/abstract/48/8/1672; H. Olschewski, Med. U., Graz, Austria; horst.olschewski@meduni-graz.at
* Are Drug-Eluting Stents Cost-Effective?: It Depends on Whom You Ask; Drug-Eluting Stents: The Price Is Not Right [point–counterpoint], in
Circulation, 2006; 114: 1736–44; 1745–54. Reprints: http://circ.ahajournals.org/current.shtml; J. Ryan et al.; M. J. Eisenberg et al.
* Excuses To Continue Smoking: The Role of Disengagement Beliefs in Smoking Cessation, in
Addictive Behaviors, 2006; 31: 2223–37. Reprints: www.sciencedirect.com/science; M. Kleinjan, Addiction Research Inst. (IVO), Rotterdam, the Netherlands; Kleinjan@ivo.nl
* Understanding The American Public’s Health Priorities: A 2006 Perspective, in
Health Affairs, 2006 (Web exclusive): doi: 10.1377/hlthaff.25.w508. Reprints: http://content.healthaffairs.org/cgi/content/abstract/hlthaff.25.w508; R. J. Blendon, Harvard Sch. of Public Health, Boston.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Oct. 24, 2006 * Vol. 13, No. 204
Providing news and information about medications and their proper use

>>>Ciclesonide Approved for Allergic Rhinitis
FDA has approved ciclesonide nasal spray (Omnaris, Altana Pharma US), a new corticosteroid for treatment of nasal symptoms associated with seasonal and perennial allergic rhinitis in adults and children 12 years of age and older. The intranasal spray is approved in doses of 200 mcg administered once daily. FDA also issued an approvable letter to Altana for use of the product in children ages 2 to 11 years, making expansion of approved age range likely.
Ciclesonide is approved in 39 countries worldwide for treatment of persistent asthma, and Altana has filed a new drug application with FDA for this indication using an inhaled formulation. The company is also working on a fixed combination product that includes ciclesonide plus a long-acting beta-agonist, currently in Phase II of clinical development. Altana’s U.S. partner is Sanofi Aventis.
Ciclesonide nasal spray was studied in four clinical trials ranging in duration from 2 weeks to 1 year. Compared with placebo, ciclesonide significantly reduced hay fever symptoms (runny nose, nasal itching, sneezing, and nasal congestion).
The most common adverse effects in clinical studies of ciclesonide were headache, nosebleeds, and inflammation of the nose and throat linings.

>>>Internal Medicine Report
Source:
Oct. 23 issue of Archives of Internal Medicine (www.archinternmed.com; 2006; 166).
Mental Health & Opioids: Attention to potential psychiatric disorders is warranted for patients who present with chronic noncancer pain for which opioid therapy is being considered, according to an analysis of longitudinal data showing an association among common mental health disorders, problem drug use, and regular prescription opioid use (pp. 2087-93). Sifting through the survey results on 6,439 participants in the 1998 and 2001 waves of the Healthcare for Communities, researchers found: “Two hundred thirty-seven subjects (3.6%) reported regular prescription opioid use in 2001. In unadjusted logistic regression models, respondents with a common mental health disorder in 1998 (1,165 [12.6%]; major depression, dysthymia, generalized anxiety disorder, or panic disorder) were more likely to report opioid use in 2001 than those without any of these disorders (odds ratio [OR], 4.43; 95% confidence interval [CI], 3.64–5.38; P < .001). Risk was increased for initiation (OR, 3.26; 95% CI, 2.44–4.34; P < .001) and continuation (OR, 2.30; 95% CI, 1.02–5.17; P = .04) of opioids. Respondents reporting problem drug use (136 [2.0%]; OR, 3.57; 95% CI, 2.32–5.50; P < .001) but not problem alcohol use (401 [6.5%]; OR, 0.73; 95% CI, 0.43–1.24; P = .25) reported higher rates of prescribed opioid use than those without problem use. In multivariate logistic regression models controlling for 1998 demographic and clinical variables, common mental health disorder (OR, 1.96; 95% CI, 1.47–2.62; P < .001) and problem drug use (OR, 2.98; 95% CI, 1.68–5.30; P < .001) remained significant predictors of opioid use in 2001.” (M. D. Sullivan, sullimar@u.washington.edu)
DVT Guideline Compliance: A significant decrease in frequency of deep-vein thrombosis followed implementation of a multifaceted prophylactic intervention targeting 1,373 post–acute care patients (pp. 2065-71). Using an evidence-based guideline for pharmacologic and mechanical prophylaxis at 33 hospital-based clinics in France, researchers noted: “A DVT was found in 91 patients (12.8%) in the preintervention phase and in 52 patients (7.8%) in the postintervention phase (P = .002). The decrease in DVT involved the calf (7.1% vs 3.6%; P = .005) and the proximal venous segments (5.8% vs 4.2%; P = .18) and remained significant after adjusting for risk factors (adjusted odds ratio of any DVT, 0.58; 95% confidence interval, 0.39–0.86). Pharmacologic prophylaxis with either low-molecular-weight heparin at the high-risk dose, unfractionated heparin, and vitamin K antagonist was similar in the 2 study groups, whereas patients in the postintervention group were more likely to use graduated compression stockings (27.4% vs 34.6%; P = .004) and less likely to receive low-molecular-weight heparin at the low-risk dose (24.7% vs 18.5%; P = .006), which was not recommended by our guideline.” (J. Labarere, U. Hosp., Grenoble, France; JLabarere@chu-grenoble.fr)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Oct. 25, 2006 * Vol. 13, No. 205
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Oct. 25 issue of JAMA (www.jama.com; 2006; 296).
Flu Vaccine Safety in Young Children: The safety of trivalent inactivated influenza vaccine in infants and young children is confirmed in a retrospective cohort study of 45,356 children who received 69,359 vaccinations at eight managed-care organizations between 1991 and May 2003 (pp. 1990-7). Focusing on any medically attended event significantly associated with trivalent inactivated influenza vaccine in risk windows of 0 to 3 days, 1 to 14 days (primary analysis), 1 to 42 days, or 15 to 42 days after vaccination, the researchers found: “Before chart review, only 1 diagnosis, gastritis/duodenitis, was more likely to occur in the 14 days after trivalent inactivated influenza vaccine (matched odds ratio [OR], 5.50; 95% confidence interval [CI], 1.22–24.81 [before vaccination], and matched OR, 4.33; 95% CI, 1.23–15.21 [after the risk window]). Thirteen medically attended events were less likely to occur after trivalent inactivated influenza vaccine, including acute upper respiratory tract infection, asthma, bronchiolitis, and otitis media. After chart review, gastritis/duodenitis was not significantly associated with trivalent inactivated influenza vaccine (matched OR, 4.00; 95% CI, 0.85–18.84 [before vaccination]; matched OR, 3.34; 95% CI, 0.92–12.11 [after the risk window]).” (S. J. Hambidge, Kaiser Permanente Colorado, Denver; simon.hambidge@dhha.org)
Hepatitis C from Radiopharmaceutical: Blood contamination of an injected radiopharmaceutical during preparation in the pharmacy resulted in hepatitis C virus infections in 16 patients, according to a CDC report (pp. 2005-11). An Oct. 2004 outbreak of HCV at outpatient cardiology clinics in Maryland led investigators to assess procedures at a nuclear pharmacy, with these results: “Sixteen patients with acute HCV infection were identified from 3 separate clinics. All patients received radiopharmaceutical injections drawn from a single pharmacy vial (vial 1). None of the 59 tested patients who received doses from 6 other vials had acute HCV infection. Blood from a potential source patient with HCV and human immunodeficiency virus (HIV) infection was processed for a radiolabeled white blood cell study in the pharmacy 12 hours before vial 1 was prepared. The HCV quasispecies sequences from this potential source patient were nearly identical to those from cases (97.8%–98.5% similarity). No acute HIV infections were identified. Pharmacy practices that could have led to blood cross-contamination included reuse of needles and syringes during dilutions and use of common flow hoods for some steps in the preparation of sterile and blood-derived products.”
The authors conclude: “All compounding pharmacies should comply with US Pharmacopeia standards and establish policies to ensure sterile equipment and environments, standardized compounding procedures, and training of employees on aseptic technique. Nuclear pharmacies that handle blood products should additionally recognize the risks for blood contamination of radiopharmaceuticals and implement appropriate precautionary measures to prevent such contamination. The safety of parenteral medications and diagnostic pharmaceuticals depends on careful application of aseptic techniques across the entire spectrum of their preparation and administration. The findings from this investigation, as well as other reported outbreaks, underscore a need for heightened awareness and renewed vigilance.” (P. R. Patel,
ppatel@cdc.gov)
Racial Disparities in Care: Clinical performance on HEDIS measures for Medicare managed care enrollees with diabetes, hypertension, or history of a coronary event was significantly poorer for black patients than for whites in the same health plan (pp. 1998-2004). Concluding that the “disparities vary widely and are only weakly correlated with the overall quality of care,” the authors explain that “plan-specific performance reports of racial disparities on outcome measures would provide useful information not currently conveyed by standard HEDIS reports.” (J. Z. Ayanian, ayanian@hcp.med.harvard.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Oct. 26, 2006 * Vol. 13, No. 206
Providing news and information about medications and their proper use

>>>Telbivudine Approved for Chronic Hepatitis B
FDA has approved telbivudine (Tyzeka; Idenix, Novartis) for treatment of adults with chronic hepatitis B virus (HBV) infections. The orally active nucleoside analogue is administered once daily with or without food.
Data from the pivotal Phase III clinical trial, the GLOBE study, compared telbivudine with lamivudine in 1,367 patients. The primary efficacy endpoint of the GLOBE study was therapeutic response at 1 year, a composite endpoint coupling viral suppression (serum HBV DNA suppression below 100,000 copies/mL) with either improved liver disease markers (ALT normalization) or loss of detectable hepatitis B e-antigen (HBeAg). In HBeAg-positive patients, therapeutic response was 75% among patients treated with telbivudine and 67% for those patients treated with lamivudine, while the response for HBeAg-negative patients after 1 year was 75% versus 77%, respectively. In the GLOBE study, patients who achieved nondetectable HBV DNA levels at 24 weeks were more likely to undergo e-antigen seroconversion, achieve undetectable levels of HBV DNA, normalize liver enzymes, and minimize resistance at 1 year.
Telbivudine was generally well tolerated in these trials, and most reported adverse events were mild to moderate. Frequently occurring adverse events (> 5%) were upper respiratory tract infection (14%), fatigue/malaise (12%), abdominal pain (12%), nasopharyngitis (11%), headache (11%), increased creatine phosphokinase levels (9%), cough (7%), nausea/vomiting (7%), influenza/influenza-like symptoms (7%), postprocedural pain (7%), diarrhea and loose stools (7%), and pharyngolaryngeal pain (5%).
Also, after several weeks to months of telbivudine use, some patients developed symptoms ranging from transient muscle pain to muscle weakness. Those who developed muscle weakness experienced significant improvement in their symptoms when telbivudine was discontinued.

>>>NEJM Highlights
Source:
Oct. 26 issue of the New England Journal of Medicine (content.nejm.org; 2006; 355).
Treatment of Pemphigus Vulgaris: Rituximab plus intravenous immune globulin proved effective in a small group of patients with refractory pemphigus vulgaris, a potentially fatal blistering mucocutaneous autoimmune disease affecting the skin and the oral cavity and other mucosal surfaces (pp. 1772-9). The study used two cycles of rituximab 375 mg/sq m once weekly for 3 weeks followed by intravenous immune globulin 2 g/kg in the fourth week. Results were as follows: “Of 11 patients, 9 had rapid resolution of lesions and a clinical remission lasting 22 to 37 months (mean, 31.1). All immunosuppressive therapy, including prednisone, could be discontinued before ending rituximab treatment in all patients. Two patients were treated with rituximab only during recurrences and had sustained remissions. Titers of IgG4 antikeratinocyte antibodies correlated with disease activity. Peripheral-blood B cells became undetectable shortly after initiating rituximab therapy but subsequently returned to normal values. Side effects that have been associated with rituximab were not observed, nor were infections.” (A. R. Ahmed, New England Baptist Hosp., Boston)
D-Dimer Testing in Anticoagulation: Abnormal D-dimer levels 1 month after stopping anticoagulation are predictive of increased risk of recurrent venous thromboembolism, according to a study of patients treated for at least 3 months following a first deep-vein thrombosis or pulmonary embolism (p. 1780-9). “The D-dimer assay was abnormal in 223 of 608 patients (36.7%),” the authors note. “A total of 18 events occurred among the 120 patients who stopped anticoagulation (15.0%), as compared with 3 events among the 103 patients who resumed anticoagulation (2.9%), for an adjusted hazard ratio of 4.26 (95% confidence interval [CI], 1.23 to 14.6; P = 0.02). Thromboembolism recurred in 24 of 385 patients with a normal D-dimer level (6.2%). Among patients who stopped anticoagulation, the adjusted hazard ratio for recurrent thromboembolism among those with an abnormal D-dimer level, as compared with those with a normal D-dimer level, was 2.27 (95% CI, 1.15 to 4.46; P = 0.02).” (G. Palareti, S. Orsola-Malpighi U. Hosp., Bologna, Italy; palareti@tin.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
Oct. 27, 2006 * Vol. 13, No. 207
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Nov. issue of Diabetes Care (care.diabetesjournals.org; 2006; 29).
New Measure of Blood Glucose Variability: In a mixed group of patients with type 1 and type 2 diabetes, a new measure of blood glucose variability—the average daily risk range—was strongly associated with subsequent out-of-control glucose readings and was sensitive in its predictions of both hypoglycemia and hyperglycemia (pp. 2433-8). After constructing the ADRR model using self-monitored blood glucose data, the investigators tested its performance against other variability measures using 4 months of SMBG data from 254 adults with type 1 diabetes and 81 adults with type 2 conditions. Results showed: “From the 1st month of validation SMBG data, we computed the ADRR, blood glucose SD and coefficient of variation, daily blood glucose range and interquartile range, mean amplitude of glycemic excursion, M-value, and lability index. Then all measures were tested as predictors of low blood glucose (<2.2 mmol/l; <3.9 mmol/l) and high (>10 mmol/l; >22.2 mmol/l) events in the subsequent 3 months. The ADRR was the best predictor of both hypoglycemia and hyperglycemia, with a 6-fold increase in the likelihood of hypoglycemia and 3.5-fold increase in the likelihood of hyperglycemia across its risk categories.” (B. P. Kovatchev, boris@virginia.edu)
Durability of Pediatric Insulin Pump Therapy: More than 80% of 161 youth with type 1 diabetes maintained insulin pump therapy with good glycemic control over an average of 3.8 years, according to a study conducted from 1998 to 2001 (pp. 2355-60). Noting that patients discontinuing the pump were more likely to be nonadherent and have suboptimal A1C levels, the researchers report: “At pump start, patients (71% female) had a mean age of 14.1 ± 3.7 years, diabetes duration of 7.1 ± 4.0 years, daily blood glucose monitoring (BGM) frequency of 4.0 ± 1.2, a daily insulin dose of 1.0 ± 0.3 units/kg, and an HbA1c (A1C) of 8.4 ± 1.4%. After 1 year, mean daily BGM frequency was 4.5 ± 1.7, daily insulin dose was 0.8 ± 0.2 units/kg, and A1C was 8.1 ± 1.3% (all baseline versus 1-year data, P < 0.01). As of 2005, 29 patients (18%) had resumed injection therapy at a mean age of 17.0 ± 2.9 years after a mean duration of pump use of 2.1 ± 1.3 years. BGM frequency at baseline and at 1 year was significantly lower in the patients who resumed injection therapy (P < 0.02). In addition, patients who remained on the pump had lower A1C than those who resumed injection therapy at both 1 year (P = 0.04) and at the most recent clinic visit (P = 0.01).” (L. M. B. Laffel, lori.laffel@joslin.harvard.edu)
Long-Term Metformin Therapy: Among nonobese patients with type 2 diabetes, metformin was at least as effective as in obese patients, conclude investigators who studied 644 individuals at a Sydney, Australia, referral center (pp. 2361-4). Analyzing data on normal, overweight, and obese patients who were taking metformin or sulfonylurea monotherapy, the investigators found: “There were no differences between the initial, follow-up, and last A1C between the three metformin-treated groups. The duration of successful glycemic control with metformin monotherapy in the normal and overweight individuals and their incidences of diabetes-related complications for the entire duration of follow-up were not inferior to those of the obese individuals. The nonobese patients performed better regardless of the type of oral hypoglycemic agent used.” (D. K. Yue, Royal Prince Alfred Hosp., Camperdown, Australia; dennis@email.cs.nsw.gov.au)
Glargine Insulin v. Rosiglitazone: Acting through different mechanisms, glargine insulin and rosiglitazone were similarly effective for reducing A1C among 20 patients with type 2 diabetes who were poorly controlled on metformin plus a sulfonylurea (pp. 2371-7). Adding bedtime doses of glargine insulin (titrated) or rosiglitazone 4 mg twice daily to the regimen, the researchers found that both agents suppressed basal hepatic endogenous glucose production. “Glargine insulin reduced basal EGP by increasing plasma insulin levels, while rosiglitazone decreased basal hepatic glucose production by improving hepatic insulin sensitivity,” the group concluded. (R. A. DeFronzo, albarado@uthscsa.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 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
Oct. 30, 2006 * Vol. 13, No. 208
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Early-release articles from and Oct. 28 issue of Lancet (www.thelancet.com; 2006; 368).
Rimonabant in Type 2 Diabetes: In overweight and obese people with poorly controlled type 2 diabetes, the selective cannabinoid type 1 receptor blocker rimonabant 20 mg/day plus diet and exercise produced clinically meaningful reductions in body weight and A1c levels, researchers report (doi: 10.1016/S0140-6736(06)69571-8). For 1,047 patients with initial body mass indices of 27–40 kg/sq m and A1c levels of 6.5% to 10% despite metformin or sulfonylurea monotherapy, rimonabant 5 or 20 mg/day or placebo produced these results: “692 patients completed the 1 year follow-up; numbers in each group after 1 year were much the same. Weight loss was significantly greater after 1 year in both rimonabant groups than in the placebo group (placebo: −1.4 kg [SD 3.6]; 5 mg/day: −2.3 kg [4.2], p = 0.01 vs placebo; 20 mg/day: −5.3 kg [5.2], p < 0.0001 vs placebo). Rimonabant was generally well tolerated. The incidence of adverse events that led to discontinuation was slightly greater in the 20 mg/day rimonabant group, mainly due to depressed mood disorders, nausea, and dizziness.” (A. J. Scheen, U. Liege, Liege, Belgium; andre.scheen@chu.ulg.ac.be)
Pneumococcal Vaccine in Children: Real-world results with the seven-valent pneumococcal conjugate vaccine show that it provides protection in both healthy and chronically ill children and works even when administered on nonstandard schedules (pp. 1495-502). Among 782 cases and 2,512 control children aged 3–59 months identified through the CDC’s surveillance program, the investigators found: “Effectiveness of one or more doses against vaccine serotypes was 96% (95% CI 93–98) in healthy children and 81% (57–92) in those with coexisting disorders. It was 76% (63–85) against infections that were not susceptible to penicillin. Vaccination prevented disease caused by all seven vaccine serotypes, and by vaccine-related serotype 6A. Several schedules were more protective than no vaccination; three infant doses with a booster were more protective against vaccine-type disease than were three infant doses alone (p = 0.0323).” (C. G. Whitney, cwhitney@cdc.gov)

>>>BMJ Highlights
Source:
Early-release article from BMJ (www.bmj.org; 2006; 333).
Statins & CAP: Contrary to reports of benefits of statins in patients with sepsis, these lipid-lowering agents were not associated with reduced mortality or need for intensive care among patients at six hospitals in Alberta (doi: 10.1136/bmj.38992.565972.7C). In a population-based prospective cohort study, researchers noted a change in outcomes when confounders were accounted for: “Of 3,415 patients with pneumonia admitted to hospital, 624 (18%) died or were admitted to an intensive care unit. Statin users were less likely to die or be admitted to an intensive care unit than non-users (50/325 (15%) v 574/3,090 (19%), odds ratio 0.80, P = 0.15). After more complete adjustment for confounding, however, the odds ratios changed from potential benefit (0.78, adjusted for age and sex) to potential harm (1.10, fully adjusted including propensity scores, 95% confidence interval 0.76 to 1.60).” (S. R. Majumdar, me2.majumdar@ualberta.ca)

>>>PNN JournalWatch
* Initial Highly-Active Antiretroviral Therapy with a Protease Inhibitor Versus a Non-Nucleoside Reverse Transcriptase Inhibitor: Discrepancies Between Direct and Indirect Meta-Analyses, in Lancet, 2006; 368: 1503–15. Reprints: www.thelancet.com/journals/lancet/article/PIIS0140673606696384/abstract; R. Chou, Oregon Evidence-based Practice Center, Portland; chour@ohsu.edu
* Prophylactic Antibiotics To Prevent Pneumonia and Other Complications After Measles: Community Based Randomised Double Blind Placebo Controlled Trial in Guinea-Bissau, in
BMJ, 2006; doi: 10.1136/bmj.38989.684178.AE. Reprints: http://bmj.bmjjournals.com/cgi/content/abstract/bmj.38989.684178.AEv1; M-L Garly, Projecto de Saúde de Bandim, Bissau, Guinea-Bissau; mlg@ssi.dk
* Effects of Different Modes of Exercise Training on Glucose Control and Risk Factors for Complications in Type 2 Diabetic Patients, in
Diabetes Care, 2006; 29: 2518–27. Reprints: http://care.diabetesjournals.org/cgi/content/abstract/29/11/2518; W. Hopkins, Auckland U. Technol., Auckland, New Zealand; will@clear.net.nz

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Oct. 31, 2006 * Vol. 13, No. 209
Providing news and information about medications and their proper use

>>>Infectious Disease Report
Source:
Nov. 15 issue of Clinical Infectious Diseases (www.journals.uchicago.edu/CID; 2006; 43).
PPIs & C. difficile: Countering previous reports, use of proton-pump inhibitors was not associated with hospitalization for Clostridium difficile–associated disease in a population-based, nested case–control study of linked health care databases in Ontario from 2002 to 2005 (pp. 1272-6). “We identified 1,389 case patients and 12,303 matched control subjects,” the authors write. “Case patients were no more likely than control subjects to have received a PPI in the preceding 90 days (adjusted odds ratio, 0.9; 95% confidence interval, 0.8–1.1). Similarly, we found no association between hospitalization for CDAD and more remote use of PPIs.” (D. O. Lowe, U. Health Network, Toronto; donna.lowe@uhn.on.ca)
Outpatient Parenteral Antibiotic Therapy & ID Consultants: Optimal methods for delivery and management of outpatient parenteral antibiotic therapy need to be identified and implemented, conclude researchers who conducted a survey of members of the Infectious Diseases Society of America Emerging Infections Network in May 2004 (pp. 1290-5). Citing quality and safety concerns that derive from variable involvement of infectious disease consultants and many different ways that OPAT is used, the authors based their conclusion on these survey results: “Of the 454 respondents (54%) who completed the questionnaire, 426 (94%) indicated that patients in their primary inpatient facility were ‘frequently’ discharged while receiving OPAT, estimating that, on average, 19 patients are discharged from their hospitals while receiving OPAT each month. Although 86% of EIN members stated that they personally order OPAT for some patients, 18% indicated that they have no involvement, and 37% stated they only rarely or occasionally oversee OPAT. EIN members involved in OPAT estimated that 90% of their patients who take OPAT received therapy at home, and the members described variable monitoring and oversight methods. Of the respondents, 68% of providers collectively estimated that they encountered 1,951 infectious and serious noninfectious complications of OPAT in the past year. The most frequently used antibiotics included vancomycin, ceftriaxone, and cefazolin, most commonly used for bone and joint infections.” (L. J. Strausbaugh, VA Med. Ctr., Portland; strausba@ohsu.edu)

>>>Psychiatry Highlights
Source:
Nov. issue of the American Journal of Psychiatry (ajp.psychiatryonline.org; 2006; 163).
Medications for Refractory Depression: “Studies to identify the best multistep treatment sequences for individual patients and the development of more broadly effective treatments are needed,” concludes an analysis of acute and longer-term outcomes from the STAR*D investigators (pp. 1905-17). Noting lower acute remission rates and higher relapse rates when patients must move to third or fourth antidepressants, the authors note: “The [Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR16)] remission rates were 36.8%, 30.6%, 13.7%, and 13.0% for the first, second, third, and fourth acute treatment steps, respectively. The overall cumulative remission rate was 67%. Overall, those who required more treatment steps had higher relapse rates during the naturalistic follow-up phase. In addition, lower relapse rates were found among participants who were in remission at follow-up entry than for those who were not after the first three treatment steps.” (A. J. Rush)
Suicidality in Younger Adolescents & Children: While direct causal associations cannot be made based on these observational data, an analysis of prescribing patterns and county-level suicides shows that more SSRI prescriptions are associated with lower suicide rates among young adolescents and children (pp. 1898-904). Focusing on 5–14-year-olds rather than the more suicide-prone late adolescents, the researchers noted that these lower suicide rates “may reflect antidepressant efficacy, treatment compliance, better quality mental health care, and low toxicity in the event of a suicide attempt by overdose.” (R. D. Gibbons)

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Nov. 1, 2006 * Vol. 13, No. 210
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Nov. 1 issue of JAMA (www.jama.com; 2006; 296).
Statin Therapy in HF: Initiation of statin therapy in patients with heart failure was associated with significant declines in rates of mortality and hospitalizations, according to a Kaiser Permanente study of 1996 through 2004 data (pp. 2105-11). Patients were identified based on outpatient prescriptions for statins and followed for a median of 2.4 years. Results showed: “Among 24,598 adults diagnosed with heart failure who had no prior statin use, those initiating statin therapy (n = 12 648; 51.4%) were more likely to be younger, male, and have known cardiovascular disease, diabetes, and hypertension. There were 8,235 patients who died. Using an intent-to-treat approach, incident statin use was associated with lower risks of death (age- and sex-adjusted rate of 14.5 per 100 person–years with statin therapy vs 25.3 per 100 person–years without statin therapy; adjusted hazard ratio, 0.76 [95% confidence interval, 0.72–0.80]) and hospitalization for heart failure (age- and sex-adjusted rate of 21.9 per 100 person–years with statin therapy vs 31.1 per 100 person–years without statin therapy; adjusted hazard ratio, 0.79 [95% confidence interval, 0.74-0.85]) even after adjustment for the propensity to take statins, cholesterol level, use of other cardiovascular medications, and other potential confounders. Incident statin use was associated with lower adjusted risks of adverse outcomes in patients with or without known coronary heart disease.” (A. S. Go, Kaiser Permanente, Oakland, Calif.; Alan.S.Go@kp.org)

>>>Rheumatology Report
Source:
Nov. issue of Arthritis & Rheumatism (www3.interscience.wiley.com; 2006; 54).
NSAID Safety: In a population of 49,711 Medicare beneficiaries aged 65 or older , diclofenac and rofecoxib had the least favorable risk-benefit balance of all NSAIDs evaluated (pp. 3390-8). Looking at patients who began NSAID or selective COX-2 inhibitor therapy in 1999–2002, researchers found these risks of gastrointestinal complications and myocardial infarction in the 180 days after treatment initiation: “Compared with nonselective NSAIDs, celecoxib reduced the risk of GI complications by 1.4 per 100 users but increased the risk of MI by 0.3 per 100 users. Rofecoxib decreased GI complications by 1.1 per 100 users and increased the risk of MI by 0.3 per 100 users. Using celecoxib as the reference exposure showed an increase in the MI risk for rofecoxib (risk difference [RD] 1.40, 95% confidence interval [95% CI] –0.20, 3.01) and diclofenac (RD 6.07, 95% CI –0.02, 12.15). The RD for naproxen as well as its upper 95% CI was the lowest of all NSAIDs (RD –0.30, 95% CI –2.74, 2.14) and there was no significant difference in GI complication rates among all NSAIDs.” (S. Schneeweiss; schneeweiss@post.harvard.edu)
TNF Inhibitors in RA: Patients with long-standing, severe rheumatoid arthritis were not eligible for inclusion in major clinical trials of tumor-necrosis factor inhibitor, but these patients do benefit from treatment, according to data from RABBIT, a German biologics registry (pp. 3399-407). Patients being treated with infliximab, etanercept, or adalimumab were assessed for their eligibility in the major clinical trials that led to approval of the drugs. Looking at eligible and ineligible patients using the American College of Rheumatology 20% (ACR20) and 50% (ACR50) improvement response criteria, the researchers found: “Only 21–33% of the patients in the RABBIT register would have been eligible for the major trials. In these patients, the ACR20 and ACR50 improvement responses, indicating therapeutic effectiveness, were comparable with the response rates in the published trials. ACR response rates were lower in those patients considered ineligible for the trials; however, absolute improvement was similar to that in eligible patients. Ineligible patients had lower baseline disease activity, more comorbidity, and lower functional status.” (A. Zink, German Rheumatism Research Ctr., Berlin; Zink@DRFZ.de)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Nov. 2, 2006 * Vol. 13, No. 211
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Nov. 2 issue of the New England Journal of Medicine (content.nejm.org; 2006; 355)
Epirubicin in Early Breast Cancer: For adjuvant treatment of early breast cancer, epirubicin proved a useful addition to cyclophosphamide, methotrexate, and fluorouracil (CMF) treatment, according to results of the National Epirubicin Adjuvant Trial (NEAT) and the BR9601 trial (pp. 1851-62). Added to four cycles of CMF and compared with six cycles of CMF alone, the anthracycline provided these improved outcomes: “The two trials included 2,391 women with early breast cancer; the median follow-up was 48 months. Relapse-free and overall survival rates were significantly higher in the epirubicin–CMF groups than in the CMF-alone groups (2-year relapse-free survival, 91% vs. 85%; 5-year relapse-free survival, 76% vs. 69%; 2-year overall survival, 95% vs. 92%; 5-year overall survival, 82% vs. 75%; P < 0.001 by the log-rank test for all comparisons). Hazard ratios for relapse (or death without relapse) (0.69; 95% confidence interval [CI], 0.58 to 0.82; P < 0.001) and death from any cause (0.67; 95% CI, 0.55 to 0.82; P < 0.001) favored epirubicin plus CMF over CMF alone. Independent prognostic factors were nodal status, tumor grade, tumor size, and estrogen-receptor status (P < 0.001 for all four factors) and the presence or absence of vascular or lymphatic invasion (P = 0.01). These factors did not significantly interact with the effect of epirubicin plus CMF. The overall incidence of adverse effects was significantly higher with epirubicin plus CMF than with CMF alone but did not significantly affect the delivered-dose intensity or the quality of life.” (C.J. Poole, U. Birmingham, Birmingham, U.K.; poolecj@aol.com)
Reflecting on 30 years of adjuvant chemotherapy for breast cancer, dating back to the 1976 landmark trial by Bonadonna et al., editorialists write (pp. 1920-2): “Considerable progress has been made in the fight against breast cancer, but there is still much to be done. The addition of trastuzumab after chemotherapy is a recent exciting development. Promising new agents such as bevacizumab and lapatinib need to be tested, and additional agents developed. Important advances are also being made in the use of genetic analyses to determine the risk of recurrence and to predict a tumor’s responsiveness to chemotherapy. Thus, adjuvant therapy that is tailored for the patient who is most likely to benefit on the basis of amplification of a particular gene or gene profile may be just around the corner.” (M. N. Levine, McMaster U., Hamilton, Ont., Canada)
Reversal of Severe HF: A small, single-center study shows that severe heart failure caused by nonischemic cardiomyopathy can be reversed in some patients through use of a left ventricular assist device and a specific pharmacologic regimen (pp. 1873-84). After implantation of left ventricular assist devices, patients were treated with lisinopril, carvedilol, spironolactone, and losartan to enhance reverse remodeling, the authors reported. To prevent myocardial atrophy, a beta-2-adrenergic–receptor agonist, clenbuterol, was added after left ventricular enlargement had regressed. During 4 years of monitoring, 11 of 15 patients treated in this manner were able to have the assist device removed. Only two patients died after the assist device was removed, one of arrhythmias 24 hours later and the other of lung carcinoma after 27 months. Overall, 100% and 88.9% of patients survived without recurrent heart failure at 1 and 4 years after removal of the device, the authors add, concluding, “Our regimen of mechanical and pharmacologic therapy may enhance the frequency and durability of myocardial recovery as compared with other therapeutic approaches, although a direct comparison of treatment protocols was not performed.” (M. H. Yacoub, Royal Brompton and Harefield Hosp., Middlesex, U.K.; m.yacoub@ic.ac.uk)

>>>PNN NewsWatch
* FDA yesterday approved the first generic formulation of metronidazole vaginal gel, a 0.75% strength from QLT USA, Inc.
* The $21 billion merger of
CVS and Caremark announced yesterday was a response to Wal-Mart’s recent $4 prescription promotion, reports USA Today. The move follows CVS’s Sept. purchase of Minute Clinic, the largest U.S. operator of in-store health clinics.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Nov. 3, 2006 * Vol. 13, No. 212
Providing news and information about medications and their proper use

>>>Pediatrics Highlights
Source:
Nov. issue of Pediatrics (www.pediatrics.org; 2006; 118).
New Errors with CPOE: About 1 in 5 medication errors detected among pediatric patients were computer related, reports a new study of computerized physician order entry (pp. 1872-9). Researchers examined retrospectively 352 randomly selected pediatric inpatients who were admitted 3–12 months after CPOE implementation. “Among 6,916 medication orders in 1,930 patient-days, there were 104 pediatric medication errors, of which 71 were serious (37 serious medication errors per 1,000 patient-days). Of all pediatric medication errors detected, 19% (7 serious and 13 with little potential for harm) were computer related. The rate of computer-related pediatric errors was 10 errors per 1,000 patient-days, and the rate of serious computer-related pediatric errors was 3.6 errors per 1,000 patient-days. The following 4 types of computer-related errors were identified: duplicate medication orders (same medication ordered twice in different concentrations of syrup, to work around computer constraints; 2 errors), drop-down menu selection errors (wrong selection from a drop-down box; 9 errors), keypad entry error (5 typed instead of 50; 1 error), and order set errors (orders selected from a pediatric order set that were not appropriate for the patient; 8 errors). In addition, 4 preventable adverse drug events in drug ordering occurred that were not considered computer-related but were not prevented by the computerized physician order entry system.” (K. E. Walsh, U. Mass. Med. Sch., Worcester)
Compliance with Flu Vaccine Recommendations: Among children who receive their first dose of trivalent inactivated influenza vaccine, most never receive the second dose, muting the impact of the vaccine, authors report (pp. 2032-7). At health-maintenance organizations participating in the Vaccine Safety Datalink project, 125,928 children aged 6 months to 8 years received their first injection of influenza vaccine over a 3-year period. “The proportion of first-vaccinated children who received a second vaccination was 44% in 2001–2002, 54% in 2002–2003, and 29% in 2003–2004,” write the researchers. “Among children 2 to 8 years of age, the corresponding proportions were 15%, 24%, and 12%, respectively. In all seasons, compliance with the second vaccination was highest in children first vaccinated by mid-November.” The authors conclude, “The recently expanded recommendation for universal vaccination of children 6 to 59 months of age and their household contacts will substantially increase the number of children targeted for a first influenza vaccination. Noncompliance with the 2-dose trivalent inactivated influenza vaccine series may be associated with suboptimal protection against infection, which may impact the magnitude of the direct and indirect benefits achieved by the vaccination program.” (L. A. Jackson, Group Health Ctr. for Health Studies, Seattle)
Influenza-Related Hospitalizations: Direct medical costs for influenza-related hospitalizations among children are considerably higher than previously estimated, topping $13,000 per patient on average, reports a retrospective cohort study (e1321-7). At a children’s hospital, 727 pediatric patients hospitalized in 2000–04 for influenza had mean total hospitalization costs of $7,030 for those cared for solely on the wards and $39,792 for patients requiring intensive care. (R. Keren, Children’s Hosp., Philadelphia)
Provider Influence on Parental Vaccination Decisions: Health professionals can affect the views of parents about vaccine safety, according to a study from the National Immunization Survey (e1287-92). Among parents of 7,695 children aged 19–35 months, parents who reported that their health providers were influential were twice as likely to view vaccines as safe for children, the study shows. “Among children whose parents believed that vaccines were not safe, those whose parents’ decision to vaccinate was influenced by a health care provider had an estimated vaccination coverage rate that was significantly higher than the estimated coverage rate among children whose parents’ decision was not influenced by a health care provider (74.4% vs 50.3%; estimated difference: 24.1%),” the investigators report. (P. J. Smith, CDC, Atlanta)

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Nov. 6, 2006 * Vol. 13, No. 213
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Nov. 4 issue of Lancet (www.thelancet.com; 2006; 368).
Tuberculosis & HIV in South Africa: Mortality is high in patients coinfected with extensively drug-resistant tuberculosis and HIV, according to a surveillance study conducted in a rural area of South Africa (pp. 1575-80). Using sputum cultures and drug susceptibility testing to detect multidrug-resistant and XDR tuberculosis, the investigators report: “From January, 2005, to March, 2006, sputum was obtained from 1,539 patients. We detected MDR tuberculosis in 221 patients, of whom 53 had XDR tuberculosis. Prevalence among 475 patients with culture-confirmed tuberculosis was 39% (185 patients) for MDR and 6% (30) for XDR tuberculosis. Only 55% (26 of 47) of patients with XDR tuberculosis had never been previously treated for tuberculosis; 67% (28 of 42) had a recent hospital admission. All 44 patients with XDR tuberculosis who were tested for HIV were co-infected. 52 of 53 patients with XDR tuberculosis died, with median survival of 16 days from time of diagnosis (IQR 6–37) among the 42 patients with confirmed dates of death. Genotyping of isolates showed that 39 of 46 (85%, 95% CI 74–95) patients with XDR tuberculosis had similar strains.” (N. R. Gandhi, negandhi@montefiore.org)
HIV-Med Adherence in Home Programs: Good adherence and response to antiretroviral therapy can be achieved in the home setting in resource-limited areas, concludes a study conducted in a rural African area (pp. 1587-94). Group education, personal adherence plans developed with trained counselors, a medicine companion, and weekly home delivery of antiretroviral therapy by trained lay field officers were assessed, with these results for 987 adults who had received no previous antiretroviral therapy: “[Pill count adherence] of less than 95% was calculated for 0.7–2.6% of participants in any quarter and [medication possession ratio] of less than 95% for 3.3–11.1%. Viral load was below 1000 copies per mL for 894 (98%) of 913 participants in the second quarter and for 860 (96%) of 894 of participants in the fourth quarter. In separate multivariate models, viral load of at least 1,000 copies per mL was associated with both PCA below 95% (second quarter odds ratio 10·6 [95% CI 2.45–45.7]; fourth quarter 14.5 [2.51–83.6]) and MPR less than 95% (second quarter 9.44 [3.40–26.2]; fourth quarter 10.5 [4.22–25.9]).” (P. J. Weidle, pweidle@cdc.gov)

>>>BMJ Highlights
Source:
Early-release article from BMJ (www.bmj.org; 2006; 333).
Isoniazid Prophylaxis in Children with HIV: In settings with high prevalence of tuberculosis, prophylaxis with isoniazid provides “an early survival benefit and reduces incidence of tuberculosis in children with HIV,” concludes a study conducted at two tertiary health centers in South Africa (doi:10.1136/bmj.39000.486400.55). “Data on 263 children (median age 24.7 months) were available when the data safety monitoring board recommended discontinuing the placebo arm; 132 (50%) were taking isoniazid. Median follow-up was 5.7 (interquartile range 2.0–9.7) months. Mortality was lower in the isoniazid group than in the placebo group (11 (8%) v 21 (16%), hazard ratio 0.46, 95% confidence interval 0.22 to 0.95, P = 0.015) by intention to treat analysis. The benefit applied across Centers for Disease Control clinical categories and in all ages. The reduction in mortality was similar in children on three times a week or daily isoniazid. The incidence of tuberculosis was lower in the isoniazid group (5 cases, 3.8%) than in the placebo group (13 cases, 9.9%) (hazard ratio 0.28, 0.10 to 0.78, P = 0.005). All cases of tuberculosis confirmed by culture were in children in the placebo group. (H. J. Zar, Red Cross Children’s Hosp., Cape Town, South Africa; hzar@ich.uct.ac.za)

>>>PNN JournalWatch
* Medically Important Venomous Animals: Biology, Prevention, First Aid, and Clinical Management, in Clinical Infectious Diseases, 2006; 43: 1309–17. Reprints: www.journals.uchicago.edu/CID/journal/issues/v43n10/39322/brief/39322.abstract.html; T. Junghanss, U. Hosp., Heidelberg, Germany.
* Implications of New Technology for Infectious Diseases Practice, in
Clinical Infectious Diseases, 2006; 43: 1318–23. Reprints: www.journals.uchicago.edu/CID/journal/issues/v43n10/39686/brief/39686.abstract.html; E. J. Baron, Stanford U. Med. Ctr., Stanford, Calif.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Nov. 7, 2006 * Vol. 13, No. 214
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Nov. 7 issue of the Annals of Internal Medicine (www.annals.org; 2006; 145).
Hypothyroidism after Sunitinib Treatment for GIST: Thyroid function should be monitored in patients receiving sunitinib, according to a 42-patient study of treatment of gastrointestinal stromal tumors (pp. 660-4). Over a median of 37 weeks, investigators observed these changes in thyroid-stimulating hormone: “Abnormal serum TSH concentrations were documented in 26 of 42 patients (62%): 15 (36%) developed persistent, primary hypothyroidism; 4 (10%) developed isolated TSH suppression; and 7 (17%) experienced transient, mild TSH elevations. The risk for hypothyroidism increased with the duration of sunitinib therapy. Six of 15 (40%) hypothyroid patients had suppressed TSH concentrations before developing hypothyroidism, suggesting thyroiditis. Two hypothyroid patients evaluated with thyroid ultrasonography had no visualized thyroid tissue despite normal baseline thyroid function.” Proposing a possible new indication for sunitinib, the researchers add, “Although the mechanism by which this complication occurs is unknown, the observations of preceding TSH suppression and subsequent absence of visualized thyroid tissue in some patients suggest that sunitinib may induce a destructive thyroiditis through follicular cell apoptosis. This provides a rationale for further investigation of sunitinib treatment in patients with advanced thyroid cancer.” (E. K. Alexander, ekalexander@partners.org)
Editorialists advise against using military terms such as “magic bullets” and “targeted therapy” in clinical oncology (pp. 702-3): “Our terminal ballistics [the study of motion and consequent effects of projectiles as they interact with intended targets] report on tyrosine kinase inhibitors suggests that they are anything but ‘magic bullets.’ To avoid deluding ourselves and misguiding our colleagues and patients, it is time to discard the term ‘targeted therapy,’ which implies a simplistic mentality first conceived almost 100 years ago. In fact, decade after decade, as we have improved cancer detection and care, the ‘magic bullet’ has eluded us. The growing collection of drugs with several targets and associated mechanism-dependent and mechanism-independent toxicities combined with tumor gene expression profiling (for example, with microarrays) provides us an opportunity to individualize treatment according to a carefully selected matrix of variables. This matrix would include the use of emerging diagnostic tests, as well as careful clinical observation of efficacy and toxicity. Furthermore, we should acknowledge that drugs have many targets, some of which will result in substantial harm to our patients. Although we have learned a great deal about the biology of cancer in recent decades, we might better serve our patients by studying the terminal ballistics of new agents rather than persisting in our search for the ‘magic bullet.’” (M. J. Ratain,
mratain@medicine.bsd.uchicago.edu)
Inhaled Insulin Therapy: Inhaled insulin is “an alternative noninvasive option for premeal insulin administration,” one with efficacy slightly less than that of subcutaneous insulin but greater than orally administered hypoglycemic agents, conclude authors of a meta-analysis of 16 open-label trials of 4,032 patients with type 1 or type 2 diabetes (pp. 665-75). “Severe hypoglycemia was more likely to occur with inhaled insulin than with oral agents (risk ratio, 3.1 [CI, 1.0 to 9.1]), but there was no increased risk compared with subcutaneous insulin,” write the authors. “There was an increased incidence of mild to moderate nonprogressive dry cough in patients treated with inhaled insulin (risk ratio, 3.5 [CI, 2.2 to 5.6]) and a mild decrease in certain pulmonary function testing variables, which did not progress over 2 years. Patients preferred inhaled insulin over subcutaneous insulin.” (A. G. Pittas, apittas@tufts-nemc.org)
Countering Perceptions on Long-Acting Beta-Agonists: A recent Annals meta-analysis (see PNN, June 6) failed to include pivotal beneficial trials of long-acting beta-agonists in asthma, authors argue (pp. 692-4). Prescribers should continue using LABAs as they usually have until results of an independent meta-analysis of LABA/corticosteroid use can be conducted. (A. McIvor, St. Joseph’s Healthcare, Hamilton, Ont., Canada; amcivor@stjosham.on.ca)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 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
Nov. 8, 2006 * Vol. 13, No. 215
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Nov. 8 issue of JAMA (www.jama.com; 2006; 296)
Prevention of Malaria in Long-term Travelers: People traveling for several months to areas with endemic malaria need an individualized plan for prevention, one that includes carrying a sufficient supply of medications with them on the trip, concludes a review article (pp. 2234-44). Looking at reports published through July 2006, the authors write: “Long-term travelers have a higher risk of malaria than short-term travelers. Long-term travelers underuse personal protective measures and adhere poorly to continuous chemoprophylaxis regimens. A number of strategies are used during long-term stays: discontinuation of chemoprophylaxis after the initial period, sequential regimens with different medications for chemoprophylaxis, stand-by emergency self-treatment, and seasonal chemoprophylaxis targeting high-incidence periods or locations. All strategies have advantages and drawbacks. Counterfeit drugs sold in countries endemic for malaria pose serious concern for long-term travelers who purchase their medications overseas. Vivax malaria causes significant illness in travelers, but relapses of vivax malaria are not prevented with the current first-line chemoprophylaxis regimens. Consensus guidelines are needed for prevention of malaria in long-term travelers.” (L. H. Chen, lchen@hms.harvard.edu)
Palliative Care for Frail Older Adults: Pharmacist consultants are important members of interdisciplinary teams formed to assess symptoms and provide management suggestions for frail older adults, according to a Clinician’s Corner article (pp. 2245-53). “Frailty in older adults is increasingly a recognized syndrome of decline, sometimes subtle, in function and health that may be amenable to available approaches to care,” the authors explain. “Frailty manifests the following core clinical features: loss of strength, weight loss, low levels of activity, poor endurance or fatigue, and slowed performance. The presence of 3 or more of these features is associated with adverse outcomes including falls, new or worsened function impairment, hospitalization, and death. In this article, we use the case of Mrs K to describe the challenges of recognizing frailty in clinical practice, common problems and symptoms that frail older adults experience, and approaches to these issues that clinicians may incorporate into their practices. We discuss the importance of advance care planning, provider–patient communication, and appropriate palliative care and hospice referral for frail older adults. Frailty is associated with symptomatic long-term disease, decline in function, and abbreviated survival. Therefore, when frailty is severe, delivery of palliative care focused on relief of discomfort and enhancement of quality of life is highly appropriate. The application of multidisciplinary, team-based palliative approaches and of up-to-date geriatrics knowledge is beneficial for treating these patients because of the complexity of their coexisting social, psychological, and medical needs.” (K. Boockvar, VA Med. Ctr., Bronx, N.Y.; kenneth.boockvar@mssm.edu).

>>>PNN NewsWatch
* The Democratic takeover of the U.S. House of Representatives could mean a revisiting—or perhaps rewriting—of fundamental aspects of the Medicare Part D benefit, including the reliance on private prescription drug plans, the numbers and types of medications included in preferred drug lists, and the so-called “doughnut hole” in coverage. If combined with a Democratic majority in the Senate (Virginia and Montana Senate races are undecided this morning, and both must be captured by Democrats to give the party a majority in that house), the results of yesterday’s midterm elections will place the party in key committee chairs during a Congressional term when fundamental questions are also slated to be addressed about the way in which FDA approves new drugs and monitors medications once they are on the market. An interesting twist on the new Congress is that many of the newly elected Democrats are more conservative than party leaders such as Nancy Pelosi—a San Francisco Democrat who is heir apparent to the Speaker’s post—and these new solons may find themselves voting with President Bush and Republican colleagues on some issues.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Nov. 9, 2006 * Vol. 13, No. 216
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Nov. 9 issue of the New England Journal of Medicine (content.nejm.org; 2006; 355).
Chloroquine Antimalarial Efficacy: Twelve years after its use was stopped in Malawi, chloroquine is once again an effective treatment for malaria, according to a study of 210 children with uncomplicated Plasmodium falciparum malaria (pp. 1959-66). Treated with either chloroquine or sulfadoxine–pyrimethamine and followed for 28 days, the children had these outcomes: “Treatment failure occurred in 1 of 80 participants assigned to chloroquine, as compared with 71 of 87 participants assigned to sulfadoxine–pyrimethamine. The cumulative efficacy of chloroquine was 99% (95% confidence interval [CI], 93 to 100), and the efficacy of sulfadoxine–pyrimethamine was 21% (95% CI, 13 to 30). Among children treated with chloroquine, the mean time to parasite clearance was 2.6 days (95% CI, 2.5 to 2.8) and the mean time to the resolution of fever was 10.3 hours (95% CI, 8.1 to 12.6). No unexpected adverse events related to the study drugs occurred.” (C. V. Plowe, cplowe@medicine.umaryland.edu)
Noting that the death of a child from infectious diseases is rare in developed countries but common in poorer parts of the world, the author of a Commentary article says now is the “time to act” (pp. 1956-7): “With strong leadership and the singularity of purpose that characterized the successful campaign to eradicate smallpox, malaria can be rolled back. We already have the necessary tools: insecticides, insecticide-treated bed nets, and good drugs. An effective and affordable vaccine would be wonderful, but we do not need to wait for it. It is time to turn the tide on malaria. We can do it now, and it won’t cost that much.” (N. J. White, Mahidol U., Bangkok)
Antirejection Drugs in Renal Transplant: Induction therapy with a 5-day course of antithymocyte globulin, as compared with basiliximab, reduced the incidence and severity of acute rejection but not the incidence of delayed graft function in a study of 289 recipients of cadaveric renal transplants (pp. 1967-77). “Patients taking cyclosporine, mycophenolate mofetil, and prednisone were randomly assigned to receive either rabbit antithymocyte globulin (1.5 mg per kilogram of body weight daily, 141 patients) during transplantation (day 0) and on days 1 through 4 or basiliximab (20 mg, 137 patients) on days 0 and 4,” the authors report. Using a primary end point was a composite of acute rejection, delayed graft function, graft loss, and death, investigators found: “At 12 months, the incidence of the composite end point was similar in the two groups (P = 0.34). The antithymocyte globulin group, as compared with the basiliximab group, had lower incidences of acute rejection (15.6% vs. 25.5%, P = 0.02) and of acute rejection that required treatment with antibody (1.4% vs. 8.0%, P = 0.005). The antithymocyte globulin group and the basiliximab group had similar incidences of graft loss (9.2% and 10.2%, respectively), delayed graft function (40.4% and 44.5%), and death (4.3% and 4.4%). Though the incidences of all adverse events, serious adverse events, and cancers were also similar between the two groups, patients receiving antithymocyte globulin had a greater incidence of infection (85.8% vs. 75.2%, P = 0.03) but a lower incidence of cytomegalovirus disease (7.8% vs. 17.5%, P = 0.02).” (D. C. Brennan, Washington U., St. Louis; dbrennan@wustl.edu)
Several polyclonal antibodies are available for antirejection uses, an editorialist explains, including basiliximab, daclizumab, OKT3 (muromonab-CD3), and alemtuzumab (pp. 2033-5). She provides this perspective on current use: “Despite anticipated changes in immunosuppressive regimens, the study by Brennan et al. shows that induction with antithymocyte globulin (as compared with basiliximab) helps win an important battle — reducing the incidence and severity of clinically significant acute cellular rejection. However, at least in the short term, winning that battle does not mean winning the war. Graft survival and function were not altered at 12 months, but for long-term survival and function, only time will tell. For now, some centers may switch to antithymocyte globulin, but both treatments — antithymocyte globulin and basiliximab — will continue to have their supporters.” (M. A. Josephson, University of Chicago, Chicago)

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Nov. 10, 2006 * Vol. 13, No. 217
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Nov. issue of Pharmacotherapy (www.pharmacotherapy.org; 2006; 26).
Drug-Related Hospitalizations: At a large tertiary care hospital in Canada, one fourth of hospitalizations resulted from medication-related problems, according to a prospective observational study (pp. 1578-86). Analyzing 5,655 consecutive adult inpatients over a 12-week period, the authors found: “The frequency of drug-related hospitalization was 24.1% (95% confidence interval [CI] 20.6–27.8%), of which 72.1% (95% CI 63.7–79.4%) were deemed preventable. Severity was classified as mild, moderate, severe, and fatal in 8.1% (95% CI 4.1–14.0%), 83.8% (95% CI 76.5–89.6%), 7.4% (95% CI 3.6–13.1%), and 0.7% (95% CI 0.0–4.0%), respectively, of the hospitalizations. The most common classifications of drug-related hospitalization were adverse drug reactions (35.3% [95% CI 27.3–43.9%]), improper drug selection (17.6% [95% CI 11.6–25.1%]), and noncompliance (16.2% [95% CI 10.4–23.5%]). No independent risk factors for drug-related hospitalization were identified with regression modeling.” (P, J. Zed, zed@interchange.ubc.ca)
Role of Newer Agents in PCI: The place of newer antiplatelet and antithrombin drugs that may be used during percutaneous coronary intervention are reviewed in an article that provides expert opinion from the American Heart Association’s Diagnostic and Interventional Catheterization Committee and Council on Clinical Cardiology and the American College of Clinical Pharmacy’s Cardiology Practice Research Network (pp. 1537-56). The recommendations call for greater involvement by pharmacists in assuring rational drug therapy in this setting: “Significant advances in pharmacotherapy for patients undergoing PCI have occurred during the past decade, including the introduction and approval of new antithrombin and antiplatelet therapies, as well as modifications in dosing, administration, and/or duration of older pharmacotherapy regimens. Also, off-label (i.e., not approved by the United States Food and Drug Administration) use of certain agents has become common. Given the novel nature of these agents and the nuances of therapy, the pharmacist and other health care professionals should play an integral role in collaboration with interventional cardiologists in development of hospital protocols, determination of appropriate agent selection, assessment of patient renal function and hematologic status, dosing, and monitoring for adverse effects.” (S. A. Spinler, U. Sciences in Philadelphia)
Epoetin Responses: Epoetin 40,000 units administered twice weekly provided no greater erythropoietic responses than did once-weekly doses (pp. 1587-94). Among 60 patients who were evaluated on days 7 and 14, reticulocyte counts and hemoglobin concentrations were not significantly different between those on once- versus twice-weekly injections. (M. Darveau, Hotel-Dieu de Levis, Levis, Quebec, Canada; martin_darveau@ssss.gouv.qc.ca)

>>>PNN NewsWatch
* A recall announced yesterday by FDA affects some 11 million bottles of store-brand acetaminophen distributed nationally in the U.S., including many large retailers. Conducted by Perrigo Company of Allegan, Mich., the recall includes 383 lots of acetaminophen 500 mg caplets and resulted from presence of small metal fragments found in a few of these caplets. No illness or injuries related to this problem have been reported, and FDA believes the probability of serious adverse health consequences is remote. If a consumer were to swallow a caplet containing metal fragments, it could cause minor stomach discomfort and/or possible cuts to the mouth or throat. Consumers should consult their physician if they suspect they have been harmed by use of this product. More information about the store brands involved and lot numbers is available on the FDA Web site, and consumers can call Perrigo’s Consumer Affairs Department at 877-546-0454 for further instructions. Any adverse reactions experienced with the use of this product should be reported to Perrigo at the above number and the FDA’s MedWatch Program by phone at 800/FDA-1088, by fax at 800/FDA-0178, or on the MedWatch Web site.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Nov. 13, 2006 * Vol. 13, No. 218
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Nov. 11 issue of Lancet (www.thelancet.com; 2006; 368).
Lifestyle Interventions in Diabetes: Counseling of overweight patients with impaired glucose tolerance on lifestyle interventions had sustained benefits on weight loss, incidence of diabetes, and other clinical indicators (pp. 1673-9). Interventions were provided to 172 men and 350 women for a median of 4 years, and those free of diabetes at that point were followed for a median of 3 more years. Compared with control interactions, intensive lifestyle interventions produced these results: “During the total follow-up, the incidence of type 2 diabetes was 4.3 and 7.4 per 100 person–years in the intervention and control group, respectively (log-rank test p = 0.0001), indicating 43% reduction in relative risk. The risk reduction was related to the success in achieving the intervention goals of weight loss, reduced intake of total and saturated fat and increased intake of dietary fibre, and increased physical activity. Beneficial lifestyle changes achieved by participants in the intervention group were maintained after the discontinuation of the intervention, and the corresponding incidence rates during the post-intervention follow-up were 4.6 and 7.2 (p = 0.0401), indicating 36% reduction in relative risk.” (J. Lindström, National Public Health Inst., Helsinki, Finland; jaana.lindstrom@ktl.fi)

>>>BMJ Highlights
Source:
Early-release articles from BMJ (www.bmj.org; 2006; 333).
CEA of Simvastatin: A cost-effectiveness analysis of treatment of 20,536 men and women with coronary disease, other occlusive arterial diseases, or diabetes shows that statin treatment is worth the money in a broader population than routinely treated at present (doi: 10.1136/bmj.38993.731725.BE). “At the April 2005 UK price of 4.87 pounds (7 euros; $9) per 28 day pack of generic 40 mg simvastatin, lifetime treatment was cost saving in most age groups and vascular disease risk groups studied directly,” the authors report. “Gains in life expectancy and cost savings decreased with increasing age and with decreasing risk of vascular disease. People aged 40–49 with 5 year risks of major vascular events of 42% and 12% at start of treatment gained 2.49 and 1.67 life years, respectively. Treatment with statins remained cost saving or cost less than 2,500 pounds per life year gained in people as young as 35 years or as old as 85 with 5 year risks of a major vascular event as low as 5% at the start of treatment.” (Heart Protection Study Collaborative Group, hps@ctsu.ox.ac.uk)
Antibiotics in CAP: Among patients hospitalized in nonintensive-care settings for severe community-acquired pneumonia, early switches from intravenous to oral antibiotics was safe and decreased length of stay by 2 days, investigators report (doi: 10.1136/bmj.38993.560984.BE). At five teaching hospitals and two university medical centers in the Netherlands, 3 days of treatment with intravenous antibiotics were followed randomly by oral antibiotics or 7 days of intravenous antibiotics in patients who were clinically stable. Results showed: “302 patients were randomised (mean age 69.5 (standard deviation 14.0), mean pneumonia severity score 112.7 (26.0)). 37 patients were excluded from analysis because of early dropout before day 3, leaving 265 patients for intention to treat analysis. Mortality at day 28 was 4% in the intervention group and 6% in the control group (mean difference 2%, 95% confidence interval –3% to 8%). Clinical cure was 83% in the intervention group and 85% in the control group (2%, –7% to 10%). Duration of intravenous treatment and length of hospital stay were reduced in the intervention group, with mean differences of 3.4 days (3.6 (1.5) v 7.0 (2.0) days; 2.8 to 3.9) and 1.9 days (9.6 (5.0) v 11.5 (4.9) days; 0.6 to 3.2), respectively.” (A. I. M. Hoepelman, U. Med. Ctr., Utrecht, the Netherlands; i.m.hoepelman@umcutrecht.nl)

>>>PNN JournalWatch
* Pediatric Cyanide Poisoning: Causes, Manifestations, Management, and Unmet Needs, in Pediatrics, 2006; 118: 2146–58. Reprints: http://pediatrics.aappublications.org/cgi/content/abstract/118/5/2146; R. J. Geller, Emory U., Atlanta.
* Therapy for Lyme Arthritis: Strategies for the Treatment of Antibiotic-Refractory Arthritis, in
Arthritis & Rheumatism, 2006; 54: 3079–86. Reprints: www3.interscience.wiley.com/cgi-bin/abstract/113383826/ABSTRACT; A. C. Steere, Mass. Genl. Hosp., Boston.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Nov. 14, 2006 * Vol. 13, No. 219
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Nov. 13 issue of the Archives of Internal Medicine (www.archinternmed.com; 2006; 166).
Guillain-Barré Syndrome After Influenza Vaccination: The risk of hospitalization for Guillain-Barré syndrome is slightly but significantly elevated in the months after influenza vaccination, according to one of two studies from Ontario (pp. 2217-21). Researchers first used population-based health care data to determine the rate of GBS hospitalization in the 43 weeks after probable influenza vaccination, which was assumed to occur in Oct. and Nov. of study years. A time-series analysis was then used to determine whether GBS hospitalizations increased following implementation of a universal influenza vaccination program in 2000. Results showed the following: “From April 1, 1992, to March 31, 2004, we identified 1,601 incident hospital admissions because of GBS in Ontario. In 269 patients, GBS was diagnosed within 43 weeks of vaccination against influenza. The estimated relative incidence of GBS during the primary risk interval (weeks 2 through 7) compared with the control interval (weeks 20 through 43) was 1.45 (95% confidence interval, 1.05–1.99; P = .02). This association persisted in several sensitivity analyses using risk and control intervals of different durations. However, a separate time-series analysis demonstrated no evidence of seasonality and revealed no statistically significant increase in hospital admissions because of GBS after the introduction of the universal influenza immunization program.”
The authors conclude that these findings should be interpreted cautiously and risk versus benefit of influenza vaccination needs to be considered for individual patients. However, the group adds, “Individuals who receive the influenza vaccine should be advised of the potential risk for GBS, particularly in light of the serious consequences of the illness. Our findings also suggest that it would be prudent to implement active surveillance for GBS as an essential component of any mass vaccination program that is instituted against pandemic influenza.” (K. Wilson, Toronto Genl. Hosp., Toronto)
Blood Pressure v. Blood Glucose: The risk of developing diabetes is higher among hypertensive patients taking chlorthalidone, compared with other antihypertensive agents, but fasting glucose levels in these patients typically increase regardless of the blood pressure medication being taken (pp. 2191-201). This conclusion comes from a post hoc analysis of data from ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial), which showed these results for 18,411 nondiabetic participants who were monitored during a median of 4.9 years of treatment with chlorthalidone, amlodipine, or lisinopril: “Mean FG levels increased during follow-up in all treatment groups. At year 2, those randomized to the chlorthalidone group had the greatest increase (+8.5 mg/dL [0.47 mmol/L] vs +5.5 mg/dL [0.31 mmol/L] for amlodipine and +3.5 mg/dL [0.19 mmol/L] for lisinopril). The odds ratios for developing DM with lisinopril (0.55 [95% confidence interval, 0.43-0.70]) or amlodipine (0.73 [95% confidence interval, 0.58-0.91]) vs chlorthalidone at 2 years were significantly lower than 1.0 (P < .01). There was no significant association of FG level change at 2 years with subsequent coronary heart disease, stroke, cardiovascular disease, total mortality, or end-stage renal disease. There was no significant association of incident DM at 2 years with clinical outcomes, except for coronary heart disease (risk ratio, 1.64; P = .006), but the risk ratio was lower and nonsignificant in the chlorthalidone group (risk ratio, 1.46; P = .14).” (B. R. Davis, U. Texas Sch. of Public Health, Houston; barry.r.davis@uth.tmc.edu)

>>>PNN NewsWatch
* A pharmacy care program at Walter Reed Army Med. Ctr. significantly improved patient adherence and blood pressures, according to an article released by JAMA yesterday in advance of publication. More details will be in tomorrow’s PNN.
* Self-injury and delirium among patients, particularly children, taking
oseltamivir (Tamiflu, Roche) have been added to product labeling by FDA. Most reports of the problems have come from Japan (see PNN, Nov. 18, 2005).

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Nov. 15, 2006 * Vol. 13, No. 220
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Early-release articles and the Nov. 15 issue of JAMA (www.jama.com; 2006; 296).
Pharmacy Care for Chronic Conditions: Medication adherence and persistence and blood pressure were improved during provision of pharmacy care services to 200 elderly patients (77% men; 92% with coronary risk factors; 81% with hyperlipidemia) taking at least four long-term medications (doi: 10.1001/jama.296.21.joc60162). Following provision of standardized medication education, regular follow-up by pharmacists, and medications dispensed in time-specific packs for 6 months, patients were randomized to usual pharmacy services or continued pharmacy care, and the authors observed these results: “Mean (SD) baseline medication adherence was 61.2% (13.5%). After 6 months of intervention, medication adherence increased to 96.9% (5.2%; P < .001) and was associated with significant improvements in systolic BP (133.2 [14.9] to 129.9 [16.0] mm Hg; P = .02) and LDL-C (91.7 [26.1] to 86.8 [23.4] mg/dL; P = .001). Six months after randomization, the persistence of medication adherence decreased to 69.1% (16.4%) among those patients assigned to usual care, whereas it was sustained at 95.5% (7.7%) in pharmacy care (P < .001). This was associated with significant reductions in systolic BP in the pharmacy care group (–6.9 mm Hg; 95% CI, –10.7 to –3.1 mm Hg) vs the usual care group (–1.0 mm Hg; 95% CI, –5.9 to 3.9 mm Hg; P = .04), but no significant between-group differences in LDL-C levels or reductions.” (A. J. Taylor, Walter Reed Army Med. Ctr., Washington, D.C.; allen.taylor@na.amedd.army.mil)
Pharmacists can play a key role in meeting the “challenges for improving medication adherence,” writes an editorialist (doi: 10.1001/jama.296.21.jed60074), adding: “Multifaceted interventions that incorporate structural and counseling components and include appropriately skilled and motivated pharmacists appear useful to promote medication adherence and persistence. Future studies are needed to confirm that interventions incorporating these components will result in increased and sustained patient adherence and, better yet, will improve outcomes.” (R. J. Simpson, Jr.,
rsimpson@med.unc.edu)
Tolterodine/Tamsulosin for Urinary/Bladder Symptoms: Among men with moderate to severe lower urinary tract symptoms including overactive bladder, tolterodine extended release plus tamsulosin for 12 weeks provided significant benefits, according to a trial conducted at 95 U.S. urology clinics (pp. 2319-28). “A total of 172 men (80%) receiving tolterodine ER plus tamsulosin reported treatment benefit by week 12 compared with 132 patients (62%) receiving placebo (P < .001), 146 (71%) receiving tamsulosin (P = .06 vs placebo), or 135 (65%) receiving tolterodine ER (P = .48 vs placebo). Patients receiving tolterodine ER plus tamsulosin compared with placebo experienced significant reductions in urgency urinary incontinence (–0.88 vs –0.31, P = .005), urgency episodes without incontinence (–3.33 vs –2.54, P = .03), micturitions per 24 hours (–2.54 vs –1.41, P < .001), and micturitions per night (–0.59 vs –0.39, P < .02). Patients receiving tolterodine ER plus tamsulosin demonstrated significant improvements on the total International Prostate Symptom Score (–8.02 vs placebo, –6.19, P = .003) and QOL item (–1.61 vs –1.17, P = .003). All interventions were well tolerated. The incidence of acute urinary retention requiring catheterization was low (tolterodine ER plus tamsulosin, 0.4%; tolterodine ER, 0.5%; tamsulosin, 0%; and placebo, 0%).” (S. A. Kaplan, kaplans@med.cornell.edu)
Commenting on men’s health, the theme of this issue of
JAMA, editorialists advocate health professionals being role models for patients (pp. 2373-5): “Male physicians ... should consider making a pledge to adopt well-established components of a healthy lifestyle, including a more healthful diet, regular exercise, smoking cessation, weight control, and stress reduction. Despite increased professional pressures and clinical demands, male physicians must somehow find the time and devote the effort to staying healthy—for their families, for their significant others, and for themselves. And in doing so, what better way to set an example for their male patients about what it means to be a healthy man.” (P. B. Fontanarosa, phil.fontanarosa@jama-archives.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
Nov. 16, 2006 * Vol. 13, No. 221
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Nov. 16 issue of the New England Journal of Medicine (content.nejm.org; 2006; 355).
Target Hemoglobin Level in Kidney Disease: An open-label trial supports a target hemoglobin level of 11.3 g/dL, finding that it was less risky and provided equivalent quality of life as 13.5 g/dL in 1,432 patients with chronic kidney disease (pp. 2085-98). Patients randomly received epoetin alfa doses over a median of 16 months to one of those two hemoglobin levels, with these results: “A total of 222 composite events occurred: 125 events in the high-hemoglobin group, as compared with 97 events in the low-hemoglobin group (hazard ratio, 1.34; 95% confidence interval, 1.03 to 1.74; P = 0.03). There were 65 deaths (29.3%), 101 hospitalizations for congestive heart failure (45.5%), 25 myocardial infarctions (11.3%), and 23 strokes (10.4%). Seven patients (3.2%) were hospitalized for congestive heart failure and myocardial infarction combined, and one patient (0.5%) died after having a stroke. Improvements in the quality of life were similar in the two groups. More patients in the high-hemoglobin group had at least one serious adverse event.” (A. K. Singh, asingh@partners.org)
Commenting on this and a second study showing that early complete correction of anemia of chronic kidney disease did not reduce cardiovascular risks (pp. 2071-84; T. B. Drüeke, Université Paris-V, Paris;
drueke@necker.fr), editorialists write of these “payoffs and problems” concerning correction of anemia (pp. 2144-6): “Taken together, these two studies suggest caution in the full correction of anemia in patients with chronic kidney disease. Currently, there are several additional multicenter trials of complete as compared with partial correction of anemia in patients with chronic kidney disease.... Although we need more information about the ideal target level and should consider the present guidelines incomplete, it seems wisest to refrain from complete correction of anemia in persons with chronic kidney disease.” (G. Remuzzi, Mario Negri Inst. for Pharmacological Research, Bergamo, Italy)
Tolvaptan for Hyponatremia: The oral vasopressin V2-receptor antagonist tolvaptan lowered serum sodium levels acutely and over a 30-day period in 448 patients with euvolemic or hypervolemic hyponatremia (pp. 2099-112). Compared with placebo, tolvaptan 15 mg daily with as-needed increases to 30 or 60 mg/day produced these results: “Serum sodium concentrations increased more in the tolvaptan group than in the placebo group during the first 4 days (P < 0.001) and after the full 30 days of therapy (P < 0.001). The condition of patients with mild or marked hyponatremia improved (P < 0.001 for all comparisons). During the week after discontinuation of tolvaptan on day 30, hyponatremia recurred. Side effects associated with tolvaptan included increased thirst, dry mouth, and increased urination. A planned analysis that combined the two trials showed significant improvement from baseline to day 30 in the tolvaptan group according to scores on the Mental Component of the Medical Outcomes Study 12-item Short-Form General Health Survey.” (R. W. Schrier, U. Colorado Health Sci. Ctr., Denver; robert.schrier@uchsc.edu)
An editorialist notes the “progress and promise” of vasopressin antagonists, including the approved injectable agent conivaptan (Vaprisol, Astellas; see
PNN, Jan. 4), and provides this current assessment (pp. 2146-8): “The study is encouraging in terms of the efficacy of tolvaptan as a V2-receptor antagonist and its use, at least during a limited period, in the outpatient setting. At the same time, it is clear that careful oversight of the use of this agent is required, not only by means of frequent clinic visits and measurement of serum sodium, but also through daily measurement of body weight by patients. An important question is the extent to which added benefits might be realized if the V1A-mediated actions of vasopressin were brought under control with the use of combined V1A/V2-receptor antagonists. This question remains to be answered in future studies of this promising new generation of receptor antagonists.” (R. M. Hays, Albert Einstein Coll. of Med., Bronx, 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
Nov. 17, 2006 * Vol. 13, No. 222
Providing news and information about medications and their proper use

>>>Circulation Highlights
Source:
Early-release articles from and Nov. 14 issue of Circulation (circ.ahajournals.org; 2006; 114).
Antidote-Controlled Anticoagulation: A novel RNA aptamer and its complementary oligonucleotide antidote were safely used as an anticoagulant system in a placebo-controlled trial of 85 healthy volunteers (doi: 10.1161/CIRCULATIONAHA.106.668434). The anticoagulation system (REG1, Regado Biosciences) was developed using a protein-binding oligonucleotide to factor IXa (drug, RB006) and its complementary oligonucleotide antidote (RB007), the authors report. Volunteers received a bolus of drug or placebo followed by a bolus of antidote or placebo 3 hours later, with these results: “No significant differences were found in median hemoglobin, platelet, creatinine, or liver function studies. There were no significant bleeding signals associated with RB006, and overall, both drug and antidote were well tolerated. One serious adverse event, an episode of transient encephalopathy, occurred in a subject receiving the low intermediate dose of RB006. The subject’s symptoms resolved rapidly, and no further sequelae occurred. A predictable dose–pharmacodynamic response, reflected in activated partial thromboplastin time measurements, was seen after administration of the bolus of drug, with a clear correlation between the peak posttreatment activated partial thromboplastin time and post hoc weight-adjusted dose of drug (correlation coefficient, 0.725; P < 0.001). In subjects treated with drug, antidote administration reversed the pharmacological activity of the drug, with a rapid (mean time, 1 to 5 minutes across all dose levels) and sustained return of activated partial thromboplastin time to within the normal range. The activated clotting time followed a similar anticoagulant response and reversal pattern. As anticipated, prothrombin time remained unchanged compared with baseline.” (C. K. Dyke, Duke Clin. Res. Inst., Durham, N.C.; cdyke@alaskaheart.com)
ACE Inhibition During High-Dose Chemotherapy: Early treatment with enalapril prevented development of late cardiotoxicity secondary to high-dose chemotherapy among 114 high-risk patients (doi: 10.1161/CIRCULATIONAHA.106.635144). Study participants had increased troponin I levels soon after HDC started. Beginning 1 month after HDC began and continuing for 1 year, they received either enalapril 20 mg/day or usual care. The authors report these results based on a primary end point of absolute decrease of more than 10 percentage units in left ventricular ejection fraction that places the patient below the normal limit value: “A significant reduction in left ventricular ejection fraction and an increase in end-diastolic and end-systolic volumes were observed only in untreated patients. According to the Kaplan–Meier analysis, the incidence of the primary end point was significantly higher in control subjects than in the angiotensin-converting enzyme inhibitor group (43% versus 0%; P < 0.001).” (D. Cardinale, European Institute of Oncology; daniela.cardinale@ieo.it)
Free Fatty Acids & the Failing Heart: Use of the lipolysis inhibitor acipimox to lower free fatty acids was unexpectedly detrimental in a group of 18 nondiabetic patients with idiopathic dilated cardiomyopathy (pp. 2130-7). The patients with heart failure and 8 matched healthy control patients all had reduced cardiac work after serum FFA were acutely depleted. “In healthy hearts, this is accompanied by parallel decrease in oxidative metabolism, and myocardial efficiency is preserved,” the researchers write. “In failing hearts, FFA depletion did not downregulate oxidative metabolism, and myocardial efficiency deteriorated. Thus, failing hearts are unexpectedly more dependent than healthy hearts on FFA availability. We propose that both glucose and fatty acid oxidation are required for optimal function of the failing heart.” (J. Knuuti, Turku PET Ctr., Turku, Finland; juhani.knuuti@utu.fi)

>>>PNN NewsWatch
* In response to the epoetin alfa study in yesterday’s New England Journal of Medicine (see PNN, Nov. 16), FDA issued an alert emphasizing that clinicians should not exceed the target hemoglobin recommendations in the product labeling for Procrit, Epogen, and Aranesp (12 g/dL).


PNN Pharmacotherapy Line is published via e-mail each business day except 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
Nov. 20, 2006 * Vol. 13, No. 223
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Nov. 18 issue of Lancet (www.thelancet.com; 2006; 368).
Thrombotic Events with Etoricoxib Versus Diclofenac: In the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) trial, thrombotic cardiovascular events occurred just as frequently in patients with arthritis receiving etoricoxib as among those taking diclofenac (pp. 1771-81). Etoricoxib 60 or 90 mg daily was compared with diclofenac 150 mg daily in patients as follows: “34,701 patients (24,913 with osteoarthritis and 9,787 with rheumatoid arthritis) were enrolled. Average treatment duration was 18 months (SD 11.8). 320 patients in the etoricoxib group and 323 in the diclofenac group had thrombotic cardiovascular events, yielding event rates of 1.24 and 1.30 per 100 patient-years and a hazard ratio of 0.95 (95% CI 0.81–1.11) for etoricoxib compared with diclofenac. Rates of upper gastrointestinal clinical events (perforation, bleeding, obstruction, ulcer) were lower with etoricoxib than with diclofenac (0.67 vs 0.97 per 100 patient–years; hazard ratio 0.69 [0.57–0.83]), but the rates of complicated upper gastrointestinal events were similar for etoricoxib (0.30) and diclofenac (0.32).” (C. P. Cannon, cpcannon@partners.org)
EC in Scotland: Use of emergency contraception is low among women in Scotland, leading researchers to conclude that increased emphasis is needed on regular means of contraception in this country (pp. 1782-7). Among 2,908 women provided antenatal care and 907 provided abortion services, the investigators found these behaviors and attitudes: “814 (89.7%) of 907 pregnancies among women requesting abortion were unintended compared with only 250 (8.6%) among 2,908 women who planned to continue pregnancy. However, only 1,909 (65.6%) of continuing pregnancies were intended. The rest of the women were ambivalent about pregnancy intention. In women who continued with their pregnancies intendedness was related to age, with unintended pregnancy most probable in young women (p < 0.0001). Emergency contraception was used by 113 (11.8%) of women who requested abortion but only 40 (1%) of those planning to continue pregnancy. In those whose pregnancy was continuing, the proportions reporting use of emergency contraception were higher in young women than in older women and in those who reported that their pregnancies were unintended than in those who meant to become pregnant (both p < 0.0001).” (A. Glasier, NHS Lothian Family Planning Svc., Edinburgh; Anna.Glasier@lpct.scot.nhs.uk)

>>>BMJ Highlights
Source:
Early-release article from BMJ (www.bmj.org; 2006; 333).
European Case Management for Frail Elderly: The Evercare approach to case management of frail elderly patients failed to reduce hospital admissions at nine primary care trusts in England in 2003–05 (doi: 10.1136/bmj.39020.413310.55). Focusing on about 7,000 patients considered to be at high risk for emergency admission, case management through advanced primary nurses had no significant effect on rates of emergency admissions, emergency bed–days, or mortality. The authors predict similar results will be found with a recently instituted program that uses “community matrons” for similar interventions. (M. Roland, U. Manchester, Manchester; m.roland@manchester.ac.uk)

>>>PNN JournalWatch
* Restless Legs Syndrome: A Clinical Update, in Chest, 2006; 130: 1596–604. Reprints: www.chestjournal.org/cgi/content/abstract/130/5/1596; C. E. Gamaldo, Johns Hopkins U., Baltimore; cgamald1@jhmi.edu
* Whooping Cough: The Current Scene, in
Chest, 2006; 130: 1547–553. Reprints: www.chestjournal.org/cgi/content/abstract/130/5/1547; M. Singh, Post Graduate Inst. of Med. Educ. and Res., Chandigarh, India; kritmeds@gmail.com
* The Practice of Travel Medicine: Guidelines by the Infectious Diseases Society of America, in
Clinical Infectious Diseases, 2006; 43: 1499–539. Reprints: www.journals.uchicago.edu/CID/journal/issues/v43n12/40908/40908.html; D. R. Hill, Natl. Travel Health Network and Ctr., Hosp. for Tropical Dis., London; david.hill@uclh.org
* Aromatase Inhibitors and Bone Health in Women With Breast Cancer, in
Journal of Clinical Oncology, 2006; 24: 5305–12. Reprints: www.jco.org/content/vol24/issue33/ - REVIEW_ARTICLE; A. J. Chien.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Nov. 21, 2006 * Vol. 13, No. 224
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Nov. 21 issue of the Annals of Internal Medicine (www.annals.org; 2006; 145).
Pharmacogenomics Review: Moving from the study of variations in single genes (pharmacogenetics) to the cataloguing of variants across human genomes (pharmacogenomics) will require overcoming many challenges, authors write on behalf of the Pharmacogenetics Research Network (pp. 749-57). “Pharmacogenomics is a young field that holds considerable promise of contributing to our understanding of the mechanisms underlying variability in human physiology and its response to drug therapy, with the potential to improve therapy,” the group concludes. “Indeed, studies in the field have discovered new biological mechanisms and have identified certain molecules, such as CYP2D6 or KCNH2, that are now routinely considered in drug development to enhance drug safety and are identifying new targets for drug action. Ultimately, identification of DNA variants before prescribing medication may become a routine feature of any patient–physician encounter. Although there are many challenges to be overcome in the implementation of pharmacogenetic vision in clinical practice, potential solutions are also evolving rapidly.” (D. M. Roden, dan.roden@vanderbilt.edu)
Clostridium difficile Epidemic: Cases of enteric disease associated with a more virulent strain of Clostridium difficile have become increasingly common, and clinicians need to respond with proven strategies, an author writes (pp. 758-64): “During the recent past (2003 to 2006), C. difficile has been more frequent, more severe, more refractory to standard therapy, and more likely to relapse. This pattern is widely distributed in the United States, Canada, and Europe and is now attributed to a new strain of C. difficile designated BI, NAP1, or ribotype 027 (which are synonymous terms). This strain appears more virulent, possibly because of production of large amounts of toxins, and fluoroquinolones are now major inducing agents along with cephalosporins, which presumably reflects newly acquired in vitro resistance and escalating rates of use. The recent experience does not change principles of management of the individual patient, but it does serve to emphasize the need for better diagnostics, early recognition, improved methods to manage severe disease and relapsing disease, and greater attention to infection control and antibiotic restraint.” (J. G. Bartlett, Johns Hopkins U., Baltimore; jb@jhmi.edu)
Dementia Guidelines: Substantial improvements in quality of care for patients with dementia resulted from a disease management program that used 23 guideline recommendations (pp. 713-26). Over periods of at least 12 months at 18 primary care clinics in southern California, 408 patients had these outcomes: “The mean percentage of per-patient guideline recommendations to which care was adherent was significantly higher in the intervention group than in the usual care group (63.9% vs. 32.9%, respectively; adjusted difference, 30.1% [95% CI, 25.2% to 34.9%]; P < 0.001). Participants who received the intervention had higher care quality on 21 of 23 guidelines (P ≤ 0.013 for all), and higher proportions received community agency assistance (P ≤ 0.03) than those who received usual care. Patient health-related quality of life, overall quality of patient care, caregiving quality, social support, and level of unmet caregiving assistance needs were better for participants in the intervention group than for those in the usual care group (P < 0.05 for all). Caregiver health-related quality of life did not differ between the 2 groups.” (B. G. Vickrey, bvickrey@ucla.edu)
Commenting on this and a related study (pp. 727-38; R. Schulz,
schulz@pitt.edu), editorialists envision “better approaches for dementia care” (pp. 780-1): “The need for these changes is compelling, but [these patients] need advocates and champions. Patients with dementia will probably not be forming a lobby anytime soon, and their caregivers are too busy. It is time for the medical profession to advocate on their behalf.” (K. E. Covinsky, ken.covinsky@ucsf.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Nov. 22, 2006 * Vol. 13, No. 225
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Nov. 22 issue of JAMA (www.jama.com; 2006; 296).
Botulism Following Cosmetic Injections: Four laboratory-confirmed, symptomatic cases of botulism resulted from cosmetic injections of an unlicensed botulinum preparation (pp. 2476-9). All four patients had been injected with a highly concentrated preparation of botulinum toxin A, intended for laboratory research, labeled accordingly, and not licensed or intended for human use. Clinic staff had diluted a 100-mcg vial of pure neurotoxin with diluent and drew up the resulting solution into syringes for clinical use. The physician working at the clinic administered 4 case–patients (including himself) 4 to 6 injections of this toxin solution in the facial area, with these results: “Clinical characteristics of the 4 case–patients were consistent with those of naturally occurring botulism. All case–patients had been injected with a highly concentrated, unlicensed preparation of botulinum toxin A and may have received doses 2,857 times the estimated human lethal dose by injection. Pretreatment serum toxin levels in 3 of the 4 case–patients were equivalent to 21 to 43 times the estimated human lethal dose; pretreatment serum from the fourth epidemiologically linked case–patient was not available. A 100-mcg vial of toxin taken from the same manufacturer’s lot as toxin administered to the case–patients contained a toxin amount sufficient to kill approximately 14,286 adults by injection if disseminated evenly.” (D. S. Chertow, Fla. Dept. of Health, Tallahassee; sindia4@hotmail.com)
Surgery for Lumbar Disk Herniation: Patients with lumbar disk herniation who had surgery or nonoperative treatments showed similar levels of improvement in the reduction of pain over a 2-year period, according to results of the Spine Patient Outcomes Research Trial (SPORT; pp. 2441-50). In a companion article, detailing the observational arm of SPORT, patients with persistent sciatica who had diskectomy or usual care reported improvement over 2 years, although patients who chose surgery experienced greater improvement (pp. 2451-9) (J. N. Weinstein, james.n.weinstein@dartmouth.edu)
In two accompanying editorials, clinicians debate what future research is needed and what procedures should be recommended to patients with lumbar disk herniation. One writer calls for direct comparison of actual with sham surgical procedures in a blinded trial because of the need to rely on subjective outcomes in these studies (pp. 2483-5; D. R. Flum,
daveflum@u.washington.edu).
The second editorialist maintains that the SPORT findings should be incorporated now into a more cautious approach to care of these patients (pp. 2485-7): “These findings suggest that in most cases there is no clear reason to advocate strongly for surgery apart from patient preference. For the patient with emotional, family, and economic resources to handle mild or moderate sciatica, surgery may have little to offer. In fact, this was the profile of many patients who opted against surgery in the SPORT trial: older participants with higher income and higher education but with milder pain and disability. Furthermore, the SPORT data clearly show that the risk of serious problems (neurologic deterioration, cauda equina syndrome, or progression of spinal instability) when receiving nonoperative care is extremely small. The fear of many patients and surgeons that not removing a large disk herniation will likely have catastrophic neurologic consequences is simply not borne out. Thus, these data help both clinicians and patients make better informed decisions based each patient’s needs and expectations.” (E. Carragee,
carragee@stanford.edu)

>>>PNN NewsWatch
* Responding to FDA’s delay of a decision on Novartis’s DPP-4 inhibitor, vildagliptin (Galvus), because of concerns about skin lesions in monkeys, Merck released details of preclinical studies it conducted with sitagliptin (Januvia) and a nonselective compound. Merck’s conclusion is that necrotic skin lesions observed are not a DPP-4 inhibitors class effect but rather “off-target activity not observed with sitagliptin.”
*
PNN will not be published on Thurs. and Fri., Nov. 23–24, Thanksgiving.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Nov. 27, 2006 * Vol. 13, No. 226
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Nov. 23 issue of the New England Journal of Medicine (www.nejm.org; 2006; 355).
Aprotinin & Drug Safety: “Full disclosure and a transparent process are essential in evaluating the findings of all studies germane to drug safety and the public health,” concludes the chair of FDA’s Cardiovascular and Renal Drugs Advisory Committee (pp. 2171-3). Writing in a private capacity, the author recounts the events that led to the FDA panel deciding on Sept. 21 that “there was insufficient evidence to require an additional warning on aprotinin’s labeling and agreed that the clinical data supported an acceptable safety and efficacy profile for aprotinin.” However, the author adds, “Days after the committee meeting, the FDA was made aware of additional observational data from the sponsor that had not been presented at the meeting. Bayer evidently had commissioned an observational study involving 67,000 patients who were given aprotinin. According to the initial FDA review of data from that study, aprotinin may be associated with ‘increased risk for death, kidney failure, congestive heart failure and stroke.’ The failure of Bayer to disclose all its data on aprotinin seriously undermined the advisory committee process and hindered the safety review.” (W. R. Hiatt, U. Colorado, Denver)
Noting that September 30 is becoming “a day of infamy for drug safety” (2004, Vioxx market withdrawal; 2006,
New York Times article on the above Bayer situation), a commentator adds these observations (pp. 2169-71): “On September 30, 1982, six people in the Chicago area died after taking acetaminophen (Tylenol) that had been laced with cyanide. The tragedy riveted the country’s attention for months. We should be able to muster at least a fraction of that concern to address more clinically relevant adverse drug effects that could sicken or kill thousands of patients. How can we capture such interest in less sensational problems of medication safety? A good start would be to make a national commitment to publicly supported studies of drug risks so that no company could take possession of critical findings for its own purposes. The results of that research could be discussed openly at an annual conference on the risks and benefits of drugs. To keep everyone’s attention focused on medication safety, perhaps the conference could be held every year on September 30.” (J. Avorn, Brigham and Women’s Hosp., Boston)

>>>Lancet Highlights
Source:
Nov. 25 issue of Lancet (www.thelancet.com; 2006; 368).
Timing of Ancrod in Stroke: New research indicates that ancrod should not be recommended for use in acute ischemic stroke beyond a 3-hour window after symptom onset (pp. 1871-8). The European Stroke Treatment with Ancrod Trial sought to establish effectiveness of the snake-venom derivative when administered within 6 hours of stroke onset, but the 1,222 study participants had no significant difference in the primary study outcome of functional success at 3 months, as defined by survival, a Barthel Index of 95 or 100, or return to prestroke level (42% with ancrod versus 42% with placebo; P = 0.94; odds ratio, 0.99; 95% CI, 0.76–1.29). (M. G. Hennerici, U. Heidelberg, Mannheim, Germany; Hennerici@neuro.ma.uni-heidelberg.de)

>>>PNN JournalWatch
* Uninsured Americans and the New Democratic Congress, in BMJ, 2006; doi: 10.1136/bmj.39042.375544.BE. Reprints: www.bmj.com/cgi/rapidpdf/bmj.39042.375544.BEv1; U. E. Reinhardt, reinhardt@princeton.edu
* Employment-Based Health Insurance: Past, Present, And Future, in
Health Affairs, 2006; 25: 1538–47. Reprints: http://content.healthaffairs.org/cgi/content/abstract/25/6/1538; A. C. Enthoven.
* Practice Parameter: Diagnostic Assessment of the Child with Status Epilepticus (An Evidence-Based Review), in
Neurology, 2006; 67: 1542–50. Reprints: www.neurology.org/cgi/content/abstract/67/9/1542; American Academy of Neurology, guidelines@aan.com
* Pharmacologic Rationale for Treating Allergic and Nonallergic Rhinitis, in
Journal of Allergy and Clinical Immunology, 2006; 118: 985–96. Reprints: www.jacionline.org/article/PIIS0091674906013807/abstract; A. N. Greiner, Allergy and Asthma Medical Group and Res. Ctr., San Diego
* Eosinophilic Esophagitis: Pathogenesis, Genetics, and Therapy, in
Journal of Allergy and Clinical Immunology, 2006; 118: 1054–9. Reprints: www.jacionline.org/article/PIIS0091674906015909/abstract; M. Rothenberg, Children’s Hosp., Cincinnati.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Nov. 28, 2006 * Vol. 13, No. 227
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Nov. 27 issue of the Archives of Internal Medicine (www.archinternmed.com; 2006; 166).
Nontreatment of LUTS: Lower urinary tract symptoms went virtually untreated among a population of 5,506 Massachusetts residents who participated in the Boston Area Community Health (BACH) survey (pp. 2381-7). Assessing symptoms and outcomes with the SF-12 and another instrument, the researchers found: “The overall prevalence of LUTS was 18.7% and increased with age (10.5% at age 30–39 years to 25.5% at age 70–79 years) but did not differ by sex or race/ethnicity. Quality of life was significantly reduced among those with LUTS, as measured by the bother of symptoms and the SF-12 component scores. Prevalence of prescription medication use for urinary symptoms was low even among participants with LUTS, with more than 90% of participants reporting no medication use.” (V. Kupelian, New England Research Institutes, Watertown, Mass.; vkupelian@neriscience.com)
Statins in Primary Prevention: HMG-CoA reductase inhibitors are effective means of preventing major coronary and cerebrovascular events in patients without pre-existing cardiovascular disease, but they do not reduce deaths from coronary heart disease or lower overall mortality, according to a meta-analysis (pp. 2307-13). In randomized controlled trials with follow-up of 1 year or more, more than 100 major CV events reported, and populations with more than 80% of participants free of CV disease, the researchers calculated these relative risks: “Seven trials with 42,848 patients were included. Ninety percent had no history of CV disease. Mean follow-up was 4.3 years. Statin therapy reduced the RR of major coronary events, major cerebrovascular events, and revascularizations by 29.2% (95% CI, 16.7%–39.8%) (P < .001), 14.4% (95% CI, 2.8%–24.6%) (P = .02), and 33.8% (95% CI, 19.6%–45.5%) (P < .001), respectively. Statins produced a nonsignificant 22.6% RR reduction in coronary heart disease mortality (95% CI, 0.56–1.08) (P = .13). No significant reduction in overall mortality (RR, 0.92 [95% CI, 0.84–1.01]) (P = .09) or increases in cancer or levels of liver enzymes or creatine kinase were observed.” (N. K. Choudhry, nchoudhry@partners.org)
Treating Depression Collaboratively: Compared with usual primary care management, collaborative approaches to management of depression are significantly more effective for improving outcomes in both short and longer terms, conclude authors of a cumulative meta-analysis and review (pp. 2314-21). Collaborative care included a range of interventions of varying intensity, the authors explain, ranging from simple telephone interventions to encourage medication adherence to more complex interventions that involve intensive follow-up and incorporate a form of structured psychosocial intervention. “We found 37 randomized studies including 12,355 patients with depression receiving primary care,” the investigators note. “Random effects meta-analysis showed that depression outcomes were improved at 6 months [with collaborative care] (standardized mean difference, 0.25; 95% confidence interval, 0.18–0.32), and evidence of longer-term benefit was found for up to 5 years (standardized mean difference, 0.15; 95% confidence interval, 0.001–0.31). When exploring determinants of effectiveness, effect size was directly related to medication compliance and to the professional background and method of supervision of case managers. The addition of brief psychotherapy did not substantially improve outcome, nor did increased numbers of sessions. Cumulative meta-analysis showed that sufficient evidence had emerged by 2000 to demonstrate the statistically significant benefit of collaborative care.” (S. Gilbody, U. York, York, U.K.; sg519@york.ac.uk)

>>>PNN NewsWatch
* FDA is warning prescribers to watch for drug interactions that can increase serum methadone levels and to caution patients on the drug to adhere closely to prescribe doses. The agency acted in the wake of reports of death and life-threatening adverse effects, including slowed or stopped breathing and cardiac arrhythmias.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Nov. 29, 2006 * Vol. 13, No. 228
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Dec. issue of Diabetes Care (care.diabetesjournals.org; 2006; 29).
Sitagliptin as Monotherapy: Compared with placebo, sitagliptin 100 and 200 mg administered orally once daily improved glycemic control in the fasting and postprandial states, improved measures of beta-cell function, and was well tolerated among 741 patients with type 2 diabetes (pp. 2632-37). Investigators report these results from the 24-week study: “Sitagliptin 100 and 200 mg produced significant (P < 0.001) placebo-subtracted reductions in A1C (–0.79 and –0.94%, respectively) and fasting plasma glucose (–1.0 mmol/l [–17.1 mg/dl] and –1.2 mmol/l [–21.3 mg/dl], respectively). Patients with baseline A1C 9% had greater reductions in placebo-subtracted A1C with sitagliptin 100 and 200 mg (–1.52 and –1.50%, respectively) than those with baseline A1C <8% (–0.57 and –0.65%) or 8 to <9.0% (–0.80 and –1.13%, respectively). In a meal tolerance test, sitagliptin 100 and 200 mg significantly decreased 2-h postprandial glucose (PPG) (placebo-subtracted PPG –2.6 mmol/l [–46.7 mg/dl] and –3.0 mmol/l [–54.1 mg/dl], respectively). Results for the above key efficacy parameters were not significantly different between sitagliptin doses. Homeostasis model assessment of beta-cell function and proinsulin-to-insulin ratio improved with sitagliptin. The incidence of hypoglycemia was similar, and overall gastrointestinal adverse experiences were slightly higher with sitagliptin. No meaningful body weight changes from baseline were observed with sitagliptin 100 (–0.2 kg) or 200 mg (–0.1 kg). The body weight change with placebo (–1.1 kg) was significantly (P < 0.01) different from that observed with sitagliptin.” (D. Williams-Herman, debora_williamsherman@merck.com)
Sitagliptin with Metformin: Added to ongoing metformin that was inadequate as monotherapy, sitagliptin 100 mg once daily was beneficial among 701 patients with type 2 diabetes (pp. 2638-43). “At week 24, sitagliptin treatment led to significant reductions compared with placebo in A1C (–0.65%), fasting plasma glucose, and 2-h postmeal glucose,” report the researchers. “Fasting insulin, fasting C-peptide, fasting proinsulin-to-insulin ratio, postmeal insulin and C-peptide areas under the curve (AUCs), postmeal insulin AUC–to–glucose AUC ratio, homeostasis model assessment of beta-cell function, and quantitative insulin sensitivity check index were significantly improved with sitagliptin relative to placebo. A significantly greater proportion of patients achieved an A1C <7% with sitagliptin (47.0%) than with placebo (18.3%). There was no increased risk of hypoglycemia or gastrointestinal adverse experiences with sitagliptin compared with placebo. Body weight decreased similarly with sitagliptin and placebo.” (G. Meininger, gary_meininger@merck.com)
Botulinum Toxin in Diabetic Neuropathy: Botulinum neurotoxin type A was beneficial for treating oropharyngeal dysphagia related to diabetic neuropathy in an uncontrolled study of 12 patients with type 2 diabetes (pp. 2650-3). Complete recovery was observed in 10 patients during the 24-week study, and the other 2 patients had clinical improvements that were evident within an average of 4 days. (D. Gullo, Garibaldi Hosp., Catania, Italy; damiano.gullo@poste.it)
Antihypertensive Drugs & Glucose Tolerance: Trandolapril/verapamil-SR was superior to a fixed-dose combination of losartan/hydrochlorothiazide in its effects on glucose tolerance in 240 patients with hypertension and impaired glucose tolerance (pp. 2592-7). Followed for up to 1 year, the patients had these outcomes in this open-label trial with a mean of 46.9 weeks of follow-up: “Changes at study end were noted in 2-h [oral glucose tolerance test] glucose (T/V –0.21 ± 0.36 vs. L/H +1.44 ± 0.36 mmol/l; P < 0.001) and insulin level (–30.13 ± 38.38 vs. +84.86 ± 38.33 pmol/l, respectively; P = 0.025). Worsening of insulin resistance occurred by week 12 (T/V 0.000 ± 0.001 vs. L/H –0.005 ± 0.001; P = 0.016). A higher incidence of new-onset diabetes (T/V 11.0 vs. L/H 26.6%; P = 0.002) and HbA1c >7% (2.6 vs. 9.6%, respectively; P = 0.05) occurred at study end.” (G. Bakris, gbakris@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
Nov. 30, 2006 * Vol. 13, No. 229
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Nov. 30 issue of the New England Journal of Medicine (content.nejm.org; 2006; 355).
Episodic Antiretroviral Therapy: Use of CD4+ counts to guide episodic provision of combination antiretroviral therapy performed poorly in the Strategies for Management of Antiretroviral Therapy (SMART) study (pp. 2283-96). Episodic use was deferral of therapy until the CD4+ count decreased to less than 250/cu mm and then the use of therapy until the CD4+ count increased to more than 350/cu mm. SMART investigators reported these results: “A total of 5,472 participants (2,720 assigned to drug conservation and 2,752 to viral suppression) were followed for an average of 16 months before the protocol was modified for the drug conservation group. At baseline, the median and nadir CD4+ counts were 597 per cubic millimeter and 250 per cubic millimeter, respectively, and 71.7% of participants had plasma HIV RNA levels of 400 copies or less per milliliter. Opportunistic disease or death from any cause occurred in 120 participants (3.3 events per 100 person–years) in the drug conservation group and 47 participants (1.3 per 100 person–years) in the viral suppression group (hazard ratio for the drug conservation group vs. the viral suppression group, 2.6; 95% confidence interval [CI], 1.9 to 3.7; P < 0.001). Hazard ratios for death from any cause and for major cardiovascular, renal, and hepatic disease were 1.8 (95% CI, 1.2 to 2.9; P = 0.007) and 1.7 (95% CI, 1.1 to 2.5; P = 0.009), respectively. Adjustment for the latest CD4+ count and HIV RNA level (as time-updated covariates) reduced the hazard ratio for the primary end point from 2.6 to 1.5 (95% CI, 1.0 to 2.1).” (W. M. El-Sadr, New York; wme1@columbia.edu)
Editorialists add this perspective on “the toxicity of undertreated HIV infection” (pp. 2359-61): “Should the findings of the SMART trial end the study of intermittent therapy in patients infected with HIV? Perhaps, but it is still unknown whether intermittent antiretroviral strategies may be appropriate in certain circumstances, such as in the setting of acute HIV infection, in women with CD4+ counts of more than 350 cells per cubic millimeter who receive antiretroviral therapy to prevent mother-to-child transmission of the virus, or with the use of shorter episodes of treatment interruption in patients with chronic HIV infection. We may learn that the only people in whom therapy can be safely interrupted for long periods are those who do not require it in the first place. Given the deleterious effects of uncontrolled HIV replication, we must continue to reevaluate the optimal criteria for the initiation of antiretroviral therapy. In the future, we can only hope to be smart enough to identify ways to make antiretroviral therapy less costly and less toxic.” (J. S. Currier, UCLA)
Pioglitazone for Nonalcoholic Steatohepatitis: Metabolic and histologic improvement were observed with pioglitazone therapy among 55 patients with nonalcoholic steatohepatitis and impaired glucose tolerance or type 2 diabetes mellitus (pp. 2297-307). Comparing pioglitazone 45 mg daily versus placebo supplementation of a hypocaloric diet over a 6-month period, the investigators observed: “Diet plus pioglitazone, as compared with diet plus placebo, improved glycemic control and glucose tolerance (P < 0.001), normalized liver aminotransferase levels as it decreased plasma aspartate aminotransferase levels (by 40% vs. 21%, P = 0.04), decreased alanine aminotransferase levels (by 58% vs. 34%, P < 0.001), decreased hepatic fat content (by 54% vs. 0%, P < 0.001), and increased hepatic insulin sensitivity (by 48% vs. 14%, P = 0.008). Administration of pioglitazone, as compared with placebo, was associated with improvement in histologic findings with regard to steatosis (P = 0.003), ballooning necrosis (P = 0.02), and inflammation (P = 0.008). Subjects in the pioglitazone group had a greater reduction in necroinflammation (85% vs. 38%, P = 0.001), but the reduction in fibrosis did not differ significantly from that in the placebo group (P = 0.08). Fatigue and mild lower-extremity edema developed in one subject who received pioglitazone; no other adverse events were observed.” (K. Cusi, cusi@uthscsa.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 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
Dec. 1, 2006 * Vol. 13, No. 230
Providing news and information about medications and their proper use

>>>JAPhA Highlights
Source:
Nov/Dec issue of the Journal of the American Pharmacists Assoc. (www.japha.org; 2006; 46).
MTM Services Under Medicare Part D: Several articles explore how medication therapy management has developed under the Medicare Part D drug benefit.
MTM programs being offered during by June 30, 2006, were “highly variable” and often used interventions that lacked “definitive evidence [of] effectiveness,” concludes a survey of 21 programs representing 70 health insurance plans covering 12.1 million Medicare enrollees (pp. 683-91). But some of the larger plans are using more proven techniques through face-to-face interactions at local pharmacies, the authors write: “Of the MTM programs offered, 90.5% restricted their enrollment based on number of diseases, with a median of 3 (range, 2–5) diseases required; 57.1% restricted enrollment based on the type of chronic condition; and 95.2% had requirements for the number of medications (median, 6; range, 2–24) necessary for enrollment in the program. The most frequently provided MTM services were patient education (75.0% of programs), patient adherence (70.0%), and medication review (60.0%). The median number of different service types provided by MTM programs was 3 (range, 2–7). MTM program services included the use of mailed interventions (76.1%) and in-house call centers (90.4%). While only 4 of the 21 MTM programs contracted with pharmacies to provide some or all of their MTM services, these plans covered a large number of beneficiaries (7.5 million lives).” (D. R. Touchette,
drtouche@uic.edu)
A survey conducted around the time of Part D implementation of 97 contacts at Medicare Advantage or standalone prescription drug plans finds limited plans for implementation of MTM services at the local pharmacy level (pp. 692-9). “Almost all respondents had a plan in place for MTM services,” note the researchers. “The majority of PDPs perceived that MTM would have a moderate benefit to their organization. Most PDPs planned to focus efforts on diabetes, heart failure, and other forms of cardiovascular disease.... Only 8.2% of respondents planned to use a ‘traditional’ pharmacist, such as a community, long-term care, hospital, or clinic pharmacist. The majority of PDPs (53.6%) planned to employ managed care pharmacists to administer MTM services.” (S. T. Boyd,
Sboyd1@xula.edu)
A third survey, conducted about a year before implementation of Medication Part D, finds that only 28% of 262 N.C. pharmacies were planning to offer MTM services under the new drug benefit program and that most lacked in-place systems for doing so (pp. 700-6). In Jan. 2005, “Approximately 42% of respondents (n = 110) indicated that they [were providing] some type of cognitive service,” the authors explain. “Comprehensive MTM services, or services consistent with the professionwide consensus definition, were provided by 31% of respondents (n = 81). Independent pharmacies were more likely to offer some type of service compared with chain pharmacies (58% versus 31%, respectively; P < .001). Pharmacy managers with a doctor of pharmacy degree were less likely than pharmacy managers with a bachelor’s degree to offer services in their pharmacies (P = .02), and pharmacies with pharmacists on staff who had received certificate training were more likely to offer cognitive services (P = .03).” (R. A. Hansen,
rahansen@unc.edu)
“We can look at [the first] two surveys and see that PDPs are not using pharmacists in the community, hospital, and long-term care pharmacies for MTM services to the extent that the profession had hoped for during the initial year of Medicare Part D,” writes an editorialist (pp. 680-1): “A sizable number of MTM-eligible members have had or now have access to consultations conducted by a pharmacist. Pharmacists will need to make changes in the way they practice to manage the medication therapies of this population. As Medicare Part D enters year 2, the opportunity for pharmacists to conduct MTM services will expand. Pharmacists cannot afford to miss this golden opportunity. Even if the operations of programs differ in the beginning, pharmacists should do whatever they can to participate in these MTM programs while the opportunity is at hand.” (R. McMahan,
rmcmahan@humana.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
Dec. 4, 2006 * Vol. 13, No. 231
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from and Dec. 2 issue of BMJ (www.bmj.org; 2006; 333).
Vaccinating Long-Term Care Workers for Influenza: Evidence of a protective herd immunity against influenza comes from a trial of vaccination of staff at 66 U.K. nursing homes (doi: 10.1136/bmj.39010.581354.55 ). Comparing resident infection rates at 44 homes where vaccinations were offered with staff at 22 control facilities, the authors report: “In 2003–4 vaccine coverage in full time staff was 48.2% (407/884) in intervention homes and 5.9% (51/859) in control homes. In 2004–5 uptake rates were 43.2% (365/844) and 3.5% (28/800). National influenza rates were substantially below average in 2004–5. In the 2003–4 period of influenza activity significant decreases were found in mortality of residents in intervention homes compared with control homes (rate difference –5.0 per 100 residents, 95% confidence interval –7.0 to –2.0) and in influenza-like illness (P = 0.004), consultations with general practitioners for influenza-like illness (P = 0.008), and admissions to hospital with influenza-like illness (P = 0.009). No significant differences were found in 2004–5 or during periods of no influenza activity in 2003–4.” (A. C. Hayward, U. Coll., London; a.hayward@pcps.ucl.ac.uk)
Childhood Epilepsy: Behavioral adverse effects were similar with phenobarbital and carbamazepine in an analysis of treatments for pediatric epilepsy among 108 children in Bangladesh (doi: 10.1136/bmj.39022.436389.BE). In the randomized controlled trial, generalized tonic–clonic seizures and partial and secondary generalized seizures were treated initially with one of the two drugs, with these results: “91 children were followed up for 12 months. Six required a change of antiepilepsy drug. Side effects were compared in 85 children. In the last quarter of the 12 month follow-up, 71 children were seizure free after one year’s treatment. Thirty two in the phenobarbital group and 39 in the carbamazepine group had no seizures in 74 and 102 days after randomisation, respectively. Ten children had increased behavioural problems, which were unacceptable in four (one in the phenobarbital group and three in the carbamazepine group). Independent t tests, however, showed no difference between the two trial drugs.” (B. Neville, Inst. of Child Health, London; bneville@ncype.org.uk)

>>>PNN NewsWatch
* Saturday evening’s announcement that Pfizer was discontinuing development of the HDL cholesterol–raising agent torcetrapib throws into doubt development of this once-promising class of drugs. Three years into a Phase III trial of the drug, a monitoring committee found that 82 patients taking the drug had died, significantly more than the 51 who died in the control group during this time, according to reports in the lay media. Significantly more cardiovascular events were also reported with torcetrapib, and the increased mortality rates were observed among patient subgroups with heart failure as well as other clinical problems.

>>>PNN JournalWatch
* Hyperglycemic Crises in Adult Patients with Diabetes: A Consensus Statement from the American Diabetes Association, in Diabetes Care, 2006; 29: 2739–48. Reprints: http://care.diabetesjournals.org/cgi/content/extract/29/12/2739; A. E. Kitabchi, akitabchi@utmem.edu
* Guidelines for Monitoring and Management of Pediatric Patients During and After Sedation for Diagnostic and Therapeutic Procedures: An Update, in
Pediatrics, 2006; 118: 2587–602. Reprints: http://pediatrics.aappublications.org/cgi/content/abstract/118/6/2587; American Academy of Pediatrics, American Academy of Pediatric Dentistry.
* AAP Principles Concerning Retail-Based Clinics, in
Pediatrics, 2006; 118: 2561–2. Reprints: http://pediatrics.aappublications.org/cgi/content/extract/118/6/2561; American Academy of Pediatrics Retail-Based Clinic Policy Work Group.
* The Coulee Region Community Pharmacy Asthma Intervention Study, in
Journal of the American Pharmacists Assoc., 2006; 46: 738–48. Reprints: www.japha.org; E. Laufenberg–Horstmann, MD Group LLC, DeForest, Wis.; ehorstmann@mdgroupllc.net
* Pharmacotherapy Considerations in Advanced Cardiac Life Support, in
Pharmacotherapy, 2006; 26: 1703–19. Reprints: www.pharmacotherapy.org; W. E. Dager, william.dager@ucdmc.ucdavis.edu
* Entecavir: A New Nucleoside Analog for the Treatment of Chronic Hepatitis B Infection, in
Pharmacotherapy, 2006; 26: 1745–57. Reprints: www.pharmacotherapy.org; A. M. Woodland, St. Louis Coll. of Pharm., St. Louis, Mo.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Dec. 5, 2006 * Vol. 13, No. 232
Providing news and information about medications and their proper use

>>>Pediatrics Highlights
Source:
Dec. issue of the Archives of Pediatrics & Adolescent Medicine (archpedi.ama-assn.org; 2006; 160).
Dextromethorphan Abuse: Abuse of dextromethorphan increased between 1999 and 2004 in California, based on an analysis of calls to the Calif. Poison Control System (pp. 1217-22). Noting that the trend was most evident among adolescents, the investigators report: “A total of 1,382 CPCS cases were included in the study. A 10-fold increase in CPCS dextromethorphan abuse cases from 1999 (0.23 cases per 1,000 calls) to 2004 (2.15 cases per 1,000 calls) (odds ratio, 1.48; 95% confidence interval, 1.43–1.54) was identified. Of all CPCS dextromethorphan abuse cases, 74.5% were aged 9 to 17 years; the frequency of cases among this age group increased more than 15-fold during the study (from 0.11 to 1.68 cases per 1,000 calls). Similar trends were seen in the [American Association of Poison Control Centers] and [Drug Abuse Warning Network] databases. The highest frequency of dextromethorphan abuse occurred among adolescents aged 15 and 16 years. The most commonly abused product was Coricidin HBP Cough & Cold Tablets.” (I. B. Anderson, iba@calpoison.org)
Alcohol Misuse Among Marine Recruits: Risks for alcohol misuse among young adults are quantified in a study of men starting military training at the Marine Corps Recruit Depot in San Diego (pp. 1207-14): “Of 41,482 young men, 6,128 (14.8%) were identified as risky drinkers, 18,693 (45.1%) as nonrisky drinkers, and 16,661 (40.2%) as nondrinkers. Among drinkers, early initiation of alcohol use was strongly associated with risky drinking, with a 5.5-fold risk if age at onset of drinking was 13 years or younger. Other associated factors included tobacco use, rural or small hometown, higher education, motivation to join the military for travel or adventure or to leave problems at home, numerous close friends and relatives, household alcohol abuse or mental illness, and childhood sexual or emotional abuse. When the comparison group included nondrinkers, additional associated factors included childhood physical abuse and domestic violence.” (M. A. K. Ryan, Naval Health Res. Ctr., San Diego; ryan@nhrc.navy.mil)
Maternal Influenza Vaccination During Pregnancy: Vaccination of pregnant women against influenza did not significantly reduce the rate of respiratory illness visits for their babies, concludes a study of 41,129 infants born to 3,160 vaccinated and 37,969 unvaccinated mothers in 1995–2001 (pp. 1277-83). “During the peak influenza weeks, infant visit rates were 15.4 and 17.1 per 100 person–months for exposed and unexposed infants, respectively (incident rate ratio, 0.90; 95% confidence interval, 0.80–1.02). Adjusted IRRs for the 4 periods found a protective effect of infant female sex, whereas Medicaid status and maternal high-risk status increased infant visit rates. Maternal influenza vaccination did not reduce visit rates during any of the 4 time periods (IRR for peak influenza season, 0.96; 95% confidence interval, 0.86–1.07) and did not delay the onset of first respiratory illness.” (E. K. France, Kaiser Permanente, Denver; eric.k.france@kp.org)

>>>PNN NewsWatch
* ASHP’s Midyear Clinical Meeting has convened in Anaheim, with the usual cast of thousands in attendance. At a news conference on Monday that followed a highly attended and humorous keynote address by comedian Dany Carvey, ASHP officers and CEO Henri Manasse emphasized several areas of current Society activity: Drug safety, including a new partnership with Lexi-Comp that will extend the reach of ASHP drug information services; a continuing partnership with Consumer Union to provide printed drug information to patients; the need to address the shortage of pharmacists and leadership skills among health-system pharmacists; creation of a new section on informatics for pharmacists and technicians who are specializing in this area; continued growth of ASHP activities in the student pharmacist/new practitioner arenas; and participation in intensive discussions the possibility of submitting a petition for recognition of ambulatory care pharmacy (including medication therapy management activities) as a specialty to the Board of Pharmaceutical Specialties.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Dec. 6, 2006 * Vol. 13, No. 233
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Early-release article from and Dec. 6 issue of JAMA (www.jama.com; 2006/2007; 296/297).
Clopidogrel Use After Stent Implantation: Extended use of clopidogrel was associated with reduced risk of death and of death or myocardial infarction in a study of patients receiving drug-eluting stents (DES) for treatment of coronary artery disease (doi: 10.1001/jama.297.2.joc60179). Comparing outcomes with four combinations of DES or bare metal stents (BMS) and use of clopidogrel or placebo, researchers found these outcomes at 24 months: “Among patients with DES who were event-free at 6 months (637 with and 579 without clopidogrel), clopidogrel use was a significant predictor of lower adjusted rates of death (2.0% with vs 5.3% without; difference, –3.3%; 95% CI, –6.3% to –0.3%; P = .03) and death or MI (3.1% vs 7.2%; difference, –4.1%; 95% CI, –7.6% to –0.6%; P = .02) at 24 months. However, among patients with BMS (417 with and 1,976 without clopidogrel), there were no differences in death (3.7% vs 4.5%; difference, –0.7%; 95% CI, –2.9% to 1.4%; P = .50) and death or MI (5.5% vs 6.0%; difference, –0.5%; 95% CI, –3.2% to 2.2%; P = .70). Among patients with DES who were event-free at 12 months (252 with and 276 without clopidogrel), clopidogrel use continued to predict lower rates of death (0% vs 3.5%; difference, –3.5%; 95% CI, –5.9% to –1.1%; P = .004) and death or MI (0% vs 4.5%; difference, –4.5%; 95% CI, –7.1% to –1.9%; P < .001) at 24 months. However, among patients with BMS (346 with and 1,644 without clopidogrel), there continued to be no differences in death (3.3% vs 2.7%; difference, 0.6%; 95% CI, –1.5% to 2.8%; P = .57) and death or MI (4.7% vs 3.6%; difference, 1.0%; 95% CI, –1.6% to 3.6%; P = .44).” (E. L. Eisenstein, eric.eisenstein@duke.edu)
Cardiovascular Indicators with Pioglitazone v. Glimepiride: In 462 adults with type 2 diabetes, mellitus, pioglitazone slowed the progression of carotid artery intima-media thickness during 18 months of treatment (pp. 2572-81). Study participants took either pioglitazone hydrochloride 15–45 mg/day or glimepiride 1–4 mg/day, with these results: “Mean change in CIMT was less with pioglitazone vs glimepiride at all time points (weeks 24, 48, 72). At week 72, the primary end point of progression of mean CIMT was less with pioglitazone vs glimepiride (–0.001 mm vs +0.012 mm, respectively; difference, –0.013 mm; 95% confidence interval, –0.024 to –0.002; P = .02). Pioglitazone also slowed progression of maximum CIMT compared with glimepiride (0.002 mm vs 0.026 mm, respectively, at 72 weeks; difference, –0.024 mm; 95% confidence interval, –0.042 to –0.006; P = .008). The beneficial effect of pioglitazone on mean CIMT was similar across prespecified subgroups based on age, sex, systolic blood pressure, duration of DM, body mass index, HbA1c value, and statin use.” (T. Mazzone, MD, tmazzone@uic.edu)
Postpartum Mental Disorders: In a study from Denmark, mothers had an increased risk of severe mental disorders in the months following childbirth, while new fathers had no excess risk of admission or outpatient care for such conditions (pp. 2582-9). “We documented the strong temporal association between childbirth and prevalence of severe mental disorders among primiparous women, for both first-time hospital admissions and outpatient contacts, but we did not find any indication of such an association among men who become fathers,” the researchers write. “Men who do become fathers are, of course, not protected against developing mental disorders; hence, fatherhood and mental disorders will co-occur. Our results, however, do not support fatherhood as a specific risk factor for severe mental disorder and challenge the concept of severe paternal postpartum mental disorder.” (T. Munk–Olsen, U. Aarhus, Aarhus, Denmark; tmo@ncrr.dk)

>>>PNN NewsWatch
* Susan C. Winckler, a pharmacist–attorney who left the APhA staff in Sept. to join FDA, yesterday was named the agency’s Acting Chief of Staff. In this role, she will coordinate staff activities in the Office of the Commissioner and serve as the principal liaison to U.S. Department of Health and Human Services.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Dec. 7, 2006 * Vol. 13, No. 234
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Dec. 7 issue of the New England Journal of Medicine (content.nejm.org; 2006; 355).
Imatinib in CML: Continuous imatinib treatment in patients with chronic myeloid leukemia induces durable responses in most patients for up to 60 months, report investigators of the International Randomized Study of Interferon and STI571 (IRIS; pp. 2408-17). “Kaplan–Meier estimates of cumulative best rates of complete cytogenetic response among patients receiving imatinib were 69% by 12 months and 87% by 60 months,” the authors write. “An estimated 7% of patients progressed to accelerated-phase CML or blast crisis, and the estimated overall survival of patients who received imatinib as initial therapy was 89% at 60 months. Patients who had a complete cytogenetic response or in whom levels of BCR-ABL transcripts had fallen by at least 3 log had a significantly lower risk of disease progression than did patients without a complete cytogenetic response (P < 0.001). Grade 3 or 4 adverse events diminished over time, and there was no clinically significant change in the profile of adverse events.” (B. J. Druker, Oregon Health and Science U. Cancer Inst., Portland; drukerb@ohsu.edu)
Klebsiella oxytoca Involved in Antibiotic-Associated Hemorrhagic Colitis: Some cases of antibiotic-associated hemorrhagic colitis are caused by Klebsiella oxytoca rather than the more common Clostridium difficile, authors report based on analysis of 22 consecutive patients (pp. 2418-26). Noting that their results and animal research fulfilled Koch’s postulates, the researchers reported: “Of the 22 patients, 6 had findings on colonoscopy that were consistent with the diagnosis of antibiotic-associated hemorrhagic colitis, and 5 of these 6 patients had positive cultures for K. oxytoca. No other common enteric pathogens were found in the five patients. Before the onset of colitis, all five were receiving penicillins, and two were also taking nonsteroidal antiinflammatory drugs (NSAIDs). All isolated K. oxytoca strains produced cytotoxin. K. oxytoca was found in 1.6% of the healthy subjects. In the animal model, K. oxytoca was found only in the colon of rats that received amoxicillin–clavulanate in addition to being inoculated with K. oxytoca. In these rats, infection with K. oxytoca induced a right-sided hemorrhagic colitis that was not observed in uninfected animals that received amoxicillin–clavulanate, indomethacin (an NSAID), or both.” (C. Högenauer, Med. U. Graz, Graz, Austria; christoph.hoegenauer@meduni-graz.at)
Treating Type 2 DM: Among 4,360 patients with type 2 diabetes, rosiglitazone outperformed metformin and glyburide as initial monotherapy, according to results from A Diabetes Outcome Progression Trial (ADOPT; pp. 2427-43). Using time to monotherapy failure (confirmed level of fasting plasma glucose of more than 180 mg/dL) as the primary outcome, investigators report: “Kaplan–Meier analysis showed a cumulative incidence of monotherapy failure at 5 years of 15% with rosiglitazone, 21% with metformin, and 34% with glyburide. This represents a risk reduction of 32% for rosiglitazone, as compared with metformin, and 63%, as compared with glyburide (P < 0.001 for both comparisons). The difference in the durability of the treatment effect was greater between rosiglitazone and glyburide than between rosiglitazone and metformin. Glyburide was associated with a lower risk of cardiovascular events (including congestive heart failure) than was rosiglitazone (P < 0.05), and the risk associated with metformin was similar to that with rosiglitazone. Rosiglitazone was associated with more weight gain and edema than either metformin or glyburide but with fewer gastrointestinal events than metformin and with less hypoglycemia than glyburide (P < 0.001 for all comparisons).” (S. E. Kahn, skahn@u.washington.edu)
Peginterferon and Ribavirin for Chronic Hepatitis C: A case vignette is presented involving a 44-year-old woman with chronic hepatitis C (pp. 2444-51). Combination therapy using peginterferon and ribavirin is recommended for the patient and discussed in the article. (J. A. Hoofnagle, hoofnaglej@extra.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
Dec. 8, 2006 * Vol. 13, No. 235
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Dec. issue of Pharmacotherapy (www.pharmacotherapy.org; 2006; 26).
Needle-Free Enfuvirtide Administration: In an open-label crossover study, 27 patients preferred a needle-free device over standard subcutaneous needle administration of enfuvirtide (pp. 1679-86). Patients randomly received enfuvirtide 90 mg with either the Biojector 2000 or a 27-gauge, 0.5-inch needle, with a 1-week washout period between treatments. After noting that bioavailability of enfuvirtide, safety profiles, and injection-site reactions were all equivalent with the two devices, the investigators report these details about patient preference: “Survey results showed 18 patients (69%) had a positive overall impression of the B2000 and 14 (54%) felt safer injecting with this device. Overall, 17 patients (65%) preferred the B2000 over the needle–syringe.” (A. L. True, Trimeris, Inc., Morrisville, N.C.; atrue@trimeris.com)
Procainamide in Neonates: While procainamide can be safely used intravenously in neonates at dosages similar to those for older infants and children, regimens may need to be modified for premature infants and babies with renal dysfunction (pp. 1687-93). Reporting retrospective findings for 7 preterm and 14 full-term infants, researchers note: “No patients experienced hemodynamic instability or other adverse effects due to procainamide. Procainamide was given as a mean ± SD 9.6 ± 1.5-mg/kg bolus in 20 of 21 patients before continuous infusion. The mean ± SD dose at which two therapeutic levels were achieved was 37.56 ± 13.52 µg/kg/minute. Procainamide clearance was 6.36 ± 8.85 ml/kg/minute and correlated with creatinine clearance (r = 0.78, p < 0.00001) and age at day of sampling (r = 0.49, p < 0.00001). The NAPA:procainamide ratio at steady state was 0.84 ± 0.53; two patients were determined to be fast acetylators (ratio > 1). Preterm infants had lower mean clearance rates (p < 0.001) but higher NAPA:procainamide ratios (p < 0.01) than those of term infants. Five patients experienced seven supratherapeutic levels while receiving therapy; four of these patients were preterm, and all had creatinine clearances less than 30 ml/minute/1.73 m2. Three patients had four pairs of levels obtained after discontinuation of procainamide, and elimination rate constant and half-life were calculated.” (B. S. Moffett, bsmoffet@texaschildrenshospital.org)
Pharmacoeconomics of Overactive Bladder Treatments: Solifenacin 5 mg had the lowest costs and greatest effectiveness in the treatment of overactive bladder, concludes a cost-effectiveness analysis of antimuscarinic agents (pp. 1694-702). Analyzing costs for darifenacin, solifenacin, trospium, immediate-release oxybutynin, extended-release oxybutynin, transdermal oxybutynin, immediate-release tolterodine, and extended-release tolterodine from the payer’s perspective, the authors found: “Expected costs for each patient with OAB ranged from $3,373 when treated with solifenacin to $3,769 when treated with immediate-release oxybutynin. The average cost/patient with continued and successful treatment was lowest for solifenacin ($6,863). Solifenacin dominated all other antimuscarinic agents because they were associated with high costs and low effectiveness. Success rates were the key parameters driving the sensitivity analysis.” (Y. Ko, ko@pharmacy.arizona.edu)

>>>PNN NewsWatch
* FDA is warning consumers about the dangers of using compounded topical anesthetic products. In addition, the agency issued warning letters to five firms—Triangle Compounding Pharmacy, University Pharmacy, Custom Scripts Pharmacy, Hal’s Compounding Pharmacy, and New England Compounding Center—asking them to stop compounding and distributing standardized versions of topical anesthetic creams that are marketed for general distribution rather than responding to the unique medical needs of individual patients. Two deaths have been connected to compounded topical anesthetic creams made by Triangle Compounding Pharmacy and University Pharmacy, FDA reported.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2006, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Dec. 11, 2006 * Vol. 13, No. 236
Providing news and information about medications and their proper use

>>>Psychiatry Highlights
Source:
Dec. issue of American Journal of Psychiatry (ajp.psychiatryonline.org; 2006; 163).
Cost-Effectiveness of Antipsychotics: A variety of threats to validity compromise interpretation of previously published cost-effectiveness analyses of second-generation antipsychotic agents, conclude authors of a review article (pp. 2047-56). Considering eight studies that were based on six randomized clinical trials, the authors provide these results and conclusion: “The ... cost-effectiveness studies of antipsychotic medications faced a variety of threats to validity related to 1) measurement of costs, 2) measurement of effectiveness, 3) analysis of costs, 4) measurement of sampling uncertainty, 5) analysis of incomplete cost data, 6) minimizing loss to follow-up, and 7) threats to external validity.... Economic claims made by the authors of a number of trial-based economic evaluations have generally been favorable to second-generation antipsychotics. However, the methodological issues the authors of the current study identified suggest that there is no clear evidence that atypical antipsychotics generate cost savings or are cost-effective in general use among all schizophrenia patients. Psychiatrists, researchers, and administrators should consider the methodological issues highlighted in interpreting study results. These issues should be addressed in future trial designs.” (D. Polsky)
Metformin Treatment with Second-Generation Antipsychotics: Metformin proved to be a safe and effective means of reducing the weight gain associated with use of second-generation antipsychotic agents in a group of 39 children and adolescents (pp. 2072-9). Study participants had experienced at least 10% gain in weight during less than 1 year of treatment with olanzapine, risperidone, or quetiapine. Metformin or placebo therapy produced these results during this 16-week trial: “Weight was stabilized in subjects receiving metformin, while those receiving placebo continued to gain weight (0.31 kg/week). Because the study was conducted with growing children, metformin treatment resulted in reduction in z scores for both weight and body mass index. The homeostasis model assessment, a surrogate indicator of insulin sensitivity, decreased in treated subjects. Overt diabetes was diagnosed in two subjects before treatment (elevated baseline fasting glucose and insulin values) and in two placebo-treated subjects (one at week 12 and the other after study completion). One subject taking placebo developed impaired fasting glucose. Placebo treatment was associated with the need to perform oral glucose tolerance testing upon study completion, by which three additional subjects were identified with impaired glucose tolerance. No serious adverse events resulted from metformin treatment.” (D. J. Klein)
>>>PNN JournalWatch
* Pregnancy After Breast Cancer: Population Based Study, in BMJ, doi: 10.1136/bmj.39035.667176.55. Reprints: www.bmj.com/cgi/content/abstract/bmj.39035.667176.55v1; A. Ives, U. Western Australia, Crawley, Western Australia; angela.ives@uwa.edu.au
* Attention Deficit Hyperactivity Disorder and Substance Use Disorders, in
American Journal of Psychiatry, 2006; 163: 2059–63. Reprints: http://ajp.psychiatryonline.org/cgi/content/full/163/12/2059; T. E. Wilens.
* Atypical Antipsychotics in the Treatment of Schizophrenia During Pregnancy and the Postpartum, in
American Journal of Psychiatry, 2006; 163: 2064–70. Reprints: http://ajp.psychiatryonline.org/cgi/content/full/163/12/2064; D. Yaeger.
* Cooperative Dementia Care Clinics: A New Model for Managing Cognitively Impaired Patients, in
Journal of the American Geriatrics Society, 2006; 54: 1937 ff. Reprints: www.blackwell-synergy.com/doi/abs/10.1111/j.1532-5415.2006.00975.x; M. Lessig.
* Detrusor Underactivity: Clinical Features and Pathogenesis of an Underdiagnosed Geriatric Condition, in
Journal of the American Geriatrics Society, 2006; 54: 1920 ff. Reprints: www.blackwell-synergy.com/doi/abs/10.1111/j.1532-5415.2006.00917.x; J. A. Taylor III.
* Randomized Controlled Trials of Autologous Hematopoietic Stem Cell Transplantation for Autoimmune Diseases: The Evolution from Myeloablative to Lymphoablative Transplant Regimens, in
Arthritis & Rheumatism, 2006; 54: 3750–60. Reprints: www3.interscience.wiley.com/cgi-bin/abstract/113490193/ABSTRACT; R. K. Burt, rburt@northwestern.edu
* Update in Rheumatology, in
Annals of Internal Medicine, 2006; 145: 834–8. Reprints: www.annals.org/cgi/content/full/145/11/834; D. B. Hellmann, Johns Hopkins Bayview Med. Ctr., Baltimore; hellmann@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
Dec. 12, 2006 * Vol. 13, No. 237
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Dec. 11/25 issue of Archives of Internal Medicine (www.archinternmed.com; 2006; 166).
Vitamin E & Cognitive Functioning: Among 39,876 healthy older women, long-term vitamin E supplementation had no significant effects on cognition (pp. 2462-8). In the Women’s Health Study, alpha-tocopherol acetate 600 IU on alternate days or placebo was begun between 1992 and 1995. Women aged 65 years or older (n = 6,377) participated in a substudy that began in 1998 in which cognition was assessed, with these results: “There were no differences in global score between the vitamin E and placebo groups at the first assessment (5.6 years after randomization: mean difference, –0.01; 95% confidence interval [CI], –0.04 to 0.03) or at the last assessment (9.6 years of treatment: mean difference, 0.00; 95% CI, –0.04 to 0.04). Mean cognitive change over time was also similar in the vitamin E group compared with the placebo group for the global score (mean difference in change, 0.02; 95% CI, –0.01 to 0.05; P = .16). The relative risk of substantial decline in the global score in the vitamin E group compared with the placebo group was 0.92 (95% CI, 0.77 to 1.10).” (J. H. Kang, Channing Laboratory, Boston; nhjhk@channing.harvard.edu)
Editorialists call for continued efforts to address cognitive declines associated with normal aging (pp. 2433-4): “There remains a great and increasing need to identify effective interventions for the prevention and management of cognitive decline. Against the backdrop of the complex and multifactorial disease processes of cognitive aging, clear treatment perspectives have so far been difficult to establish. It is likely that cognitive interventions will vary in effectiveness depending on an individual’s genetic background, current cognitive status, cognitive trajectory, concomitant disorders, and other exogenous risk factors. Until further work is done in identifying mechanisms and subtyping individuals, treatment effects seen in clinical trials may, as broad averages, appear small and unimportant. This complexity, however, should not dissuade us from this important task.” (M. A. Espeland, Wake Forest U., Winston-Salem, N.C.;
mespelan@wfubmc.edu)
Medication Discontinuance for Elective Surgery: Warfarin is frequently discontinued unintentionally following elective surgical procedures, according to results of a population-based, cohort study from Ontario (pp. 2525-31). Administrative records for patients aged 66 years and older showed these rates of discontinuation between 1997 and 2002: “Rates of drug treatment discontinuation after overnight hospitalizations, after ambulatory procedures, and after no procedures were 11.4%, 7.5%, and 4.8%, respectively, in the warfarin group; 4.0%, 3.9%, and 3.9%, respectively, in the statin group; and 8.4%, 8.9%, and 7.9%, respectively, in the ophthalmic drops group. The adjusted odds ratio (OR) was 2.6 (95% confidence interval [CI], 2.0–3.4) for discontinuation of warfarin therapy after overnight hospitalizations and 1.6 (95% CI, 1.4–1.7) after ambulatory procedures. In contrast, there was no increased risk of discontinuing treatment with either statins (OR for overnight hospitalization, 1.0 [95% CI, 0.9–1.2]; OR for ambulatory procedure, 1.0 [95% CI 1.0–1.1]) or ophthalmic drops (OR for overnight hospitalization, 1.0 [95% CI, 0.8–1.5]; OR for ambulatory procedure, 1.1 [95% CI, 1.0–1.2]).” (C. M. Bell, St. Michael’s Hosp., Toronto; bellc@smh.toronto.on.ca)
Health Benefits of Alcohol Use: Low to moderate levels of alcohol intake are associated with lower total mortality, concludes an updated meta-analysis of 34 prospective studies (pp. 2437-45). “A J-shaped relationship between alcohol and total mortality was confirmed in adjusted studies, in both men and women,” write the authors. “Consumption of alcohol, up to 4 drinks per day in men and 2 drinks per day in women, was inversely associated with total mortality, maximum protection being 18% in women (99% confidence interval, 13%-22%) and 17% in men (99% confidence interval, 15%-19%). Higher doses of alcohol were associated with increased mortality. The inverse association in women disappeared at doses lower than in men. When adjusted and unadjusted data were compared, the maximum protection was only reduced from 19% to 16%. The degree of association in men was lower in the United States than in Europe.” (L. Iacoviello, Catholic U., Campobasso, Italy; licia.iacoviello@rm.unicatt.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
Dec. 13, 2006 * Vol. 13, No. 238
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Dec. 13 issue of JAMA (www.jama.com; 2006; 296).
Treating vs. Watching Prostate Cancer: Survival advantages were evident with treatment in all subgroups of men aged 65–80 years of age with low- or intermediate-risk prostate cancer (pp. 2683-93). Using Medicare data in an observational cohort study, investigators gauged outcomes in 32,022 men who were treated with radical prostatectomy or radiation therapy in the first 6 months after diagnosis of prostate cancer, comparing them with 12,608 similarly diagnosed men who had no claims for those interventions or for hormonal therapy. The authors report: “At the end of the 12-year study period, 4,663 men (37%) in the observational group and 7,639 men (23.8%) in the treatment group had died. The treatment group had longer 5- and 10-year survival than the observation group. After using propensity scores to adjust for potential confounders (tumor characteristics, demographics, and comorbidities), there was a statistically significant survival advantage associated with treatment (hazard ratio, 0.69; 95% confidence interval, 0.66–0.72). A benefit associated with treatment was seen in all subgroups examined, including older men (aged 75-80 years at diagnosis), black men, and men with low-risk disease.” (Y-N Wong, Fox Chase Cancer Ctr., Philadelphia; Y_Wong@fccc.edu)
Editorialists question whether these data represent “survival or selection” of the fittest (pp. 2733-4): “Improvement in the quality of care for men with prostate cancer may best be achieved not by treating more patients but by treating them more discerningly. Clinicians must remain steadfast in their efforts to reduce overtreatment and undertreatment by thoughtfully defining each patient’s unique balance between the natural history of prostate cancer and that individual patient’s life expectancy. To this end, an important recent advance is the development of refined strategies for active surveillance with selective, delayed intervention. As Whitmore articulated more than 3 decades ago, the persistent clinical quandary is that ‘for men in whom cure is possible it may not be necessary, while for men in whom cure is necessary, it may not be possible.’” (M. S. Litwin,
mlitwin@ucla.edu)
Folic Acid & CVD: A meta-analysis of 12 randomized controlled trials shows that folic acid failed to reduce the risk of cardiovascular disease or all-cause mortality among 16,958 patients with prior histories of vascular disease (pp. 2720-6). “Several ongoing trials with large sample sizes might provide a definitive answer to this important clinical and public health question,” the authors conclude, providing these details about the meta-analysis: “The overall relative risks (95% confidence intervals) of outcomes for patients treated with folic acid supplementation compared with controls were 0.95 (0.88–1.03) for cardiovascular diseases, 1.04 (0.92–1.17) for coronary heart disease, 0.86 (0.71–1.04) for stroke, and 0.96 (0.88–1.04) for all-cause mortality. The relative risk was consistent among participants with preexisting cardiovascular or renal disease.” (L. A. Bazzano, lbazzano@tulane.edu)

>>>PNN NewsWatch
* FDA yesterday ordered firms to stop marketing unapproved drug products containing the antimalarial agent quinine, citing serious safety concerns (665 reports of adverse events with serious outcomes, including 93 deaths, since 1969). Multiple unapproved products containing quinine are currently marketed, FDA indicated, adding that only one quinine product—Qualaquin from Mutual Pharmaceutical Company—is approved by the agency. FDA also cautioned consumers about off-label use of quinine to treat leg cramps. Because malaria is life-threatening, the risks associated with quinine use are justified for that condition, FDA maintained. But because of the quinine’s adverse effects and narrow therapeutic index, FDA said that it believes the drug should not be used to prevent or treat leg cramps.
* Access to
investigational drugs would be expanded under new rules proposed this week by FDA. If adopted, the rule would also clarify what costs can be recouped by manufacturers for investigational agents when made available to individual patients, small patient groups, and larger populations with serious illness.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Dec. 14, 2006 * Vol. 13, No. 239
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Dec. 14 issue of the New England Journal of Medicine (content.nejm.org; 2006; 355).
Flu Vaccine Efficacy: In a head-to-head comparison, injected inactivated vaccine performed surprisingly better than the intranasal live attenuated product, despite antigenic drift of circulating viruses in the 2004–05 season of the trial (pp. 2513-22). Healthy adults were included in the study, randomly receiving either Fluzone (Sanofi Pasteur), FluMist (MedImmune), or placebo. Results showed the following: “A total of 1,247 persons were vaccinated between October and December 2004. Influenza activity in Michigan began in January 2005 with the circulation of an antigenically drifted type A (H3N2) virus, the A/California/07/2004-like strain, and of type B viruses from two lineages. The absolute efficacy of the inactivated vaccine against both types of virus was 77% (95% confidence interval [CI], 37 to 92) as measured by isolating the virus in cell culture, 75% (95% CI, 42 to 90) as measured by either isolating the virus in cell culture or identifying it through real-time polymerase chain reaction, and 67% (95% CI, 16 to 87) as measured by either isolating the virus or observing a rise in the serum antibody titer. The absolute efficacies of the live attenuated vaccine were 57% (95% CI, –3 to 82), 48% (95% CI, –7 to 74), and 30% (95% CI, –57 to 67), respectively. The difference in efficacy between the two vaccines appeared to be related mainly to reduced protection of the live attenuated vaccine against type B viruses.” (S. E. Ohmit, sohmit@umich.edu)
A school-based influenza vaccination program significantly reduced most measures of influenza-like illness (pp. 2523-32). In four states, 11 demographically similar clusters of elementary schools were identified, with each cluster consisting of one school participating in the program and one or two schools that did not participate. “In all, 47% of students in intervention schools received live attenuated influenza vaccine,” report the investigators. “As compared with control-school households, intervention-school households had significantly fewer influenza-like symptoms and outcomes during the recall week. Paradoxically, intervention-school households (both children and adults) had higher rates of hospitalization per 100 persons than did control-school households. However, there was no difference in the overall hospitalization rates for children or adults in households with vaccinated children, as compared with those with unvaccinated children, regardless of study-group assignment. Rates of school absenteeism for any cause (based on school records) were not significantly different between intervention and control schools.” (J. C. King, Jr.,
jking@peds.umaryland.edu)
Commenting on the above studies, editorialists note the importance of a three-pronged approach to pandemic prevention (pp. 2586-7): “The WHO recently convened international experts to help address issues related to preparedness for pandemic influenza and to develop a ‘global pandemic influenza action plan to increase vaccine supply.’ This plan is timely because of rising concerns about pandemic influenza. It emphasizes the fact that the increased use of influenza vaccine, the increased and more broadly distributed capacity to produce influenza vaccine, and accelerated research to develop better influenza vaccines are needed to address all forms of influenza.” (K. Fukuda, World Health Organization, Geneva)

>>>PNN NewsWatch
* The debate over suicidality associated with antidepressant therapy resumed yesterday at an FDA advisory committee meeting near Washington, D.C. FDA proposed extending the black-box warning to include adults younger than 25 years of age, and the panel agreed with this action in a 6–2 vote. But according to news reports emanating from the meeting, psychiatrists are pushing back strongly on the proposal, and the FDA itself now says that its data show that antidepressants are strongly protective against suicidality in older adults, including the important over-65 age group.
* Another FDA advisory panel convenes today to discuss labeling for
telithromycin (Ketek, Sanofi Aventis), but more importantly, the group will review how the agency handled the approval process for this antibiotic.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Dec. 15, 2006 * Vol. 13, No. 240
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
Dec. 19 issue of the Journal of the American College of Cardiology (content.onlinejacc.org; 2006; 48).
Emerging Therapies for Decompensated Heart Failure: Reasons for optimism in treating decompensated heart failure are described by authors of a bench-to-bedside review article (pp. 2397-409). “Unprecedented wealth of pharmacologic innovation may soon transform the management of these challenging patients,” the article notes. “Agents that target contractility, such as cardiac myosin activators and novel adenosine triphosphate-dependent transmembrane sodium-potassium pump inhibitors, provide inotropic support without arrhythmogenic increases in cytosolic calcium or side effects of more traditional agents. Adenosine receptor blockade may improve glomerular filtration and diuresis by exerting a direct beneficial effect on glomerular blood flow while vasopressin antagonists promote free water excretion without compromising renal function and may simultaneously inhibit myocardial remodeling. Urodilatin, the renally synthesized isoform of atrial natriuretic peptide, may improve pulmonary congestion via vasodilation and enhanced diuresis. Finally, metabolic modulators such as perhexiline may optimize myocardial energy utilization by shifting adenosine triphosphate production from free fatty acids to glucose, a unique and conceptually appealing approach to the management of heart failure. These advances allow optimism not only for the advancement of our understanding and management of decompensated heart failure syndromes but for the translational research effort in heart failure biology in general.” (E. A. Ashley, euan@stanford.edu)
Phosphodiesterase Inhibition for PAD: Improvements in laboratory- and ambulatory-based exercise performance was noted among patients treated for peripheral arterial disease with NM-702, an inhibitor of phosphodiesterase and thromboxane A2 synthase (pp. 2539-45). Among 386 patients in this dose-ranging trial, these results were identified: “After 24 weeks of treatment, 8 mg NM-702 was associated with a statistically significant increased peak walking time on a graded treadmill as compared with placebo (p = 0.004). Peak walking time after 24 weeks was increased by 17.1 ± 49.0% in the placebo arm, 22.1 ± 60.1% in the 4-mg NM-702 arm, and 28.1 ± 50.5% in the 8-mg NM-702 arm. NM-702 at the 8-mg dose for 24 weeks was associated with statistically significant improvements in the treadmill claudication onset time as compared with placebo. In addition, as compared with placebo, NM-702 improved the physical component and physical functioning scores of the Medical Outcomes Study 36-Item Short Form and the walking distance and stair climbing domains of the Walking Impairment Questionnaire. NM-702 was generally well tolerated, but adverse events typical of vasodilators were common.” (E. Brass, ebrass@ucla.edu)

>>>PNN NewsWatch
* At the San Antonio Breast Cancer Conference, researchers today report progress toward a breast cancer vaccine. George Peoples, MD, reported that all patients vaccinated with a HER2 vaccine showed a rapid increase in immunologic response through month 4. Months after the vaccination series, vaccinated patients had a 50% reduction in breast cancer recurrence.
* Meeting yesterday, an FDA advisory panel voted 11–8 against proceeding with the U.S. Navy’s proposed Phase IIb/III, 1100-patient study of a controversial blood substitute developed by Biopure Corp.
Hemoglobin glutamer–250 (bovine) (Hemopure) is an oxygen-carrying product being tested for out-of-hospital treatment of hemorrhagic shock resulting from traumatic injury. Navy officials contend that Hemopure could be used in battlefield situations in which saline products are inadequate and blood products are not available. Committee members had doubts, citing concerns over whether data from trials of U.S. civilians would translate to combat injuries and questioning the safety of the product based on earlier trials. Committee members instead suggested that a prehospital Phase II/IIb study be conducted to test safety and efficacy in a smaller patient population, Biopure reported in a news release.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 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
Dec. 18, 2006 * Vol. 13, No. 241
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Dec. 16 issue of Lancet (www.thelancet.com; 2006; 368).
Initial HIV Regimens: For treatment-naive patients with HIV, initial treatment is equally appropriate with regimens containing a protease inhibitor plus nucleoside reverse transcriptase inhibitor or a non-nucleoside reverse transcriptase inhibitor plus NRTI (pp. 2125-35). Concluding that the two basic approaches should not be used in a three-class approach for early treatment of HIV infections, the FIRST trial investigators note: “NNRTI versus PI hazard ratios (HRs) for the composite endpoint, for AIDS or death, for death, and for virological failure were 1.02 (95% CI 0.79–1.31), 1.07 (0.80–1.41), 0.95 (0.66–1.37), and 0.66 (0.56–0.78), respectively. 1,196 patients were assessed for the three-class versus combined two-class primary endpoint. Mean change in CD4 cell count at or after 32 months was +234 cells per mm3 and +227 cells per mm3 for the three-class and the combined two-class strategies (p = 0.62), respectively. HRs (three-class vs combined two-class) for AIDS or death and virological failure were 1.15 (0.91–1.45) and 0.87 (0.75–1.00), respectively. HRs (three-class vs combined two-class) for AIDS or death were similar for participants with baseline CD4 cell counts of 200 cells per mm3 or less and of more than 200 cells per mm3 (p = 0.38 for interaction), and for participants with baseline HIV RNA concentrations less than 100,000 copies per mL and 100,000 copies per mL or more (p = 0·26 for interaction). Participants assigned the three-class strategy were significantly more likely to discontinue treatment because of toxic effects than were those assigned to the two-class strategies (HR 1.58; p < 0.0001).” (R. D. MacArthur, Wayne State U., Detroit; rdmacarthur@mac.com)
Multidrug-Resistant TB: Multidrug-resistant tuberculosis has emerged as a “serious challenge” in countries of the former Soviet Union and some provinces of China, a research study shows, even as the U.S. and other countries report decreasing prevalence of such strains (pp. 2142-54). Data gathered during the third round of the Global Project (1999–2002) show: “The median prevalence of resistance to any of the four antituberculosis drugs in new cases of tuberculosis identified in 76 countries or geographical settings was 10.2% (range 0.0–57.1). The median prevalence of multidrug resistance in new cases was 1.0% (range 0.0–14.2). Kazakhstan, Tomsk Oblast (Russia), Karakalpakstan (Uzbekistan), Estonia, Israel, the Chinese provinces Liaoning and Henan, Lithuania, and Latvia reported prevalence of multidrug resistance above 6.5%. Trend analysis showed a significant increase in the prevalence of multidrug resistance in new cases in Tomsk Oblast (p < 0.0001). Hong Kong (p = 0.01) and the USA (p = 0.0002) reported significant decreasing trends in multidrug resistance in new cases of tuberculosis.” (M. Raviglione, raviglionem@who.int)

>>>PNN NewsWatch
* FDA has approved revised labeling for aprotinin injection (Trasylol—Bayer) to strengthen its safety warnings and limit its approved usage to specific situations. The new labeling specifies that aprotinin should only be given to patients who are at an increased risk for blood loss and blood transfusion in the setting of coronary bypass graft surgery when patients undergo cardiopulmonary bypass. The changes also include a warning that aprotinin increases the possible risk for kidney damage, and suggest ways to manage and reduce the patient’s risk for hypersensitivity reactions.
* An FDA advisory panel on Friday recommended removal of acute bacterial exacerbation of chronic bronchitis and acute bacterial sinusitis as approved indications for
telithromycin (Ketek, Sanofi Aventis). Panelists voted that for pneumonia, benefits of the drug exceed risks, but the group would like to see a black-box warning cautioning of liver and other adverse effects.

>>>PNN JournalWatch
* Risk of Suicide During Treatment with Venlafaxine, Citalopram, Fluoxetine, and Dothiepin: Retrospective Cohort Study, in BMJ, doi: 10.1136/bmj.39041.445104.BE. Reprints: www.bmj.com/cgi/content/abstract/bmj.39041.445104.BEv1; A.. Rubino, RTI Health Solutions, Research Triangle Park, N.C.; arubino@rti.org
* Drug Interactions with Lipid-Lowering Drugs: Mechanisms and Clinical Relevance, in
Clinical Pharmacology & Therapeutics, 2006; 80: 565–81. Reprints: www.sciencedirect.com/science; P. J. Neuvonen, U. Helsinki, Helsinki, Finland; pertti.neuvonen@hus.fi

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Dec. 19, 2006 * Vol. 13, No. 242
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release article and Dec. 19 issue of the Annals of Internal Medicine (www.annals.org; 2006; 146).
Agalsidase-Beta for Fabry Disease: In 82 patients with advanced Fabry disease and mild to moderate kidney disease, agalsidase-beta therapy slowed progression of renal, cardiac, and cerebrovascular complications and death, compared with placebo (early release). Noting the potential benefits of earlier intervention with this agent before irreversible organ damage has occurred, the investigators note these results in the current study: “Thirteen (42%) of the 31 patients in the placebo group and 14 (27%) of the 51 patients in the agalsidase-beta group experienced clinical events. Primary intention-to-treat analysis that adjusted for an imbalance in baseline proteinuria showed that, compared with placebo, agalsidase beta delayed the time to first clinical event (hazard ratio, 0.47 [95% CI, 0.21 to 1.03]; P = 0.06). Secondary analyses of protocol-adherent patients showed similar results (hazard ratio, 0.39 [CI, 0.16 to 0.93]; P = 0.034). Ancillary subgroup analyses found larger treatment effects in patients with baseline estimated glomerular filtration rates greater than 55 mL/min per 1.73 m2 (hazard ratio, 0.19 [CI, 0.05 to 0.82]; P = 0.025) compared with 55 mL/min per 1.73 m2 or less (hazard ratio, 0.85 [CI, 0.32 to 2.3]; P = 0.75) (formal test for interaction, P = 0.09). Most treatment-related adverse events were mild or moderate infusion-associated reactions, reported by 55% of patients in the agalsidase-beta group and 23% of patients in the placebo group.” (R. J. Desnick, Mount Sinai Sch. of Med., New York; admin.desnick@mssm.edu)
Black Cohosh for Menopausal Symptoms: Used alone or in combination with other botanicals, black cohosh failed to alleviate vasomotor symptoms of menopause in a placebo-controlled study of 351 women (pp. 869-79). Compared in the Herbal Alternatives for Menopause Trial (HALT) were black cohosh 160 mg daily; multibotanical with black cohosh 200 mg daily and 9 other ingredients; multibotanical plus dietary soy counseling; conjugated equine estrogen 0.625 mg daily, with or without medroxyprogesterone acetate 2.5 mg daily; and placebo, with these results: “Vasomotor symptoms per day, symptom intensity, Wiklund Vasomotor Symptom Subscale score did not differ between the herbal interventions and placebo at 3, 6, or 12 months or for the average over all the follow-up time points (P > 0.05 for all comparisons) with 1 exception: At 12 months, symptom intensity was significantly worse with the multibotanical plus soy intervention than with placebo (P = 0.016). The difference in vasomotor symptoms per day between placebo and any of the herbal treatments at any time point was less than 1 symptom per day; for the average over all the follow-up time points, the difference was less than 0.55 symptom per day. The difference for hormone therapy versus placebo was –4.06 vasomotor symptoms per day for the average over all the follow-up time points (95% CI, –5.93 to –2.19 symptoms per day; P < 0.001).” (K. M. Newton, PhD, Group Health Cooperative, Seattle; newton.k@ghc.org)

>>>PNN NewsWatch
* Two more cases of fatal progressive multifocal leukoencephalopathy (PML) have been reported in patients on rituximab therapy (Rituxan, Genentech). PML is caused by reactivated JC virus, and latent forms of this virus are present in 80% of adults, FDA reports. The product labeling for Rituxan had been updated in Feb. 2006 to warn of PML in patients on this agent being treated for non-Hodgkin’s lymphoma. Now, two patients with systemic lupus erythematosus have died of PML after treatment with rituximab. In an advisory posted to its Web site yesterday, FDA says that patients on the drug who develop new neurologic signs or symptoms should be evaluated for PML.
*
FDA has approved Cyanokit (hydroxocobalamin, intravenous tubing and a sterile spike for reconstituting the drug product with saline; EMD Pharmaceuticals) for treatment of known or suspected cyanide poisoning. The product is intended for use in potential terrorist emergencies, and it was approved based on evidence of the drug’s effectiveness when tested in animals.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Dec. 20, 2006 * Vol. 13, No. 243
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Dec. 20 issue of JAMA (www.jama.com; 2006; 296).
Cancer Incidence with Kidney Transplantation: Immune suppression following kidney transplantation is a likely explanation for an increased risk of cancers following kidney transplantation, according to a population-based cohort study of 28,855 patients with end-stage kidney disease who underwent renal replacement therapy (RRT; pp. 2823-31). Assessing standardized incidence ratios (SIRs) of cancer corrected for demographic and geographic characteristics of participants, the investigators note: “The overall incidence of cancer, excluding nonmelanoma skin cancer and those cancers known to frequently cause end-stage kidney disease, was markedly increased after transplantation (n = 1,236; SIR, 3.27; 95% confidence interval [CI], 3.09–3.46). In contrast, cancer incidence was only slightly increased during dialysis (n = 870; SIR, 1.35; 95% CI, 1.27–1.45) and before RRT (n = 689; SIR, 1.16; 95% CI, 1.08–1.25). After transplantation, cancer occurred at significantly increased incidence at 25 sites, and risk exceeded 3-fold at 18 of these sites. Most of these cancers were of known or suspected viral etiology.”
The group concludes: “Because SIRs for most types of cancer were not increased before transplantation, immune suppression may be responsible for the increased risk. These data suggest a broader than previously appreciated role of the interaction between the immune system and common viral infections in the etiology of cancer.” (C. M. Vajdic, U. New South Wales, Darlinghurst, Australia;
cvajdic@nchecr.unsw.edu.au)
Vitamin D Levels and MS Risk: A trial of vitamin D supplementation in first-degree relatives of people with multiple sclerosis is justified by results of a case–control study among more than 7 million U.S. military personnel (pp. 2832-8). Comparing 257 case patients with MS and 2 matched control patients per case, investigators found a 41% decrease in MS risk among whites for every 50-nmol/L increase in 25-hydroxyvitamin D. MS risk was highest among those in the bottom quintile and lowest among those in the top quintile of 25-hydroxyvitamin D levels. Those in the top quintile had a 62% lower risk of MS compared with those in the bottom quintile. The inverse relation with multiple sclerosis risk was particularly strong for 25-hydroxyvitamin D levels measured before age 20 years. Among blacks and Hispanics, who had lower 25-hydroxyvitamin D levels than whites, no significant associations between vitamin D and multiple sclerosis risk were found. (A. Ascherio, aascheri@hsph.harvard.edu)

>>>PNN NewsWatch
* FDA yesterday proposed to amend the labeling regulations on over-the-counter (OTC) Internal Analgesic, Antipyretic, and Antirheumatic (IAAA) drug products to include important safety information regarding the potential for stomach bleeding and liver damage and when to consult a physician. OTC IAAA drug products contain acetaminophen and NSAIDs, including single- and multi-ingredient formulations intended for a variety of uses. For acetaminophen, new warnings would highlight the potential for liver toxicity, particularly when using acetaminophen in high doses, when taking more than one product with acetaminophen, and when taking the drug with moderate amounts of alcohol. For NSAID-containing products, new warnings would highlight the potential for stomach bleeding in persons over age 60, in persons who have had prior ulcers or bleeding, in persons who take a blood thinner, when taking more than one product containing an NSAID, when taken with moderate amounts of alcohol, and when taking for longer time than directed. For both types of products, the proposed regulations would require that the ingredients acetaminophen or the name of the NSAID medication be prominently identified on the product’s principal display panel of the immediate container, and the outer carton (if applicable). The proposal is scheduled to be published in the Dec. 26 Federal Register.
*
Celecoxib (Celebrex, Pfizer) has been approved by FDA for a new indication, relief of the signs and symptoms of juvenile rheumatoid arthritis in patients 2 years of age and older. FDA’s Arthritis Advisory Committee had voted 15–1 in favor of this new use.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Dec. 21, 2006 * Vol. 13, No. 244
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Dec. 21 issue of the New England Journal of Medicine (content.nejm.org; 2006; 355).
Ertapenem for Colorectal Surgery: The carbapenem antibiotic ertapenem proved more effective than cefotetan for prevention of surgical-site infection in patients undergoing elective colorectal surgery, but patients receiving the drug had more instances of Clostridium difficile infection (pp. 2640-51). These results were recorded during the 4 postoperative weeks: “Of the 1,002 patients randomly assigned to study groups, 901 (451 in the ertapenem group and 450 in the cefotetan group) qualified for the modified intention-to-treat analysis, and 672 (338 in the ertapenem group and 334 in the cefotetan group) were included in the per-protocol analysis. After adjustment for strata, in the modified intention-to-treat analysis, the rate of overall prophylactic failure was 40.2% in the ertapenem group and 50.9% in the cefotetan group (absolute difference, –10.7%; 95% confidence interval [CI], –17.1 to –4.2); in the per-protocol analysis, the failure rate was 28.0% in the ertapenem group and 42.8% in the cefotetan group (absolute difference, –14.8%; 95% CI, –21.9 to –7.5). Both analyses fulfilled statistical criteria for the superiority of ertapenem. In the modified intention-to-treat analysis, the most common reason for failure of prophylaxis in both groups was surgical-site infection: 17.1% in the ertapenem group and 26.2% in the cefotetan group (absolute difference, –9.1; 95% CI, –14.4 to –3.7). In the treated population, the overall incidence of Clostridium difficile infection was 1.7% in the ertapenem group and 0.6% in the cefotetan group (P = 0.22).” (K. M. F. Itani, kitani@med.va.gov)
An editorialist provides these questions for surgeons to ponder in deciding which prophylactic antibiotic to use (pp. 2693-5): “Traditionally, the choice of any antimicrobial agent for use as prophylaxis or treatment hinged on two key questions: Is the drug safe, and is it effective? Perhaps the concept of safety should include the risk of promotion of antimicrobial resistance that can harm the individual patient, as well as others in the community. Further data on the safety and efficacy of other widely used agents in colorectal surgery (derived from the strict criteria used by Itani et al.) would allow us to answer three important unanswered questions. Does the benefit of ertapenem as prophylaxis for colorectal surgery outweigh the risk of further promoting carbapenem resistance in the community? Is ertapenem as good as or better than commonly used regimens other than cefotetan? Finally, will the use of ertapenem as surgical prophylaxis aggravate an already worrisome and serious trend of infection caused by carbapenem-resistant organisms?” (D. J. Sexton, Duke U. Med. Ctr., Durham, N.C.)
CVD Biomarkers: Use of 10 emerging biomarkers for cardiovascular disease added only moderately to standard risk factors, report investigators (pp. 2631-9). Tested and adding little overall among 3,209 participants in the Framingham Offspring Study were levels of C-reactive protein, B-type natriuretic peptide, N-terminal pro–atrial natriuretic peptide, aldosterone, renin, fibrinogen, D-dimer, plasminogen-activator inhibitor type 1, and homocysteine; and the urinary albumin-to-creatinine ratio. (T. J. Wang, tjwang@partners.org)

>>>PNN NewsWatch
* Paliperidone, the principal active metabolite of risperidone, has been approved by FDA for treatment of schizophrenia. Developed by Alza and to be marketed by Janssen as Invega, paliperidone was studied in three 6-week, placebo-controlled trials. In 1,665 participating adults using doses of 3–15 mg a day, paliperidone relieved the symptoms of schizophrenia significantly more than placebo treatment. The recommended dose range for paliperidone is 3–12 mg/day. Among the commonly reported adverse events with paliperidone were restlessness, extrapyramidal symptoms, tachycardia, and sleepiness. Like other second-generation (atypical) antipsychotic agents, paliperidone has been associated with an increased mortality rate, compared with placebo, in elderly patients with dementia-related psychosis and should not be used in these patients.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 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
Dec. 22, 2006 * Vol. 13, No. 245
Providing news and information about medications and their proper use

>>>Allergy/Immunology Report
Source:
Dec. issue of the Journal of Allergy and Clinical Immunology (www.jacionline.org; 2006; 118).
Asthma & Influenza Vaccination: The use of inactivated and live attenuated influenza vaccine in children with asthma is reviewed (pp. 1199-206): “Exacerbations of asthma in children are usually triggered by virus infections. Many different respiratory viruses are associated with these exacerbations, but influenza viruses are frequently associated with those requiring hospitalization and are the only ones for which specific treatment and prophylaxis are available. Current studies have shown that influenza vaccines are safe for patients with asthma. The efficacy of inactivated influenza vaccines in preventing exacerbations of asthma has been questioned. The live attenuated influenza vaccine has been licensed recently in the United States, and studies have shown it to be safe and protective. A direct comparison of the inactivated and live attenuated influenza vaccines in children with asthma demonstrated superior protection by the latter. Live attenuated influenza vaccine, given by nasal spray, is better accepted by children for annual vaccination and is easier to administer. Universal vaccination of all children in school-based clinics will facilitate control of epidemic influenza and provide an infrastructure for control of future influenza pandemics.” (W. P. Glezen, Baylor Coll. of Med., Houston)
Identifying Children with Severe Asthma: Severe asthma should be suspected in children with exacerbations that have poor response to inhaled corticosteroids, airway obstruction, and high measurements of exhaled nitric oxide, conclude authors of a 75-patient study (pp. 1218-25). Looking at children with a median age of 10 years, the investigators provide these results based on longitudinal follow-up of 28 patients over 6 months: “Children with severe versus mild-to-moderate asthma had more symptoms, greater airway obstruction, more gas trapping, and increased bronchial responsiveness to methacholine. Subjects with severe asthma also had higher concentrations of FENO and significantly greater sensitization to aeroallergens. With long-term study, both the reduction in FEV1 and increase in FENO persisted in the severe versus mild-to-moderate group. Furthermore, despite adjustments in ICS doses, the frequency of exacerbations was significantly higher in subjects with severe (83%) versus mild-to-moderate asthma (43%).” (A. M. Fitzpatrick, Emory U., Atlanta)
Early Vitamin Therapy & Allergy: Use of water-soluble forms of vitamins A and D produced more allergies in 4,089 children over the first 4 years of life than did formulations in peanut oil (pp. 1299-304). Using questionnaires from the 90% of parents who responded at year 4 and allergen-specific IgE testing in 2,614 participating children, the authors note: “Vitamins A and D were given to 98% of the children in infancy, and vitamins based in peanut oil dominated (90%). Children supplemented with vitamins A and D in water-soluble form during the first year of life had an almost 2-fold increased risk of asthma (adjusted odds ratio [OD], 2.18; 95% CI, 1.45–3.28), food hypersensitivity (adjusted OR, 1.89; 95% CI, 1.33–2.65), and sensitization to common food and airborne allergens (adjusted OR, 1.88; 95% CI, 1.34–2.64) at age 4 years compared with those receiving vitamins in peanut oil. No increased risk of IgE antibodies to peanut was seen in children receiving vitamins in peanut oil.” (I. Kull, Dept. of Occupational and Environmental Health, Stockholm, Sweden)
Biologic Immune Modifiers: The “trials and tribulations” associated with use of biologic immune modifiers are explored in a review article (pp. 1209-15). “As we learn how to modify and alter the inflammatory and immune processes with these new biologic agents, clinicians will enter a new era of treatment options available for their patients with allergic disorders,” the author concludes. (M. Ballow, State U. New York, Buffalo)

>>>PNN NewsWatch
* PNN will not be published on Mon. and Tues., Dec. 25–26, Christmas holidays.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Dec. 27, 2006 * Vol. 13, No. 246
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Dec. 27 issue of JAMA (www.jama.com; 2006; 296).
Interrupting Alendronate Therapy After Menopause: Whether to stop or continue alendronate therapy after 5 years of postmenopausal prophylaxis with alendronate is still unclear, despite the addition of new evidence from the Fracture Intervention Trial (FIT; pp. 2927-38). Among 1,099 women who had taken alendronate for 5 years in FIT, these bone mineral density and fracture results were observed when the women were randomized to either continued alendronate at doses of 5 or 10 mg/day or placebo: “Compared with continuing alendronate, switching to placebo for 5 years resulted in declines in BMD at the total hip (–2.4%; 95% confidence interval [CI], –2.9% to –1.8%; P < .001) and spine (–3.7%; 95% CI, –4.5% to –3.0%; P < .001), but mean levels remained at or above pretreatment levels 10 years earlier. Similarly, those discontinuing alendronate had increased serum markers of bone turnover compared with continuing alendronate: 55.6% (P < .001) for C-telopeptide of type 1 collagen, 59.5% (P < .001) for serum N = propeptide of type 1 collagen, and 28.1% (P < .001) for bone-specific alkaline phosphatase, but after 5 years without therapy, bone marker levels remained somewhat below pretreatment levels 10 years earlier. After 5 years, the cumulative risk of nonvertebral fractures (RR, 1.00; 95% CI, 0.76–1.32) was not significantly different between those continuing (19%) and discontinuing (18.9%) alendronate. Among those who continued, there was a significantly lower risk of clinically recognized vertebral fractures (5.3% for placebo and 2.4% for alendronate; RR, 0.45; 95% CI, 0.24–0.85) but no significant reduction in morphometric vertebral fractures (11.3% for placebo and 9.8% for alendronate; RR, 0.86; 95% CI, 0.60–1.22). A small sample of 18 transilial bone biopsies did not show any qualitative abnormalities, with bone turnover (double labeling) seen in all specimens.” (D. M. Black, dblack@psg.ucsf.edu)
Hip Fracture with PPI Therapy: In a nested case–control analysis of data from the U.K. General Practice Research Database, long-term therapy with proton-pump inhibitors was associated with an increased risk of hip fracture, especially when high doses of PPIs were used (pp. 2947-53). “There were 13,556 hip fracture cases and 135,386 controls,” the authors note. “The adjusted odds ratio (AOR) for hip fracture associated with more than 1 year of PPI therapy was 1.44 (95% confidence interval [CI], 1.30–1.59). The risk of hip fracture was significantly increased among patients prescribed long-term high-dose PPIs (AOR, 2.65; 95% CI, 1.80–3.90; P < .001). The strength of the association increased with increasing duration of PPI therapy (AOR for 1 year, 1.22 [95% CI, 1.15–1.30]; 2 years, 1.41 [95% CI, 1.28–1.56]; 3 years, 1.54 [95% CI, 1.37–1.73]; and 4 years, 1.59 [95% CI, 1.39–1.80]; P < .001 for all comparisons).” The authors attribute this finding to a decreased dissolution of calcium in gastric juices whose acidity is decreased by PPI therapy, and they offer this advice to clinicians: “For elderly patients who require long-term and particularly high-dose PPI therapy, it may be prudent to reemphasize increased calcium intake, preferably from a dairy source, and coingestion of a meal when taking insoluble calcium supplements.” (Y-X Yang, yangy@mail.med.upenn.edu)

>>>PNN JournalWatch
* Estimation of Potential Global Pandemic Influenza Mortality on the Basis of Vital Registry Data from the 1918–20 Pandemic: a Quantitative Analysis, in Lancet, 2006; 368: 2211–8. Reprints: www.thelancet.com/journals/lancet/article/PIIS0140673606698954/abstract; C. J. L. Murray; christopher_murray@harvard.edu
* Alcohol Abuse in the Critically Ill Patient, in
Lancet, 2006; 368: 2231–42. Reprints: www.thelancet.com/journals/lancet/article/PIIS0140673606694907/abstract; M. Moss, U. Colorado Health Sci. Ctr., Denver; Marc.Moss@uchsc.edu
* Triglycerides and the Risk of Coronary Heart Disease. 10,158 Incident Cases Among 262,525 Participants in 29 Western Prospective Studies, in
Circulation, doi: 10.1161/CIRCULATIONAHA.106.637793. Reprints: circ.ahajournals.org/cgi/content/abstract/CIRCULATIONAHA.106.637793v1; J. Danesh, U. Cambridge. Cambridge, U.K.; john.danesh@phpc.cam.ac.uk
* Cardiopulmonary Resuscitation: History, Current Practice, and Future Direction, in
Circulation, 2006; 114: 2839–49. Reprints: http://circ.ahajournals.org/cgi/content/full/114/25/2839; J. A. Cooper.

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Dec. 28, 2006 * Vol. 13, No. 247
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Dec. 28 issue of the New England Journal of Medicine (content.nejm.org; 2006; 355).
Lapatinib for Breast Cancer: In 324 women with locally advanced or metastatic breast cancer that had progressed after treatment with an anthracycline, a taxane, and trastuzumab, lapatinib was a useful addition to capecitabine treatment (pp. 2733-43). Lapatinib 1,250 mg/day continuously and/or capecitabine 2,000 mg/sq m on days 1–14 of a 21-day cycle produced these results: “The interim analysis of time to progression met specified criteria for early reporting on the basis of superiority in the combination-therapy group. The hazard ratio for the independently assessed time to progression was 0.49 (95% confidence interval, 0.34 to 0.71; P < 0.001), with 49 events in the combination-therapy group and 72 events in the monotherapy group. The median time to progression was 8.4 months in the combination-therapy group as compared with 4.4 months in the monotherapy group. This improvement was achieved without an increase in serious toxic effects or symptomatic cardiac events.” (C. E. Geyer, Allegheny Genl. Hosp., Pittsburgh; cgeyer@wpahs.org)
An editorialist describes the economic and ethical dilemmas presented by expensive targeted therapies for breast cancer that prolong life but do not cure the disease (pp. 2783-5): “Almost all currently approved targeted agents are used in conjunction with conventional chemotherapy regimens, thereby adding costs to the health care system. When the goal is to improve the chance for a cure, these new treatments seem well worth the expenditure. However, when the goal is to improve the quality of life or delay the time to disease progression by several months, as it is with many treatments for metastatic breast cancer, it is less clear whether the health care system can and should bear these expenses. In the current health care environment, not all patients who are likely to benefit from the new treatments have access to them. Government leaders and the public, with guidance from health care professionals, now face hard decisions regarding the use of innovative and expensive treatments for metastatic disease. Before we celebrate the advent of new ways of treating cancer, we must ensure that all who might benefit from these treatments have a chance to receive them.” (H. B. Muss, U. Vermont, Burlington)
Antidepressants & the Teenage Suicide Quandary: The uncertainty about suicide risk in adolescents being treated with antidepressants is the focus of a Perspective article (pp. 2722-3). But the potential increase in suicidality is just one of many problems in the treatment of depression in the age group, the writer notes: “Among 10,000 children and adolescents who begin taking antidepressants for depression, approximately 6 will die by suicide during the next 6 months, and another 30 will be hospitalized after a serious suicide attempt. For adults, the corresponding numbers are 4 suicide deaths and 10 hospitalizations for suicide attempts. Of those 10,000 children and adolescents, approximately 3,000 will stop taking their medication within a few weeks, 4,000 will never return for a follow-up visit, and 6,000 will not recover from depression during the next 6 months. Although the rates of antidepressant use have increased dramatically among both adults and adolescents during the past 20 years, the disappointing quality and outcomes of depression treatment have changed little. Our treatment of depression is growing wider, but it is often only inches deep.” (G. E. Simon, Group Health Cooperative, Seattle)
Team Approach to Decreasing Catheter-Related Septicemia: An evidence-based approach to decreasing catheter-related bloodstream infections proved effective, reducing the rates by up to 66% in 108 participating intensive-care units (pp. 2725-32). Using coaching strategies and local team leaders to champion the cause, the approach emphasized hand washing, using full-barrier precautions during the insertion of central venous catheters, cleaning the skin with chlorhexidine, avoiding the femoral site if possible, and removing unnecessary catheters. (P. Pronovost, Johns Hopkins U., Baltimore)

PNN Pharmacotherapy Line is published via e-mail each business day except 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
Dec. 29, 2006 * Vol. 13, No. 248
Providing news and information about medications and their proper use

>>>PNN’s Top 10 of 2006
Doors closed and doors opened during 2006, for both pharmacists and the medications they work with. Here’s how the year that was looked through the pages of PNN.
1. Medicare Part D: While many complained of defects when the Medicare Part D began (Mar. 30), services were implemented reasonably well, given the program’s size and complexity (June 1). The question mark for pharmacists was just how much difference medication therapy management services would make in their business models in the long run (Dec. 1).
2. Recognition of Pharmacists’ Capabilities: Even as MTM services lagged, several events converged to increase recognition of pharmacists as both effective gatekeepers and competent clinical practitioners. FDA placed a dual-status emergency contraceptive in the profession’s hands, while Congress combatted the meth epidemic by moving pseudoephedrine products behind pharmacy counters nationwide (Aug. 25). The actions moved the country closer than ever to creating the third class of drugs that has worked well in Europe. Complimenting these dispensing-oriented trends, the medical literature was filled with articles of pharmacists’ impact on care of a variety of patient types, including ambulatory elderly patients (Nov. 15), inpatients (May 9), patients being discharged from hospitals (Mar. 14), and patients with diabetes (Jul. 26).
3. New Meds for Diabetes: Building on the clinical acceptance of exenatide, new agents for diabetes provided clinicians with unique ways to counter this epidemic. Sitagliptin was launched (Oct. 18), and inhaled insulin finally made its much-anticipated debut (Jan. 30). Other agents are on the way (Sept. 15), if safety concerns at FDA are allayed (Nov. 22).
4. New Vaccines: The number of new vaccines was unusual in 2006, with zoster (May 30), human papilloma virus (June 9), and rotavirus vaccines (Feb. 6) being licensed along with a fifth brand of influenza vaccine (Oct. 6). Researchers were testing vaccines for avian influenza (Feb. 13, Mar. 30, May 15, Sept. 11) in preparation for a possible pandemic, and use of vaccines was being explored for conditions such as breast cancer (Dec. 15).
5. New Drugs That Didn’t Make It: The failure of a couple of promising agents to make it out of clinical testing was disappointing. Rimonabant, a cannabinoid blocker that might help with obesity, tests well (Feb. 15, May 10, Oct. 30), so perhaps soon the clinical data will appease FDA reviewers. The HDL cholesterol–raising agent torcetrapib had been studied for years, but increased mortality in a large Phase III trial caused Pfizer to pull the plug on the agent (Dec. 4).
6. FDA Shows Its Age: FDA, which celebrated its 100th anniversary during 2006, was already scheduled for Congressional scrutiny in 2007 (Apr. 24, Oct. 10), but Democratic control of the legislative branch (Nov. 8) could increase the volatility of the upcoming review. A new commissioner is finally in place at the agency (Aug. 1), but fundamental changes in the way FDA approves and monitors drugs may be in the offing.
7. Drug Efficacy, Safety: With drug safety having been such a focus in late 2004 and 2005, FDA issued dozens of alerts and warnings during 2006. Concern continued over suicidality with antidepressants (Dec. 14), and the ineffectiveness of oral phenylephrine (Jul. 21) was a factor in the launch of recent TV ads noting that Claritin D kept pseudoephedrine as its decongestant even though it meant the product must be obtained from behind pharmacy counters.
8. Med Errors: The Institute of Medicine issued another report in its ongoing “Quality Chasm” series. “Preventing Medication Errors” highlighted the roles that pharmacists should play in addressing this vexing problem (Jul. 21)
9. Alternative Meds Falter: As studies of herbal agents and other dietary supplements continued to emerge, the relative ineffectiveness of some popular agents—vitamins/minerals (May 18) and black cohosh (Dec. 19) in particular— was exposed.
10. Microbes’ Strength: The age-old battle between man and microbe continued, and methicillin-resistant Staphylococcus aureus seemed to be winning at times (Mar. 7, June 26, Aug. 17, Oct. 4).

>>>PNN NewsWatch
* PNN will not be published on Mon., Jan. 1, New Year’s 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.