Mar 2008

PNN Quarterly File—First Quarter 2008

PNN Pharmacotherapy Line
Jan. 2, 2008 * Vol. 15, No. 1
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Jan. 2 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2008; 299).
Testosterone Effects in Aging Men: Functional status and cognition were not improved by 6 months’ testosterone supplementation in 207 men with low normal levels of the hormone, but the male hormone improved lean body mass and had mixed metabolic effects, investigators report (pp. 39-52). Comparing testosterone undecenoate 80 mg with placebo, the researchers found: “During the study, lean body mass increased and fat mass decreased in the testosterone group compared with the placebo group but these factors were not accompanied by an increase of functional mobility or muscle strength. Cognitive function and bone mineral density did not change. Insulin sensitivity improved but high-density lipoprotein cholesterol decreased; by the end of the study, 47.8% in the testosterone group vs 35.5% in the placebo group had the metabolic syndrome (P = .07). Quality-of-life measures were no different except for one hormone-related quality-of-life measure that improved. No negative effects on prostate safety were detected.” (M. H. Emmelot-Vonk, U. Med. Ctr., Utrecht, the Netherlands; m.h.emmelotvonk@umcutrecht.nl)
Trends in Opioid Prescribing: Following national quality improvement initiatives in the late 1990s, opioid prescribing for patients making a pain-related visit to the emergency department improved but race-related differences remained, according to data from 1993 through 2005 (pp. 70-8). Researchers analyzed data from the National Hospital Ambulatory Medical Care Survey, finding: “Pain-related visits accounted for 156 729 of 374 891 (42%) emergency department visits. Opioid prescribing for pain-related visits increased from 23% (95% confidence interval [CI], 21%–24%) in 1993 to 37% (95% CI, 34%–39%) in 2005 (P < .001 for trend), and this trend was more pronounced in 2001–2005 (P = .02). Over all years, white patients with pain were more likely to receive an opioid (31%) than black (23%), Hispanic (24%), or Asian/other patients (28%) (P < .001 for trend), and differences did not diminish over time (P = .44), with opioid prescribing rates of 40% for white patients and 32% for all other patients in 2005. Differential prescribing by race/ethnicity was evident for all types of pain visits, was more pronounced with increasing pain severity, and was detectable for long-bone fracture and nephrolithiasis as well as among children. Statistical adjustment for pain severity and other factors did not substantially attenuate these differences, with white patients remaining significantly more likely to receive an opioid prescription than black patients (adjusted odds ratio, 0.66; 95% CI, 0.62–0.70), Hispanic patients (0.67; 95% CI, 0.63–0.72), and Asian/other patients (0.79; 95% CI, 0.67–0.93).” (M. J. Pletcher, mpletcher@epi.ucsf.edu)

>>>PNN NewsWatch
* FDA last week approved a synthetic starch product, Voluven ((6% hydroxyethyl starch 130/0.4 in 0.9% sodium chloride injection; Fresenius Kabi, Bad Homburg, Germany), for prevention and treatment of loss of blood volume during and after surgery. It should not be used in patients with hypersensitivities to hydroxyethyl starch, fluid overload, kidney failure not related to low blood volume, hypernatremia, hyperchloremia, or intracranial bleeding, or in those on dialysis.
* Several
dietary supplements marketed for treatment of erectile dysfunction and sexual enhancement contain sildenafil, FDA is warning consumers and health professionals. Included in the warning are Super Shangai (sic), Strong Testis, Shangai Ultra, Shangai Ultra X, Lady Shangai, and Shangai Regular (also known as Shangai Chaojimengnan). These products are illegal, FDA warned, and may interact detrimentally with prescription drug products containing nitrates.

>>>PNN JournalWatch
* Use of Epoetin and Darbepoetin in Patients with Cancer: 2007 American Society of Clinical Oncology/American Society of Hematology Clinical Practice Guideline Update, in Journal of Clinical Oncology, 2007; 10.1200/JCO.2007.14.3396
* Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy: Update Regarding Thiazolidinediones: A Consensus Statement from the American Diabetes Association and the European Association for the Study of Diabetes, in
Diabetes Care, 2008; 31: 173–5. Reprints: D. M. Nathan, dnathan@partners.org

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 3, 2008 * Vol. 15, No. 2
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Jan. 3 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2008; 358).
Capecitabine, Oxaliplatin for Advanced Esophagogastric Cancer: Among 1,002 patients with previously untreated esophagogastric cancer, capecitabine and oxaliplatin proved as effective as fluorouracil and cisplatin, respectively, researchers report (pp. 36-46). Comparing triple therapy with epirubicin and cisplatin plus either fluorouracil (ECF) or capecitabine (ECX) or triple therapy with epirubicin and oxaliplatin plus either fluorouracil (EOF) or capecitabine (EOX), the Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom found: “For the capecitabine–fluorouracil comparison, the hazard ratio for death in the capecitabine group was 0.86 (95% confidence interval [CI], 0.80 to 0.99); for the oxaliplatin–cisplatin comparison, the hazard ratio for the oxaliplatin group was 0.92 (95% CI, 0.80 to 1.10). The upper limit of the confidence intervals for both hazard ratios excluded the predefined noninferiority margin of 1.23. Median survival times in the ECF, ECX, EOF, and EOX groups were 9.9 months, 9.9 months, 9.3 months, and 11.2 months, respectively; survival rates at 1 year were 37.7%, 40.8%, 40.4%, and 46.8%, respectively. In the secondary analysis, overall survival was longer with EOX than with ECF, with a hazard ratio for death of 0.80 in the EOX group (95% CI, 0.66 to 0.97; P = 0.02). Progression-free survival and response rates did not differ significantly among the regimens. Toxic effects of capecitabine and fluorouracil were similar. As compared with cisplatin, oxaliplatin was associated with lower incidences of grade 3 or 4 neutropenia, alopecia, renal toxicity, and thromboembolism but with slightly higher incidences of grade 3 or 4 diarrhea and neuropathy.” (D. Cunningham, Royal Marsden Hosp., London)
Mechanisms of Depression: Major depressive disorder can result from either monoamine depletion or abnormal glucocorticoid function, according to authors of a review article (pp. 55-68). Noting that the etiology of depression in middle-aged or elderly patients may relate to cardiovascular disease but that genetics is more important for patients presenting in their late teens or early 20s with severe depression, the writers conclude: “Avoidance of premature closure on any one scientific theory of the mechanism of depression will best serve the search for new, more effective treatments. It is likely that the pathogenesis of acute depression is different from that of recurrent or chronic depression, which is characterized by long-term declines in function and cognition. Mood can be elevated (by stimulants, by brain stimulation, or by ketamine) or depressed (by monoamine depletion in recovered patients) for short periods, but longer-term improvement may require reduction of the abnormal glucocorticoid function induced by stress or increases in brain neurotrophic factors.” (R. H. Belmaker, Beersheba Mental Health Ctr., Beersheba, Israel; belmaker@bgu.ac.il)

>>>PNN NewsWatch
* The first rapid blood test for methicillin-resistant Staphylococcus aureus has been cleared for marketing by FDA. The BD GeneOhm StaphSR Assay (BD Diagnostics) uses molecular methods to identify which patients are colonized with a MRSA strain and which have a S. aureus strain with usual antibiotic sensitivities. The test provides results within 2 hours, enabling clinicians to implement specific rather than empiric therapies. FDA cleared the BD GeneOhm StaphSR assay based on the results of a multicenter trial during which the new assay identified 100% of MRSA-positive specimens and 98% percent of garden-variety S. aureus specimens. The test should only be used in those suspected of having a staph infection and cannot be used to monitor treatment. BD has recently submitted subsequent applications to FDA for this assay to add nasal swab and wound claims. BD is also developing rapid tests for the detection of vanA and vanB genes associated with vancomycin-resistant enterococci and the toxin gene associated with Clostridium difficile, the company reports.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 4, 2008 * Vol. 15, No. 3
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Jan. issue of Diabetes Care (http://care.diabetesjournals.org/current.shtml; 2008; 31).
Insulin Dosing Regimens: Significantly improved glycemic parameters were produced by prandial premixed therapy (PPT) with insulin lispro mix 50/50, compared with basal bolus therapy (BBT) with insulin glargine at bedtime plus mealtime lispro (pp. 20-5). In an open-label, 24-week study of 374 patients with type 2 diabetes, investigators sought but failed to demonstrate that the PPT regimen was not inferior to BBT (that is, did not produce a 0.3% greater change in A1C). However, PPT significantly improved A1C levels (6.78% versus 6.95%), percentages of patients achieving A1C of 7% or less (54% versus 69%), and percentages of patients achieving A1C of 6.5% or less (35% versus 50%). (J. Rosenstock, Dallas Diabetes and Endocrine Ctr. at Medical City, Dallas; juliorosenstock@dallasdiabetes.com)
Vildagliptin in Impaired Glucose States: Two research studies explore the effects of the dipeptidyl peptidase-IV inhibitor vildagliptin in patients with impaired glucose states.
Vildagliptin reduced postprandial glucose excursions, measured by the change in area under the glucose–time curve from 0 to 2 hours, by 32% in a 12-week study of 179 patients with impaired glucose tolerance (pp. 30-5). Comparing 50-mg daily doses of the investigational agent with placebo, the authors found significant increases in intact glucagon-like peptide 1 and gastric inhibitory polypeptide and decreases in glucagon but no significant changes in postprandial insulin levels. (M. A. Baron,
michelle.baron@novartis.com)
Insulin sensitivity and beta-cell function were significantly improved by vildagliptin in 22 patients with impaired fasting glucose, compared with baseline, in a single-blind study (pp. 108-13). Concluding that the drug may prevent the progression to diabetes in high-risk subjects, the researchers report these results with a 2-week run-in phase of placebo, 8 weeks of treatment with vildagliptin 100 mg daily, and 2 weeks of a placebo wash-out phase: “Fasting plasma glucose did not change after 6 weeks of vildagliptin treatment. With treatment, mean ± SEM [acute insulin response to glucose] increased from 224 ± 44 to 286 ± 52 pmol/l (P < 0.05), and [insulin sensitivity index] improved from 2.8 ± 0.5 to 3.5 ± 0.5 x 10
–5 • min–1 • pmol–1 • l (P < 0.01), resulting in an increase in the disposition index from 688 ± 180 to 1,164 ± 318 x 10–5/min (P < 0.05). These effects were not sustained after washout. During [a 2-hour meal tolerance test], the incremental area under the glucose curve was significantly decreased after treatment (240 ± 15 vs. 191 ± 14 mmol • l–1 · min–1; P = 0.002), but this effect was not sustained after washout.” (K. M. Utzschneider, kutzschn@u.washington.edu)
Cinnamon? No Thanks: In a meta-analysis of five randomized controlled trials, cinnamon did not significantly improve A1C, fasting blood glucose, or lipid parameters in patients with type 1 or type 2 diabetes (pp. 41-3). “Subgroup and sensitivity analyses did not significantly change the results,” the authors added. (C. I. Coleman, Hartford Hosp., Hartford, Conn.; ccolema@harthosp.org)

>>>PNN NewsWatch
* Two more studies have shown an increased risk of death or more rapid tumor growth among patients with breast or advanced cervical cancers who received erythropoiesis-stimulating agents for anemia during chemotherapy, FDA said yesterday. In light of a total of eight studies showing similar effects of ESAs in patients with breast, non-small cell lung, head and neck, lymphoid or cervical cancers, FDA indicated that it will “revisit the risks and benefits of using ESAs in patients with chemotherapy-induced anemia at a public advisory committee meeting in the next few months.”
* The
xTAG Respiratory Viral Panel (Luminex Molecular Diagnostics), just cleared by FDA for marketing, simultaneously detects and identifies 12 respiratory viruses, including respiratory syncytial virus subtype A and B; parainfluenza 1, 2, and 3; rhinovirus; and adenovirus. It is also the first test that detects and differentiates influenza A subtypes H1 and H3.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 7, 2008 * Vol. 15, No. 4
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Jan. 5 issue of Lancet (www.thelancet.com; 2008; 371).
Adjuvant Chemotherapy in Breast Cancer: Long-term administration of adjuvant chemotherapy begun between 1972 and 1993 was safe and effective for reducing 10-year mortality rates in 6,000 women with estrogen-poor breast cancer, according to a meta-analysis (pp. 29-40). The 46 earlier trials used non-taxane-based polychemotherapy, while the later 50 trials typically included tamoxifen. Results showed the following: “Polychemotherapy significantly reduced recurrence, breast cancer mortality, and death from any cause, in those younger than 50 years and those aged 50–69 years at entry into trials of polychemotherapy versus not. In those aged younger than 50 years (1,907 women, 15% node-positive), the 10-year risks were: recurrence 33% versus 45% (ratio of 10-year risks 0.73, 2p <0.00001), breast cancer mortality 24% versus 32% (ratio 0.73, 2p = 0.0002), and death from any cause 25% versus 33% (ratio 0.75, 2p = 0.0003). In women aged 50–69 years (3,965 women, 58% node-positive), the 10-year risks were: recurrence 42% versus 52% (ratio 0.82, 2p <0.00001), breast cancer mortality 36% versus 42% (ratio 0.86, 2p = 0.0004), and death from any cause 39% versus 45% (ratio 0.87, 2p = 0.0009). Few were aged 70 years or older. Tamoxifen had little effect on recurrence or death in women who were classified in these trials as having ER-poor disease, and did not significantly modify the effects of polychemotherapy.” (EBCTCG Secretariat, Oxford, U.K.; bc.overview@ctsu.ox.ac.uk)
At-Home Amoxicillin for Pneumonia: In a randomized, open-label equivalency trial of 2,037 children with severe pneumonia without underlying complications, high-dose oral amoxicillin administered at home was equivalent to hospitalization and parenteral ampicillin for treatment (pp. 49-56). Conducted in Pakistan, the trial identified these outcomes when amoxicillin 80–90 mg/kg/day in two doses was compared with in-hospital injectable ampicillin 100 mg/kg/day in four doses: “There were 87 (8.6%) treatment failures in the hospitalised group and 77 (7.5%) in the ambulatory group (risk difference 1.1%; 95% CI −1.3 to 3.5) by day 6. Five (0.2%) children died within 14 days of enrolment, one in the ambulatory group and four in the hospitalised group. In each case, treatment failure was declared before death and the antibiotic had been changed. None of the deaths were considered to be associated with treatment allocation; there were no serious adverse events reported in the trial.” (D. M. Thea, Boston U., Boston; dthea@bu.edu\)
Antipsychotic Agents for Aggression: Used for treating aggression in 86 nonpsychotic patients with intellectual disability, neither haloperidol nor risperidone was significantly more effective at placebo, report authors of a 26-week study (pp. 57-63). “80 patients had adherence of 80% or more to prescribed drug,” note the authors. “Aggression decreased substantially with all three treatments by 4 weeks, with the placebo group showing the greatest change (median decrease in [modified overt aggression scale] score after 4 weeks = 9 [95% CI 5–14] for placebo, 79% from baseline; 7 [4–14] for risperidone, 58% from baseline; 6.5 [5–14] for haloperidol, 65% from baseline; p = 0.06). Furthermore, although no important differences between the treatments were recorded, including adverse effects, patients given placebo showed no evidence at any time points of worse response than did patients assigned to either of the antipsychotic drugs.” (P. Tyrer, Imperial Coll., London; p.tyrer@imperial.ac.uk)

>>>PNN JournalWatch
* Viral Meningitis, in BMJ, 2008; 336: 36–40. Reprints: E. MacMahon, Guy’s and St. Thomas’ NHS Foundation Trust, London; eithne.macmahon@gstt.nhs.uk
* Recommended Immunization Schedules for Children and Adolescents—United States, 2008, in
Pediatrics, 2008; 121: 219–20. Reprints: Committee on Infectious Diseases.
* Perimenopausal Depression, in
American Journal of Psychiatry, 2008; 165: 23–7. Reprints: B. L. Parry.
* Host–Bacterial Interactions in
Helicobacter pylori Infection, in Gastroenterology, 2008; 134: 306–23. Reprints: E. M. El-Omar, Aberdeen U., Aberdeen, Scotland.
* Exploring Relative Mortality and Epoetin Alfa Dose Among Hemodialysis Patients, in
American Journal of Kidney Diseases, 2008; 51: 62–70. Reprints: B. D. Bradbury; bradbury@amgen.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 © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 8, 2008 * Vol. 15, No. 5
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release article from and Jan. 1 issue of the Annals of Internal Medicine (http://www.annals.org/current.shtml; 2008; 148).
Medicare Part D & Drug Utilization: During the initial months of the Medicare Part D benefit, those enrolled in the plan had increased rates of drug utilization and paid less out of pocket for their medications, according to an analysis conducted using prescription information from Walgreens (early release). Analyzing prescriptions obtained in Sept. 2004 to Apr. 2007 and pharmacy claims data for both brick-and-mortar and mail-service prescriptions for both those enrolled in the plan and control nonenrollees (those aged 60–63 who were not eligible for Part D at the time), the researchers found: “During the penalty-free Part D enrollment period (January 2006 to May 2006), average monthly drug utilization increased by 1.1% (95% CI, 0.5% to 1.7%; P < 0.001), and out-of-pocket expenditures decreased by 8.8% (CI, 6.6% to 11.0%; P < 0.001). After enrollment stabilized (June 2006 to April 2007), average monthly drug utilization increased 5.9% (CI, 5.1% to 6.7%; P < 0.001) and out-of-pocket expenditures decreased 13.1% (CI, 9.6% to 16.6%; P = 0.003). Compared with eligible nonenrollees, enrollees had higher out-of-pocket expenditures and utilization at baseline but experienced significantly larger decreases in expenditures and increases in utilization after enrollment.” More study is needed to assess the impact of increased medication use on clinical outcomes, the authors conclude. (G. C. Alexander, galexand@uchicago.edu)
Epinephrine Ratio Labeling & Dosing Errors: Medication errors are more likely when concentrations of epinephrine are expressed as ratios rather than mass per volume, a simulation study concludes (pp. 11-4). In a randomized, blinded, controlled study, 28 physicians were asked to manage a simulated pediatric acute anaphylaxis scenario using epinephrine ampules labeled with mass concentration (1 mg in 1 mL) or a ratio (1 mL of a 1:1000 solution), with these results: “Compared with providers using ampules with mass concentration labels, those using ratio labels gave more epinephrine (adjusted mean dose, 213 mcg above target [95% CI, 76.4 to 350.1 mcg]; P = 0.003), and took longer to do so (adjusted mean delay, 91 seconds, [CI, 61.0 to 122.1 seconds]; P ≤ 0.0001).” (D. W. Wheeler, U. Cambridge, Cambridge, U.K.; dww21@cam.ac.uk)
Benefits, Risks of Angiotensin Inhibition: Two review articles and an editorial, released previously in advance of print publication, explore the safety and efficacy of ACE inhibitors and angiotensin-receptor blockers in patients with hypertension and/or proteinuria (pp. 16-29, 30-48, 76-7). Caution is merited when these drugs are used in those with late-stage kidney disease, the editorialist concludes.

>>>PNN NewsWatch
* Severe and sometimes incapacitating bone, joint, and/or muscle pain can occur in patients taking bisphosphonates, FDA cautioned yesterday. Although severe musculoskeletal pain is included in the prescribing information for all bisphosphonates, the association between bisphosphonates and severe musculoskeletal pain may be overlooked by health professionals, the agency said, delaying diagnosis, prolonging pain and/or impairment, and necessitating the use of analgesics. The severe musculoskeletal pain may occur within days, months, or years after starting a bisphosphonate. Some patients have reported complete relief of symptoms after discontinuing the bisphosphonate, whereas others have reported slow or incomplete resolution. The risk factors for and incidence of severe musculoskeletal pain associated with bisphosphonates are unknown. This severe musculoskeletal pain is in contrast to the acute phase response characterized by fever, chills, bone pain, myalgias, and arthralgias that sometimes accompanies initial administration of intravenous bisphosphonates and may occur with initial exposure to once-weekly or once-monthly doses of oral bisphosphonates. The symptoms related to the acute phase response tend to resolve within several days with continued drug use. FDA concluded that health professionals should consider whether bisphosphonate use might be responsible for severe musculoskeletal pain in patients who present with these symptoms and consider temporary or permanent discontinuation of the drug.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 9, 2008 * Vol. 15, No. 6
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Jan. 9/16 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2008; 299).
Effects of Meningococcal Vaccine in Infants: A meningococcal tetravalent (serogroup ACWY) glycoconjugate vaccine used in adolescents was well tolerated and immunogenic in a group of 421 infants (pp. 173-84). Comparing the product’s effects with those of a Neisseria meningitidis serogroup C monovalent meningococcal glycoconjugate vaccine, the investigators report high titers of target serogroups over the course of the two or three doses of the two vaccines, with more than 90% of babies responding. Pain on leg movement was reported in 2% of those receiving the tetravalent vaccine and 4% of those receiving the monovalent product; those percentages were reversed when the group was assessed for postimmunization temperature greater than 38° C. (M. D. Snape, Churchill Hosp., Oxford, England; matthew.snape@paediatrics.ox.ac.uk)
Describing this study as “a major advance in the vaccine prevention of meningococcal disease,” an editorialist describes the potential impact of the research (pp. 217-9): “The United States, which experienced the dramatic emergence of serogroup Y meningococcal disease during the 1990s and also has some serogroup W-135 disease, most likely will benefit from the use of this vaccine in infants. Serogroup Y strains, which accounted for only about 2% of meningococcal disease cases in the United States in the late 1980s, dramatically increased in incidence and, by the mid-1990s, accounted for around a third of all cases. Use of the study vaccine in infants would complement the current US recommendation for universal immunization of adolescents. Other countries, such as Canada and South Africa, also have serogroup Y disease.” (L. H. Harrison,
lharriso@edc.pitt.edu)
Treatment of Antipsychotic-Induced Weight Gain: A combination of lifestyle interventions plus metformin enabled 128 adult patients with schizophrenia to reduce their body mass index following antipsychotic-induced weight gain (pp. 185-93). All patients included in the randomized controlled trial had gained more than 10% of their predrug weight when they were assigned to one of four treatment groups (12 weeks of placebo, metformin 750 mg/day, metformin 750 mg/day plus lifestyle intervention, or lifestyle intervention only), with these results: “All 128 first-episode schizophrenia patients maintained relatively stable psychiatric improvement. The lifestyle-plus-metformin group had mean decreases in body mass index (BMI) of 1.8 (95% confidence interval [CI], 1.3–2.3), insulin resistance index of 3.6 (95% CI, 2.7–4.5), and waist circumference of 2.0 cm (95% CI, 1.5–2.4 cm). The metformin-alone group had mean decreases in BMI of 1.2 (95% CI, 0.9–1.5), insulin resistance index of 3.5 (95% CI, 2.7–4.4), and waist circumference of 1.3 cm (95% CI, 1.1–1.5 cm). The lifestyle-plus-placebo group had mean decreases in BMI of 0.5 (95% CI, 0.3–0.8) and insulin resistance index of 1.0 (95% CI, 0.5–1.5). However, the placebo group had mean increases in BMI of 1.2 (95% CI, 0.9–1.5), insulin resistance index of 0.4 (95% CI, 0.1–0.7), and waist circumference of 2.2 cm (95% CI, 1.7–2.8 cm). The lifestyle-plus-metformin treatment was significantly superior to metformin alone and to lifestyle plus placebo for weight, BMI, and waist circumference reduction.” (J-P Zhao, Central South U., Changsha, Hunan, China; wurenrong2005@yahoo.com.cn)
Transforming Clinical Practice Guidelines Into Legislative Mandates: “Abundant caution” is indicated when legislators move to transform clinical practice guidelines into law, the author of a commentary advises (pp. 208-10). Focusing on Texas efforts to mandate the recommendations of the Screening for Heart Attack Prevention and Education (SHAPE) Task Force, the author maintains that national professional organizations should oppose the bill if it is reintroduced this year, cardiology groups should convene a consensus conference to discuss the SHAPE guidelines, and medical organizations should design processes for evaluating such guidelines before their they are used widely. (P. D. Jacobson, pdj@umich.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 10, 2008 * Vol. 15, No. 7
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Jan. 10 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2008; 358).
Hydrocortisone in Septic Shock: Hydrocortisone failed to improve overall survival or reverse septic shock in a controlled comparison with placebo (pp. 111-24). The only potential benefit of intravenous hydrocortisone 50 mg every 6 hours for 5 days was a faster reversal of shock, when that occurred: “Of the 499 patients in the [Corticosteroid Therapy of Septic Shock (CORTICUS) study], 233 (46.7%) did not have a response to corticotropin (125 in the hydrocortisone group and 108 in the placebo group). At 28 days, there was no significant difference in mortality between patients in the two study groups who did not have a response to corticotropin (39.2% in the hydrocortisone group and 36.1% in the placebo group, P = 0.69) or between those who had a response to corticotropin (28.8% in the hydrocortisone group and 28.7% in the placebo group, P = 1.00). At 28 days, 86 of 251 patients in the hydrocortisone group (34.3%) and 78 of 248 patients in the placebo group (31.5%) had died (P = 0.51). In the hydrocortisone group, shock was reversed more quickly than in the placebo group. However, there were more episodes of superinfection, including new sepsis and septic shock.” (C.L. Sprung, Hadassah Hebrew U. Med. Ctr., Jerusalem, Israel; sprung@cc.huji.ac.il)
Noting the lack of evidence supporting some common clinical practices, an editorialist writes (pp. 188-90): “Although the CORTICUS study was unable to define the role of corticosteroids in septic shock, the investigators performed a valuable service. They reminded us that few critical care practices or treatment recommendations are based on unequivocal evidence and that, in some instances, critical appraisal and an open mind may be more appropriate than unquestioning adherence to guidelines. Perhaps the greatest service we can do our patients is to conduct the large, high-quality trials needed to base our clinical practice on truly robust evidence.” (S. Finfer, U. Sydney, Sydney)
Insulin Therapy and Fluids in Sepsis: Critically ill patients with sepsis were at increased risk for serious hypoglycemic events when treated with intensive insulin therapy, and fluid resuscitation with a low-molecular-weight hydroxyethyl starch proved harmful, researchers report (pp. 125-39). These results came from a comparison of intensive with conventional insulin therapy and HES 200/0.5 with modified Ringer’s lactate: “The trial was stopped early for safety reasons. Among 537 patients who could be evaluated, the mean morning blood glucose level was lower in the intensive-therapy group (112 mg per deciliter [6.2 mmol per liter]) than in the conventional-therapy group (151 mg per deciliter [8.4 mmol per liter], P < 0.001). However, at 28 days, there was no significant difference between the two groups in the rate of death or the mean score for organ failure. The rate of severe hypoglycemia (glucose level, 40 mg per deciliter [2.2 mmol per liter]) was higher in the intensive-therapy group than in the conventional-therapy group (17.0% vs. 4.1%, P < 0.001), as was the rate of serious adverse events (10.9% vs. 5.2%, P = 0.01). HES therapy was associated with higher rates of acute renal failure and renal-replacement therapy than was Ringer’s lactate.” (K. Reinhart, Friedrich Schiller U., Jena, Germany; konrad.reinhart@med.uni-jena.de)

>>>PNN NewsWatch
* FDA said yesterday that it has sent letters warning seven pharmacy operations warning that the claims they make about the safety and effectiveness of bioidentical hormone replacement therapy are unsupported by medical evidence, and are considered false and misleading by the agency. The pharmacy operations have 15 days to respond to the letters, which maintain that use of the terms “bio-identical hormone replacement therapy” and “BHRT” implies that their drugs are natural or identical to the hormones made by the body. The pharmacy operations also make unsupported claims that their drugs are better than FDA-approved menopausal hormone therapy drugs and can be used to prevent and treat serious diseases such as Alzheimer’s disease, stroke, and various forms of cancer, FDA claimed. The agency emphasized that its action does not target pharmacists who practice traditional pharmacy compounding and who do not make false or misleading claims about compounded products.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 11, 2008 * Vol. 15, No. 8
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Jan. issue of Pharmacotherapy (www.pharmacotherapy.org; 2008; 28).
2006 Clinical Pharmacy Services Survey: Veterans Affairs hospitals outdistanced other facilities in providing clinical pharmacy services, according to a 2006 national survey (pp. 1-13). Based on 1,125 surveys representing 46% of the 31 million hospital admissions in that year, the researchers found: “In all hospitals, the clinical pharmacy services with the greatest growth from 1989–2006 were pharmacist-provided admission drug histories (300% increase), pharmacist participation on medical rounds (292.3% increase), drug protocol management (208% increase), pharmacist-conducted clinical research (166.7% increase), pharmacist-provided drug information (150% increase), and pharmacist-provided pharmacokinetic consultation (117.5% increase). A total of 864 hospitals (76.8%) had pharmacists providing drug protocol management (collaborative drug management). Pharmacists managed a mean ± SD of 9.18 ± 10.23 different drugs/hospital (7,932 protocols). Drugs commonly managed included aminoglycosides (64.4% of hospitals), vancomycin (63.8%), warfarin (37.8%), low-molecular-weight heparins (32.7%), unfractionated heparin (30.0%), fluoroquinolones (30.0%), antiparkinsonian drugs (22.8%), proton pump inhibitors (22.7%), human immunodeficiency virus drugs (21.9%), and cephalosporins (19.7%). The mean number of medication errors reported/hospital increased by 151.4% between 1995 and 2006. The percentage of patients who experienced a medication error increased from 4.7% to 6.5% between 1995 and 2006 (a 38.3% increase). A total of 220 hospitals (19.6%) had computerized prescriber order entry systems, 263 (23.4%) had bar coding for drug administration, and 439 (39.0%) used robotics for dispensing.” (C. A. Bond, cab.bond@ttuhsc.edu)
INR Control After Discharge from Pharmacist Anticoagulation Clinic: Patients whose anticoagulation therapy was stabilized in pharmacist-managed clinics experienced significant decreases in INR control, increased need for medical care, and lower patient satisfaction after discharge, according to a retrospective medical record review (pp. 20-6). For 40 patients who were stabilized on warfarin therapy at a pharmacist-managed clinic, the investigators report these results after transfer to physician care: “Thirty-two percent of first INR values measured after transition from the clinic were in target range, and the median time to first follow-up INR was 41 days. The number of INR values above 4.5 and below 1.5 increased significantly after transition from the anticoagulation clinic (p < 0.0001 and p = 0.01, respectively, chi-square test). Before transition from the anticoagulation clinic, two anticoagulation-related emergency department visits were reported in one patient. After transition, 13 cases of additional medical care were reported among seven patients; seven of the 13 cases required an office visit with the physician, and six resulted in emergency room evaluation. None of these cases resulted in hospitalization. Patient satisfaction with clinical care provided by the anticoagulation clinic was significantly higher before transition.” (C. L. Garwood, Wayne State U., Detroit)
Review of Integrase Inhibitors: Authors of a review article provide this assessment of the integrase inhibitors raltegravir and elvitegravir (pp. 90-101): “These agents prevent viral DNA integration into the CD4+ cell chromosome. Both drugs showed potent antiviral activity in large clinical trials that were performed in treatment-experienced, multidrug-resistant patients. Promising results have also been seen in an initial dose-ranging study with raltegravir in treatment-naive patients. Preliminary data describe integrase inhibitor resistance profiles, but more data are needed in this area. Both agents were well tolerated in clinical trials, with favorable pharmacokinetic profiles for once- or twice-daily dosing. Raltegravir and elvitegravir differ in their metabolism, resulting in distinct drug-interaction profiles for each agent. Based on available data, this new class of antiretrovirals will soon be widely used in antiretroviral-experienced patients infected with HIV. In the future, this class of drugs may become a reasonable treatment option for antiretroviral-naive patients, but more data are needed in that patient population.” (O. M. Klibanov, klibanov@temple.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 14, 2008 * Vol. 15, No. 9
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Jan. 12 issue of Lancet (www.thelancet.com; 2008; 371).
Statins in Patients with Diabetes: Most patients with diabetes are at increased risk of vascular events and should therefore be treated with statins, conclude investigators from the Cholesterol Treatment Trial (pp. 117-25). Assessing data on 1,466 patients with type 1 diabetes and 18,686 individuals with the type 2 form of the disease, the researchers found: “During a mean follow-up of 4.3 years, there were 3,247 major vascular events in people with diabetes. There was a 9% proportional reduction in all-cause mortality per mmol/L reduction in LDL cholesterol in participants with diabetes (rate ratio [RR] 0.91, 99% CI 0.82–1.01; p = 0.02), which was similar to the 13% reduction in those without diabetes (0.87, 0.82–0.92; p < 0.0001). This finding reflected a significant reduction in vascular mortality (0.87, 0.76–1.00; p = 0.008) and no effect on non-vascular mortality (0.97, 0.82–1.16; p = 0.7) in participants with diabetes. There was a significant 21% proportional reduction in major vascular events per mmol/L reduction in LDL cholesterol in people with diabetes (0.79, 0.72–0.86; p < 0.0001), which was similar to the effect observed in those without diabetes (0.79, 0.76–0.82; p < 0.0001). In diabetic participants there were reductions in myocardial infarction or coronary death (0.78, 0.69–0.87; p < 0.0001), coronary revascularisation (0.75, 0.64–0.88; p < 0.0001), and stroke (0.79, 0.67–0.93; p = 0.0002). Among people with diabetes the proportional effects of statin therapy were similar irrespective of whether there was a prior history of vascular disease and irrespective of other baseline characteristics. After 5 years, 42 (95% CI 30–55) fewer people with diabetes had major vascular events per 1,000 allocated statin therapy.” (CTT Secretariat, Clinical Trial Service Unit and Epidemiological Studies Unit, Oxford U., Oxford, U.K.; ctt@ctsu.ox.ac.uk)

>>>BMJ Highlights
Source:
Jan. 12 issue of BMJ (www.bmj.org; 2008; 336).
Pneumonia Treatment in Children: Among children aged 2–59 months in low resource settings, injectable ampicillin plus gentamicin was superior to injectable chloramphenicol for the treatment of very severe community-acquired pneumonia (pp. 80-4). “More children failed treatment with chloramphenicol at day 5 (16% v 11%; relative risk 1.43, 95% confidence interval 1.03 to 1.97) and also by days 10 and 21. Overall, 112 bacterial isolates were obtained from blood and lung aspirates in 110 children (11.5%), with the most common organisms being Staphylococcus aureus (n = 47) and Streptococcus pneumoniae (n = 22). In subgroup analysis, bacteraemia with any organism increased the risk of treatment failure at 21 days in the chloramphenicol group (2.09, 1.41 to 3.10) but not in the ampicillin plus gentamicin group (1.12, 0.59 to 2.13). Similarly, isolation of S pneumoniae increased the risk of treatment failure at day 21 (4.06, 2.73 to 6.03) and death (5.80, 2.62 to 12.85) in the chloramphenicol group but not in the ampicillin plus gentamicin group. No difference was found in treatment failure for children with S aureus bacteraemia in the two groups, but the power to detect a difference in this subgroup analysis was low. Independent predictors of treatment failure by multivariate analysis were hypoxaemia (oxygen saturation <90%), receiving chloramphenicol, being female, and poor immunisation status.” (D. M. Thea, Boston U., Boston; dthea@bu.edu)

>>>PNN NewsWatch
* Clarification: In the INR control article from Pharmacotherapy summarized in Friday’s PNN, note that the declines in clinical and other indicators occurred after patients were transitioned to physician care, not while the patients were being seen in the pharmacist-managed anticoagulation clinic.

>>>PNN JournalWatch
* Tension-Type Headache, in BMJ, 2008; 336: 88–92. Reprints: E. Loder, eloder@partners.org
* Insulin-Resistant Cardiomyopathy: Clinical Evidence, Mechanisms, and Treatment Options, in
Journal of the American College of Cardiology, 2008; 51: 93–102. Reprints: R. M. Witteles, witteles@stanford.edu
* Fluid Therapy in Resuscitated Sepsis: Less Is More, in
Chest, 2008; 133: 252–63. Reprints: G. A. Schmidt, gregory-a-schmidt@uiowa.edu
* National Health Spending In 2006: A Year Of Change For Prescription Drugs, in
Health Affairs, 2008; 27: 14–29. Reprints: A. Catlin.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 15, 2008 * Vol. 15, No. 10
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release articles from and Jan. 15 issue of the Annals of Internal Medicine (www.annals.org/current.shtml; 2008; 148).
Sexual Transmission of MRSA Among MSM: The emergence of a multidrug-resistant strain of Staphylococcus aureus among men who have sex with men leads researchers to conclude that the community-acquired organism is being transmitted sexually (early release). Analyzing culture-proven MRSA infections at nine San Francisco hospitals and two outpatient clinics in that city and Boston, the investigators found these trends: “The overall incidence of multidrug-resistant USA300 infection in San Francisco was 26 cases per 100,000 persons (95% CI, 16 to 36 cases per 100,000 persons); the incidence was higher in 8 contiguous ZIP codes with a higher proportion of male same-sex couples. Male–male sex was a risk factor for multidrug-resistant USA300 infection (relative risk, 13.2 [CI, 1.7 to 101.6]; P < 0.001) independent of past MRSA infection (relative risk, 2.1 [CI, 1.2 to 3.7]; P = 0.007) or clindamycin use (relative risk, 2.1 [1.2 to 3.6]; P = 0.007). The risk seemed to be independent of HIV infection. In San Francisco, multidrug-resistant USA300 manifested most often as infection of the buttocks, genitals, or perineum. In Boston, multidrug-resistant USA300 was recovered exclusively from men who have sex with men.” (B. A. Diep, bdiep@epi-center.ucsf.edu)
Pain in Patients with Sickle Cell Disease: Pain in adults with sickle cell disease is more common and more severe than previously believed, according to a prospective cohort study conducted in academic and community practices in Virginia (pp. 94-101). Home treatment of symptoms contributes to underestimation of the impact of the disease, the investigators concluded, adding these details about 232 patients in the study: “Pain (with or without crisis or utilization of care) was reported on 54.5% of 31,017 analyzed patient–days (adjusted probability, 56%). Crises without utilization were reported on 12.7% of days and utilization on only 3.5% (unadjusted). In total, 29.3% of patients reported pain in greater than 95% of diary days, whereas only 14.2% reported pain in 5% or fewer diary days (adjusted). The frequency of home opiate use varied and independently predicted pain, crises, and utilization. Mean pain intensity on crisis days, noncrisis pain days, and total pain days increased as the percentage of pain days increased (P < 0.001). Intensity was significantly higher on utilization days (P < 0.001). However, utilization was not an independent predictor of crisis, after controlling for pain intensity.” (W. R. Smith, wrsmith@vcu.edu)
Comparing DMARDs in Rheumatoid Arthritis: For adults with early rheumatoid arthritis, available agents used as monotherapy or in combination are poorly studied in head-to-head trials, making firm conclusions impossible about first- versus second-line treatment choices, according to authors of a review that was published online in advance of publication (see PNN, Nov. 20) (pp. 124-34). In a systematic review, researchers considered studies of disease-modifying antirheumatic drugs with at least 100 participants and having a minimum of 12 weeks’ follow-up, finding that: “Head-to-head trials (n = 23) showed no clinically important differences in efficacy among synthetic DMARDs (limited to methotrexate, leflunomide, and sulfasalazine) or among anti–tumor necrosis factor drugs (adalimumab, etanercept, and infliximab). Monotherapy with anti–tumor necrosis factor drugs resulted in better radiographic outcomes than did methotrexate but no important differences in clinical outcomes (for example, 20%, 50%, or 70% improvement according to American College of Rheumatology response criteria).” (K. E. Donahue, U. North Carolina, Chapel Hill)

>>>PNN NewsWatch
* Natalizumab (Tysabri, Biogen) has been approved by FDA for treatment of moderate-to-severe Crohn’s disease in patients with evidence of inflammation who have had an inadequate response to, or are unable to tolerate, conventional Crohn’s disease therapies. Patients with Crohn’s disease using the drug must be enrolled in a special restricted distribution program, the Crohn’s Disease–Tysabri Outreach Unified Commitment to Health (CD TOUCH) Prescribing Program.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 16, 2008 * Vol. 15, No. 11
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Jan. 14 issue of the Archives of Internal Medicine (http://archinte.ama-assn.org/current.dtl; 2008; 168).
Short-term Interruption of Warfarin Therapy: The risk of thromboembolism was acceptably low during procedure-related interruptions in warfarin therapy of 5 days or fewer in patients with a variety of indications for long-term anticoagulation (pp. 63-9). Results of the prospective observational cohort study 1,293 episodes of warfarin therapy interruption in 1,024 individuals were as follows: “The most common procedures were colonoscopy and oral and ophthalmic surgery. Perioperative heparin or low-molecular-weight heparin was used in only 8.3% of cases overall. Seven patients (0.7%; 95% confidence interval [CI], 0.3%-1.4%) experienced postprocedure thromboembolism within 30 days. None of the 7 patients who experienced thromboembolism received periprocedural bridging therapy. Six patients (0.6%; 95% CI, 0.2%-1.3%) experienced major bleeding, whereas an additional 17 patients (1.7%; 95% CI, 1.0%-2.6%) experienced a clinically significant, nonmajor bleeding episode. Of these 23 patients who had bleeding episodes, 14 received periprocedural heparin or low-molecular-weight heparin. The duration of warfarin therapy interruption was variable; however, more than 80% of patients had warfarin therapy withheld for 5 days or fewer.” (D. A. Garcia, U. New Mexico, Albuquerque)
Thrombocytopenia After Prolonged Heparin Therapy: Thrombocytopenia is a common occurrence during prolonged heparin administration and is a significant predictor of poor clinical outcomes, including increased mortality, researchers report (pp. 94-102).:“We enrolled 2,420 patients (median age, 65.2 years; 43.8% women) in 48 US hospitals. Thrombocytopenia occurred in 881 patients (36.4%; 95% confidence interval [CI], 34.5%-38.3%). Of those who developed thrombocytopenia, 5.1% died, compared with 1.6% of those without thrombocytopenia (odds ratio [OR], 3.4; 95% CI, 2.1–5.6; P < .001). Thrombocytopenia was also associated with greater risk of myocardial infarction (OR, 2.1; 95% CI, 1.5–2.8; P < .001) and congestive heart failure (OR, 1.3; 95% CI, 1.1–1.6; P = .01). After adjustment for important covariates, thrombocytopenia remained an independent predictor of thrombotic and hemorrhagic events. A relative reduction in platelet count of more than 70% was the strongest independent predictor of death (OR, 13.4; 95% CI, 6.5–27.6; P < .001), followed by a relative reduction in platelet count of 50% to 70%, worse Killip class, occurrence of thromboembolic complications, older age, and longer duration of heparin therapy.” (C. B. Granger, grang001@mc.duke.edu)

>>>PNN NewsWatch
* The news in yesterday’s lay media about the combination lipid-lowering agents ezetimibe (Zetia) and simvastatin (marketed in combination as Vytorin) comes from an abstract being considered for presentation at the American College of Cardiology annual meeting in late March. Merck said that in the ENHANCE (Effect of Combination Ezetimibe and High-Dose Simvastatin vs. Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia) trial, the mean change in intima-media thickness in the carotid arteries was not significantly different between patients taking ezetimibe/simvastatin 10/80 mg versus patients treated with simvastatin 80 mg alone over a 2-year period. The 720 patients included in the ENHANCE trial all had heterozygous familial hypercholesterolemia, a rare condition that affects approximately 0.2% of the population. In response to the announcement, the American College of Cardiology recommended “that major clinical decisions not be made on the basis of the ENHANCE study alone,” suggesting instead, “This study deserves serious thought and follow-up. The overall incidence rates of cardiac events were nearly identical between both treatment groups, and both medicines were generally well tolerated. There should no be reason for patients to panic. The difference in IMT changes between the simvastatin group and the Vytorin group was 0.006 mm vs. 0.011 mm.” Recommending that patients talk with health professionals and make no changes in regimens without professional advice, the College also emphasized that this was an imaging trial, one that did not measured hard clinical outcomes.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 17, 2008 * Vol. 15, No. 12
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Jan. 17 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2008; 358).
Etanercept for Pediatric Plaque Psoriasis: Disease severity was significantly reduced by etanercept therapy in 211 children and adolescents with moderate-to-severe plaque psoriasis, according to a 48-week study (pp. 241-51). During a double-blind portion of the study, patients received either etanercept 0.8 mg/kg once weekly or placebo. This was followed by 24 weeks of open-label, once-weekly etanercept and then a 12-week randomization to active drug or placebo to study withdrawal and retreatment. Judging responses according to the percentage improvements shown in the psoriasis area-and-severity index, the authors found: “At week 12, 57% of patients receiving etanercept achieved PASI 75, as compared with 11% of those receiving placebo (P < 0.001). A significantly higher proportion of patients in the etanercept group than in the placebo group had PASI 50 (75% vs. 23%), PASI 90 (27% vs. 7%), and a physician’s global assessment of clear or almost clear (53% vs. 13%) at week 12 (P < 0.001). At week 36, after 24 weeks of open-label etanercept, rates of PASI 75 were 68% and 65% for patients initially assigned to etanercept and placebo, respectively. During the withdrawal period from week 36 to week 48, response was lost by 29 of 69 patients (42%) assigned to placebo at the second randomization. Four serious adverse events (including three infections) occurred in three patients during treatment with open-label etanercept; all resolved without sequelae.” (A. S. Paller, apaller@northwestern.edu)
Selective Publication of Antidepressant Trials: Selective publication of data from clinical trials of antidepressants has led to potential bias in favor of efficacy of recently marketed agents, researchers report (pp. 252-60). Looking at studies of 12 antidepressants that included 12,564 patients, the authors report: “Among 74 FDA-registered studies, 31%, accounting for 3,449 study participants, were not published. Whether and how the studies were published were associated with the study outcome. A total of 37 studies viewed by the FDA as having positive results were published; 1 study viewed as positive was not published. Studies viewed by the FDA as having negative or questionable results were, with 3 exceptions, either not published (22 studies) or published in a way that, in our opinion, conveyed a positive outcome (11 studies). According to the published literature, it appeared that 94% of the trials conducted were positive. By contrast, the FDA analysis showed that 51% were positive. Separate meta-analyses of the FDA and journal data sets showed that the increase in effect size ranged from 11 to 69% for individual drugs and was 32% overall.” (E. H. Turner, Portland VA Med. Ctr., Portland, Oreg.; turnere@ohsu.edu)
Treatment of Avian Influenza: A review article assesses experiences to date with avian influenza A (H5N1) viruses (pp. 261-73): “Early treatment with oseltamivir is recommended, and data from uncontrolled clinical trials suggest that it improves survival, although the optimal dose and duration of therapy are uncertain. Mortality remains high despite administration of oseltamivir; late initiation of therapy appears to be a major factor. Uncontrolled viral replication, as reflected in the detection of persistent pharyngeal RNA after completion of standard therapy, is associated with a poor prognosis. Higher levels of viral replication and slower clearance of infection probably occur in the lower respiratory tract. The oral bioavailability of oseltamivir in patients with severe diarrhea or gastrointestinal dysfunction related to influenza A (H5N1) virus infection or those in whom the drug has been administered extemporaneously (e.g., by means of a nasogastric tube) is uncertain.” (F. G. Hayden, haydenf@who.int)

>>>PNN NewsWatch
* Children and adults have died when they were mistakenly given Edetate Disodium instead of Edetate Calcium Disodium (Calcium Disodium Versenate) or when Edetate Disodium was used for “chelation therapies” and other unapproved uses, FDA warned yesterday. These two drugs have very similar names and are commonly referred to only as “EDTA.” The agency said it is reviewing the benefit/risk profile of Edetate Disodium to determine if the benefits for its intended use continue to outweigh the serious risks.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 18, 2008 * Vol. 15, No. 13
Providing news and information about medications and their proper use

>>>Pediatrics Highlights
Source:
Jan. issue of Pediatrics (http://pediatrics.aappublications.org/current.shtml; 2008; 121).
Influenza in Children with Asthma: Asthma is a common comorbidity among young children hospitalized for influenza, according to an analysis of data from three U.S. counties (pp. 1-8). Focusing on children aged 6–59 months, the investigators found: “Of 81 children 6 to 59 months of age with influenza-confirmed hospitalizations in 2000 to 2004, 19 (23%) had asthma. Average annual influenza-attributable hospitalization rates were significantly higher among children with asthma than among healthy children 6 to 23 months of age (2.8 vs 0.6 cases per 1,000 children) but not children 24 to 59 months of age (0.6 vs 0.2 case per 1,000 children). Of 249 children 6 to 59 months of age with influenza-confirmed outpatient visits in 2002 to 2004, 38 (15%) had asthma. Estimated outpatient influenza-attributable visit rates were higher among children with asthma than among healthy children 6 to 23 months of age (316 vs 152 cases per 1000 children) and 24 to 59 months of age (188 vs 102 cases per 1000 children) in 2003 to 2004. Few parents reported that their children had been vaccinated, including <30% of children with asthma.” (E. K. Miller, Vanderbilt U., Nashville, Tenn.)
Breastfeeding by Women Taking Methadone: Methadone can be safely continued during breastfeeding, based on findings in eight women and their infants (pp. 106-14). Analysis of drug concentrations in mothers’ blood and milk and babies’ blood and assessment of short-term neurobehavioral outcomes showed the following: “Concentrations of methadone in breast milk were low (range: 21.0–462.0 ng/mL) and not related to maternal dose. There was a significant increase in methadone concentrations in breast milk over time for all 4 sampling times. Concentrations of methadone in maternal plasma were not different between groups and were unrelated to maternal dose. Concentrations of methadone in infant plasma were low (range: 2.2–8.1 ng/mL) in all samples. Infants in both groups underwent neurobehavioral assessments on days 3, 14, and 30; there were no significant effects of breastfeeding on neurobehavioral outcomes. Fewer infants in the breastfed group required pharmacotherapy for neonatal abstinence syndrome, but this was not a statistically significant finding.” (L. M. Jansson, Johns Hopkins U., Baltimore, Md.)
Safety of Inhaled Ciclesonide: In 661 prepubertal children with mild persistent asthma, the new inhaled corticosteroid ciclesonide had no effect on growth velocity at any dose, investigators report (pp. e1-14). Comparing doses of 40 and 160 mcg once daily with placebo, the authors found: “Mean linear growth velocity during run-in was comparable between groups: 160 mcg, 6.20 cm/year; 40 mcg, 6.59 cm/year; placebo, 6.49 cm/year. Mean differences from placebo (5.75 cm/year) in growth velocity over the double-blind treatment period were –0.02 cm/year for ciclesonide 40 mcg and –0.15 cm/year for ciclesonide 160 mcg. Both ciclesonide treatments were noninferior to placebo with respect to growth velocity. The overall incidence of adverse events was comparable between groups, and no significant changes in 10-hour overnight or 24-hour urinary free cortisol levels were noted between groups during the double-blind treatment period.” (D. P. Skoner, Allegheny Genl. Hosp., Pittsburgh)

>>>PNN NewsWatch
* Parents and caregivers should not use nonprescription cough and cold products to treat infants and children younger than 2 years of age because serious and potentially life-threatening adverse effects can result, FDA warned yesterday. The announcement, a follow-up to FDA’s Oct. hearings on the subject (see PNN, Oct. 22), did not include any advice about use of nonprescription decongestants, expectorants, antihistamines, and antitussives in children aged 2 to 11 years. The agency promised a final recommendation for that age group “as soon as the review is complete.”
*
PNN will not be published on Mon., Jan. 21, M. L. King 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 © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 22, 2008 * Vol. 15, No. 14
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Jan. 19 issue of Lancet (www.thelancet.com; 2008; 371).
Prednisone for Morning Stiffness in RA: Addressing the altered circadian rhythms in patients with rheumatoid arthritis, researchers demonstrated that modified-release prednisone reduces morning stiffness of joints in addition to providing other previously known benefits of the drug (pp. 205-14). In a 12-week trial of 288 patients with active RA, prednisone released 4 hours after bedtime ingestion showed these results, compared with immediate-release prednisone: “The mean relative change in duration of morning stiffness of the joints from baseline to end of treatment was significantly higher with modified-release prednisone than with immediate-release prednisone (−22.7% vs −0.4%; difference = 22.4% [95% CI 0.49–44.30]; p = 0.045). Patients in the prednisone modified-release group achieved a mean reduction of 44.0 (SD 136.6) min compared with baseline. The absolute difference between the treatment groups was 29.2 min (95% CI −2.59 to 61.9) in favour of modified-release prednisone (p = 0.072). The safety profile did not differ between treatments.” (F. Buttgereit, Charité U. Medicine, Berlin; frank.buttgereit@charite.de)

>>>BMJ Highlights
Source:
Early-release article from BMJ (www.bmj.org; 2008; 336).
Aspirin “Resistance” and Cardiovascular Morbidity: Long-term, clinically relevant cardiovascular morbidity occurs more often in patients with aspirin “resistance” than in those whose platelets are sensitive to the drug, according to a systematic review and meta-analysis of 20 studies involving 2,930 patients (doi: 10.1136/bmj.39430.529549.BE). “Most studies used aspirin regimens, ranging from 75–325 mg daily, and six studies included adjunct antiplatelet therapy,” the authors note. “Compliance was confirmed directly in 14 studies and by telephone or interviews in three. Information was insufficient to assess compliance in three studies. Overall, 810 patients (28%) were classified as aspirin resistant. A cardiovascular related event occurred in 41% of patients (odds ratio 3.85, 95% confidence interval 3.08 to 4.80), death in 5.7% (5.99, 2.28 to 15.72), and an acute coronary syndrome in 39.4% (4.06, 2.96 to 5.56). Aspirin resistant patients did not benefit from other antiplatelet treatment.” (M. R. Buchanan, mbuchan@mcmaster.ca)

>>>PNN NewsWatch
* The nonnucleoside reverse transcriptase inhibitor etravirine (Intelence, Tibotec Therapeutics) has been approved for treatment of HIV infection in adults who have failed treatment with other antiretroviral agents. FDA reviewed the drug on a priority basis based primarily on data from 599 adults who received etravirine in two randomized, double-blind, placebo-controlled trials. After 24 weeks of treatment, more of the patients who received etravirine along with background therapy experienced reductions in the level of HIV in their blood than did those who received a placebo and background therapy. The most common adverse events reported were rash and nausea, and rare cases of serious skin reactions such as Stevens-Johnson syndrome and erythema multiforme were reported. Drug interactions, detailed in the product labeling, are a concern. The long-term effects of etravirine are not known, and its safety and effectiveness in children ages 16 years and younger has not been studied. Etravirine also has not been studied in pregnant women.
* The risk of developing venous thromboembolism (VTE) is higher with
Ortho Evra Contraceptive Transdermal (Skin) Patch (ethinyl estradiol and norelgestromin; Ortho McNeil) than with oral contraceptives, FDA warned on Friday. Product labeling for the patch is being changed based on a study conducted by the Boston Collaborative Drug Surveillance Program on behalf of Johnson and Johnson. These findings support an earlier study that also concluded that women in this group were at higher risk for VTE.

>>>PNN JournalWatch
* Advice to Use Topical or Oral Ibuprofen for Chronic Knee Pain in Older People: Randomised Controlled Trial and Patient Preference Study, in BMJ, 2008; 336: 138–42. Reprints: M. Underwood, U. London, London; m.underwood@qmul.ac.uk
* Human Papillomavirus Vaccine and Cervical Cancer Prevention: Practice and Policy Implications for Pharmacists, in
Journal of the American Pharmacists Assoc., 2008; 48: e1–17. Reprints: J. McIntosh, Northeastern U., Boston; j.mcintosh@nue.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 © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 23, 2008 * Vol. 15, No. 15
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Jan. 23 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2008; 299).
Androgen Suppression in Prostate Cancer: Overall survival was improved by addition of 6 months of androgen-suppression therapy to radiation in 206 men with localized but unfavorable-risk prostate cancer (pp. 289-95). Concluding that these findings may pertain only to men with no or minimal comorbidity, the authors add these details about their prospective study with randomization in 1995–2001: “As of January 15, 2007, with a median follow-up of 7.6 (range, 0.5–11.0) years, 74 deaths have occurred. A significant increase in the risk of all-cause mortality (44 vs 30 deaths; hazard ratio [HR], 1.8; 95% confidence interval [CI], 1.1–2.9; P = .01) was observed in men randomized to RT compared with RT and AST. However, the increased risk in all-cause mortality appeared to apply only to men randomized to RT with no or minimal comorbidity (31 vs 11 deaths; HR, 4.2; 95% CI, 2.1–8.5; P < .001). Among men with moderate or severe comorbidity, those randomized to RT alone vs RT and AST did not have an increased risk of all-cause mortality (13 vs 19 deaths; HR, 0.54; 95% CI, 0.27–1.10; P = .08).” (A. V. D’Amico, adamico@partners.org)
Pharmacogenetic Influences of Antihypertensive Effects: Variations in the gene for a precursor of atrial natriuretic polypeptide, NPPA, can lead to differences in patient responses to various classes of antihypertensives, according to a post-hoc analysis of 38,462 participants in the ALLHAT trial (pp. 296-307). The Genetics of Hypertension Associated Treatment (GenHAT) study identified minor NPPA genotypes (G664A and T2238C) and related these to responses to the four study drugs, concluding that more favorable responses occurred when minor C allele carriers were treated with a diuretic and TT allele carriers received a calcium-channel blocker: “Depending on genotype, the event rates per 1,000 person–years were 15.3 to 19.7 for CHD, 9.6 to 15.4 for stroke, and 27.4 to 30.7 for all-cause mortality. For the NPPA T2238C variant, lower event rates were found for the C allele carriers than for the TT homozygous individuals when comparing chlorthalidone and amlodipine (CHD: CC = 0.86; TC = 0.90; TT = 1.09; P = .03 [dominant model]; stroke: CC = 1.18; TC = 0.82; TT = 1.26; P = .01 [additive and dominant models]; all-cause mortality: CC = 0.87; TC = 0.98; TT = 1.12; P = .05 [dominant model]). Combined end points yielded similar results. Consistent with these clinical findings, 6-month changes in systolic BP for those with the CC genotype showed larger reductions with chlorthalidone (–6.5 mm Hg) than with amlodipine (–3.8 mm Hg), lisinopril (–2.4 mm Hg), or doxazosin (–3.8 mm Hg). Among those with the TT genotype, systolic BP differences between drugs were less (range, –5.4 to –7.5 mm Hg; P value, <.001 to .003 for interaction); diastolic BP showed similar results. We found no pharmacogenetic associations with the NPPA G664A variant.” (D. K. Arnett, arnett@ms.soph.uab.edu)
Gastric Banding for Diabetes: Greater weight loss among patients who underwent gastric banding surgery enabled remission of type 2 diabetes more often than in those treated with conventional therapies, according to a study of 60 obese, newly diagnosed patients (pp. 316-23). Based on 55 patients who completed a 2-year follow-up, the researchers report: “Remission of type 2 diabetes was achieved by 22 (73%) in the surgical group and 4 (13%) in the conventional-therapy group. Relative risk of remission for the surgical group was 5.5 (95% confidence interval, 2.2-14.0). Surgical and conventional-therapy groups lost a mean (SD) of 20.7% (8.6%) and 1.7% (5.2%) of weight, respectively, at 2 years (P < .001). Remission of type 2 diabetes was related to weight loss (R2 = 0.46, P < .001) and lower baseline HbA1c levels (combined R2 = 0.52, P < .001). There were no serious complications in either group.” Use of pharmacotherapy was also decreased in the surgical group, with 26 patients requiring no medications at 2 years, compared with 8 patients in the conventional therapy group. (J. B. Dixon, Monash U., Melbourne, Victoria, Australia; john.dixon@med.monash.edu.au)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 24, 2008 * Vol. 15, No. 16
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Jan. 24 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2008; 358).
Drug-Eluting Stents: Two research articles and an editorial examine the best uses of drug-eluting stents.
Coronary-artery bypass grafting remains the best choice for patients with multivessel coronary disease, performing better than drug-eluting stents in a New York State study (pp. 331-41). Among more than 17,000 patients with two- or three-vessel disease, 18-month rates of death and of death or myocardial infarction were significantly lower with CABG than with drug-eluting stents. Significantly lower rates of repeat revascularization were also identified in the CABG group. (E. L. Hannan, State U. New York, U. Albany, Rensselaer, N.Y.;
elh03@health.state.ny.us)
Used for off-label indications, drug-eluting stents provided a lower rate of repeat revascularization, compared with bare-metal stents (pp. 342-52). Mortality and MI rates were similar with the two types of stents, which in this study were used in patients with restenotic lesions, lesions in a bypass graft, left main coronary artery disease, or ostial, bifurcated, or totally occluded lesions, as well as use in patients with a reference-vessel diameter of less than 2.5 mm or greater than 3.75 mm or a lesion length of more than 30 mm. (O. C. Marroquin,
marroquinoc@upmc.edu)
An editorialist writes that these studies push “the envelope beyond the labels” (pp. 405-7): “These two observational studies should provide valuable guidance regarding off-label use of drug-eluting stents. The New York State registries affirm that CABG remains the standard of care for patients who require multivessel coronary revascularization. However, stents may be an alternative for patients at high risk for surgical complications or when an informed patient chooses a less invasive option. Additional studies are needed before the findings for off-label use reported by Marroquin et al. can be considered the final word. Randomized trials provide complementary data and address some of the limitations of these observational studies. Although we confront clinical decisions in the absence of the totality of data, these two studies go a long way toward making these decisions more evidence based.” (J. P. Carrozza, Jr., Harvard Med. Sch., Boston)
Organ Transplant Without Immunosuppression: Commenting on three articles describing small numbers of organ-transplant recipients “in whom allografts have maintained good function for up to 5 years without immunosuppressive treatment,” an editorialist writes (pp. 407-11): “The results reported in all three articles are consistent with the axiom that organ engraftment is a form of variable tolerance, the completeness of which can be crudely estimated by the need for maintenance immunosuppressive therapy. In all six patients, this need reached zero. The presumed balance between donor cells and antidonor T cells in the patients described by Kawai et al. is extremely close. It resembles the balance in recipients with partial tolerance or those who are not receiving immunosuppressive therapy; this balance can be produced with pretreatment with anti–T-cell antibodies and minimal post-transplantation immunosuppressive therapy. It appears that all six recipients are analogous to asymptomatic carriers of intracellular (noncytopathic) microbes. Perhaps it will be possible to systematically achieve stable organ engraftment with very low dependence on—or in some cases complete freedom from—long-term treatment. To do so will require just the right dose and timing of immunosuppressive therapy with or without the aid of adjunct hematopoietic stem cells.” (T. E. Starzl, U. Pittsburgh Med. Ctr. Montefiore, Pittsburgh)
Health Care Reform Not Inevitable: After analyzing why “the amazing noncollapsing U.S. health care system” has not imploded, the author of a Perspective article provides this forecast (pp. 325-7): “Though deeply dysfunctional by most standards, the U.S. health care system remains disturbingly stable. That no one really likes it does not translate into the inevitability of real change. Because the system is unlikely to collapse from within, reformers’ best hopes lie with shifts in public sentiment and the election of activist and reform-minded political leaders. Such shifts can happen ... but [they] do not guarantee comprehensive health care reforms.” (L. D. Brown, Columbia U., New York)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 25, 2008 * Vol. 15, No. 17
Providing news and information about medications and their proper use

>>>Rheumatology Report
Source:
Jan. issue of Arthritis & Rheumatism (www3.interscience.wiley.com/journal/76509746/home; 2008; 58).
Administration Route of Methotrexate in RA: Subcutaneous administration of methotrexate is more effective than oral dosing of the drug, according to a study of 375 MTX-naive patients with active rheumatoid arthritis (pp. 73-81). Assessing 20% and 70% improvement in symptoms using the American College of Rheumatology criteria, the investigators found: “At week 24, significantly more patients treated with SC MTX than with oral MTX showed ACR20 (78% versus 70%) and ACR70 (41% versus 33%) responses. Patients with a disease duration ≥12 months had even higher ACR20 response rates (89% for SC administration and 63% for oral). In 52 of the ACR20 nonresponders (14%), treatment was switched at week 16 [based on lack of response]. Changing from oral to SC MTX and from 15 mg to 20 mg of SC MTX resulted in 30% and 23% ACR20 response rates, respectively, in these patients. MTX was well tolerated. The rate of adverse events was similar in all groups.” (J. Braun, Rheumazentrum Ruhrgebiet, Herne, Germany; J.Braun@rheumazentrum-ruhrgebiet.de)
Infliximab in Ankylosing Spondylitis: In a 58-week study of patients with active ankylosing spondylitis, continuous administration of infliximab was more effective than on-demand therapy, and addition of methotrexate to the regimen provided no benefit (pp. 88-97). Patients initially received infusions of the anti-tumor necrosis factor alpha agent at weeks 4, 6, and 10, followed by infusions every 6 weeks or upon symptom recurrence. Those in the on-demand group received either infliximab plus MTX or infliximab alone. Based on ASsessment in AS International Working Group criteria for 20% improvement, results showed: “Of 247 patients, 124 were assigned to receive infliximab every 6 weeks and 123 to receive on-demand treatment. Among the latter, 62 received MTX, and 61 received infliximab alone. A greater proportion of patients receiving infliximab every 6 weeks fulfilled ASAS20 response criteria at week 58 than did patients receiving on-demand treatment (75% versus 46%; P < 0.0001). Patients in the continuous treatment group received more infliximab infusions after week 10 than did those in the on-demand group (mean ± SD 5.8 ± 2.2 versus 3.5 ± 2; P < 0.0001). Addition of MTX did not significantly affect the proportion of patients with an ASAS20 response at week 58, nor the number of infliximab infusions administered.” (M. Breban, Hôpital Ambroise Paré, Boulogne, France; maxime.breban@apr.aphp.fr)

>>>Circulation Highlights
Source:
Jan. 22 issue of Circulation (http://circ.ahajournals.org/; 2008; 117).
Electronic Alerts for Dyslipidemia Treatments: Screening and treatment for dyslipidemia was significantly improved by an alerting version of clinical decision support systems, compared with versions that provided input only on demand, in a clustered randomized trial (pp. 371-8). Over 12 months, 77 physicians in 38 Dutch general practices caring for 87,886 patients received either alerts, on-demand support, or no interventions, with these results: “In the alerting group, 65% of the patients requiring screening were screened (relative risk versus control = 1.76; 95% confidence interval, 1.41 to 2.20) compared with 35% of patients in the on-demand group (relative risk versus control = 1.28; 95% confidence interval, 0.98 to 1.68) and 25% of patients in the control group. In the alerting group, 66% of patients requiring treatment were treated (relative risk versus control = 1.40; 95% confidence interval, 1.15 to 1.70) compared with 40% of patients (relative risk versus control = 1.19; 95% confidence interval, 0.94 to 1.50) in the on-demand group and 36% of patients in the control group.” (J. van der Lei, Erasmus U. Med. Ctr., Rotterdam, the Netherlands; j.vanderlei@erasmusmc.nl)

>>>PNN NewsWatch
* The current liquid formulation of sargramostim (Leukine) is being withdrawn from the market, Bayer and FDA announced yesterday. An upward trend in spontaneous reports of adverse reactions, including syncope, has been temporally correlated with inclusion of EDTA in the formulation, a trend not observed with lyophilized Leukine. Health professionals should immediately stop using liquid Leukine and return unused vials to the manufacturer.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 28, 2008 * Vol. 15, No. 18
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Jan. 26 issue of Lancet (www.thelancet.com; 2008; 371).
Ovarian Cancer & Oral Contraceptives: Oral contraceptives significantly lower the risk of developing ovarian cancer, report authors of a reanalysis of data from 45 epidemiological studies in 21 countries (pp. 303-14). Approximately 200,000 ovarian cancers and 100,000 deaths from the disease have been prevented, the investigators estimate, predicting the annual number of prevented cancers will exceed 30,000: “Overall 7,308 (31%) cases and 32,717 (37%) controls had ever used oral contraceptives, for average durations among users of 4.4 and 5.0 years, respectively. The median year of cancer diagnosis was 1993, when cases were aged an average of 56 years. The longer that women had used oral contraceptives, the greater the reduction in ovarian cancer risk (p < 0.0001). This reduction in risk persisted for more than 30 years after oral contraceptive use had ceased but became somewhat attenuated over time—the proportional risk reductions per 5 years of use were 29% (95% CI 23–34%) for use that had ceased less than 10 years previously, 19% (14–24%) for use that had ceased 10–19 years previously, and 15% (9–21%) for use that had ceased 20–29 years previously. Use during the 1960s, 1970s, and 1980s was associated with similar proportional risk reductions, although typical oestrogen doses in the 1960s were more than double those in the 1980s. The incidence of mucinous tumours (12% of the total) seemed little affected by oral contraceptives, but otherwise the proportional risk reduction did not vary much between different histological types. In high-income countries, 10 years use of oral contraceptives was estimated to reduce ovarian cancer incidence before age 75 from 1.2 to 0.8 per 100 users and mortality from 0.7 to 0.5 per 100; for every 5,000 woman–years of use, about two ovarian cancers and one death from the disease before age 75 are prevented.” (Secretariat, Cancer Res. UK Epidemiology Unit, Oxford, U.K.; collaborations@ceu.ox.ac.uk)
In a related editorial (p. 275) and podcast,
Lancet editors argue for nonprescription availability of oral contraceptives: “We strongly endorse more widespread over-the-counter access to a preventive agent that can not only prevent cancers but also demonstrably save the lives of tens of thousands of women.”

>>>PNN NewsWatch
* Serratia marcescens contamination in two lots has prompted a nationwide recall of all lots of heparin and saline prefilled flush syringes manufactured by AM2 PAT, Inc., of Angier, N.C., FDA has announced. These syringes are marketed as Sierra Pre-filled, Inc., and B. Braun, and sold in fill sizes of 3, 5, and 10 mL and syringe sizes of 6 and 12 mL. Use of these products should be stopped immediately, FDA said, and health facilities should quarantine products in their inventory and return them to the distributor. Consumers should return the syringes to the location from which they were received and let health providers know of the use of the recalled syringes.
* Based on the preliminary results of the Effect of Combination Ezetimibe and High-Dose Simvastatin vs. Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia (ENHANCE) trial announced earlier this month by Merck and Schering,
FDA on Friday issued an “early communication” stating that it will conduct a review of Vytorin (ezetimibe/simvastatin) once the final study results are received. The agency also noted, “The study was not designed to detect any difference in risk of having a heart attack or stroke between the two treatments. An ongoing trial, Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE IT), is under way which is designed to evaluate the effect of Vytorin versus Zocor on heart disease and stroke.”

>>>PNN JournalWatch
* The Maxwell Finland Lecture: For the Duration—Rational Antibiotic Administration in an Era of Antimicrobial Resistance and Clostridium difficile, in Clinical Infectious Diseases, 2008; 46: 491–6. Reprints: L. B. Rice, louis.rice@va.gov
* Role of Folate Antagonists in the Treatment of Methicillin-Resistant
Staphylococcus aureus Infection, in Clinical Infectious Diseases, 2008; 46: 584–93. Reprints: R. A. Proctor, rap@facstaff.wisc.edu
* Unhealthy Drinking Patterns in Older Adults: Prevalence and Associated Characteristics, in
Journal of the American Geriatrics Society, 2008; 56: 214–23. Reprints: E. L. Merrick, merrick@brandeis.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 © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 29, 2008 * Vol. 15, No. 19
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Jan. 28 issue of the Archives of Internal Medicine (http://archinte.ama-assn.org/current.dtl; 2008; 168).
Clinical Trial Participants Differ from Medicare Beneficiaries: Demographics of the Medicare population are significantly different from those of the participants in cardiovascular clinical trials used for making national coverage determinations, researchers report (pp. 136-40). Comparing meta-analytic data on 40,009 individuals in 141 trials of six cardiovascular diseases with data from the Medicare program, the investigators report: “Clinical trial participants, compared with beneficiaries, are more likely to be younger (60.1 vs 74.7 years), male (75.4% vs 41.8%), and non-US residents (60% vs 0%). The clinical trials, moreover, rarely included outcome stratification by age, sex, and race.” (R. F. Redberg, redberg@medicine.ucsf.edu)
Non-GI Bleeding with SSRIs Plus Coumarins: Risk of hospitalization for nongastrointestinal bleeding was significantly increased among patients using coumarin derivatives and SSRIs, according to an analysis of Dutch pharmacy records and hospitalization data (pp. 180-5). In a case–control analysis of data on 2 million patients, the authors note: “We identified 1,848 case patients with abnormal bleeding. Users of SSRIs were at significantly increased risk of hospitalization because of nongastrointestinal tract bleeding ... (adjusted OR, 1.7; 95% CI, 1.1–2.5) but not because of gastrointestinal tract bleeding ... (adjusted OR, 0.8; 95% CI, 0.4–1.5). Users of nonsteroidal anti-inflammatory drugs had a similar increased risk of nongastrointestinal bleeding (adjusted OR, 1.7; 95% CI, 1.3–2.2), whereas the risk of gastrointestinal bleeding was higher (adjusted OR, 4.6; 95% CI, 3.3–6.5).” (T. Schalekamp, Utrecht Inst. for Pharm. Sci., Utrecht, the Netherlands; t.schalekamp@pharm.uu.nl)
Treating Hypertension in Patients with Metabolic Syndrome: No preference for antihypertensive agents with favorable metabolic profiles (calcium channel blockers, alpha-blockers, or ACE inhibitors) can be found in ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) results, especially among blacks, concludes a subgroup analysis of the 42,418-participant study (pp. 207-17). “Significantly higher rates of heart failure were consistent across all treatment comparisons in those with MetS,” the researchers write. “Relative risks (RRs) were 1.50 (95% confidence interval, 1.18–1.90), 1.49 (1.17–1.90), and 1.88 (1.42–2.47) in black participants and 1.25 (1.06–1.47), 1.20 (1.01–1.41), and 1.82 (1.51–2.19) in nonblack participants for amlodipine, lisinopril, and doxazosin comparisons with chlorthalidone, respectively. Higher rates for combined cardiovascular disease were observed with lisinopril–chlorthalidone (RRs, 1.24 [1.09–1.40] and 1.10 [1.02–1.19], respectively) and doxazosin–chlorthalidone comparisons (RRs, 1.37 [1.19–1.58] and 1.18 [1.08–1.30], respectively) in black and nonblack participants with MetS. Higher rates of stroke were seen in black participants only (RR, 1.37 [1.07–1.76] for the lisinopril–chlorthalidone comparison, and RR, 1.49 [1.09–2.03] for the doxazosin–chlorthalidone comparison). Black patients with MetS also had higher rates of end-stage renal disease (RR, 1.70 [1.13–2.55]) with lisinopril compared with chlorthalidone.” (S. Pressel, U. Tex., Houston; Sara.L.Pressel@uth.tmc.edu)
Prostate Cancer Following Testosterone Supplementation: Within months after starting daily supplementation with the same testosterone dietary supplement, two men developed unusual cases of clinically aggressive prostate cancer, clinicians report (pp. 235-6). After seeing an advertisement for the supplement in a fitness magazine, the men purchased the product through the Internet. Both patients had had normal prostate-specific antigen levels and digital rectal examinations within 11 months of the onset of widely metastatic prostate cancer. Physicians caring for the men filed adverse event reports with FDA, and the supplement has been withdrawn from the market. (S. F. Shariat, Shahrokh.Shariat@UTSouthwestern.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 © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 30, 2008 * Vol. 15, No. 20
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Jan. 30 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2008; 299).
Drug-Eluting Stents in Everyday Practice: Among 2,098 men and women in the Danish SORT OUT II trial, no significant difference between sirolimus- and paclitaxel-eluting stents was observed (pp. 409-16). Looking at a composite clinical end point of major adverse cardiac events (cardiac death, acute myocardial infarction, target lesion revascularization, or target vessel revascularization) in patients treated at five university hospitals, the researchers found: “The sirolimus- and the paclitaxel-eluting stent groups did not differ significantly in major adverse cardiac events (98 [9.3%] vs 114 [11.2%]; hazard ratio, 0.83 [95% confidence interval, 0.63–1.08]; P = .16) or in any of the secondary end points. The stent thrombosis rates were 27 (2.5%) and 30 (2.9%) (hazard ratio, 0.87 [95% confidence interval, 0.52–1.46]; P = .60), respectively.” (A. M. Galløe, Gentofte U. Hosp., Copenhagen, Denmark; anders@galloe.dk)
With second-generation drug-eluting stents soon to be commercially available, editorialists make this forecast (pp. 454-5): “In 2008, clinicians will have additional choices of drug-eluting stents with the availability of second-generation devices—namely, the everolimus-eluting stent, which yielded similar or fewer major adverse cardiac events among patients as compared with the paclitaxel-eluting stent, and the zotarolimus-eluting stent, which was shown to be noninferior to the paclitaxel-eluting stent. The ongoing choice of a drug-eluting stent will likely depend on multiple factors that will include safety, effectiveness, deliverability, and—given recent cuts in reimbursement—cost of the device. The current literature for drug-eluting stents can be challenging to interpret because of differing criteria for study enrollment, definitions for acute stent thrombosis and other clinical end points, and varied intervals of dual antiplatelet therapy and follow-up after stent implantation. Similarly, current real-world registries are usually limited by lack of valid control groups and often use historical controls. A large longitudinal database for patients receiving these various drug-eluting stents with open entry to fully capture all procedures may help determine the safest and most effective revascularization practice possible and should help guide future recommendations.” (D. J. Moliterno,
moliterno@uky.edu)
Taking Systems Seriously: To make a difference in patient safety, clinicians need to “take systems seriously,” write authors of a Commentary (pp. 445-7). This “requires implementation of systems thinking throughout the organization and across organizations, the development and empowerment of teams, a foundation of information that is used for accountability and learning, and shared responsibility for system improvement,” they note, adding: “Organizational leadership is required to promote systems thinking and the daily use of process improvement tools such as those represented by human factors engineering. This will be greatly enhanced by the further diffusion of electronic medical record information and decision support systems and the creation of effective health care teams trained in patient safety methods and that involve patients, interacting with continuous data feedback across the system of care. Progress on patient safety must also recognize and address an emerging issue involving the mismatch between the increased racial, ethnic, and socioeconomic diversity of the population seeking care and the composition of the heath care professional workforce. Lack of shared communication and understanding can contribute to an environment of distrust and uncertainty that can lead to increased safety problems. Ultimately patient safety must be based on trust—trust between patients and their physicians and between patients and their health care teams across settings of care—trust that the system will ‘first (and last) do no harm.’” (S. M. Shortell, shortell@berkeley.edu)

>>>PNN NewsWatch
* J. Lyle Bootman, PhD, ScD, a pioneer, researcher, and leader in outcomes and pharmacoeconomics research, will receive the profession’s highest honor, the Remington Honor Medal, on Mar. 16 during APhA2008 in San Diego.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 31, 2008 * Vol. 15, No. 21
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Feb. issue of Diabetes Care (31; 2008; http://care.diabetesjournals.org/current.shtml).
Hypoglycemics & Bone Fracture: A case–control study exploring use of insulin and various oral hypoglycemic agents appears to debunk the theory that increased risk of bone fractures in patients using thiazolidinediones is the result of a general reduction of insulinemia (pp. 199-203). Insulin-sensitizing therapy with metformin was not associated with a higher incidence of bone fractures, the researchers report: “In a model including treatment with insulin secretagogues metformin and insulin for at least 36 months during the previous 10 years, no significant association was observed between bone fractures and medications. In an alternative model considering treatments at the time of fracture, insulin treatment was significantly associated with bone fractures in men (OR 3.20 [95% CI 1.32–7.74]) but not in women (1.41 [0.73–2.73]).” (E. Mannucci, U. Florence, Florence, Italy; edoardo.mannucci@fastwebnet.it)
Coccinia cordifolia Extract in Newly Detected Diabetes: A potential hypoglycemic action of Coccinia cordifolia extract was noted in a double-blind, placebo-controlled, 90-day trial of 60 patients with mild type 2 diabetes (pp. 216-20). Testing the effects of a 1-gram alcoholic extract of the herb, which grows abundantly in India, the researchers found: “There was a significant decrease in the fasting, postprandial blood glucose and A1C of the experimental group compared with that of the placebo group. The fasting and postprandial blood glucose levels of the experimental group at day 90 significantly decreased, by 16 and 18%, respectively. There were no significant changes observed in the serum lipid levels.” (R. Kuriyan, St. John’s Natl. Academy of Health Sci., Bangalore, India; rebecca@iphcr.res.in)
Treating Hypertension in Metabolic Syndrome: Thiazide-like diuretic therapy offered similar and in some cases superior antihypertensive effects in patients with metabolic syndrome, compared with calcium-channel blockers and ACE inhibitors, in a subgroup analysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) (pp. 353-60). Comparing metabolic, cardiovascular, and renal outcomes in individuals assigned to initial hypertension treatment with chlorthalidone, amlodipine, or lisinopril in nondiabetic individuals with or without metabolic syndrome, the investigators found: “In participants with metabolic syndrome, at 4 years of follow-up, the incidence of newly diagnosed diabetes (fasting glucose 126 mg/dl) was 17.1% for chlorthalidone, 16.0% for amlodipine (P = 0.49, chlorthalidone vs. amlodipine) and 12.6% for lisinopril (P < 0.05, lisinopril vs. chlorthalidone). For those without metabolic syndrome, the rate of newly diagnosed diabetes was 7.7% for chlorthalidone, 4.2% for amlodipine, and 4.7% for lisinopril (P < 0.05 for both comparisons). There were no differences in relative risks (RRs) for outcomes with amlodipine compared with chlorthalidone in those with metabolic syndrome; in those without metabolic syndrome, there was a higher risk for heart failure (RR 1.55 [95% CI 1.25–1.35]). In comparison with lisinopril, chlorthalidone was superior in those with metabolic syndrome with respect to heart failure (1.31 [1.04–1.64]) and combined cardiovascular disease (CVD) (1.19 [1.07–1.32]). No significant treatment group–metabolic syndrome interaction was noted.” (J. Barzilay, Kaiser Permanente, Tucker, Ga.; joshua.barzilay@kp.org)
Aspirin Less Effective in Diabetes: In a cohort study of 2,499 patients with unstable coronary artery disease, aspirin reduced mortality less than other secondary prevention agents (pp. 363-5). Patients with acute coronary syndrome were recruited from 11 U.K. hospitals, and multivariable analysis of all-cause mortality risk showed these results: “Aspirin was not associated with significant mortality benefit in diabetes sufferers (95% CI 0.50–1.08); nondiabetic patients derived a 48% mortality reduction (P < 0.001). The interaction between diabetes and aspirin use was statistically significant (P = 0.037), indicating that patients with diabetes experience less effective mortality reduction from aspirin use.” (M. T. Kearney, U. Leeds, Leeds, U.K.; m.t.kearney@leeds.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 © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 1, 2008 * Vol. 15, No. 22
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Feb. issue of Pharmacotherapy (www.pharmacotherapy.org; 2008; 28).
Genetic Testing for Warfarin Dosing “Not Yet Ready for Prime Time”: Editorialists argue that the media, research, and FDA attention to the use of pharmacogenetic testing in patients on warfarin therapy is premature (pp. 141-3). After noting the potential benefit of more quickly getting patients into therapeutic range with the drug, the authors conclude that the limitations of the approach—including lack of significant benefit in practice, increased health costs, and increased risk through misuse of information—currently outweigh the potential pluses. (H. I. Bussey, U. Texas Health Sci. Ctr., San Antonio)
VTE Risk with Antidepressants: In a nested case–control study, patients on antidepressants had increased risk of venous thromboembolism, but subgroup analysis revealed amitriptyline to be the problematic agent (pp. 144-50). Based on experiences with 782 cases and 3,085 matched controls, the authors report: “Current exposure to tricyclic antidepressants was associated with a small increased risk of idiopathic venous thromboembolism compared with nonuse (odds ratio [OR] 1.4, 95% confidence interval [CI] 1.1–1.8), whereas we found no increased risk among users of selective serotonin reuptake inhibitors or other antidepressant drugs. When we evaluated individual drugs, we found that amitriptyline conferred an increased risk of thromboembolism (OR 1.7, 95% CI 1.2–2.4) that increased with increasing dose (> 25 mg/day). No other individual antidepressant drug was associated with an increase in risk of venous thromboembolism.” (S. S. Jick, sjick@bu.edu)
Overuse, Abuse of Stimulants Among College Students: Physicians need to “be vigilant” in monitoring for possible overuse and diversion of medications for attention-deficit/hyperactivity disorder among college students who require the drugs for medical reasons (pp. 156-69). Personal interviews of 1,253 first-year college students at a large public university in the mid-Atlantic region showed the following: “Of 1,208 students who were not using prescription stimulants medically for ADHD (ADHD&ndashWinking, 218 (18.0%) engaged in NPS. Of 45 ADHD+ students, 12 (26.7%) overused their ADHD drug at least once in their lifetime, and seven (15.6%) nonmedically used someone else’s prescription stimulants at least once in their lifetime. Among 225 nonmedical users, [nonmedical use of prescription stimulants (NPS)] was infrequent and mainly associated with studying, although 35 (15.6%) used prescription stimulants to party or to get high. Lifetime NPS was associated with past-year other drug use. Both NPS and overuse of prescribed stimulants for ADHD were independently associated with past- year use of five drugs, holding constant sociodemographic characteristics; NPS was also associated with alcohol and marijuana dependence.” (A. M. Arria, aarria@cesar.umd.edu)
Pharmacy Business Model for Ambulatory Settings: A toolkit developed by an ACCP task force provides managers and clinical pharmacy practitioners with a business-practice model for ambulatory settings (p. 285). The document includes assessment, operational, legal and regulatory, and financial aspects. (American College of Clinical Pharmacy, accp@accp.com, www.accp.com)

>>>PNN NewsWatch
* All patients who are currently taking or starting any antiepileptic drug should be closely monitored for notable changes in behavior that could indicate the emergence or worsening of suicidal thoughts or behavior or depression, FDA warned yesterday. In an agency analysis, patients receiving any of 11 antiepileptic drugs (carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, zonisamide) had approximately twice the risk of suicidal behavior or ideation (0.43%) than patients receiving placebo (0.22%). The increased risk of suicidal behavior and suicidal ideation was observed as early as 1 week after starting the antiepileptic drug and continued through 24 weeks. The results were generally consistent among the 11 drugs and across various patient conditions, including epilepsy, psychiatric disorders, and other conditions. The relative risk for suicidality was higher in the patients with epilepsy compared with patients who were given one of the drugs in the class for psychiatric or other conditions.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 4, 2008 * Vol. 15, No. 23
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Feb. 2 issue of Lancet (www.thelancet.com; 2008; 371).
VTE Prophylaxis Underused in Hospitalized Patients: Medical and surgical patients at risk for venous thromboembolism received appropriate prophylaxis in only 40% and 59% of cases, respectively, reports the ENDORSE (Epidemiologic International Day for the Evaluation of Patients at Risk for Venous Thromboembolism in the Acute Hospital Care Setting) study (pp. 387-94). At 358 hospitals in 32 countries, patients were assessed based on the 2004 American College of Chest Physicians evidence-based consensus guidelines, with these results: “68,183 patients were enrolled; 30,827 (45%) were categorised as surgical, and 37,356 (55%) as medical. On the basis of ACCP criteria, 35,329 (51.8%; 95% CI 51.4–52.2; between-country range 35.6–72.6) patients were judged to be at risk for VTE, including 19,842 (64.4%; 63.8–64.9; 44.1–80.2) surgical patients and 15,487 (41.5%; 41.0–42.0; 21.1–71.2) medical patients. Of the surgical patients at risk, 11,613 (58.5%; 57.8–59.2; 0.2–92.1) received ACCP-recommended VTE prophylaxis, compared with 6,119 (39.5%; 38.7–40.3; 3.1–70.4) at-risk medical patients.” (A. T. Cohen, King’s College Hosp., London; alexander.cohen@kcl.ac.uk)

>>>BMJ Highlights
Source:
Feb. 2 issue of BMJ (www.bmj.org; 2008; 336).
Adverse Effects with Calcium Supplements: Cardiovascular event rates were increased in a study of 1,471 healthy postmenopausal women taking calcium supplements (pp. 262-6). Compared with placebo, those on calcium 1 gram (as the citrate salt) showed these increased risks: “Myocardial infarction was more commonly reported in the calcium group than in the placebo group (45 events in 31 women v 19 events in 14 women, P = 0.01). The composite end point of myocardial infarction, stroke, or sudden death was also more common in the calcium group (101 events in 69 women v 54 events in 42 women, P = 0.008).... When unreported events were added from the national database of hospital admissions in New Zealand the relative risk of myocardial infarction was 1.49 (0.86 to 2.57) and that of the composite end point was 1.21 (0.84 to 1.74).” (I. R. Reid, U. Auckland, Auckland, New Zealand; i.reid@auckland.ac.nz)

>>>PNN NewsWatch
* Patients should tell their health care provider about any history of psychiatric illness before starting smoking-cessation therapy with varenicline (Chantix, Pfizer), FDA warned on Friday. Chantix may cause worsening of current psychiatric illness even if it is currently under control. The agency also cautioned health professionals, patients, patients’ families, and caregivers to be alert to and monitor for changes in mood and behavior in patients treated with the drug, including anxiety, nervousness, tension, depressed mood, unusual behaviors, and thinking about or attempting suicide. FDA warned patients to report changes in mood and behavior to their physicians immediately; cautioned that vivid, unusual, or strange dreams may occur while taking varenicline; and advised patients taking varenicline that they may experience impairment of the ability to drive or operate heavy machinery.
*
FDA on Friday approved the Endeavor Zotarolimus-Eluting Coronary Stent (Medtronic) for use in treating patients with narrowed coronary arteries. The safety and effectiveness of the Endeavor stent in smaller diameter arteries or for longer blockages requiring more than two stents has not been studied, FDA noted, and there has been no evaluation of the stent’s safety and effectiveness in patients who are having an acute heart attack, patients who had previous intravascular radiation treatment, or patients who have their blockage in a bypass graft, in the left main coronary artery, or in more than one vessel. Patients who are allergic to zotarolimus or to cobalt, nickel, chromium, or molybdenum should not receive an Endeavor stent. Caution is also recommended for people who have had recent cardiac surgery and for women who are nursing or who may be pregnant.

>>>PNN JournalWatch
* Oncogenes and Cancer, in New England Journal of Medicine, 2008; 358: 502–11. Reprints: C. M. Croce, carlo.croce@osumc.edu
* Preparing for Pediatric Emergencies: Drugs to Consider, in
Pediatrics, 2008; 121: 433–43. Reprints: M. A. Hegenbarth and the Committee on Drugs

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 5, 2008 * Vol. 15, No. 24
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release articles from and Feb. 5 issue of the Annals of Internal Medicine (http://www.annals.org/current.shtml; 2008; 148).
Localized Prostate Cancer Treatments: Because of limitations in published trials and a paucity of direct comparisons of primary treatments, deciding on the best approach for treating localized prostate cancer is difficult (early release). In a systematic review of 18 randomized controlled trials and 473 observational studies, investigators found these trends: “One RCT enrolled mostly men without prostate-specific antigen (PSA)–detected disease and reported that compared with watchful waiting, radical prostatectomy reduced all-cause mortality (24% vs. 30%; P = 0.04) and prostate cancer–specific mortality (5% vs. 10%; P = 0.01) at 10 years (P = 0.04). Effectiveness was limited to men younger than age 65 years but was not associated with Gleason score or baseline PSA level. An older, smaller trial found no significant overall survival differences between radical prostatectomy and watchful waiting (risk difference, 0% [95% CI, –19% to 18%]). Radical prostatectomy reduced disease recurrence at 5 years compared with external-beam radiation therapy in 1 small, older trial (14% vs. 39%; risk difference, 21%; P = 0.04). No external-beam radiation regimen was superior to another in reducing mortality. No randomized trials evaluated primary androgen deprivation. Androgen deprivation used adjuvant to radical prostatectomy did not improve biochemical progression compared with radical prostatectomy alone (risk difference, 0% [CI, –7% to 7%]). No randomized trial evaluated brachytherapy, cryotherapy, robotic radical prostatectomy, photon-beam or intensity-modulated radiation therapy. Observational studies showed wide and overlapping effectiveness estimates within and between treatments. Adverse event definitions and severity varied widely. The Prostate Cancer Outcomes Study reported that urinary leakage (1 event/d) was more common with radical prostatectomy (35%) than radiation therapy (12%) or androgen deprivation (11%). Bowel urgency occurred more often with radiation (3%) or androgen deprivation (3%) than radical prostatectomy (1%). Erectile dysfunction occurred frequently after all treatments (radical prostatectomy, 58%; radiation therapy, 43%; androgen deprivation, 86%). A higher risk score incorporating histologic grade, PSA level, and tumor stage was associated with increased risk for disease progression or recurrence regardless of treatment.” (T. J. Wilt, tim.wilt@med.va.gov)
BC Gene Expression Profiling: In women with early-stage breast cancer, gene expression assays can improve predictions of prognosis and treatment benefit, conclude authors of a systematic review (early release). Comparing three prognostic breast cancer tests (Oncotype DX (Genomic Health), MammaPrint (Agendia BV), and H/I (AvariaDX), the investigators found: “The body of evidence showed that this new generation of tests may improve prognostic and therapeutic prediction, but the tests are at different stages of development. Evidence shows that the tests offer clinically relevant, improved risk stratification over standard predictors. Oncotype DX has the strongest evidence, closely followed by MammaPrint and the H/I test (which is still maturing).” (S. N. Goodman, sgoodman@jhmi.edu)
Initiating HIV Treatment: Combination antiretroviral therapy should be initiated earlier than current recommendations advise, according to developers of a decision model that estimated quality-adjusted life expectancy using data from the Veterans Aging Cohort Study (pp. 178-85). Comparing 5,742 patients with HIV infection with 11,484 matched uninfected controls, the authors found: “Although the simulation was biased against earlier treatment initiation because it used an upper-bound assumption for therapy-related toxicity, earlier treatment increased life expectancy and QALYs at age 30 years regardless of viral load (life expectancies with CD4 initiation thresholds of 500, 350, and 200 cells/mm3 were 18.2 years, 17.6 years, and 17.2 years, respectively, for a viral load of 10 000 copies/mL and 17.3 years, 15.9 years, and 14.5 years, respectively, for a viral load of 300,000 copies/mL), and increased life expectancies at age 40 years if viral loads were greater than 30,000 copies/mL (life expectancies were 12.5 years, 12.0 years, and 11.4 years, respectively, for a viral load of 300,000 copies/mL).” (R. S. Braithwaite, Ronald.Braithwaite@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 © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 6, 2008 * Vol. 15, No. 25
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Feb. 6 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2008; 299).
Cannabis Smoking & Periodontal Disease: Independent of tobacco use, cannabis smoking appears to increase risk of periodontal disease, a New Zealand study finds (pp. 525-31). A complete birth cohort from Dunedin in 1972–73 was studied prospectively, and periodontal combined attachment loss (CAL) in 903 participants who survived to age 32 showed these patterns: “Three cannabis exposure groups were determined: no exposure (293 individuals, or 32.3%), some exposure (428; 47.4%), and high exposure (182; 20.2%). At age 32 years, 265 participants (29.3%) had 1 or more sites with 4 mm or greater CAL, and 111 participants (12.3%) had 1 or more sites with 5 mm or greater CAL. Incident attachment loss between the ages of 26 and 32 years in the none, some, and high cannabis exposure groups was 6.5%, 11.2%, and 23.6%, respectively. After controlling for tobacco smoking (measured in pack–years), sex, irregular use of dental services, and dental plaque, the relative risk estimates for the highest cannabis exposure group were as follows: 1.6 (95% confidence interval [CI], 1.2–2.2) for having 1 or more sites with 4 mm or greater CAL; 3.1 (95% CI, 1.5–6.4) for having 1 or more sites with 5 mm or greater CAL; and 2.2 (95% CI, 1.2–3.9) for having incident attachment loss (in comparison with those who had never smoked cannabis).” (W. M. Thomson, Sir John Walsh Res. Inst., Dunedin, New Zealand; murray.thomson@otago.ac.nz)
“Destructive periodontal disease may well be the canary in the coal mine for chronic noncommunicable diseases (CNCDs),” an editorialist adds. “Smoking and unhealthy eating habits lead to destructive periodontal disease as well as to CNCDs such as diabetes, cardiovascular disease, and certain cancers in late adulthood. The presence of strong common causal factors suggests the need for a synergistic approach to preventing a substantial proportion of both destructive periodontal disease and CNCD cases; primary prevention of destructive periodontal disease should help reduce CNCDs, and primary prevention of CNCDs should help reduce destructive periodontal disease. The latter may already have occurred; successful smoking prevention and cessation programs aimed at reducing cancer and cardiovascular mortality may have inadvertently reduced the incidence of destructive periodontal disease, even before tobacco use became widely recognized as a cause of destructive periodontal disease.” (P. P. Hujoel,
hujoel@u.washington.edu)
Adverse Events After Stopping Clopidogrel Following ACS: A potential “clopidogrel rebound effect” may be responsible for a rash of death and myocardial infarctions observed in a retrospective cohort study of 3,137 patients with acute coronary syndrome after discharge from VA hospitals in 2003–05 (pp. 532-9). Looking at the timing of events and clopidogrel discontinuance, the researchers observed: “Mean (SD) follow-up after stopping treatment with clopidogrel was 196 (152) days for medically treated patients with ACS without stents (n = 1568) and 203 (148) days for patients with ACS treated with percutaneous coronary intervention (PCI) (n = 1569). Among medically treated patients, mean (SD) duration of clopidogrel treatment was 302 (151) days and death or AMI occurred in 17.1% (n = 268) of patients, with 60.8% (n = 163) of events occurring during 0 to 90 days, 21.3% (n = 57) during 91 to 180 days, and 9.7% (n = 26) during 181 to 270 days after stopping treatment with clopidogrel. In multivariable analysis including adjustment for duration of clopidogrel treatment, the first 90-day interval after stopping treatment with clopidogrel was associated with a significantly higher risk of adverse events (incidence rate ratio [IRR], 1.98; 95% confidence interval [CI], 1.46–2.69 vs the interval of 91-180 days). Similarly, among PCI-treated patients with ACS, mean (SD) duration of clopidogrel treatment was 278 (169) days and death or AMI occurred in 7.9% (n = 124) of patients, with 58.9% (n = 73) of events occurring during 0 to 90 days, 23.4% (n = 29) during 91 to 180 days, and 6.5% (n = 8) during 181 to 270 days after stopping clopidogrel treatment. In multivariable analysis including adjustment for duration of clopidogrel treatment, the first 90-day interval after stopping clopidogrel treatment was associated with a significantly higher risk of adverse events (IRR, 1.82; 95% CI, 1.17–2.83).” (J. S. Rumsfeld, John.Rumsfeld@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 © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 7, 2008 * Vol. 15, No. 26
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Feb. 7 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2008; 358).
Pharmacogenetic Testing for Abacavir Hypersensitivity: The risk of hypersensitivity reaction to abacavir can be reduced through pretherapy genetic screening for presence of the HLA-B*5701 allele, a research study shows (pp. 568-79). Among 1,956 patients from 19 countries who were infected with HIV, testing and exclusion of HLA-B*5701–positive patients showed these results in comparison with usual care: “The prevalence of HLA-B*5701 was 5.6% (109 of 1956 patients). Of the patients receiving abacavir, 72% were men, 84% were white, and 18% had not previously received antiretroviral therapy. Screening eliminated immunologically confirmed hypersensitivity reaction (0% in the prospective-screening group vs. 2.7% in the control group, P <0.001), with a negative predictive value of 100% and a positive predictive value of 47.9%. Hypersensitivity reaction was clinically diagnosed in 93 patients, with a significantly lower incidence in the prospective-screening group (3.4%) than in the control group (7.8%) (P <0.001).” (S. Mallal, Murdoch U, Murdoch, Australia, s.mallal@murdoch.edu.au)
In supporting the cost-effectiveness of prescreening for this marker in routine clinical practice, an editorialist writes (pp. 637-9): “The drug industry is usually very hesitant to release drugs requiring pharmacogenetic testing, because the basis for prescription is more complex than for drugs not requiring testing. However, the rate of prescription of abacavir has increased in the United Kingdom since prospective HLA-B*5701 genotyping was introduced (Pirmohamed M, University of Liverpool: personal communication). Thus, the use of validated pharmacogenetic biomarkers might result in increased, rather than decreased, use of medication and, in my opinion, the development of pharmacogenetic biomarkers may in many cases constitute an integral part of drug development.
“HLA-B*5701 genotyping appears to be an effective pharmacogenomic test in white populations, with high sensitivity and modest specificity, allowing clinicians to avert a specific toxic effect of a drug. It is also an important precedent for further pharmacogenomic research toward safer, more effective individualized drug therapy.” (M. Ingelman-Sundberg, Karolinska Institutet, Stockholm)

>>>PNN NewsWatch
* Diabetes researchers are reeling following yesterday’s termination of the intensive glucose management arm of the ACCORD trial, prompting reassessment of basic assumptions about “lower is always better” treatment of this disease. In the Action to Control Cardiovascular Risk in Diabetes study, NIH said that, among 10,251 participants over 4 years of treatment, 257 in the intensive treatment group (with a target A1C level of less than 6%) had died, compared with 203 within the standard treatment group (target A1C, 7.0–7.9%). Patients in the intensive-control arm are being switched to a less-intensive intervention, and the trial will continue with two study groups through its scheduled completion in June 2009.
* A prodrug of aprepitant (Emend,
Merck), has been approved by FDA and will be marketed as Emend for Injection. Fosaprepitant dimeglumine provides an intravenous option for use in combination with other antiemetic medicines for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic and highly emetogenic cancer chemotherapy, including high-dose cisplatin.
* Unapproved
injectable colchicine products are being targeted for action, FDA announced yesterday. Spurred by more than 50 reports of adverse events and 23 deaths associated with use of the products, FDA noted that colchicine is both manufactured by pharmaceutical companies and formulated on a small scale by compounding pharmacies for use in treating back pain, an unapproved use. Some products associated with deaths were 8 times more potent than the labeled amount.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 8, 2008 * Vol. 15, No. 27
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
Feb. 12 issue of the Journal of the American College of Cardiology (http://content.onlinejacc.org/current.dtl; 2008; 51).
Good & Bad HDL: Searching for an explanation of the increased mortality observed with the HDL-raising agent torcetrapib, researchers have found that large HDL particles can increase cardiac risk, perhaps because they serve as cholesterol donors rather than scavengers (pp. 634-42). Showing that HDL cholesterol levels in excess of 70 mg/dL may be detrimental, the researchers report these findings from post-hoc analyses of data from the IDEAL (Incremental Decrease in End Points through Aggressive Lipid Lowering; n = 8,888) trial (comparing the efficacy of high-dose to usual-dose statin treatment for the secondary prevention of cardiovascular events) and the EPIC (European Prospective Investigation into Cancer and Nutrition)–Norfolk case–control study: “In the IDEAL study, higher HDL-C proved a significant major cardiac event risk factor following adjustment for age, gender, smoking, apoA-I, and apoB. A similar association was observed for HDL particle size in EPIC-Norfolk. Increased risk estimates were particularly present in the high ends of the distributions. In contrast, apoA-I remained negatively associated across the major part of its distribution in both studies.” (J. J. P. Kastelein, Academic Med. Ctr., Amsterdam, the Netherlands; j.j.kastelein@amc.uva.nl)
Cardiovascular Care in Older Adults: The special needs of geriatric patients are explored in an editorial that announces a cooperative educational effort being directed at cardiology fellows (pp. 672-3). “Essentials of Cardiovascular Care in Older Adults” has been developed by the American College of Cardiology and the Society of Geriatric Cardiology to achieve these goals among fellows and their teachers (J. T. Dove, American College of Cardiology, Washington, D.C.):
* Raise awareness of age-specific changes and how they impact disease assessment and management
* Appreciate evidence-based care of older adults
* Identify and pursue gaps in our knowledge
* Stimulate research efforts to fill the gap
* Reduce morbidity and mortality through judicious and individualized care

>>>Geriatrics Highlights
Source:
Feb. issue of the Journal of the American Geriatrics Society (http://www.blackwell-synergy.com/toc/jgs/56/2; 2008; 56).
Melatonin in Patients with Alzheimer’s Disease: Among 50 patients institutionalized with Alzheimer’s disease, melatonin plus light treatment improved daytime wake time, activity levels, and rest–activity rhythms (pp. 239-46). Testing bright-light therapy (1 hour of morning light exposure) with either melatonin 5 mg or placebo each evening, the investigators found these results in the 10-week trial: “No significant differences in nighttime sleep variables were found between groups. At the end of the intervention, the [light–melatonin] group showed significant improvement in daytime somnolence as indicated by a reduction in the duration of daytime sleep, an increase in daytime activity, and an improvement in day:night sleep ratio. The [light–melatonin] group also evidenced a significant increase in rest–activity rhythm amplitude and goodness of fit to the cosinor model.” (G. A. Dowling, glenna.dowling@nursing.ucsf.edu)
Alcohol Use in Older Adults: Recommended drinking limits are exceeded by nearly 10% of Medicare beneficiaries, according to an analysis of data from the 2003 Access to Care file of the Medicare Current Beneficiary Survey (pp. 214-23). “Nine percent of elderly Medicare beneficiaries reported unhealthy drinking, with higher prevalence in men (16%) than women (4%),” report the authors. “In logistic regression analyses with the full sample, higher education and income; better health status; male sex; younger age; smoking; being white; and being divorced, separated, or single were associated with higher likelihood of unhealthy drinking. Among drinkers, in addition to sociodemographic variables, self-reported depressive symptoms were positively associated with unhealthy drinking. Among unhealthy drinkers, race and ethnicity variables were associated with likelihood of heavy episodic drinking.” (E. L. Merrick, merrick@brandeis.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 © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 11, 2008 * Vol. 15, No. 28
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Feb. 9 issue of Lancet (www.thelancet.com; 2008; 371).
Gene Locus for LDL-Cholesterol: Using genome-wide association data from 11,685 people, researchers identified three single nucleotide polymorphisms at chromosomal locus 1p13.3 that correlated with circulating LDL-cholesterol concentrations (pp. 483-91). Further analysis using data from a second genome-wide array from 4,337 participants showed that two of the SNPs— rs599839 and rs646776—explained about 1% of the LDL-cholesterol variation and were associated with 15% of the standard-deviation change in LDL-cholesterol per allele. Identification of these loci may provide fertile avenues for research into new therapeutic modalities, the researchers conclude. (M. S. Sandhu, U. Cambridge, Cambridge, U.K.; manj.sandhu@srl.cam.ac.uk)

>>>BMJ Highlights
Source:
Early-release article from BMJ (www.bmj.org; 2008; 336).
Medication Errors & Depressed Residents: Medical residents with depression made more medication errors than nondepressed peers, according to a study of 123 physicians in three pediatric residency programs (doi: 10.1136/bmj.39469.763218.BE). In a prospective cohort study, investigators determined that burnout was very common, but it did not affect medication-error rates: “24 (20%) of the participating residents met the criteria for depression and 92 (74%) met the criteria for burnout. Active surveillance yielded 45 errors made by participants. Depressed residents made 6.2 times as many medication errors per resident month as residents who were not depressed: 1.55 (95% confidence interval 0.57 to 4.22) compared with 0.25 (0.14 to 0.46, P <0.001). Burnt out residents and non-burnt out residents made similar rates of errors per resident month: 0.45 (0.20 to 0.98) compared with 0.53 (0.21 to 1.33, P = 0.2).” (A. M. Fahrenkopf, Harvard Med. Sch., Boston; amy.fahrenkopf@tch.harvard.edu)

>>>PNN NewsWatch
* Respiratory failure and death have been linked to use of botulinum toxin type A for both FDA-approved and -unapproved indications, FDA cautioned the public on Friday. The most severe adverse effects were found in children treated for spasticity in their limbs associated with cerebral palsy, an unapproved use of Botox. FDA said that the adverse reactions appear to be related to the spread of the toxin to areas distant from the site of injection, and mimic symptoms of botulism, which may include difficulty swallowing, weakness, and breathing problems.

>>>PNN JournalWatch
* Effect of Aprotinin on Renal Dysfunction in Patients Undergoing On-Pump and Off-Pump Cardiac Surgery: A Retrospective Observational Study, in Lancet, 2008; 371: 475–82. Reprints: K. Zacharowski, Bristol Royal Infirmary, Bristol, U.K.; kai.zacharowski@bristol.ac.uk
* Effects of Antenatal Multiple Micronutrient Supplementation on Children’s Weight and Size at 2 Years of Age in Nepal: Follow-up of a Double-Blind Randomised Controlled Trial, in
Lancet, 2008; 371: 492–9. Reprints: D. Osrin, UCL Centre for International Health and Development, London; d.osrin@ich.ucl.ac.uk
* Soft Drinks, Fructose Consumption, and the Risk of Gout in Men: Prospective Cohort Study, in
BMJ, 2008; 336: 309–12. Reprints: H. K. Choi, U. British Columbia, Vancouver; hchoi@arthritisresearch.ca
* Targeting TNF-alpha: A Novel Therapeutic Approach for Asthma, in
Journal of Allergy and Clinical Immunology, 2008; 121: 5–10. Reprints: C. Brightling, U. Leicester, Leicester, U.K.; ceb17@le.ac.uk
* Cigarette Smoking and Adenomatous Polyps: A Meta-analysis, in
Gastroenterology, 2008; 134: 388–95. Reprints: E. Botteri, European Inst. of Oncology, Milan, Italy; edoardo.botteri@ieo.it
* Microbial Influences in Inflammatory Bowel Diseases, in
Gastroenterology, 2008; 134: 577–94. Reprints: R. B. Sartor, rbs@med.unc.edu
* A Meta-analysis of Hemodialysis Catheter Locking Solutions in the Prevention of Catheter-Related Infection, in
American Journal of Kidney Diseases, 2008; 51: 233–41. Reprints: C. W. McIntyre, Derby City Hosp., Derby, U.K.; chris.mcintyre@nottingham.ac.uk
* Potentially Inappropriate Prescribing for the Elderly: Effects of Geriatric Care at the Patient and Health Care System Level, in
Medical Care, 2008; 46: 167–73. Reprints: M. J. Pugh.
* Successful Treatment of Resistant Pseudogout with Anakinra, in
Arthritis & Rheumatism, 2008; 58: 631–3. Reprints: D. McGonagle, U. Leeds, Leeds U.K.; d.g.mcgonagle@leeds.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 © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 12, 2008 * Vol. 15, No. 29
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Feb. 11 issue of the Archives of Internal Medicine (http://archinte.ama-assn.org/current.dtl; 2008; 168).
Nonadherence with Antihypertensives: Therapy intensification often does not work for treating hypertension in patients with coronary artery disease, researchers report, primarily because patients are not taking the medications (pp. 271-36). Rather, what is needed to reduce elevated systolic blood pressures is a combination of intensification and attention to medication adherence, the study shows, based on these data gathered in a retrospective cohort study of 10,447 patients with CAD: “Three SBP trajectory groups were identified: (1) patients with BP that remained controlled (ie, SBP, 140 mm Hg) over time (n = 9,114 [87.2%]); (2) patients with high BP that became controlled (n = 779 [7.5%]); and (3) patients with BP that remained high over time (n = 554 [5.3%]). In multivariable analyses, therapy intensification (odds ratio, 1.31; 95% confidence interval, 1.01–1.70) and medication nonadherence (odds ratio, 1.73; 95% confidence interval, 1.34–2.24) were associated with uncontrolled BP compared with high SBP that became controlled over time.” (P. M. Ho, VA Med. Ctr., Denver; Michael.ho@uchsc.edu)
Asking whether information is “the answer for hypertension control,” an editorialist writes about the importance of bringing prescription-refill data to the prescriber’s attention (pp. 259-60): “Online pharmacy data would ... augment the information loop. Assume such data were readily available in the clinician’s office, then a physician could determine the degree to which failure to reach blood pressure control was related to adherence issues. Taken 1 step further, online pharmacy systems, linked to decision support, could also be used to proactively remind patients and/or alert their physicians if important therapies were consistently missed.” (E. D. Peterson,
peter016@mc.duke.edu)
Dietary Habits Deteriorating Among Patients with Hypertension: Dietary profiles of Americans with hypertension is bad and getting worse, according to an analysis of data from the 1988–1994 and 1999–2004 National Health and Nutrition Examination Surveys (NHANES) (pp. 308-14). Comparing eating patterns with those recommended in the DASH (Dietary Approaches to Stop Hypertension trial) diet, the researchers found: “Based on 4,386 participants with known HTN in the recent survey period (1999–2004), the mean (SE) DASH score, after adjustment for age and energy intake, was 2.92 (0.05), with 19.4% (1.2%) classified as DASH accordant. In multivariable logistic regression models, DASH accordance was associated with older age, nonblack ethnicity, higher education, and known diabetes mellitus. Accordance with DASH was 7.3% lower in the recent survey period compared with NHANES 1988–1994 (26.7% [1.1%]) (P < .001), reflecting fewer patients with HTN meeting nutrient targets for total fat, fiber, and magnesium.” (P. B. Mellen, Hypertension Center of the Hattiesburg Clinic, Hattiesburg, Miss.; philip.mellen@hattiesburgclinic.com)

>>>PNN NewsWatch
* Baxter has suspended manufacturing of multidose vials of heparin because of 350 reports of adverse events associated with use of the product since year end. This compares with only 100 such reports during all of 2007, FDA reports. Patients on hemodialysis have been affected most frequently. If the suspension lasts long, a shortage will likely result, as Baxter supplies one-half the nation’s supply of 1 million multidose vials each month. Reactions to the drug have included difficulty breathing, nausea, vomiting, excessive sweating, and rapidly falling blood pressure that can lead to life-threatening shock. Four people have died after receiving heparin, although the relationship to the drug is unclear. Baxter’s heparin is supplied from China, and FDA said that it will look into procedures at both the U.S. plant where the finished product is produced and the overseas plant where the biologic product originates.
* Consumer reports of first, second, and third degree burns as well as skin irritation with
Icy Hot Heat Therapy products has resulted in a recall of all lots and sizes of the product, FDA and Chattem announced yesterday.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 13, 2008 * Vol. 15, No. 30
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Feb. 13 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2008; 299).
Root Cause Analysis & Preventable Medication Errors: Use of root cause analysis in investigation of medication and other medical errors has limited utility, writers argue, and at a minimum has not been assessed for effectiveness (pp. 658-7). The technique, which the authors note was developed in psychology and systems engineering to identify “the basic and causal factor(s) that underlie variation in performance,” has many problems (RCAs may be performed incorrectly or incompletely, do not produce usable results, are used inappropriately to find single causes or explanation, and tend to run independently for each error with little attention to broader issues) and does not typically aid in formulating corrective actions. The group concludes: “Root cause analysis has been widely adopted as a central method to learn from mistakes and mitigate hazards. Although there have been some benefits, including increased awareness of faulty processes and fixes to specific problems, there is an undercurrent of sentiment that this approach has limited effectiveness. Many health care organizations, particularly smaller ones, may be spending a substantial portion of their quality improvement resources on interventions that have little chance of diminishing risks or harms. The next step is to evaluate RCA processes for effectiveness and utility, and make RCA more useful. More emphasis should be placed on understanding variations in the implementation of RCA and developing a greater evidence base for the best way to conduct them. Follow-up for implementation and outcomes should become a standard element of the process.” (A. W. Wu, World Alliance for Patient Safety, World Health Organization, Geneva, Switzerland; awu@jhsph.edu)
Treating Advanced Testicular Cancer: In a Clinician’s Corner review article, authors provide this perspective on medical treatment of advanced testicular cancer (pp. 672-84): “The treatment of advanced testicular germ cell tumors with cisplatin combination chemotherapy is based on risk stratification (good, intermediate, or poor prognosis) according to pretreatment clinical features of prognostic value. Clinical trials have demonstrated that approximately 90% of patients classified as having a good prognosis achieve a durable complete remission to either 4 cycles of etoposide and cisplatin or 3 cycles of cisplatin, etoposide, and bleomycin. Complete responses are achieved less frequently for patients with intermediate- and poor-risk germ cell tumors, in whom 4 cycles of bleomycin, etoposide, and cisplatin remains the standard of care. Second- and third-line programs, including high-dose chemotherapy, also have curative potential. Chronic toxicities associated with therapy include cardiovascular disease, infertility, and secondary malignancies. Late relapses may also occur.” (R. J. Motzer, Memorial Sloan-Kettering Cancer Ctr., New York; motzerr@mskcc.org)
Healthy Aging: The medical challenges of improving quality of life in a population with ever-increasing life expectancy are reviewed by authors of a Commentary article (pp. 668-90): “The capacity of individuals is closely linked to nutrition, physical activities, and good lifestyle habits over the entire life cycle (even at old age). The recent identification of midlife vascular risk factors in older adults that may predict diseases and disability emphasizes the importance of maintaining normal weight, blood pressure, and plasma cholesterol levels early in life. Avoiding habits negatively associated with successful aging such as smoking or physical inactivity should also be encouraged, not only for their immediate benefits but also because of their contribution to longevity and healthy aging.” (J-P Michel, U. Geneva, Thônex-Geneva, Switzerland; jean-pierre.michel@hcuge.ch)

>>>PNN NewsWatch
* Seeking to compete more effectively with energy drinks, candy manufacturers are beginning to pack products “full of caffeine” and vitamins, today’s Wall Street Journal reports. Buzz Bites, Snickers Charged, and Extreme Sport Beans are examples of what the newspaper describes as a “burgeoning ‘energy candy’ category.”

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 14, 2008 * Vol. 15, No. 31
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Feb. 14 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2008; 358).
Rituximab in Relapsing–Remitting MS: A two-dose course of rituximab reduced inflammatory brain lesions and clinical relapses for 48 weeks among 104 patients with relapsing–remitting multiple sclerosis, providing evidence of B-cell involvement in the pathophysiology of this disease, researchers report (pp. 676-88). In a Phase II trial, patients received rituximab 1,000 mg or placebo on days 1 and 15, and these findings were noted on gadolinium-enhanced magnetic resonance imaging scans of the brain at weeks 12, 16, 20, and 24: “As compared with patients who received placebo, patients who received rituximab had reduced counts of total gadolinium-enhancing lesions at weeks 12, 16, 20, and 24 (P <0.001) and of total new gadolinium-enhancing lesions over the same period (P <0.001); these results were sustained for 48 weeks (P <0.001). As compared with patients in the placebo group, the proportion of patients in the rituximab group with relapses was significantly reduced at week 24 (14.5% vs. 34.3%, P = 0.02) and week 48 (20.3% vs. 40.0%, P = 0.04). More patients in the rituximab group than in the placebo group had adverse events within 24 hours after the first infusion, most of which were mild-to-moderate events; after the second infusion, the numbers of events were similar in the two groups.” (S. L. Hauser, hausers@neurology.ucsf.edu)
Terming the B cell an “old player” trying out a “new position on the team,” an editorialist discusses what is known about the causes of MS (pp. 664-5): “Although the mechanisms underlying the effect of rituximab on disease activity in multiple sclerosis are not known, the findings suggest that we need to explore the role of B cells in the disease process beyond the ability of antimyelin antibodies to contribute to demyelination. Few human diseases provide a better opportunity to dissect the role of B cells in autoimmunity. A phase 2 trial leaves many questions unanswered; these include the duration of the treatment effect, the effect of progression of disability, and—most important — the types of adverse events that may occur at low frequency. Just as manipulation of a complicated immune response may provide treatment opportunities and improved understanding of disease processes, it may also bring unexpected difficulties.” (H. F. McFarland, Natl. Inst. of Neurological Disorders and Stroke, Bethesda, Md.)
Paclitaxel During Angioplasty of the Leg: Paclitaxel-coated angioplasty balloons reduced late lumen loss and target-lesion revascularization during percutaneous treatment of femoropopliteal disease in a study of 154 patients (pp. 689-99). Looking at late lumen loss at 6 months as the primary end point, investigators determined: “The mean (± SD) age of the patients was 68 ± 8 years, 24% were smokers, and 49% had diabetes. Twenty-seven percent of the lesions were total occlusions, and 36% were restenotic lesions. The mean lesion length was 7.4 ± 6.5 cm. There were no significant differences in baseline characteristics between the groups. There were no adverse events attributable to the paclitaxel-coated balloons. At 6 months, the mean late lumen loss was 1.7 ± 1.8 mm in the control group, as compared with 0.4 ± 1.2 mm (P <0.001) in the group treated with paclitaxel-coated balloons and 2.2 ± 1.6 mm (P = 0.11) in the group treated with paclitaxel in the contrast medium. The rate of revascularization of target lesions at 6 months was 20 of 54 (37%) in the control group, 2 of 48 (4%) in the group treated with paclitaxel-coated balloons (P <0.001 vs. control), and 15 of 52 (29%) in the group treated with paclitaxel in the contrast medium (P = 0.41 vs. control); at 24 months, the rates increased to 28 of 54 (52%), 7 of 48 (15%), and 21 of 52 (40%), respectively.” (G. Tepe, Eberhard-Karls-Universität Tübingen, Tübingen, Germany; gunnar-tepe@med.uni-tuebingen.de)

>>>PNN NewsWatch
* The Chinese plant that produced heparin for Baxter has never been inspected by FDA, the Wall Street Journal reports this morning. The revelation casts doubt on FDA’s decision not to press for a recall of the company’s multidose vials, saying doing so would cause a shortage of heparin. Baxter’s heparin products have been linked to 350 adverse events and 4 deaths in 2008.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 15, 2008 * Vol. 15, No. 32
Providing news and information about medications and their proper use

>>>Chest Highlights
Source:
Feb. issue of Chest (http://www.chestjournal.org/current.shtml; 2008; 133).
Sputum Eosinophils & Steroid Response in Asthma: Measurement of sputum eosinophil percentage holds promise as a measure of response to inhaled corticosteroids in exercise-induced bronchoconstriction, according to a study of 26 steroid-naive patients with asthma (pp. 404-11). In a trial that compared low and high doses of daily ciclesonide (40 versus 160 mcg and 80 versus 320 mcg in crossover fashion), the investigators found: “Data were pooled and demonstrated that 10 subjects had baseline sputum eosinophilia ≥5%. Only high-dose ICS therapy (ie, 160 and 320 mcg) significantly attenuated the sputum eosinophil percentage. Sputum eosinophil percentage significantly correlated with EIB severity, and predicted the magnitude and temporal response of EIB to high-dose therapy, but not to low-dose therapy (ie, 40 and 80 mcg). Low-dose ICS therapy provided a significant reduction in EIB at 1 week, with little additional improvement thereafter, irrespective of baseline sputum eosinophil counts. In contrast, high-dose ICS therapy provided a significantly greater improvement in EIB in subjects with sputum eosinophilia compared to those with an eosinophil count of <5%. The difference between the eosinophilic groups in the magnitude of improvement in EIB was evident after the first week of high-dose ICS therapy and increased with time.” (M. Duong, duongmy@mcmaster.ca)
Mycophenolate Mofetil in Scleroderma: Mycophenolate mofetil improved vital capacity among 13 patients with scleroderma- associated interstitial lung disease (pp. 455-60). Researchers retrospectively identified those with systemic sclerosis and lung changes who had received MMF 1 gram/day for 6 months or more and noted these results: “Among 13 patients who met inclusion criteria, MMF was associated with a significant improvement in VC (mean, +159 mL; confidence interval [CI], +30 to +289 mL; and +4% of the predicted normal value; CI, +2 to +7%) after 12 months of treatment. In contrast, patients had a significant decrease in VC (mean, –239 mL; CI, –477 to –0.5 mL; and –5% of the predicted normal value; CI, –11 to –0.3%) in the 12 months prior to MMF treatment. [Diffusion capacity of the lung for carbon monoxide] did not change significantly during MMF treatment (mean, +1% of the predicted normal value; CI, –2 to +5%) but decreased significantly in the 12 months prior to treatment (mean, –5% of the predicted normal value; CI, –10 to –1%).” (A. J. Gerbino, Virginia Mason Med. Ctr., Seattle; cidajg@vmmc.org)

>>>Infectious Diseases Report
Source:
Mar. 1 issue of Clinical Infectious Diseases (www.journals.uchicago.edu/toc/cid/current; 2008; 46).
Vancomycin-Resistant Staphylococcus aureus: Spread of vanA-positive vancomycin-resistant Staphylococcus aureus beyond seven patients in the U.S. was prevented by prompt detection and adherence to recommended infection control procedures, note authors of a research report (pp. 668-74): “Seven cases were identified from 2002 through 2006; 5 were reported from Michigan, 1 was reported from Pennsylvania, and 1 was reported from New York. All VRSA isolates were vanA positive and had a median vancomycin minimum inhibitory concentration of 512 mcg/mL. All case patients had a history of prior methicillin-resistant S. aureus and enterococcal infection or colonization; all had several underlying conditions, including chronic skin ulcers; and most had received vancomycin therapy prior to their VRSA infection. Person-to-person transmission of VRSA was not identified beyond any of the case patients. Infection-control precautions were evaluated and were consistent with established guidelines.” (D. M. Sievert, Sievert@cdc.gov">DSievert@cdc.gov)
Ceftobiprole Medocaril for Skin Infections: The investigational agent ceftobiprole provides a monotherapy option for treating skin and skin-structure infections caused by a variety of gram-positive and -negative pathogens, researchers report (pp. 647-55). Cure rates among 485 patients were comparable for this agent in comparison with vancomycin–ceftazidime. (G. J. Noel, Johnson & Johnson, Raritan, N.J.; GNoel1@prdus.jnj.com)

>>>PNN NewsWatch
* PNN will not be published on Mon., Feb. 18, Presidents’ 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 © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 19, 2008 * Vol. 15, No. 33
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Early-release articles from and Feb. 16 issue of Lancet (www.thelancet.com; 2008; 371).
Probiotics in Severe Pancreatitis: An increased risk of mortality was observed in patients with severe pancreatitis who received a multispecies probiotic preparation (doi: 10.1016/S0140-6736(08)60207-X). Among 298 patients with APACHE II scores of 8 or more, Imrie scores of 3 or greater, and C-reactive protein levels higher than 150 mg/L, random treatment with probiotics or placebo twice daily produced these results: “Infectious complications occurred in 46 (30%) patients in the probiotics group and 41 (28%) of those in the placebo group (relative risk 1.06, 95% CI 0.75–1.51). 24 (16%) patients in the probiotics group died, compared with nine (6%) in the placebo group (relative risk 2.53, 95% CI 1.22–5.25). Nine patients in the probiotics group developed bowel ischaemia (eight with fatal outcome), compared with none in the placebo group (p = 0.004).” (H. G. Gooszen, U. Med. Ctr., Utrecht, the Netherlands; h.gooszen@umcutrecht.nl)
Immediate Transfer for PCI: In a study of 600 patients, the optimal treatment for patients who could not receive percutaneous coronary intervention within 90 minutes of the onset of ST-segment elevation myocardial infarction proved to be half-doses of reteplase plus abciximab followed by immediate transfer to a center equipped to perform PCI (pp. 559-68). “Of the 299 patients assigned to immediate PCI, 289 (97.0%) underwent angiography, and 255 (85.6%) received PCI,” investigators in the Combined Abciximab REteplase Stent Study in Acute Myocardial Infarction (CARESS-in-AMI) trial report. “Rescue PCI was done in 91 patients (30.3%) in the standard care/rescue PCI group. The primary outcome occurred in 13 patients (4.4%) in the immediate PCI group compared with 32 (10.7%) in the standard care/rescue PCI group (hazard ratio 0.40; 95% CI 0.21–0.76, log rank p = 0.004). Major bleeding was seen in ten patients in the immediate group and seven in the standard care/rescue group (3.4% vs 2.3%, p = 0.47). Strokes occurred in two patients in the immediate group and four in the standard care/rescue group (0.7% vs 1.3%, p = 0.50).” (C. Di Mario, Royal Brompton Hosp., London; c.dimario@rbht.nhs.uk)

>>>BMJ Highlights
Source:
Feb. 16 issue of BMJ (www.bmj.org; 2008; 336).
PTSD After Combat Exposure: Among U.S. military personnel deployed in Iraq and Afghanistan, new-onset posttraumatic stress disorder occurred in about 8% of those who reported combat exposures, according to a prospective cohort study (pp. 366-71). Among 50,184 participants, 40% were deployed between 2001 and 2006, and the combat theaters were the site of initial deployment for 24%. New-onset PSTD symptoms or diagnosis were reported by 7.6–8.7% of deployers with combat exposures, 1.4–2.1% of deployers without combat exposures, and 2.3–3.0% of nondeployers. (T. C. Smith, Naval Health Res. Ctr., San Diego; tyler.c.smith@med.navy.mil)

>>>PNN NewsWatch
* All lots of 25 mcg/hr Duragesic Patches sold in the United States are being recalled, PriCara and Sandoz announced last week. The patches may have a cut along one side of the drug reservoir within the patch that may result in the possible release of fentanyl gel, exposing patients or caregivers directly to fentanyl gel on the skin. Patches with a cut edge should not be used. The recalled patches, manufactured by Alza Corporation, have expiration dates of December 2009 or earlier.
*
FDA on Friday issued draft guidelines to industry on the distribution of medical journal articles on unapproved uses of FDA-approved medications and medical devices. Comments on the proposal are due in 60 days.

>>PNN JournalWatch
* Body-Mass Index and Incidence of Cancer: A Systematic Review and Meta-analysis of Prospective Observational Studies, in Lancet, 2008; 371: 569–78. Reprints: A. Renehan, U. Manchester, Manchester, U.K.; arenehan@picr.man.ac.uk
* Neuroendocrine-Immune Mechanisms of Behavioral Comorbidities in Patients with Cancer, in
Journal of Clinical Oncology, 2008; 26: 971–82. Reprints: A. H. Miller, amill02@emory.edu
* Pulmonary Complications of Novel Antineoplastic Agents for Solid Tumors, in
Chest, 2008; 133: 528–38. Reprints: B. Vahid, bobbak.vahid@mail.tju.edu
* A Meta-Analytic Review of Psychosocial Interventions for Substance Use Disorders, in
American Journal of Psychiatry, 2008; 165: 179–87. Reprints: L. Dutra.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 20, 2008 * Vol. 15, No. 34
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Feb. 20 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2008; 299).
T3 Levels During Thyroxine Therapy: Among 50 patients who had undergone near-total or total thyroidectomy, exogenous triiodothyronine (T3) administration was not needed to maintain serum T3 levels, as levothyroxine (LT4) sufficed (pp. 769-77). During administration of levothyroxine alone, the researchers noted these trends in serum levels of T3, thyroxine (T4), and thyroid stimulating hormone: “By the end of the study, there were no significant decreases in T3 concentrations in patients receiving LT4 therapy compared with their prethyroidectomy T3 levels (mean, 127.2 ng/dL; 95% confidence interval [CI], 119.5–134.9 ng/dL vs 129.3 ng/dL; 95% CI, 121.9–136.7 ng/dL; P = .64). However, free T4 concentrations were significantly higher in patients treated with LT4 therapy (mean, 1.41 ng/dL; 95% CI, 1.33–1.49 ng/dL) compared with their native free T4 levels (1.05 ng/dL; 95% CI, 1.00–1.10 ng/dL; P < .001). Serum TSH values of 4.5 mIU/L or less were achieved in 94% of patients by the end of the study. The T3 concentrations were lower in the subgroup of patients whose therapy had not resulted in a TSH level of 4.5 mIU/L or less (P < .001).” (J. Jonklaas, jj@bc.georgetown.edu)
Describing these findings as having come “full circle,” an editorialist writes (pp. 817-9): “It is unknown why some patients do not feel well even when their thyroid function is normal. Among the 50 patients studied by Jonklaas et al, there were 6 patients whose serum T
3 levels, for whatever reason, appeared to be much lower postoperatively than their T3 levels had been preoperatively. One might speculate that some patients, perhaps approximately 10%, might potentially benefit from T3 supplementation after thyroidectomy. It would, therefore, be of interest to repeat the study performed by Jonklaas et al to identify those few patients whose postoperative T3 is much lower than it had been before surgery. These patients would then be randomized to receive combined T4/T3 therapy, a higher dose of T4 monotherapy, or no change in their current T4 dose. They would then be tested to see whether any change in their regimen resulted in improvements in mood, symptoms, cognitive function, or quality of life. Approximately 75,000 patients undergo thyroidectomy annually in the United States, so the study could be performed quite easily. However, the data of Jonklaas et al seem to lay to rest, once and for all, the notion that T4 therapy alone is inadequate to replace serum T3 levels back to normal in the overwhelming majority of patients.” (D. S. Cooper, Sinai Hosp., Baltimore, Md.; dcooper@lifebridgehealth.org)
Renal Replacement Therapy in ARF: Intermittent hemodialysis and continuous renal replacement therapy provide similar outcomes in patients with acute renal failure, concludes a systematic review of 30 randomized controlled trials and 8 prospective cohort studies (pp. 793-805). “Available data comparing CRRT with intermittent hemodialysis demonstrated no clinically relevant difference between modalities, including for all-cause mortality (relative risk [RR], 1.10; 95% confidence interval [CI], 0.99–1.23; I2 = 0%) or for the requirement for chronic dialysis treatment in survivors (RR, 0.91; 95% CI, 0.56–1.49; I2 = 0%),” report the authors. “For patients treated with CRRT, limited data suggest that bicarbonate may be preferable to other forms of dialysate alkali and that citrate infusion may be an alternative to systemic anticoagulation in patients at high risk of bleeding. Among patients treated with continuous venovenous hemofiltration, the risk of death was lower at doses of 35 mL/kg per hour (RR of death compared with doses of 20 mL/kg per hour, 0.74; 95% CI, 0.63–0.88). The use of unsubstituted cellulosic membranes should be avoided in intermittent hemodialysis (RR of death compared with biocompatible membranes, 1.23; 95% CI, 1.01–1.50).” (M. Tonelli, U. Alberta, Edmonton)
Mass Antibiotics for Trachoma: Ocular Chlamydia that causes trachoma perhaps can be eliminated in severely affected areas through mass antibiotic administrations to residents once every 2 years, researchers report (pp. 778-84). In 12 Ethiopian villages, the prevalence of infectious trachoma was reduced from 31.6% pretreatment to 0.9% at 24 months through single doses of azithromycin given annually or biennially. (T. M. Lietman, tom.lietman@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 © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 21, 2008 * Vol. 15, No. 35
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Feb. 21 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2008; 358).
Safety of Aprotinin: The risk of mortality and adverse events with aprotinin—an agent whose marketing has been suspended because of safety concerns (see PNN, Nov. 5, 2007)—administration during cardiac surgery is explored in two research articles and an editorial.
Mortality was higher among patients who received aprotinin alone on the day of coronary-artery bypass graft surgery than in those receiving aminocaproic acid alone (pp. 771-83). Analyzing surgical charges recorded in the Premier Perspective Comparative Database, the investigators found: “In all, 1,512 of the 33,517 aprotinin recipients (4.5%) and 1,101 of the 44,682 aminocaproic acid recipients (2.5%) died. After adjustment for 41 characteristics of patients and hospitals, the estimated risk of death was 64% higher in the aprotinin group than in the aminocaproic acid group (relative risk, 1.64; 95% confidence interval [CI], 1.50 to 1.78). In the first 7 days after surgery, the adjusted relative risk of in-hospital death in the aprotinin group was 1.78 (95% CI, 1.56 to 2.02). The relative risk in a propensity-score–matched analysis was 1.32 (95% CI, 1.08 to 1.63). In the instrumental-variable analysis, the use of aprotinin was found to be associated with an excess risk of death of 1.59 per 100 patients (95% CI, 0.14 to 3.04). Postoperative revascularization and dialysis were more frequent among recipients of aprotinin than among recipients of aminocaproic acid.” (S. Schneeweiss,
schneeweiss@post.harvard.edu)
Among 10,275 consecutive patients undergoing cardiac surgery at Duke U. Med. Ctr., higher mortality and greater increases in serum creatinine levels were observed (pp. 784-93): “A total of 1,343 patients (13.2%) received aprotinin, 6,776 patients (66.8%) received aminocaproic acid, and 2,029 patients (20.0%) received no antifibrinolytic therapy. All patients underwent coronary-artery bypass grafting, and 1,181 patients (11.5%) underwent combined coronary-artery bypass grafting and valve surgery. In the risk-adjusted model, survival was worse among patients treated with aprotinin, with a main-effects hazard ratio for death of 1.32 (95% confidence interval [CI], 1.12 to 1.55) for the comparison with patients receiving no antifibrinolytic therapy (P = 0.003) and 1.27 (95% CI, 1.10 to 1.46) for the comparison with patients receiving aminocaproic acid (P = 0.004). As compared with the use of aminocaproic acid or no antifibrinolytic agent, aprotinin use was also associated with a larger risk-adjusted increase in the serum creatinine level (P <0.001) but not with a greater risk-adjusted incidence of dialysis (P = 0.56).” (A. D. Shaw,
andrew.shaw@duke.edu)
An editorialist, noting that the FDA amendments passed by Congress last year give the agency the authority to require head-to-head postmarketing trials of therapeutic alternatives, explains why it is important to do so
(pp. 840-2): “The key lesson from the aprotinin story is that when a new drug has alternatives, as is the case for aprotinin, head-to-head comparative trials powered for important clinical end points are needed before the drug is routinely prescribed for large numbers of patients. These randomized trials are the best way to define relative efficacy and safety, the most critical information for patients and physicians. If, as is often the case, these trials are not part of the premarketing testing, then they should be conducted as soon as possible after licensing. The manufacturer cannot be relied on to perform these studies voluntarily, because they frequently serve no commercial purpose. Indeed, several observers noted the dearth of trials comparing aprotinin with the lysine analogues and commented on the economic disincentives for direct comparisons of competing therapies. Thus, when indicated, postmarketing comparative efficacy and safety trials, supervised by the FDA, should be mandatory. To limit the risk for patients, distribution of new drugs should be restricted while these trials are being conducted, with selective extension of patents to reduce the economic burden on the manufacturer.” (W. A. Ray, Vanderbilt U., Nashville)
Follow-on Protein Drugs: Bills introduced into Congress during 2007 should lead to regulation of recombinant-protein therapeutic agents, authors note, eventually ending their “permanent patent” status (pp. 843-9; D. M. Dudzinski, 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 © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 22, 2008 * Vol. 15, No. 36
Providing news and information about medications and their proper use

>>>Pediatrics Highlights
Source:
Feb. issue of Pediatrics (http://pediatrics.aappublications.org/current.shtml; 2008; 121).
Oral Zinc for Diarrhea: Duration of acute and persistent diarrhea is reduced through administration of oral zinc, acting through an as-yet-undetermined mechanism, according to a meta-analysis of 22 randomized controlled trials (pp. 326-36). Among the nearly 20,000 patients in the trials, the authors noted: “Mean duration of acute diarrhea and persistent diarrhea was significantly lower for zinc compared with placebo. Presence of diarrhea between zinc and placebo at day 1 was not significantly different in acute diarrhea or persistent diarrhea trials. At day 3, presence was significantly lower for zinc in persistent diarrhea trials (n = 221) but not in acute diarrhea trials. Vomiting after therapy was significantly higher for zinc in 11 acute diarrhea trials (n = 4,438) and 4 persistent diarrhea trials (n = 2,969). Those who received zinc gluconate in comparison with zinc sulfate/acetate vomited more frequently. Overall, children who received zinc reported an 18.8% and 12.5% reduction in average stool frequency, 15.0% and 15.5% shortening of diarrhea duration, and a 17.9% and 18.0% probability of reducing diarrhea over placebo in acute and persistent trials, respectively.” (M. Lukacik, Med. College of Georgia, Augusta)
Hospital-Based Influenza Vaccination: Nearly one-fourth of children hospitalized for influenza infection and with a comorbidity had been inpatients within the prior 6 months, researchers report, concluding that the a hospital-based influenza vaccination effort could reach children who are at highest risk for complications (pp. 345-8). The Pediatric Health Information System database was examined for discharges in 2001–06 involving first influenza or respiratory illness between Nov. 1 and Apr. 30 of each season and for prior hospitalizations of that patient for any reason in the prior 0.5 to 6 months. Results showed: “Overall, 16% of children hospitalized with influenza and 12% of children hospitalized with influenza or a respiratory illness had a previous hospitalization during the most recent influenza-vaccination season. Approximately 23% of the children hospitalized with influenza and a comorbidity had a previous hospitalization during the most recent influenza-vaccination season.” (D. M. Zerr, Children’s Res. Inst., Seattle, Wash.)
Mercury Levels with Thimerosal: Infants receiving thimerosal-containing vaccines intramuscularly excrete the resulting ethyl mercury in feces, according to a study of 216 healthy newborns and infants (e208-14). Serum half-lives of the compound in this population were substantially shorter than those of methyl mercury in adults, invalidating exposure guidelines based on pharmacokinetics observed in older patients. (M. E. Pichichero, U. Rochester, Rochester, N.Y.)

>>>PNN NewsWatch
* Xyntha Antihemophilic Factor (Recombinant) Plasma/Albumin Free (Wyeth) was licensed by FDA yesterday for control and prevention of bleeding in patients with hemophilia A. The factor VIII product is manufactured using recombinant genes spliced into Chinese Hamster Ovary cells (CHO). These CHO cells are free from known infectious agents, and Xyntha undergoes an additional process of viral inactivation. Also, the culture in which the cells are grown is free of any human or animal material. In clinical trials, Xyntha was effective for preventing or controlling bleeding, including preventing bleeding in surgery, for patients with hemophilia A. The most frequently reported adverse reaction was headache and, during surgery, fever. Most adverse reactions were considered mild or moderate in severity. Of 89 individuals treated with the product for 50 days, 2 developed factor VIII inhibitors.
* A low-cost
global positioning system was used to measure unconstrained walking distance in a public park among 24 patients with peripheral arterial disease in a report in this week’s Circulation (pp. 897-904; P. Abraham, U. Hosp., Angers, France; Piabraham@chu-angers.fr). The authors conclude that the possibility of using GPS “opens new perspectives in the study of walking capacity for vascular patients with claudication under free-living conditions or for physicians who do not have a treadmill.”

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 25, 2008 * Vol. 15, No. 37
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release article from BMJ (www.bmj.org; 2008; 336).
Antioxidants, Folate in Down’s Syndrome: In a study of 156 infants younger than 7 months of age with trisomy 21, supplementation with antioxidants and folinic acid yielded no identifiable benefits, researchers report (doi: 10.1136/bmj.39465.544028.AE). Testing the effects of daily oral supplementation with antioxidants (selenium 10 mcg, zinc 5 mg, vitamin A 0.9 mg, vitamin E 100 mg, and vitamin C 50 mg), folinic acid 0.1 mg, both, or neither, the investigators determined: “Children randomised to antioxidant supplements attained similar developmental outcomes to those without antioxidants (mean Griffiths developmental quotient 57.3 v 56.1; adjusted mean difference 1.2 points, 95% confidence interval –2.2 to 4.6). Comparison of children randomised to folinic acid supplements or no folinic acid also showed no significant differences in Griffiths developmental quotient (mean 57.6 v 55.9; adjusted mean difference 1.7, –1.7 to 5.1). No between group differences were seen in the mean numbers of words said or signed: for antioxidants versus none the ratio of means was 0.85 (95% confidence interval 0.6 to 1.2), and for folinic acid versus none it was 1.24 (0.87 to 1.77). No significant differences were found between any of the groups in the biochemical outcomes measured. Adjustment for potential confounders did not appreciably change the results.” (S. Logan, Peninsula Med. Sch., Exeter, U.K.; stuart.logan@pms.ac.uk)

>>>Lancet Highlights
Source:
Feb. 23 issue of Lancet (www.thelancet.com; 2008; 371).
Immunosuppression in Crohn’s Disease: Among 129 patients with newly diagnosed Crohn’s disease, combined immunosuppression with infliximab plus azathioprine was significantly more effective than conventional management with corticosteroids (pp. 660-7). Looking for primary outcome measures of remission without need for as-needed corticosteroids and without bowel resection at weeks 26 and 52, the researchers found: “At week 26, 39 (60.0%) of 65 patients in the combined immunosuppression group were in remission without corticosteroids and without surgical resection, compared with 23 (35.9%) of 64 controls, for an absolute difference of 24.1% (95% CI 7.3–40.8, p = 0.0062). Corresponding rates at week 52 were 40/65 (61.5%) and 27/64 (42.2%) (absolute difference 19.3%, 95% CI 2.4–36.3, p = 0.0278). 20 of the 65 patients (30.8%) in the early combined immunosuppression group had serious adverse events, compared with 19 of 64 (25.3%) controls (p = 1.0).” (G. D’Haens, Imelda Genl. Hosp., Bonheiden, Belgium; geert.dhaens@imelda.be)

>>>PNN NewsWatch
* FDA has approved bevacizumab (Avastin), in combination with paclitaxel chemotherapy, for treatment of patients who have not received chemotherapy for their metastatic HER2-negative breast cancer, Genentech announced Friday evening. The approval, contrary to a 5–4 vote of an FDA advisory panel, was based on a Phase III study (E2100) that showed that bevacizumab in combination with paclitaxel chemotherapy resulted in a 52% reduction in the risk of disease progression or death compared with those treated with paclitaxel alone and a doubling in progression-free survival, the company noted in a news release.

>>>PNN JournalWatch
* Doctors’ Education: The Invisible Influence of Drug Company Sponsorship, in BMJ, 2008; 336: 416–7. Reprints: R. Moynihan, University of Newcastle, New South Wales, Australia; Ray.Moynihan@newcastle.edu.au
* Management of Depression in Adults, in
BMJ, 2008; 336: 435–9. Reprints: M. Timonen, U. Oulu, Oulu, Finland; markku.timonen@oulu.fi
* Trends and Cardiovascular Mortality Effects of State-Level Blood Pressure and Uncontrolled Hypertension in the United States, in
Circulation, 2008; 117: 905–14. Reprints: M. Ezzati, majid_ezzati@harvard.edu
* Contemporary Trends in the Pharmacological and Extracorporeal Management of Heart Failure: A Nephrologic Perspective, in
Circulation, 2008; 117: 975–83. Reprints: E. A. Ross, rossea@medicine.ufl.edu
* Out-Of-Pocket Spending and Medication Adherence Among Dialysis Patients in Twelve Countries, in
Health Affairs, 2008; 27(1): 89–102. Reprints: R. A. Hirth.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 26, 2008 * Vol. 15, No. 38
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Feb. 25 issue of the Archives of Internal Medicine (http://archinte.ama-assn.org/current.dtl; 2008; 168).
Antimicrobial Use Among Nursing Home Residents with Advanced Dementia: Persons with advanced dementia often receive antibiotics, even during the last 2 weeks life, researchers report (pp. 357-62). Questioning whether such antimicrobial use might foster resistance, the investigators describe these use patterns among 214 residents of 21 Boston-area nursing homes: “During an average of 322 days of follow-up, 142 residents (66.4%) with advanced dementia received at least 1 course of antimicrobial therapy (mean [SD] number of courses per resident, 4.0 [3.7]). The mean (SD) number of days of therapy per 1,000 resident-days for the entire cohort was 53.0 (4.3). Quinolones and third-generation cephalosporins were the most commonly prescribed antimicrobials, accounting for 38.3% and 15.2%, respectively, of 540 prescribed antimicrobial therapy courses. A respiratory tract infection was the most common indication (46.7% of all antimicrobial therapy courses). Among 99 decedents, 42 (42.4%) received antimicrobials during the 2 weeks before death, of which 30 of 72 courses (41.7%) were administered via the parenteral route. The number of decedents receiving antimicrobials (P < .001), the number of antimicrobials prescribed (P = .01), and the days of therapy per 1,000 resident-days (P < .001) increased significantly as subjects approached death.” (E. D’Agata, edagata@bidmc.harvard.edu)
For elderly patients with dementia, the ethical decision about treatment for infections needs to be redefined, editorialists write (pp. 349-50): “As regards the severely demented, the ethical question of treatment of bacterial infection must encompass not just the deliberation over whether to withhold or withdraw treatment, but the decision to initiate it as well. All such decisions must ultimately be made individually, based on the medical situation and the expressed wishes of the patient and family, as well as on the physician’s judgment of the benefits and risks entailed in treating vs not treating. Deliberate we must, however, in every case. The data provided by D’Agata and Mitchell1 require us to consider whether we are overusing antibiotics in the severely demented elderly population, especially at the end of life, without paying adequate attention to the ramifications of their use.” (Y. Carmeli, Tel Aviv Med. Ctr., Tel Aviv, Israel;
yehudac@tasmc.health.gov.il)
Antibiotic Timing & Pneumonia Diagnosis: A core quality of care measure—time to first antibiotic dose (TFAD) of 4 hours or less for patients with community-acquired pneumonia (CAP) presenting to emergency departments—appears to push clinicians into making errors in diagnosis, according to a retrospective review (pp. 351-6). Comparing results from a period when the core quality measure of TFAD was 8 hours or less (group 1) with care provided after the metric was reduced to 4 hours (group 2), the investigators found: “A total of 548 patients diagnosed as having CAP were studied (255 in group 1 and 293 in group 2). At admission, group 2 patients were 39.0% less likely to meet predefined diagnostic criteria for CAP than were group 1 patients (odds ratio, 0.61; 95% confidence interval, 0.42–0.86) (P = .004). At discharge, there was agreement between the ED physician’s diagnosis and the predefined criteria for CAP in 62.0% of group 1 and 53.9% of group 2 patients (P = .06) and between the ED physician’s admitting diagnosis and that of the discharging physician in 74.5% of group 1 and 66.9% of group 2 patients (P = .05). The mean (SD) TFAD was similar in group 1 (167.0 [118.6] minutes) and group 2 (157.8 [96.3] minutes).” (J. A. Welker, Franklin Square Hosp. Ctr., Baltimore, Md.; jimwelker@hotmail.com)
Neoplasms After RA Drugs: Hematologic malignant neoplasms are more common among patients being treated for rheumatoid arthritis after use of cyclophosphamide (OR, 2.21) than with methotrexate (OR, 1.18) or azathioprine (OR, 1.44), according to a case–control study from Quebec (pp. 378-81). Findings were based on analysis of 346 patients with lymphomas, 178 with leukemia, and 95 with multiple myeloma, among 23,810 study participants. (S. Bernatsky, McGill U. Health Ctr., Montreal)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 27, 2008 * Vol. 15, No. 39
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Feb. 27 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2008; 299).
Treating Resistant Adolescent Depression: Among 334 adolescent patients with depression that was not responsive to initial treatment with a selective serotonin reuptake inhibitor, addition of cognitive behavioral therapy and switching to another antidepressant resulted in a higher response rate than did changing the medication alone (pp. 901-13). Patients were newly diagnosed with major depressive disorder and had been treated with the initial SSRI for 2 months when they were switched to a different SSRI or venlafaxine or provided with cognitive behavioral therapy and switched to a different SSRI or venlafaxine. Results at 12 weeks showed: “Cognitive behavioral therapy plus a switch to either medication regimen showed a higher response rate (54.8%; 95% confidence interval [CI], 47%–62%) than a medication switch alone (40.5%; 95% CI, 33%–48%; P = .009), but there was no difference in response rate between venlafaxine and a second SSRI (48.2%; 95% CI, 41%–56% vs 47.0%; 95% CI, 40%–55%; P = .83). There were no differential treatment effects on change in the CDRS-R, self-rated depressive symptoms, suicidal ideation, or on the rate of harm-related or any other adverse events. There was a greater increase in diastolic blood pressure and pulse and more frequent occurrence of skin problems during venlafaxine than SSRI treatment.” (D. Brent, Western Psychiatric Inst. and Clinic, Pittsburgh; brentda@upmc.edu)
Mortality with ESAs in Patients with Cancer: The risks of venous thromboembolism and death are increased when anemia in patients with cancer is treated with erythropoiesis-stimulating agents, authors of a meta-analysis conclude (pp. 914-24). Using survival data from 51 clinical trials of 13,611 patients and VTE data from 38 clinical trials of 8,172 patients, the investigators determined: “Patients with cancer who received ESAs had increased VTE risks (334 VTE events among 4,610 patients treated with ESA vs 173 VTE events among 3,562 control patients; 7.5% vs 4.9%; relative risk, 1.57; 95% CI, 1.31–1.87) and increased mortality risks (hazard ratio, 1.10; 95% CI, 1.01–1.20).”
Concluding that these findings “raise concern about ESA safety for patients with cancer,” the authors note these effects unique to patients with cancer: “Expression of erythropoietin and erythropoietin receptors has been demonstrated in a variety of human cancers. Erythropoietin stimulation of cancer cells in vitro activates signal transduction pathways, including phosphatidylinositol 3-kinase-Akt and JAK-STAT (Janus kinase-Signal Transducer and Activator of Transcription). Depending on the type of cancer, activation of the erythropoietin/erythropoietin receptor signaling axis results in measurable cellular effects, including proliferation, antiapoptosis, and invasion. Erythropoietin-mediated functions may result from autocrine/paracrine signaling or recruitment of both endogenous and exogenous erythropoietin by the tumor. Clearly, many issues remain to be clarified regarding the specific actions of ESAs in human cancer cells.” (C. L. Bennett,
cbenne@northwestern.edu)

>>>PNN NewsWatch
* A new medication guide is available for dispensing to patients who are taking rosiglitazone (Avandia), FDA and GlaxoSmithKline announced yesterday. The patient information warns of new or worse heart failure and other heart problems.
*
“Medications for High Blood Pressure” is the topic of a consumer article posted this week to the FDA Web site. It discusses the types of agents used for treating hypertension and provides tips for consumers to use in managing the condition.
* In advance of a “major address” scheduled for this Friday at the National Press Club,
FDA Commissioner Andrew von Eschenbach “is under fire from an array of critics who say his agency isn’t up to the job,” reports this morning’s Wall Street Journal. The newspaper had yesterday reported that the agency will testify today on Capitol Hill about a new plan, “Safety First,” designed to emphasize drug safety at FDA.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 28, 2008 * Vol. 15, No. 40
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Feb. 28 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2008; 358).
Low-Dose Vasopressin in Septic Shock: In a head-to-head comparison in 778 patients with refractory septic shock, low-dose vasopressin was equivalent to norepinephrine in its effects on mortality (pp. 877-87). Patients were receiving norepinephrine doses of at least 5 mcg/min before randomization to either vasopressin 0.01–0.03 U/min or norepinephrine 5–15 mcg/min (both groups additionally received as-needed vasopressor support), with these results: “There was no significant difference between the vasopressin and norepinephrine groups in the 28-day mortality rate (35.4% and 39.3%, respectively; P = 0.26) or in 90-day mortality (43.9% and 49.6%, respectively; P = 0.11). There were no significant differences in the overall rates of serious adverse events (10.3% and 10.5%, respectively; P = 1.00). In the prospectively defined stratum of less severe septic shock, the mortality rate was lower in the vasopressin group than in the norepinephrine group at 28 days (26.5% vs. 35.7%, P = 0.05); in the stratum of more severe septic shock, there was no significant difference in 28-day mortality (44.0% and 42.5%, respectively; P = 0.76). A test for heterogeneity between these two study strata was not significant (P = 0.10).” (J. A. Russell, St. Paul’s Hosp., Vancouver, B.C., Canada; jrussell@mrl.ubc.ca)
Emphasizing the challenges and urgency of septic shock, an editorialist writes (pp. 954-6): “What are the lessons from this study for the practicing clinician? Although adding vasopressin to norepinephrine therapy in patients with septic shock appears to produce similar mortality rates and is safe, there is no compelling advantage to using vasopressin rather than norepinephrine. Thus, the data in this field to date suggest that it is the timing of vasopressor (and other) therapy, rather than the specific agent, that is decisive. In both clinical practice and clinical trials, once hypotension occurs in septic shock, we need to initiate immediate antimicrobial therapy, cardiovascular support, and other effective therapies recommended by current guidelines.” (J. E. Parrillo, U. Medicine and Dentistry of New Jersey, Camden)

>>>PNN NewsWatch
* The interleukin-1 blocker rilonacept (Arcalyst, Regeneron) has been approved by FDA for long-term treatment of two inherited orphan cryopyrin-associated periodic syndrome (CAPS) disorders: familial cold auto-inflammatory syndrome and Muckle–Wells syndrome (MWS). Symptoms of both of these disorders, which affect about 300 patients each in the U.S. each year, include life-long, recurrent symptoms of rash, fever/chills, joint pain, eye redness/pain, and fatigue. Intermittent, disruptive exacerbations or flares can be triggered at any time by exposure to cooling temperatures, stress, exercise, or other unknown stimuli. MWS is associated with more severe inflammation and may include hearing loss or deafness. In addition, some MWS patients may also be affected by amyloidosis. FDA based its approval on a clinical study of 47 patients with CAPS. In daily diaries kept by the patients, improvements were evident within a few days for these disease symptoms: joint pain, rash, feeling of fever/chills, eye redness/pain, and fatigue. The most commonly reported adverse effects associated with use of rilonacept were injection-site reactions and upper respiratory infections.
* Clinically significant liver injury, including markedly elevated serum hepatic enzymes and elevated total bilirubin, is being reported as early as 6 days after the first dose of
natalizumab (Tysabri), Biogen Idec, Elan, and FDA warned yesterday. The combination of transaminase elevations and elevated bilirubin without evidence of obstruction is an important predictor of severe liver injury that may lead to death or the need for a liver transplant in some patients. Natalizumab should be discontinued in patients with jaundice or other evidence of significant liver injury. Patients should be warned that natalizumab may cause liver injury and informed of signs and symptoms that may indicate hepatic problems, including nausea and vomiting, abdominal pain, yellow skin and eyes, and sometimes itching.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 29, 2008 * Vol. 15, No. 41
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Mar. issue of Diabetes Care (http://care.diabetesjournals.org/current.shtml; 2008; 31).
Antidepressants & Diabetes: Patients taking antidepressants are at increased risk of developing diabetes, according to a report from the Diabetes Prevention Program (pp. 420-6). Participants in the study took the Beck Depression Inventory (BDI) and reported their use of antidepressants during randomization to intensive lifestyle (ILS) interventions, metformin (MET), and placebo (PLB), and these associations were evident when the data were analyzed: “When other factors associated with the risk of developing diabetes were controlled, elevated BDI scores at baseline or during the study were not associated with diabetes risk in any arm. Baseline antidepressant use was associated with diabetes risk in the PLB (hazard ratio 2.25 [95% CI 1.38–3.66]) and ILS (3.48 [1.93–6.28]) arms. Continuous antidepressant use during the study (compared with no use) was also associated with diabetes risk in the same arms (PLB 2.60 [1.37–4.94]; ILS 3.39 [1.61–7.13]), as was intermittent antidepressant use during the study in the ILS arm (2.07 [1.18–3.62]). Among MET arm participants, antidepressant use was not associated with developing diabetes.” (R. R. Rubin, Johns Hopkins U., Monkton, Md.; rrubin4@jhmi.edu)
Predictors of Diabetes Progression and Medication Treatment: Among 5,804 untreated patients with type 2 diabetes with initial A1C levels of 7% or less, younger age and weight gain were important predictors of disease progression and the need for medications, researchers report (pp. 386-90). Concluding that those patients should be the “focus of aggressive diabetes management,” the authors report: “In multivariate analyses, baseline A1C (P < 0.0001), younger age (P = 0.04), and weight gain (P = 0.03) were independent predictors of progression after adjusting for race, sex, and baseline HDL levels. Each decade of increasing age reduced the risk of progression by 15%. Each 1-lb increase in weight was associated with a 2% increased odds of progression. Likelihood of medication initiation among progressors decreased by 40% (P = 0.02) with every decade of age and decreased by 2.3% (P = 0.02) with each 1-mg/dl decrease in LDL level from baseline after adjusting for race, sex, and weight change.” (L. N. Pani, MD, lpani@partners.org)

>>>PNN NewsWatch
* The recall of Baxter heparin products has been extended to include single-dose vials for injection, including Hep-Lock flushes. The only Baxter heparin products remaining on the U.S. market are large volume parenteral solutions containing 200 units of heparin per 100 mL in 500- and 1000-mL total volume bags; heparin used in these products is obtained from a different source than the recalled products. Guidance on return processes are available by calling Baxter at 800/4-BAXTER (422-9837) FDA has indicated that the number of deaths associated with Baxter is now 21, up from 4 earlier this month. The agency also posted on its Web site an inspection report from the Chinese plant that supplied heparin for Baxter, and it lists 11 “observations” ranging from “unidentified material adhering to the insides” of “cleaned” tanks used in the final step of heparin production to use of “material from an unacceptable workshop vendor” in producing heparin.
* Patients should not swallow
Spiriva and Foradil capsules, FDA warns in a public health advisory released this morning. In addition, the tiotropium bromide and formoterol fumarate contents of the respective products should be inhaled using the devices provided with the products, and the administration instructions provided with the medications should be followed. Calling on physicians, nurses, and pharmacists to discuss with patients how to use the Spiriva Handihaler and Foradil Aerolizer correctly, FDA indicated that “many reports” of patients taking the medications orally have been received at the agency and by the National Poison Control Center.
* Short-term use of
esomeprazole magnesium (Nexium, AstraZeneca) in children aged 1–11 years with gastroesophageal reflux disease has been approved by FDA. The approved doses in this age group are 10 or 20 mg daily.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 3, 2008 * Vol. 15, No. 42
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Mar. 1 issue of Lancet (www.thelancet.com; 2008; 371).
Complex Interventions in the Elderly: A variety of complex interventions can help community-dwelling older patients maintain their physical function and independence, according to a systematic review and meta-analysis (pp. 725-35). “We identified 89 trials including 97,984 people,” the authors write about interventions such as geriatric assessments, community-based care after hospital discharge, fall prevention, and group education and counseling. “Interventions reduced the risk of not living at home (relative risk [RR] 0.95, 95% CI 0.93–0.97). Interventions reduced nursing-home admissions (0.87, 0.83–0.90), but not death (1.00, 0.97–1.02). Risk of hospital admissions (0.94, 0.91–0.97) and falls (0.90, 0.86–0.95) were reduced, and physical function (standardised mean difference −0.08, −0.11 to −0.06) was better in the intervention groups than in other groups. Benefit for any specific type or intensity of intervention was not noted. In populations with increased death rates, interventions were associated with reduced nursing-home admission. Benefit in trials was particularly evident in studies started before 1993.” (A. D. Beswick, U. Bristol, Bristol, U.K.; andy.beswick@bristol.ac.uk)
Antiretroviral Therapy in Uninfected Children with HIV-Infected Family Members: In Uganda, provision of antiretroviral therapy and trimethoprim–sulfamethoxazole (co-trimoxazole) to adults with HIV and their families reduced mortality and orphanhood, researchers report (pp. 752-9). These results were recorded in a study of ART (primarily stavudine, lamivudine, and nevirapine): “233 (17%) of 1,373 participants with HIV and 40 (1%) of 4,601 HIV-uninfected household members died. During the first 16 weeks of ART and co-trimoxazole, mortality in HIV-infected participants was 55% lower than that during co-trimoxazole alone (14 vs 16 deaths per 100 person–years; adjusted hazard ratio 0.45, 95% CI 0.27–0.74, p = 0.0018), and after 16 weeks, was reduced by 92% (3 vs 16 deaths per 100 person–years; 0.08, 0.06–0.13, p <0.0001). Compared with no intervention, ART and co-trimoxazole were associated with a 95% reduction in mortality in HIV-infected participants (5 vs 27 deaths per 100 person–years; 0.05, 0.03–0.08, p <0.0001), 81% reduction in mortality in their uninfected children younger than 10 years (0.2 vs 1.2 deaths per 100 person–years; 0.19, 0.06–0.59, p = 0.004), and a 93% estimated reduction in orphanhood (0.9 vs 12.8 per 100 person–years of adults treated; 0.07, 0.04–0.13, p <0.0001).” (J. Mermin, jhm7@cdc.gov)

>>>PNN NewsWatch
* Desvenlafaxine, the major active metabolite of venlafaxine, has been approved for marketing as Pristiq by Wyeth, the company announced on Friday. The agent’s approved indication is treatment of major depressive disorder in adult patients. FDA approval was subject to several postmarketing commitments, including conducting and submitting data from a new long-term maintenance (relapse prevention) study, a sexual dysfunction study, pediatric studies, and a study exploring lower doses. The agency also requested an additional non-clinical toxicity study. At the recommended dose of 50 mg, patients in an 8-week trial discontinued therapy because of adverse experiences at similar rates for the drug (4.1%) and placebo (3.8%). Adverse effects in clinical trials included nausea, dizziness, insomnia, hyperhidrosis, constipation, somnolence, decreased appetite, anxiety, and specific male sexual function disorders.

>>>PNN JournalWatch
* Diagnosis and Management of Alcohol Use Disorders, in BMJ, 2008; 336: 496–501. Reprints: A. J. R. Parker, South London and Maudsley NHS Trust, London; andrew.parker@iop.kcl.ac.uk
* Economic Costs of Diabetes in the U.S. in 2007, in
Diabetes Care, 2008; 31: 596–615. Reprints: M. Petersen, American Diabetes Association, Alexandria, Va.; mpetersen@diabetes.org
* Bone Mineral Density Deficits in Survivors of Childhood Cancer: Long-term Follow-up Guidelines and Review of the Literature, in
Pediatrics, 2008; 121: e705–13. Reprints: K. Wasilewski-Masker.
* Iron Overload Disorders: Treatment Options for Patients Refractory to or Intolerant of Phlebotomy, in
Pharmacotherapy, 2008; 28: 331–42. Reprints: N. Partovi, Vancouver Hospital and Health Sci. Ctr., Vancouver, B.C., Canada; Partovi@interchange.ubc.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 © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 4, 2008 * Vol. 15, No. 43
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release articles from and Mar. 4 issue of the Annals of Internal Medicine (www.annals.org/current.shtml; 2008; 148).
Treating Dementia: A clinical practice guideline and supporting evidence for drug treatment of dementia are presented.
For the cholinesterase inhibitors donepezil, galantamine, rivastigmine, and tacrine, and the neuropeptide-modifying agent memantine, the guidelines recommend (pp. 370-8; A. Qaseem,
aqaseem@acponline.org):
* Clinicians should base the decision to initiate a trial of therapy with a cholinesterase inhibitor or memantine on individualized assessment. (Grade: weak recommendation, moderate-quality evidence.)
* Clinicians should base the choice of pharmacologic agents on tolerability, adverse effect profile, ease of use, and cost of medication. The evidence is insufficient to compare the effectiveness of different pharmacologic agents for the treatment of dementia. (Grade: weak recommendation, low-quality evidence.)
* There is an urgent need for further research on the clinical effectiveness of pharmacologic management of dementia.
Comparisons among the five available drugs are limited and do not suggest important differences, conclude authors of the evidence summary (pp. 379-97).Concluding that the “cholinesterase inhibitors and memantine can improve symptoms, primarily in the domains of cognition and global function” among those with dementia, the authors add: “96 publications representing 59 unique studies were eligible for this review. Both cholinesterase inhibitors and memantine had consistent effects in the domains of cognition and global assessment, but summary estimates showed small effect sizes. Outcomes in the domains of behavior and quality of life were evaluated less frequently and showed less consistent effects. Most studies were of short duration (6 months), which limited their ability to detect delay in onset or progression of dementia. Three studies directly compared different cholinesterase inhibitors and found no differences in cognition and behavior.” (P. Raina,
praina@mcmaster.ca)
Spirometry Screening for COPD: Released in advance of publication, clinical guidelines (U.S. Preventive Services Task Force; www.preventiveservices.ahrq.gov) and an evidence summary (K. Lin, Kenneth.lin@ahrq.hhs.gov) show that screening of the general U.S. population for chronic obstructive pulmonary disease using spirometry is inefficient, with hundreds of screenings needed to identify a single case of the uncommon disease.

>>>PNN NewsWatch
* In remarks delivered on Friday at the National Press Club in Washington, D.C., FDA Commissioner Andrew C. von Eschenbach, MD, claimed that FDA is “at a turning point” and ready to meet “the challenge of a rapidly changing world.” After noting the radical changes that led to the creation of FDA’s predecessor agency in the early 1900s, von Eschenbach noted: “The simple truth as I see it today is that the FDA of the 20th century is not adequate to regulate the food and drugs of the 21st century, a time when we live in a world where we can catch a fish in Chile today and eat it in Chicago tomorrow or when throughout the United States watermelon is in season every day and we expect fresh strawberries in supermarkets in February. We are now a nation that demands foods— ready to eat: cleaned, cut and cored, and even cooked. We now live in a world where medicine cabinets are filled with tablets and capsules that treat nearly every symptom. In offices and clinics we have devices that diagnose with certainty many diseases, and hospitals are equipped with drugs and devices that treat with maximum effectiveness and minimal risk almost all that ails us.” After listing five initiatives under way to improve FDA’s ability to function in the current and emerging environments that are “the first and perhaps the most critical steps in a critical transformation occurring at a critical time in an Agency that is critical to the health of every American,” the Commissioner added: “Change at the FDA truly is under way from policies and procedures to processes and programs. Rapid and for some, radical change is occurring. For a government agency, it may be described as ‘revolutionary evolution.’ For those inside the Agency, it may seem to have the radical nature of a revolution. For those outside the Agency, it may seem to have the pace of evolution.”

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 5, 2008 * Vol. 15, No. 44
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Mar. 5 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2008; 299).
Gemcitabine in Resected Pancreatic Cancer: Patients with resected pancreatic cancer lived longer when gemcitabine was added to adjuvant fluorouracil-based chemoradiation, according to a randomized controlled Phase III trial (pp. 1019-26). All patients received fluorouracil as a continuous infusion during 12 weeks of chemoradiation therapy that followed total resection of pancreatic adenocarcinoma. During the 3 weeks prior and 12 weeks after chemoradiation, patients received either continuous infusion of fluorouracil or once-weekly infusions of gemcitabine, with these results: “A total of 451 patients were randomized, eligible, and analyzable. Patients with pancreatic head tumors (n = 388) had a median survival of 20.5 months and a 3-year survival of 31% in the gemcitabine group vs a median survival of 16.9 months and a 3-year survival of 22% in the fluorouracil group (hazard ratio, 0.82 [95% confidence interval, 0.65–1.03]; P = .09). The treatment effect was strengthened on multivariate analysis (hazard ratio, 0.80 [95% confidence interval, 0.63–1.00]; P = .05). Grade 4 hematologic toxicity was 1% in the fluorouracil group and 14% in the gemcitabine group (P < .001) without a difference in febrile neutropenia or infection. There were no differences in the ability to complete chemotherapy or radiation therapy (>85%).” (W. F. Regine, U. Maryland, Baltimore; wregine@umm.edu)
Four actions are needed to improve outcomes among patients achieving an R0 (complete) resection and to help them avoid R1 (incomplete) resection, an editorialist writes (pp. 1066-7): “First, the lessons regarding the optimal selection of patients for surgical resection need to be exported more effectively into the high-surgical volume setting.... Second, further work is needed to determine which patients are most likely to benefit from chemoradiation and, if this modality is going to evolve, further emphasis should be placed on the development of more effective radiation sensitizers.... Third, based on interindividual differences in drug metabolism and DNA repair, it appears that patients who are more likely to benefit from current chemotherapy and chemoradiation strategies can be defined prospectively. These individualized approaches should be examined in prospective clinical trials.... Finally, and most importantly, efforts must be redoubled to develop a new generation of promising therapeutics, and the commitment must be increased to understand and test them in prospectively defined patient subsets—not the means to detect marginal or incremental improvements in clinical trials of large numbers of unselected patients.” (J. L. Abbruzzese,
jabbruzz@mdanderson.org)
Malignancies, Deaths After Hormone-Therapy Discontinuation: In women taking conjugated equine estrogens plus medroxyprogesterone acetate in the Women’s Health Initiative, risks of fatal and nonfatal malignancies increased in the years following hormone-therapy discontinuation, researchers report (pp. 1036-45): “The risk of cardiovascular events after the intervention was comparable by initial randomized assignments, 1.97% (annualized rate) in the CEE plus MPA (343 events) and 1.91% in the placebo group (323 events). A greater risk of malignancies occurred in the CEE plus MPA than in the placebo group (1.56% [n = 281] vs 1.26% [n = 218]; hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.04–1.48). More breast cancers were diagnosed in women who had been randomly assigned to receive CEE plus MPA vs placebo (0.42% [n = 79] vs 0.33% [n = 60]; HR, 1.27; 95% CI, 0.91–1.78) with a modest trend toward a lower HR during the follow-up after the intervention. All-cause mortality was somewhat higher in the CEE plus MPA than in the placebo group (1.20% [n = 233] vs 1.06% [n = 196]; HR, 1.15; 95% CI, 0.95–1.39). The global index of risks and benefits was unchanged from randomization through March 31, 2005 (HR, 1.12; 95% CI, 1.03–1.21), indicating that the risks of CEE plus MPA exceed the benefits for chronic disease prevention.” (G. Heiss, gerardo_heiss@unc.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 6, 2008 * Vol. 15, No. 45
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Mar. 6 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2008; 358).
Warfarin Pharmacogenetics: Variation in the pharmacologic target of warfarin is more important during initial anticoagulation than interpatient differences in the metabolizing enzyme, a research study concludes (pp. 999-1008). Assessing genotypes for CYP2C9 (CYP2C9 *1, *2, and *3), VKORC1 haplotypes (designated A and non-A), clinical characteristics, response to therapy (as determined by the international normalized ratio [INR]), and bleeding events among 297 patients who were starting warfarin therapy, the investigators determined: “As compared with patients with the non-A/non-A haplotype, patients with the A/A haplotype of VKORC1 had a decreased time to the first INR within the therapeutic range (P = 0.02) and to the first INR of more than 4 (P = 0.003). In contrast, the CYP2C9 genotype was not a significant predictor of the time to the first INR within the therapeutic range (P = 0.57) but was a significant predictor of the time to the first INR of more than 4 (P = 0.03). Both the CYP2C9 genotype and VKORC1 haplotype had a significant influence on the required warfarin dose after the first 2 weeks of therapy.” (U. I. Schwarz, Vanderbilt U., Nashville, Tenn.)
Research into pharmacogenomics is in its infancy but will increasingly result in clinically relevant results, editorialists write (pp. 1061-3): “The merits of pharmacogenomics will probably be an active area of research for some time to come. However, the study by Schwarz et al. of the relative role of genetic variants in the administration of warfarin confirms the importance of genetic variation in influencing drug metabolism and response to therapy. Ready for prime time? Perhaps not quite yet, but with gene-based clinical studies in place or planned for the near future, we can expect to have a clearer understanding of the relative merits of pharmacogenomics in everyday clinical practice.” (S. B. Shurin, NIH, Bethesda, Md.)
Manganese Levels in Parkinsonian Syndrome Among Methcathinone Users: Among 23 Latvian users of the psychostimulant methcathinone, manganese used in preparing an intravenous solution may be responsible for a distinctive extrapyramidal syndrome previously thought be associated with HIV positivity (pp. 1009-17). Studies of the patients showed the following: “The patients reported that the onset of their first neurologic symptoms (gait disturbance in 20 and hypophonia in 3) occurred after a mean of 5.8 ± 4.5 years of methcathinone use. At the time of neurologic evaluation, all 23 patients had gait disturbance and difficulty walking backward; 11 patients were falling daily, and 1 of these patients used a wheelchair. Twenty-one patients had hypophonic speech in addition to gait disturbance, and one of these patients was mute. No patient reported decline in cognitive function. T1-weighted magnetic resonance imaging (MRI) showed symmetric hyperintensity in the globus pallidus and in the substantia nigra and innominata in all 10 active methcathinone users. Among the 13 former users (2 to 6 years had passed since the last use), lesser degrees of change in the MRI signal were noted. Whole-blood manganese levels (normal level, <209 nmol per liter) averaged 831 nmol per liter (range, 201 to 2102) in the active methcathinone users and 346 nmol per liter (range, 114 to 727) in former users. The neurologic deficits did not resolve after patients discontinued methcathinone use.” (M. Donaghy, U. Oxford, Oxford, U. K.; joanna.wilkinson@clneuro.ox.ac.uk)

>>>PNN NewsWatch
* Large quantities of a so-far unidentified contaminant has been found in the recently recalled Baxter heparin products (see PNN, Feb. 29). Even though routine tests did not differentiate between heparin and this heparin-like substance, its presence became evident during nuclear magnetic resonance tests, FDA shared in a news conference. The contaminant contributes 5% to 20% of the anticoagulant effects of the formulation, but FDA said that it could not yet determine whether the substance was introduced accidentally or deliberately. The agency also said it could not say whether the contaminant is the cause of severe allergic reactions to Baxter products.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 7, 2008 * Vol. 15, No. 46
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Mar. issue of Pharmacotherapy (www.pharmacotherapy.org; 2008; 28).
Improved Lipids After HAART Switch: Patients whose highly active antiretroviral therapy was changed to a regimen based on atazanavir and ritonavir had significantly improved lipids profiles in a 36-patient study (pp. 323-30). The adult participants were initially taking non–atazanavir-containing, protease inhibitor–based HAART, and this was switched to HAART based on atazanavir 300 mg and ritonavir 100 mg without changes in nucleoside reverse transcriptase inhibitors. The investigators report: “The switch resulted in the following changes in lipid levels: total cholesterol –9% (p = 0.002), low-density lipoprotein cholesterol –13% (p <0.001), high-density lipoprotein cholesterol (HDL) –2% (p = 0.431), triglycerides –23% (p = 0.007), non–HDL –11% (p = 0.002), total cholesterol:HDL ratio –10% (p = 0.004), and triglyceride:HDL ratio –24% (p = 0.019). A subgroup analysis was conducted on the lipid profiles of nine patients who still met the strict inclusion and exclusion criteria up to 9 months after the switch; it showed that the reductions in their lipid profiles were sustained. In addition, 33% more patients achieved their National Cholesterol Education Panel (NCEP) Adult Treatment Panel (ATP) III cholesterol goals. No significant changes were noted in median (interquartile range) CD4+ counts (372 [236–551] and 361 [217–464] cells/mm3, p = 0.118) or in number of patients with undetectable HIV viral loads ([defined as < 50 copies/ml] 32/36 and 31/36 patients, p >0.05) between baseline and after the switch, respectively.” (A. J. Busti, anthony.busti@ttuhsc.edu)
Albuterol Pretreatment in Exercise-Induced Bronchospasm: Among 11 children and adolescents, pretreatment with inhaled albuterol proved a better deterrent to exercise-induced bronchospasm than oral montelukast (pp. 287-94). Based on 3–7 days of pretreatment and changes in the forced expiratory volume in 1 second, the investigators found: “The mean ± SD maximum decrease in FEV1 was 27.5 ± 7.9% at baseline. Patients receiving montelukast had an 18.3 ± 13.7% decrease in FEV1 compared with 0.7 ± 1.6% in patients receiving albuterol (p = 0.002, paired t test). Exercise-induced bronchospasm was prevented in 100% of the patients receiving albuterol compared with 55% receiving montelukast (p <0.05, McNemar’s test). The [area under the FEV1 curve during the first hour] was significantly smaller with albuterol compared with montelukast (p <0.001, Wilcoxon signed rank test). No correlations were found between [cysteinyl leukotriene] concentration and the severity of exercise-induced bronchospasm or the response to montelukast.” (H. H. Raissy, U. New Mexico, Albuquerque)
Speed of Infusion of Lansoprazole: Gastric acid suppression was significantly greater among 38 healthy volunteers when lansoprazole was infused over 2 minutes than over 30 minutes, researchers report (pp. 301-7). “After the 2-minute administration, mean peak lansoprazole concentrations were about 2-fold higher than those after the 30-minute administration on days 1 and 7,” the article notes. “Two-minute administration resulted in a greater percentage of time that the 24-hour pH was above 4 compared with the 30-minute administration (53% vs 47%, p = 0.045), with comparable 24-hour integrated gastric acidity (114.4 vs 91.6 mmol•hr/L for 2-min vs 30-min, p = 0.335). Significantly greater acid suppression occurred during the first hour after the 2-minute administration compared with that after the 30-minute administration (p ≤0.001). Safety profiles were similar among the regimens.” (D. C. Metz, david.metz@uphs.upenn.edu)

>>>PNN NewsWatch
* Manufacturers of all heparin products must begin testing for the heparin-like contaminant identified in the recalled Baxter formulations, FDA said yesterday. Posted to the agency Web site are details on detection procedures using proton nuclear magnetic resonance and capillary electrophoresis. In a possibly related development, German health authorities have announced a recall of heparin products because of a fairly large cluster of adverse events; the products involved were not produced at the Chinese plant implicated in the Baxter recall.
*
FDA expects to bring the issue of safety of long-acting beta-agonists to an advisory panel by this coming fall or winter.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 10, 2008 * Vol. 15, No. 47
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Mar. 8 issue of Lancet (www.thelancet.com; 2008; 371).
Vaccination for Hypertension: A vaccine that induces antibodies against angiotensin II lowered blood pressure among 72 patients with mild or moderate hypertension, especially in the morning, researchers report (pp. 821-7). In a Phase IIa trial, subcutaneous CYT006-AngQb 100 mcg or 300 mcg provided these results in comparison with placebo: “Two patients in the 100 mcg group, three in the 300 mcg group, and none in the placebo group discontinued study treatment. All patients were included in safety analyses; efficacy analyses did not include the five dropouts, for whom no data were available at week 14. Five serious adverse events were reported (two in the 100 mcg group, two in the 300 mcg group, and one in the placebo group); none were deemed to be treatment related. Most side-effects were mild, transient reactions at the injection site. Mild, transient influenza-like symptoms were seen in three patients in the 100 mcg group, seven in the 300 mcg group, and none in the placebo group. In the 300 mcg group, there was a reduction from baseline in mean ambulatory daytime blood pressure at week 14 by −9.0/−4.0 mm Hg compared with placebo (p = 0.015 for systolic and 0.064 for diastolic). The 300 mcg dose reduced the early morning blood-pressure surge compared with placebo (change at 0800 h −25/−13 mm Hg; p <0.0001 for systolic, p = 0.0035 for diastolic).” (M. F. Bachmann, Cytos Biotechnology AG, Schlieren, Switzerland; Martin.bachmann@cytos.com)

>>>BMJ Highlights
Source:
Mar. 8 issue of BMJ (www.bmj.org; 2008; 336).
Antidepressant Prescribing & Adolescent Suicides: No increase in suicidal behaviors followed a 2003 restriction on use of antidepressants in those under 18 years of age, according to an ecological time-series analysis of available data (pp. 542-5). “Antidepressant prescribing doubled between 1999 and 2003 but fell to the 1999 level between 2004 and 2005,” write the investigators. “These large changes in prescribing did not seem to be associated with temporal trends in suicide or self harm. In the years 1993 to 2005 the annual percentage reduction for suicide among 12–17 year olds was –3.9% (95% confidence interval –6.2% to –1.5%) in males and –3.0% (–6.6% to 0.6%) in females, with no indication of a substantial change in this rate of decrease during that period. Similarly, hospital admission rates for self harm in the years 1999 to 2005 indicated an annual percentage increase for males of 1.1% (–0.5% to 2.7%) and for females of 5.7% (3.6% to 7.8%), again with no statistical evidence of a change in rate after the regulatory action. (B. W. Wheeler, U. Bristol, Bristol, U.K.; ben.wheeler@bristol.ac.uk)
A second research study, one that assessed suicide rates among young men in England and Wales, finds markedly lower suicide rates over the past 10 years (pp. 539-42). The authors attribute the 2005 rates, which were the lowest recorded in 30 years, to reduction in poisonous gases in car exhaust gas secondary to increased use of catalytic converters and reductions in risk factors such unemployment and divorce. They add: “Possible recent reductions in alcohol use among young men and increases in prescribing of antidepressants do not seem to be temporally related to the decline in suicide.” (D. Gunnell, U. Bristol, Bristol, U.K.;
.J.Gunnell@bristol.ac.uk">D.J.Gunnell@bristol.ac.uk)

>>>PNN JournalWatch
* Systematic Review: Gene Expression Profiling Assays in Early-Stage Breast Cancer, in Annals of Internal Medicine, 2008; 148: 358–69. Reprints: S. N. Goodman, Johns Hopkins U., Baltimore; sgoodman@jhmi.edu
* Optimal Treatment of Carotid Artery Disease, in
Journal of the American College of Cardiology, 2008; 51: 979–85. Reprints: E. I. Levy, U. Buffalo Neurosurgery, Buffalo N.Y.; elevy@buffns.com
* Bevacizumab for Recurrent Malignant Gliomas: Efficacy, Toxicity, and Patterns of Recurrence, in
Neurology, 2008; 70: 779–87. Reprints: A. D. Norden, anorden@partners.org
* Medication Effects in Neuroimaging Studies of Bipolar Disorder, in
American Journal of Psychiatry, 2008; 165: 313–20. Reprints: M. L. Phillips.
* Metformin Addition Attenuates Olanzapine-Induced Weight Gain in Drug-Naive First-Episode Schizophrenia Patients: A Double-Blind, Placebo-Controlled Study, in
American Journal of Psychiatry, 2008; 165: 352–8. Reprints: R-R Wu.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 11, 2008 * Vol. 15, No. 48
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Mar. 10 issue of the Archives of Internal Medicine (http://archinte.ama-assn.org/current.dtl; 2008; 168).
Post-MI Adherence with Beta-Blockers: Two mailings to patients who had been dispensed beta-blockers after myocardial infarction significantly improved adherence to those drugs as well as aspirin, ACE inhibitors, and statins, according to research conducted in Boston, Minneapolis, Atlanta, and Portland (pp. 477-83). Looking at the impact of the “early follow-up” mailings, which were posted 2 months apart, showed these impact on adherence: “Among the cohort, 34% reported no outpatient follow-up during the month following discharge. Rates of medication prescription among appropriate candidates were similar at hospital discharge for [the] follow-up groups. Compared with those not receiving early follow-up, those receiving early follow-up were more likely to be prescribed beta-blockers (80.1% vs 71.3%; P = .001), aspirin (82.9% vs 77.1%; P = .01), or statins (75.9% vs 68.6%; P = .005) at 6 months. In multivariable analyses, a persistent relationship remained between early follow-up and beta-blocker use (risk ratio, 1.08; 95% confidence interval, 1.02–1.15). In secondary analyses, statin use was higher in patients receiving collaborative follow-up (risk ratio, 1.11; 95% confidence interval, 1.01–1.22).” (D. H. Smith, Kaiser Permanente Northwest, Portland, Ore.; david.h.smith@kpchr.org)
The importance of encouraging patients to take medications and return for follow-up care in the post-MI period is emphasized in an accompanying editorial (p. 492): “A clear benefit to early follow-up from both a primary care physician and a cardiologist resulted in improvements in use of guideline-recommended therapies at 6 months.... The development of system-based tools that health care providers can implement to improve outpatient cardiac secondary prevention efforts will likely result in reduction of recurrent cardiac events.” (E. A. Jackson,
lisjack@umich.edu)
Detecting Risk for Anticholinergic Effects in Older Adults: An Anticholinergic Risk Scale (ARS) can assess risk of anticholinergic adverse effects in older patients, concludes a retrospective review of 132 patients in a geriatric and management (GEM) cohort (pp. 508-13). Compared with a primary care cohort, GEM patients had these increased risks: “Higher ARS scores were associated with increased risk of anticholinergic adverse effects in the GEM cohort (crude relative risk [RR], 1.5; 95% confidence interval [CI], 1.3–1.8) and in the primary care cohort (crude RR, 1.9; 95% CI, 1.5–2.4). After adjustment for age and the number of medications, higher ARS scores increased the risk of anticholinergic adverse effects in the GEM cohort (adjusted RR, 1.3; 95% CI, 1.1–1.6; c statistic, 0.74) and in the primary care cohort (adjusted RR, 1.9; 95% CI, 1.5–2.5; c statistic, 0.77).” (J. L. Rudolph, jrudolph@partners.org)
Electronic Alcohol Screening and Brief Intervention: A “single dose” of electronic (computer or Web-based) screening and brief intervention (e-SBI) reduced the risk of hazardous driving among 975 university students, and the effect lasted 12 months, researchers report (pp. 530-6). Using the Alcohol Use Disorders Identification Test (AUDIT) to measure risk, the investigators found: “Relative to the control group, the single-dose e-SBI group at 6 months reported a lower frequency of drinking (rate ratio [RR], 0.79; 95% confidence interval [CI], 0.68–0.94), less total consumption (RR, 0.77; 95% CI, 0.63–0.95), and fewer academic problems (RR, 0.76; 95% CI, 0.64–0.91). At 12 months, statistically significant differences in total consumption (RR, 0.77; 95% CI, 0.63–0.95 [equivalent to 3.5 standard drinks per week]) and in academic problems (RR, 0.80; 95% CI, 0.66–0.97) remained, and the AUDIT scores were 2.17 (95% CI, –1.10 to –3.24) points lower. Relative to the control group, the multidose e-SBI group at 6 months reported a lower frequency of drinking (RR, 0.85; 95% CI, 0.73–0.98), less total consumption (RR, 0.79; 95% CI, 0.64–0.97 [equivalent to 3.0 standard drinks per week]), reduced episodic heavy drinking (RR, 0.65; 95% CI, 0.45–0.93), and fewer academic problems (RR, 0.78; 95% CI, 0.65–0.93). At 12 months, statistically significant differences in academic problems remained (RR, 0.75; 95% CI, 0.62-0.90), while the AUDIT scores were 2.02 (95% CI, –0.97 to –3.10) points lower.” (K. Kypri, U. Newcastle, Newcastle, Australia; kypros.kypri@newcastle.edu.au)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 12, 2008 * Vol. 15, No. 49
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Mar. 12 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2008; 299).
Sustaining Weight Loss: Personal contact but not technology-based interactions helped patients maintain lost weight in a 30-month follow-up trial (pp. 1139-48). Among 1,032 overweight or obese adults (38% blacks, 63% women) with hypertension, dyslipidemia, or both who had lost at least 4 kg during a 6-month weight loss program (phase 1), monthly personal contact, unlimited access to an interactive technology–based intervention, or self-directed control showed these results during phase 2 of the study: “Mean entry weight was 96.7 kg. During the initial 6-month program, mean weight loss was 8.5 kg. After randomization, weight regain occurred. Participants in the personal-contact group regained less weight (4.0 kg) than those in the self-directed group (5.5 kg; mean difference at 30 months, –1.5 kg; 95% confidence interval [CI], –2.4 to –0.6 kg; P = .001). At 30 months, weight regain did not differ between the interactive technology–based (5.2 kg) and self-directed groups (5.5 kg; mean difference –0.3 kg; 95% CI, –1.2 to 0.6 kg; P = .51); however, weight regain was lower in the interactive technology–based than in the self-directed group at 18 months (mean difference, –1.1 kg; 95% CI, –1.9 to –0.4 kg; P = .003) and at 24 months (mean difference, –0.9 kg; 95% CI, –1.7 to –0.02 kg; P = .04). At 30 months, the difference between the personal-contact and interactive technology–based group was –1.2 kg (95% CI –2.1 to –0.3; P = .008). Effects did not differ significantly by sex, race, age, and body mass index subgroups. Overall, 71% of study participants remained below entry weight.” (L. P. Svetkey, Svetk001@mc.duke.edu)
Universal MRSA Testing: In a surgical department with endemic methicillin-resistant Staphylococcus aureus but relatively low rates of MRSA infection, universal testing of all patients on hospital admission failed to reduce nosocomial MRSA infections (pp. 1149-57). Using a rapid, multiplex polymerase chain reaction to test patients admitted to intervention wards for more than 24 hours, investigators found this impact on outcomes: “Overall, 10,193 of 10,844 patients (94%) were screened during the intervention periods. Screening identified 515 MRSA-positive patients (5.1%), including 337 previously unknown MRSA carriers. Median time from screening to notification of test results was 22.5 hours (interquartile range, 12.2–28.2 hours). In the intervention periods, 93 patients (1.11 per 1,000 patient–days) developed nosocomial MRSA infection compared with 76 in the control periods (0.91 per 1,000 patient–days; adjusted incidence rate ratio, 1.20; 95% confidence interval, 0.85–1.69; P = .29). The rate of MRSA surgical site infection and nosocomial MRSA acquisition did not change significantly. Fifty-three of 93 infected patients (57%) in the intervention wards were MRSA-free on admission and developed MRSA infection during hospitalization.” (S. Harbarth, U. Geneva Hosp., Geneva, Switzerland; stephan.harbarth@hcuge.ch)

>>>PNN NewsWatch
* FDA has received reports of life-threatening adverse events and death in patients, including children, who have received UCB’s Tussionex Pennkinetic Extended-Release Suspension (hydrocodone polistirex and chlorpheniramine polistirex). The reports indicate that health professionals have prescribed Tussionex for patients younger than the approved aged group of 6 years old and older and more frequently than the labeled dosing interval of every 12 hours. The agency added that patients have administered the incorrect dose due to misinterpretation of the dosing directions and use of inappropriate devices to measure the suspension; FDA emphasized that patients and caregivers should use a properly marked measuring device to measure Tussionex to prevent overdose. Overdose of Tussionex in older children, adolescents, and adults has also been associated with life-threatening and fatal respiratory depression. FDA noted that Tussionex is contraindicated for use in patients younger than 6 years of age because of their susceptibility to life-threatening and fatal respiratory depression.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 13, 2008 * Vol. 15, No. 50
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Early-release article and the Mar. 13 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2008; 358).
Acyclovir, Herpes Simplex Virus, and HIV Infection: In a trial of young women in Tanzania, suppression of herpes simplex virus infections with acyclovir had no significant impact on new cases of HIV infection (doi: 10.1056/NEJMoa0800260). The women, aged 16–35 years and employed at recreational facilities in Tanzania, were all initially HIV-seronegative and HSV-2–seropositive, and they received either acyclovir 400 mg twice daily or placebo, with these results at every-3-month follow-up: “A total of 821 participants were randomly assigned to receive acyclovir (400 participants) or placebo (421 participants); 659 (80%) completed follow-up. Mean follow-up for the acyclovir and placebo groups was 1.52 and 1.62 years, respectively. The incidence of HIV infection was 4.27 per 100 person–years (27 participants in the acyclovir group and 28 in the placebo group), and there was no overall effect of acyclovir on the incidence of HIV (rate ratio for the acyclovir group, 1.08; 95% confidence interval, 0.64 to 1.83). The estimated median adherence was 90%. Genital HSV was detected in a similar proportion of participants in the two study groups at 6, 12, and 24 months. No serious adverse events were attributable to treatment with acyclovir.” (D. Watson-Jones, Dept. of Infectious and Tropical Diseases, London; deborah.watson-jones@lshtm.ac.uk)
Cetuximab Hypersensitivity: Patients who experienced cetuximab-induced anaphylaxis often had pre-existing IgE antibodies to galactose-alpha-1,3-galactose, researchers report (pp. 1109-17). Analyzing sera from 76 case subjects who had been treated with cetuximab at multiple centers, 72 control patients in Tennessee, 49 control patients with cancer in northern California, and 341 female control patients in Boston, the investigators found: “Among 76 cetuximab-treated subjects, 25 had a hypersensitivity reaction to the drug. IgE antibodies against cetuximab were found in pretreatment samples from 17 of these subjects; only 1 of 51 subjects who did not have a hypersensitivity reaction had such antibodies (P <0.001). IgE antibodies against cetuximab were found in 15 of 72 samples (20.8%) from control subjects in Tennessee, in 3 of 49 samples (6.1%) from northern California, and in 2 of 341 samples (0.6%) from Boston. The IgE antibodies were shown to be specific for an oligosaccharide, galactose-alpha-1,3-galactose, which is present on the Fab portion of the cetuximab heavy chain.” (T. A. E. Platts-Mills, tap2z@virginia.edu)
Adverse Renal Events with Bevacizumab: Renal thrombotic microangiopathy in patients receiving bevacizumab is likely the result of direct targeting of vascular endothelial growth factor by the antiangiogenic therapy, concludes a brief report of six patients (pp. 1129-36). The investigators used conditional gene targeting to delete VEGF from renal podocytes in adult mice and found that “this resulted in a profound thrombotic glomerular injury.” The group concludes: “Our data suggest that it may be prudent to monitor patients receiving VEGF inhibitors closely for possible kidney injury. The optimal way to monitor such patients is not known. Although there have been sporadic reports of other glomerular lesions associated with VEGF-inhibitor therapy, our findings in six patients, together with three previous case reports of renal thrombotic microangiopathy, suggest that this pathological lesion may be typical when profound changes in renal function are observed.” (S. E. Quaggin, Mount Sinai Hosp., Toronto; quaggin@mshri.on.ca)

>>>PNN NewsWatch
* With an FDA advisory committee meeting to consider new restrictions on erythropoiesis-stimulating agents looming today, Amgen and FDA yesterday announced addition of updated information to the product labeling of erythropoietin and darbepoetin. The changes describe the results of two additional studies showing that ESAs shortened overall survival and/or time to tumor progression in clinical studies in patients with breast, non–small-cell lung, head and neck, lymphoid, and cervical cancers when dosed to target a hemoglobin level of 12 g/dL or more. Among the options being presented by FDA staff to the advisory committee is a revocation of the agency’s approval for use of these drugs in patients with cancer, the Wall Street Journal is reporting.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 14, 2008 * Vol. 15, No. 51
Providing news and information about medications and their proper use

>>>JAPhA Highlights
Source:
Early-release articles from and Mar/Apr issue of the Journal of the American Pharmacists Assoc. (www.japha.org; 2008; 48).
MTM Environmental Scans: In articles being released this weekend at the APhA2008 meeting in San Diego, experiences with medication therapy management during 2007 are presented from the provider and payer perspectives (early-release articles; J. C. Schommer, schom010@umn.edu)
A total of 687 providers shared these results with MTM: “65% of survey respondents were involved in providing MTM services as defined in the consensus definition used. Of these, 47% reported that they were contracted with programs to provide MTM services. Of respondents, 35% indicated that these contracts provided a positive return on investment (ROI), 31% reported that they did not provide a positive ROI, and 34% reported that they did not know. Providers varied widely on how they implemented MTM service offerings and typically did not use specific measures to quantify the costs and benefits of MTM. In addition, they did not use systematic methods for assessing value from providing MTM services to their patients.”
Greater use of pharmacist-provided face-to-face MTM services is planned for 2008, payers reported: “20% (n = 26) of the e-mail survey respondents offered MTM services to their members as described in the consensus definition of MTM. Payers for MTM services varied widely on how they implemented and monitored their organization’s MTM programs. For 2008, MTM payer organizations plan to expand their use of face-to-face pharmacist–patient interaction.”
Diabetes Ten City Challenge: Interim results on 914 employees of self-insured employers participating in the APhA Foundation’s Diabetes Ten Challenge show that the Asheville Project methodology can be replicated in a variety of practice settings and geographic locations (pp. 181-90): “At initial visit compared with 1 year, mean A1C decreased from 7.6% to 7.2%, mean LDL cholesterol decreased from 96 to 93 mg/dL, and mean systolic blood pressure decreased from 131 to 129 mm Hg. Increases were seen for influenza vaccination rate (from 43% to 61%), eye examination rate (from 60% to 77%), and foot examination rate (from 38% to 68%) for the initial visit to the end of the analysis period. For all patients in DTCC, those who perceived that their overall diabetes care was very good to excellent increased from 39% to 87%. Overall, 97.5% reported being very satisfied or satisfied with the diabetes care provided by pharmacists.” (T. Fera, tfera@aphanet.org)
Practice-Based Research Networks in Pharmacy: Commenting on articles in this theme issue of JAPhA, leaders of APhA’s practice and science academies have this to say about the importance of practice-based research networks linking medication therapy management practitioners and researchers (pp. 138-41: “It is easy to say, ‘I just don’t have the time and support to do MTM services or participate in research.’ But if you don’t, who will? Who will get the data to provide the best evidence to support reimbursement for pharmacist primary care and MTM services if it is not you? As the leaders of APhA’s practice and science academies, we hope that this special issue provides you with the motivation to participate in a PBRN when presented with the opportunity. We hope the data presented in these articles impress upon you the value of pharmacy practice–based research and stimulate ideas about how you can participate. Please participate when the opportunities present themselves to play a direct, proactive role in your own future and keep the highway running through the pharmacy community.” (L. D. Ried, ried@cop.ufl.edu)

>>>PNN NewsWatch
* Drug-induced hepatitis has been reported in patients receiving combination therapy with darunavir (Prezista) and ritonavir, FDA and Tibotec Therapeutics cautioned yesterday. Appropriate laboratory testing should be conducted before initiating therapy with darunavir/ritonavir, and patients should be monitored during treatment. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in those with pretreatment elevations of transaminases, especially during the first several months of darunavir/ritonavir treatment.


PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 17, 2008 * Vol. 15, No. 52
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Mar. 15 issue of Lancet (www.thelancet.com; 2008; 371).
Inappropriate Use of Antibiotics in Rhinosinusitis: Use of antibiotics is not justified in patients with symptoms of rhinosinusitis even when they last for 7–10 days, according to a systematic review of 9 trials of 2,547 adults (pp. 908-14). Concluding that “common clinical signs and symptoms cannot identify patients with rhinosinusitis for whom treatment is clearly justified,” the authors write: “15 patients with rhinosinusitis-like complaints would have to be given antibiotics before an additional patient was cured (95% CI NNT[benefit] 7 to NNT[harm] 190). Patients with purulent discharge in the pharynx took longer to cure than those without this sign; the NNT was 8 patients with this sign before one additional patient was cured (95% CI NNT[benefit] 4 to NNT[harm] 47). Patients who were older, reported symptoms for longer, or reported more severe symptoms also took longer to cure but were no more likely to benefit from antibiotics than other patients.” (J. Young, U. Hosp., Basel, Switzerland; jyoung@uhbs.ch)

>>>BMJ Highlights
Source:
Mar. 15 issue of BMJ (www.bmj.org; 2008; 336).
Supplements in Children with Down’s Syndrome: Neither antioxidants nor folinic acid were of benefit among 156 infants with trisomy 21, researchers report (pp. 594-7). Focusing on those younger than 7 months of age with Down’s syndrome, the investigators found these results with antioxidants (selenium 10 mcg, zinc 5 mg, vitamin A 0.9 mg, vitamin E 100 mg, and vitamin C 50 mg), folinic acid 0.1 mg, antioxidants and folinic acid combined, or placebo: “Children randomised to antioxidant supplements attained similar developmental outcomes to those without antioxidants (mean Griffiths developmental quotient 57.3 versus 56.1; adjusted mean difference 1.2 points, 95% confidence interval –2.2 to 4.6). Comparison of children randomised to folinic acid supplements or no folinic acid also showed no significant differences in Griffiths developmental quotient (mean 57.6 v 55.9; adjusted mean difference 1.7, –1.7 to 5.1). No between group differences were seen in the mean numbers of words said or signed: for antioxidants versus none the ratio of means was 0.85 (95% confidence interval 0.6 to 1.2), and for folinic acid versus none it was 1.24 (0.87 to 1.77). No significant differences were found between any of the groups in the biochemical outcomes measured. Adjustment for potential confounders did not appreciably change the results.” (S. Logan, Peninsula Med. Sch., Exeter, U.K.; stuart.logan@pms.ac.uk)

>>>PNN NewsWatch
* At APhA2008 in San Diego this weekend, version 2.0 of the profession’s medication therapy management core elements was released. Updating the 2004 core elements for MTM, version 2.0 seeks to broaden the applicability across pharmacy practice settings. It places an increased emphasis on the patient’s role in medication self-management and the importance of transitions of care and collaboration between members of the health care team. In addition to APhA and the National Association of Chain Drug Stores Foundation, Version 2.0 is supported by the American Association of Colleges of Pharmacy, American College of Apothecaries, American College of Clinical Pharmacy, American Society of Consultant Pharmacists, American Society of Health-System Pharmacists, National Alliance of State Pharmacy Associations, and the National Community Pharmacists Association.

>>>PNN JournalWatch
* Tumor Necrosis Factor Inhibition: A Part of the Solution or a Part of the Problem of Heart Failure in Rheumatoid Arthritis?, in Arthritis & Rheumatism, 2008; 58: 637–40. Reprints: S. E. Gabriel; gabriel.sherine@mayo.edu
* Medication and Dosage Considerations in the Prophylaxis and Treatment of High-Altitude Illness, in
Chest, 2008; 133: 744–55. Reprints: A. M. Luks, aluks@u.washington.edu
* Contemporary Management of Acute Exacerbations of COPD: A Systematic Review and Metaanalysis, in
Chest, 2008; 133: 756–66. Reprints: D. D. Sin, St. Paul’s Hosp., Vancouver, B.C., Canada; dsin@mrl.ubc.ca
* Interpatient Variability in Rates of Asthma Progression: Can Genetics Provide an Answer?, in
Journal of Allergy and Clinical Immunology, 2008; 121: 573–9. Reprints: J. W. Holloway, Southampton General Hosp, Southampton, U.K.; J.W.Holloway@soton.ac.uk

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 18, 2008 * Vol. 15, No. 53
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Mar. 18 issue of the Annals of Internal Medicine (www.annals.org/current.shtml; 2008; 148).
Universal MRSA Admission Surveillance: Testing of all patients admitted to three hospitals for methicillin-resistant Staphylococcus aureus significantly reduced MRSA during hospitalization and for 30 days after discharge, researchers report (pp. 409-18). Comparing a baseline period of 12 months, another 12 months when MRSA surveillance was conducted for all admissions to the intensive care unit, and a 21-month period universal MRSA surveillance for all hospital admissions, the investigators found: “The prevalence density of aggregate hospital-associated MRSA disease (all body sites) per 10,000 patient-days at baseline, during ICU surveillance, and during universal surveillance was 8.9 (95% CI, 7.6 to 10.4), 7.4 (CI, 6.1 to 9.0; P = 0.15 compared with baseline), and 3.9 (CI, 3.2 to 4.7; P < 0.001 compared with baseline and ICU surveillance), respectively. During universal surveillance, the prevalence density of MRSA infection at each body site had a statistically significant decrease compared with baseline. The methicillin-susceptible S. aureus bacteremia rate did not statistically significantly change during the 3 periods. In a segmented regression model, the aggregate hospital-associated MRSA disease prevalence density changed by –36.2% (CI, –65.4% to 9.8%; P = 0.17) from baseline to ICU surveillance and by –69.6% (CI, –89.2% to –19.6%]; P = 0.03) from baseline to universal surveillance. During universal surveillance, the MRSA disease rate decreased during hospitalization and in the 30 days after discharge; no further reduction occurred thereafter. Surveillance with clinical cultures would have identified 17.8% of actual MRSA patient-days, and ICU-based surveillance with polymerase chain reaction would have identified 33.3%.” (L. R. Peterson, lancer@northwestern.edu)
Nonsurgical Treatments for Urinary Incontinence in Women: Pelvic floor muscle training and bladder training or treatment with anticholinergic drugs provides relief in women with urinary incontinence, while studies show that duloxetine improves but does not resolve urinary incontinence, according to a systematic review from an NIH conference (pp. 459-73). Electrostimulation, medical devices, injectable bulking agents, and local estrogen therapy were inconsistent, the authors add, writing: “Compared with regular care, pelvic floor muscle training plus bladder training resolved urinary incontinence (pooled risk difference, 0.13 [95% CI, 0.07 to 0.20]). Pelvic floor muscle training alone resolved or improved urinary incontinence compared with regular care, although the effect size was inconsistent across studies. Different injectable bulking agents and medical devices were associated with similar continence and improvement rates. Electrical stimulation failed to resolve urinary incontinence. Oral hormone administration increased rates of urinary incontinence compared with placebo in most RCTs (1,243 women). Transdermal or vaginal estrogen resulted in inconsistent improvement of urinary incontinence. Adrenergic drugs did not resolve or improve urinary incontinence. Oxybutynin or tolterodine resolved urinary incontinence compared with placebo (pooled risk difference, 0.18 [CI, 0.13 to 0.22]). Duloxetine compared with placebo improved (pooled risk difference, 0.11 [CI, 0.07 to 0.14]) but did not resolve urinary incontinence, with no significant dose–response association.” (R. L. Kane, kanex001@umn.edu)

>>>PNN NewsWatch
* During the final session of the 2008 APhA House of Delegates, held on Monday in San Diego, John A. Gans, PharmD, Executive Vice President and Chief Executive Officer, announced that he will step down from his current position in 2009, after nearly 20 years of service to the organization. He added that the group’s Board of Trustees has been actively working on plans for an executive leadership transition, retaining the Miles LeHane Company to assist in naming a new executive leader by early 2009. Additional information on the search process can be found at www.aphaceosearch.com.
* At APhA2008, the
APhA House of Delegates adopted new policies on experiential education, residency training for pharmacists, pharmacy compounding accreditation, and pharmacy technician education and training.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 19, 2008 * Vol. 15, No. 54
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Mar. 19 issue of JAMA, a theme issue on genomics (http://jama.ama-assn.org/current.dtl; 2008; 299).
Gene Variation & DVT Risk: Single nucleotide polymorphisms in several genes are associated with an increased risk of deep vein thrombosis, conclude researchers who conducted three case–control studies that analyzed 19,682 gene-centric SNPs in 443 patients with first DVT and 453 control patients (pp. 1306-14). Several SNPs occurred in the region around a key SNP in the CYP4V2 gene, the authors note, adding: “Of 9 SNPs genotyped in [Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis study]-2, 3 were strongly associated with DVT (P < .05; false discovery rate .10): rs13146272 in CYP4V2 (risk allele frequency, 0.64), rs2227589 in SERPINC1 (risk allele frequency, 0.10), and rs1613662 in GP6 (risk allele frequency, 0.84). The OR for DVT per risk allele was 1.24 (95% confidence interval [95%CI], 1.11–1.37) for rs13146272, 1.29 (95% CI, 1.10–1.49) for rs2227589, and 1.15 (95% CI, 1.01–1.30) for rs1613662. In the region of CYP4V2, we identified 4 additional SNPs (in CYP4V2, KLKB1, and F11) that were also associated with both DVT (highest OR per risk allele, 1.39; 95% CI, 1.11–1.74) and coagulation factor XI level (highest increase per risk allele, 8%; 95% CI, 5%–11%).” (F. R. Rosendaal, Leiden U. Med. Ctr., Leiden, the Netherlands; f.r.rosendaal@lumc.nl)
An editorialist writes of the “progress and promise” of gene research in DVT, including parts of the genetic code that do not result in protein production (pp. 1362-3): “The significance of most of these non–protein-coding transcripts is unknown; however, it appears that there is dispersed regulation spread throughout the genome with many regulatory sites for specific genes located at great distances from the gene. An example of noncoding transcripts is the rapidly expanding family of small noncoding regulatory RNAs, which includes small interfering RNA (si-RNA, 20–25 nucleotides), micro RNA (mi-RNA, 20–25 nucleotides), Piwi Argonaute protein–associated RNA (pi-RNA, 25–30 nucleotides), and a group of longer noncoding RNAs (70 nucleotides). A recent genome-wide association study of coronary artery disease, replicated in 6 independent populations, identified risk alleles at chromosome 9p21 on a 58-Kb haplotype devoid of known genes but with evidence for noncoding transcription. The authors speculate that the variants may be involved in gene regulation involving noncoding RNA. Studies like this in light of the [Encyclopedia of DNA Elements (ENCODE) study] observations suggest that future genotyping strategies may include a stronger focus on the intergenic as well as the intragenic genome.” (E. G. Bovill, U. Vermont, Burlington;
edwin.bovill@uvm.edu)

>>>PNN NewsWatch
* Boehringer Ingelheim recently informed FDA that ongoing safety monitoring has identified a possible increased risk of stroke in patients using tiotropium. Spiriva HandiHaler is used to treat bronchospasm associated with chronic obstructive pulmonary disease. In an early communication, FDA says that additional information is needed to further evaluate the possibility of stroke in patients using this product.
* Accepting the 2008
Remington Medal during APhA2008 in San Diego, J. Lyle Bootman, PhD, ScD, of the U. Arizona described his vision of a 2050 practice of pharmacy and issued this challenge to pharmacists: “Tonight I call on the pharmacy profession to recognize that we have the talent and knowledge within our profession to take a leadership role in developing this future of patient-centered care achieved through new technologies and the therapeutic application of advanced genomics. We do ‘get it’ and we are well-positioned to lead. We are already trusted by patients, and accessible to them without appointments. We are often the health professional most aware of a patient’s entire medication history and we are the professional best educated to understand all the possible adverse events and outcomes associated with those medications. We are in the best position to determine if the patient understands the purpose of the medication, and how to take it, and, often, whether he is taking it at all.” Bootman’s full remarks will be published in the Sept/Oct issue of the Journal of the American Pharmacists Association.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 20, 2008 * Vol. 15, No. 55
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Mar. 20 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2008; 358).
Treating Hypereosinophilic Syndrome with Mepolizumab: An anti–interleukin-5 monoclonal antibody mepolizumab proved corticosteroid-sparing among patients negative for the fusion gene FIP1L1–PDGFRA who have hypereosinophilic syndrome, according to a study of 85 patients (pp. 1215-28). Prednisone doses of 20–60 mg/day, titrated to keep eosinophil counts below 1,000 cells/µL, were tapered to a primary end point of doses of 10 mg/day for 8 or more consecutive weeks, with these results: “The primary end point was reached in 84% of patients in the mepolizumab group, as compared with 43% of patients in the placebo group (hazard ratio, 2.90; 95% confidence interval [CI], 1.59 to 5.26; P <0.001) with no increase in clinical activity of the hypereosinophilic syndrome. A blood eosinophil count of less than 600 per microliter for 8 or more consecutive weeks was achieved in 95% of patients receiving mepolizumab, as compared with 45% of patients receiving placebo (hazard ratio, 3.53; 95% CI, 1.94 to 6.45; P <0.001). Serious adverse events occurred in seven patients receiving mepolizumab (14 events, including one death; mean [± SD] duration of exposure, 6.7 ± 1.9 months) and in five patients receiving placebo (7 events; mean duration of exposure, 4.3 ± 2.6 months).” (M. E. Rothenberg, Cincinnati Children’s Hosp. and Med. Ctr., Cincinnati; rothenberg@cchmc.org)
Mepolizumab provides valuable insights into treatment of eosinophilia, an editorialist writes (pp. 1293-4): “With its ability to combat eosinophilia and prevent infiltration of and damage to organ tissue by eosinophils, anti–interleukin-5 treatment certainly brings new hope to many patients with the hypereosinophilic syndromes whose disease is currently refractory to conventional therapies or who have side effects from them. It is important to recognize that this therapy’s greatest contribution may be to teach us about the biologic characteristics of eosinophils. Advances in molecular biology lead to treatments that can be good for patients and even better for understanding the pathogenesis of their mysterious conditions. In a virtuous cycle, better understanding should lead to the identification of biomarkers that will help clinicians decide who will benefit most from exciting new therapies such as anti–interleukin-5 antibodies.” (M. E. Wechsler, Brigham and Women’s Hosp., Boston)
Hormonal Contraception in Women of Older Reproductive Age: Combination estrogen–progestin contraceptives can be safely used in women in their mid-40s who need contraception, concludes the author of a Clinical Practice article (pp. 1262-70). “Benefits include effective contraception and reductions in irregular bleeding and vasomotor symptoms associated with the perimenopausal transition,” the writer notes. “Available epidemiologic data also suggest potential long-term benefits, including reductions in the risks of fractures among postmenopausal women and of ovarian, endometrial, and colorectal cancer. However, for women of older reproductive age who are obese, smoke cigarettes, or have hypertension, diabetes, or migraine headaches, the cardiovascular risks associated with combination oral contraceptives are considered to outweigh the benefits.” (A. M. Kaunitz, U. Florida, Jacksonville)

>>>PNN NewsWatch
* On the 1-year anniversary of the identification of melamine as the offending contaminant in pet foods, oversulfated chondroitin sulfate was named by FDA yesterday as the contaminant in recalled Baxter heparin products. Chondroitin is in the heparin family and mimics the latter compound on testing, the agency noted. While chondroitin is sold as a dietary supplement, the oversulfated form here is an investigational formulation that has been tested primarily in preclinical research settings. The contaminant accounted for from 2% to 50% of the active pharmaceutical ingredient in tested samples. FDA noted that oversulfated form of chondroitin sulfate does not occur naturally, making its introduction during production either deliberate or accidental. FDA cautioned that it does not know if this contaminant is necessarily the cause of the observed adverse reactions. However, an official noted that no adverse reactions or deaths have been reported since Baxter recalled all lots of its product on Feb. 28.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 21, 2008 * Vol. 15, No. 56
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
Mar. 25 issue of the Journal of the American College of Cardiology (http://content.onlinejacc.org/current.dtl; 2008; 51).
Triple Antiplatelet Therapy After Stent Implantation: The number of patients with diabetes needing target lesion revascularization within 9 months of implantation of a drug-eluting stent was significantly reduced by 6 months of treatment with aspirin, clopidogrel, and cilostazol, compared with aspirin and clopidogrel, in the DECLARE-DIABETES trial (pp. 1181-7). Assessing in-stent late loss at 6 months as the primary end point, the researchers determined: “The in-stent (0.25 ± 0.53 mm vs. 0.38 ± 0.54 mm, p = 0.025) and in-segment (0.42 ± 0.50 mm vs. 0.53 ± 0.49 mm, p = 0.031) late loss were significantly lower in the triple versus standard group, as were 6-month in-segment restenosis (8.0% vs. 15.6%, p = 0.033) and 9-month target lesion revascularization (TLR) (2.5% vs. 7.0%, p = 0.034). At 9 months, major adverse cardiac events, including death, myocardial infarction, and TLR, tended to be lower in the triple than in the standard group (3.0% vs. 7.0%, p = 0.066). Multivariate analysis showed that sirolimus-eluting stents and the use of cilostazol were strong predictors of reduced restenosis or TLR.” (S-W Park, Asan Med. Ctr., Seoul; swpark@amc.seoul.kr)

>>>Psychiatry Highlights
Source:
Mar. issue of the American Journal of Psychiatry (http://ajp.psychiatryonline.org/current.dtl; 2008; 165).
Cycloserine for Obsessive–Compulsive Disorder: d-Cycloserine, administered in 10-mg doses 1 hour before 10 twice-weekly sessions, was a useful adjunct to behavioral therapy in 23 patients with obsessive–compulsive disorder (pp. 335-41). The benefits of this partial agonist of the N-methyl-d-aspartate (NMDA) glutamatergic receptor “extend findings in animals and other human disorders suggesting that behavior therapy acts by way of long-term potentiation of glutamatergic pathways and that the effects of behavior therapy are potentiated by an NMDA agonist,” the investigators note, adding these study results: “Relative to the placebo group, the d-cycloserine group’s OCD symptoms were significantly more improved at mid-treatment, and the d-cycloserine group’s depressive symptoms were significantly more improved at posttreatment.” (S. Wilhelm)
Poorer Outcomes in Anxious Depression: According to a new analysis from the STAR*D trial, patients with anxious depression following antidepressant treatment have poorer outcomes than those with nonanxious depression (pp. 342-51). Among 2,876 adult outpatients receiving citalopram 10 mg daily (level 1) and 1,292 nonresponders who were switched to sustained-release bupropion, sertraline, or extended-release venlafaxine or continued on citalopram that was augmented with sustained-release bupropion or buspirone, the 14-week trial showed: “In Level 1 of STAR*D, 53.2% of patients had anxious depression. Remission was significantly less likely and took longer to occur in these patients than in those with nonanxious depression. Ratings of side effect frequency, intensity, and burden, as well as the number of serious adverse events, were significantly greater in the anxious depression group. Similarly, in Level 2, patients with anxious depression fared significantly worse in both the switching and augmentation options.” (M. Fava)

>>>PNN NewsWatch
* FDA has approved bendamustine hydrochloride for injection (Treanda, Cephalon) for treatment of patients with chronic lymphocytic leukemia. Considered under a priority review by FDA, bendamustine contains two primary components, an alkylating group and a benzimidazole component, and appears to act through DNA damage leading to apoptosis and also through disruption of normal cell division through mitotic catastrophe. The agent, which will be available during April, is also being reviewed by FDA for use in treatment of patients with indolent non-Hodgkin’s lymphoma who have progressed during or following treatment with rituximab or a rituximab-containing regimen.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 24, 2008 * Vol. 15, No. 57
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Mar. 22 issue of Lancet (www.thelancet.com; 2008; 371).
Tocilizumab for RA: Two research articles examine the utility of the interleukin-6–receptor antagonist tocilizumab in rheumatoid and juvenile arthritis.
Among 622 patients with moderate or severe active RA, tocilizumab in doses of 4 or 8 mg/kg intravenously every 4 weeks improved American College of Rheumatology 20% (ACR20) responses at 24 weeks, compared with placebo (pp. 987-97). With methotrexate maintained at stable prestudy doses of 10–25 mg/ week, the new agent produced these results: “At 24 weeks, ACR20 responses were seen in more patients receiving tocilizumab than in those receiving placebo (120 [59%] patients in the 8 mg/kg group, 102 [48%] in the 4 mg/kg group, 54 [26%] in the placebo group; odds ratio 4.0 [95% CI 2.6–6.1], p <0.0001 for 8 mg/kg vs placebo; and 2.6 [1.7–3.9], p <0.0001 for 4 mg/kg vs placebo). More people receiving tocilizumab than those receiving placebo had at least one adverse event (143 [69%] in the 8 mg/kg group; 151 [71%] in the 4 mg/kg group; 129 [63%] in the placebo group). The most common serious adverse events were serious infections or infestations, reported by six patients in the 8 mg/kg group, three in the 4 mg/kg group, and two in the placebo group.” (J. S. Smolen, Med. U., Vienna;
josef.smolen@meduniwien.ac.at)
In a Phase III trial, the new agent also proved useful in managing systemic-onset juvenile idiopathic arthritis in 56 children (pp. 998-1006). Assessing responses with ACR Pediatric criteria, the investigators found: “At the end of the open-label lead-in phase, ACR Pedi 30, 50, and 70 responses were achieved by 51 (91%), 48 (86%), and 38 (68%) patients, respectively. 43 patients continued to the double-blind phase and were included in the efficacy analysis. Four (17%) of 23 patients in the placebo group maintained an ACR Pedi 30 response and a [C-reactive protein] concentration of less than 15 mg/L compared with 16 (80%) of 20 in the tocilizumab group (p <0.0001). By week 48 of the open-label extension phase, ACR Pedi 30, 50, and 70 responses were achieved by 47 (98%), 45 (94%), and 43 (90%) of 48 patients, respectively. Serious adverse events were anaphylactoid reaction, gastrointestinal haemorrhage, bronchitis, and gastroenteritis.” (S. Yokota, Yokohama City U., Yokohama, Kanagawa, Japan;
syokota@med.yokohama-cu.ac.jp)

>>>BMJ Highlights
Source:
Mar. 22 issue of BMJ (www.bmj.org; 2008; 336).
Statins in CKD: While statins reduce lipid levels and improve cardiovascular end points in patients with chronic kidney disease, a meta-analysis and meta-regression shows that the drugs do not reduce all-cause mortality (pp. 645-51). In addition, benefits of statins have not been demonstrated for primary prevention in this population, the authors conclude, adding these details from the 50 trials of 30,144 patients they analyzed: “Compared with placebo, statins significantly reduced total cholesterol (42 studies, 6,390 patients; weighted mean difference –42.28 mg/dl (1.10 mmol/l), 95% confidence interval –47.25 to –37.32), low density lipoprotein cholesterol (39 studies, 6,216 patients; –43.12 mg/dl (1.12 mmol/l), –47.85 to –38.40), and proteinuria ... (6 trials, 311 patients; –0.73 g/24 hour, –0.95 to –0.52) but did not improve glomerular filtration rate (11 studies, 548 patients; 1.48 ml/min (0.02 ml/s), –2.32 to 5.28). Fatal cardiovascular events (43 studies, 23,266 patients; relative risk 0.81, 0.73 to 0.90) and non-fatal cardiovascular events (8 studies, 22,863 patients; 0.78, 0.73 to 0.84) were reduced with statins, but statins had no significant effect on all cause mortality (44 studies, 23,665 patients; 0.92, 0.82 to 1.03).” (S. D. Navaneethan, U. Rochester, Rochester, N.Y.; sankardass@hotmail.com)

>>>PNN JournalWatch
* Systematic Review: The Effects of Growth Hormone on Athletic Performance, in Annals of Internal Medicine, 2008; early release. Reprints: H. Liu, hauliu@stanford.edu
*
Acinetobacter baumannii: Epidemiology, Antimicrobial Resistance, and Treatment Options, in Clinical Infectious Diseases, 2008; 46: 1254–63. Reprints: L. L. Maragakis, Johns Hopkins Hosp., Baltimore; lmaraga1@jhmi.edu
* Muscle Endurance in Elderly Nursing Home Residents Is Related to Fatigue Perception, Mobility, and Circulating Tumor Necrosis Factor-Alpha, Interleukin-6, and Heat Shock Protein 70, in
Journal of the American Geriatrics Society, 2008; 56: 389–96. Reprints: T. Mets, Universitair Ziekenhuis, Brussels, Belgium; tony.mets@uzbrussel.be

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 25, 2008 * Vol. 15, No. 58
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Mar. 24 issue of the Archives of Internal Medicine (http://archinte.ama-assn.org/current.dtl; 2008; 168).
Endoscopic Use of Oral Sodium Phosphate in Older Patients: Elderly patients who receive oral sodium phosphate solution (OSPS) preparations as cleansing agents before endoscopy have significant declines in glomerular filtration rates after the procedures, researchers report (pp. 593-7). Concluding that use of such products in this patient population should be discouraged, the investigators provide these details about their retrospective analysis of patients undergoing colonoscopy or sigmoidoscopy over an 8-year period: “A total of 286 patients were selected in the study group, and 125 patients were selected in the control group. Both groups had similar baseline characteristics. The baseline glomerular filtration rate (GFR) in the study group was 79 mL/min/1.73 m2, which declined to 73 mL/min/1.73 m2 at 6 months after exposure to OSPS preparation. This finding was significantly different from the control group, in whom the baseline GFR was 76 mL/min/1.73 m2 and remained stable at 6 months. Linear regression analysis showed that use of angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers and the presence of diabetes were significant determinants of the fall in GFR after use of OSPS preparation.” (A. Khurana, Scott & White Memorial Hosp. and Clinic, Temple, Tex.; khurana.anand@gmail.com)
Alcohol-Related Liver and Pancreatic Disease: Particularly common among blacks in the U.S., acute alcoholic pancreatitis (AP) is “the most common discharge diagnosis among alcohol-related liver or pancreas complications, while [cirrhosis (CH)] has the highest case fatality rate and male to female ratio,” an article concludes (pp. 649-56). Based on data in the Nationwide Inpatient Sample from 1988 to 2004, the investigators determined: “The distribution of overall hospital discharges per 100,000 persons between 1988 and 2004 was as follows: AP, 49.2; [chronic alcoholic pancreatitis (CP)], 8.1; [alcoholic hepatitis (AH)], 4.5; and CH, 13.7. Overall hospital discharges per 100,000 persons for AP plus AH were 1.8; and for CP plus CH, 0.32. There were higher male to female ratios for AH and CH, and less so for AP and CP. A markedly higher frequency of AP (63.5) and CP (11.3) was seen among blacks than among whites (AP, 29.6 and CP, 5.1), Hispanics (AP, 27.1 and CP, 3.7), Asians (AP, 12.8 and CP, 1.4), and American Indians (AP, 15.5 and CP, 2.3). This higher frequency remained stable between 1994 and 2004. Overall case fatality steadily decreased in all categories, but remains highest in CH (13.6%) with similar racial distributions.” (M. B. Omary, mbishr@stanford.edu)
Treating AF: For achieving recurrence-free survival among patients with atrial fibrillation, circumferential pulmonary vein ablation is superior to antiarrhythmic drug therapy, according to a systematic review and meta-analysis of four trials (pp. 581-6). “In total, 162 of 214 patients (75.7%) in the CPVA group had [atrial tachyarrhythmia] recurrence–free survival vs 41 of 218 patients (18.8%) in the ADT group,” the researchers write. “The random-effects pooled risk ratio for AT recurrence–free survival was 3.73 (95% confidence interval, 2.47–5.63). In addition, fewer adverse events were reported in the CPVA group compared with that in the ADT group.” (M. E. Josephson, mjoseph2@bidmc.harvard.edu)

>>>PNN NewsWatch
* Problems with heparin are spreading, as 23 lots of B. Braun Medical Inc. admixtures have been recalled because of a heparin-like contaminant found in one of the lots. B. Braun heparin was supplied by Scientific Protein Laboratories LLC, the same company that provided contaminated heparin to Baxter.
*
FDA and Medtronic have announced a Class 1 recall of Medtronic Neuromodulation Implantable Infusion Pumps, used to treat pain (with opioids), spasticity (baclofen), and cancer (chemotherapy). The company has received reports of inflammatory mass formations at or near the distal tip of intrathecal catheters. Labeling for the devices has been updated to include current patient management and treatment recommendations.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 26, 2008 * Vol. 15, No. 59
Providing news and information about medications and their proper use

>>>Nephrology Report
Source:
Apr. issue of the American Journal of Kidney Diseases (www.ajkd.org/current; 2008; 51).
Analgesic Use & Albuminuria: Self-reported habitual use of single or multiple analgesics was not associated with increased prevalence of albuminuria or reduced estimated glomerular filtration rate, according to an analysis of data from the National Health and Nutrition Examination Survey conducted in 1999–2002 (pp. 573-83). Looking at risk factors among 1,088 individuals with albuminuria in random urine samples (albumin–creatinine ratio of 30 mg/g or more) and 852 Americans with eGFRs lower than 60 mL/min/1.73 sq m, the investigators observed: “In US adults, 23.7% (95% confidence interval [CI], 21.7 to 25.6) reported habitual analgesic use. Multivariable-adjusted ORs for reduced eGFR prevalence in adults with habitual analgesic use of acetaminophen only, ibuprofen only, and aspirin only were 1.03 (95% CI, 0.6 to 1.7), 1.21 (95% CI, 0.7 to 2.1), and 0.95 (95% CI, 0.7 to 1.2) compared with non–habitual analgesic use, respectively. Corresponding ORs for prevalent albuminuria were 0.93 (95% CI, 0.7 to 1.3), 0.65 (95% CI, 0.4 to 1.2), and 0.86 (95% CI, 0.6 to 1.2). Association measures had intermediate levels for the composite marker of decreased kidney function and were not significant. No association between prevalent outcomes and habitual analgesic exposure duration of 5 years or longer or multiple product habitual analgesic consumption was observed.” (L. Y. Agodoa, agodoal@extra.niddk.nih.gov)
Treating HF in Patients with Reduced Renal Function: Educational programs are needed to improve the quality of treatment of acute heart failure in patients with reduced renal function, conclude researchers who prospectively followed 569 hospitalized patients with estimated glomerular filtration rates of 30 mL/min/1.73 sq m or less in 1995 and 2000 (pp. 594-602). Compared with 1,488 patients with intermediate eGFRs and 2,293 others with eGFR of 60 mL/min/1.73 sq m or more, those with low renal function were less like to receive ACE inhibitors or angiotensin II receptor blockers but more likely to receive beta-blockers. “Less than one third of all patients were treated with both disease-modifying therapies in 2000,” the authors note. (R. J. Goldberg, robert.goldberg@umassmed.edu)

>>>Gastroenterology Report
Source:
Mar. issue of Gastroenterology (www.gastrojournal.org/current; 2008; 134).
Rosiglitazone for Ulcerative Colitis: Among 35 patients with mild or moderately active ulcerative colitis, rosiglitazone reduced symptoms but clinical remission was rare, researchers report (pp. 688-95). Comparing twice-daily 4-mg doses of the drug with placebo in a 12-week trial, the investigators found these changes in clinical response, clinical remission, endoscopic remission, and quality of life: “After 12 weeks of therapy, 23 patients (44%) treated with rosiglitazone and 12 patients (23%) treated with placebo achieved clinical response (P = .04). Remission was achieved in 9 patients (17%) treated with rosiglitazone and 1 patient (2%) treated with placebo (P = .01). Endoscopic remission was uncommon in either treatment arm (8% rosiglitazone vs 2% placebo; P = .34). Clinical improvement was evident as early as 4 weeks after beginning treatment (P = .049). Quality of life was improved significantly at week 8 (P = .01), but not at week 4 (P = .48) or week 12 (P = .14). Serious adverse events were rare.” (J. D. Lewis, lewisjd@mail.med.upenn.edu)

>>>PNN NewsWatch
* Hepatotoxicity has been reported in patients taking darunavir ethalolate (Prezista), FDA and Tibotec Therapeutics report. While causality is not firmly established, health care providers should conduct appropriate hepatic laboratory testing before and after starting patients on this protease inhibitor. Patients should promptly seek medical attention if they experience unexplained fatigue, anorexia, nausea, jaundice, abdominal pain, or dark urine. Health professionals should consider interrupting or discontinuing darunavir if evidence of new or worsening liver injury arises, revised labeling suggests.
* Dietary supplements marketed as
“Blue Steel” or “Hero” products should not be used because they contain sildenafil analogues, FDA warns. Both products are distributed by Active Nutraceuticals or the Marion Group, Carrollton, Ga.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 27, 2008 * Vol. 15, No. 60
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Mar. 27 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2008; 358).
Coronary Calcium Score as Event Predictor: Coronary calcium score, determined through CT measurements of coronary-artery calcium, can be used to predict new-onset coronary heart disease and obtain predictive information beyond that provided by standard risk factors in the four major racial and ethnic groups in the U.S., report researchers in the Multi-Ethnic Study of Atherosclerosis (MESA) (pp. 1336-45). Based on scans of 6,722 men and women (38.6% white, 27.6% black, 21.9% Hispanic, 11.9% Chinese), the investigators made these observations over a median of 3.8 years: “There were 162 coronary events, of which 89 were major events (myocardial infarction or death from coronary heart disease). In comparison with participants with no coronary calcium, the adjusted risk of a coronary event was increased by a factor of 7.73 among participants with coronary calcium scores between 101 and 300 and by a factor of 9.67 among participants with scores above 300 (P <0.001 for both comparisons). Among the four racial and ethnic groups, a doubling of the calcium score increased the risk of a major coronary event by 15 to 35% and the risk of any coronary event by 18 to 39%. The areas under the receiver-operating-characteristic curves for the prediction of both major coronary events and any coronary event were higher when the calcium score was added to the standard risk factors.” (R. Detrano, U. California, Irvine; robert@chinacal.org)
Editorialists write that, as a means of going beyond the Framingham score, the value of calcium scoring is unproven (pp. 1394-6): “The MESA results confirm previous studies that showed that calcium scoring does predict events, as do other risk factors. But is this relatively small improvement in accuracy worth it? Does calcium scoring provide value? Here the issue is uncertain. There can be value only if patient outcomes improve (i.e., if calcium scoring can be shown to change care in such a way that there are fewer events in the future). This could happen if, for instance, control of blood pressure or lipid levels was made more aggressive in the presence of coronary calcium. Even if outcomes are improved, this does not establish value without additional consideration of the direct and indirect costs of care. In principle, if improved outcomes could be shown as a result of coronary calcium scoring, if those improved outcomes could be translated into improved survival or health status, and if the cost of calcium scoring and downstream costs related to additional testing, therapies, and events could be predicted, then the cost-effectiveness of calcium scoring could be determined. However, the cost-effectiveness of calcium scoring will depend on choosing cost-effective preventive strategies, which are not necessarily related to the test.” (W. S. Weintraub, Christiana Care Health System, Newark, Del.)
Safety v. Deadlines at FDA: Medications approved by FDA immediately before statutory deadlines are more likely to have safety problems discovered later than are drugs approved at other times, research suggests (pp. 1354-61). Looking at Cox proportional-hazard models of review times for all new molecular entities approved between 1950 and 2005, the study identified these patterns when comparing agents approved close to deadlines set by the Prescription Drug User Fee Act (PDUFA): “Initiation of the PDUFA requirements concentrated the number of approval decisions made in the weeks immediately preceding the deadlines. As compared with drugs approved at other times, drugs approved in the 2 months before their PDUFA deadlines were more likely to be withdrawn for safety reasons (odds ratio, 5.5; 95% confidence interval [CI], 1.3 to 27.8), more likely to carry a subsequent black-box warning (odds ratio, 4.4; 95% CI, 1.2 to 20.5), and more likely to have one or more dosage forms voluntarily discontinued by the manufacturer (odds ratio, 3.3; 95% CI, 1.5 to 7.5).” (D. Carpenter, dcarpenter@gov.harvard.edu)

>>>PNN NewsWatch
* Transdermal rotigotine patches (Neupro) will no longer be available after an Apr. 30 recall, UCB has announced. Some patches with visible snowflake-like patterns do not work properly, the company said. Patients should be transitioned to alternative agents before this date.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 28, 2008 * Vol. 15, No. 61
Providing news and information about medications and their proper use

>>>Diabetes Report
Source:
Apr. issue of Diabetes Care (http://care.diabetesjournals.org/current.shtml; 2008; 31).
Lipoprotein Management in Patients with Cardiovascular Disease: Treatment goals for patients with elevated cardiometabolic risks are provided by a consensus panel convened last July (pp. 811-22). For the highest-risk patients (known cardiovascular disease or diabetes, plus one or more additional CVD risk factors), goals of less than 70, 100, and 80 mg/dL are recommended for LDL cholesterol, non-HDL cholesterol, and apolipoprotein B, respectively. In high-risk patients (no diabetes or clinical CVD but two or more risk factors, or diabetes without other major CVD risk factors), the respective goals are less than 100, 130, and 90 mg/dL. (M. S. Kirkman, skirkman@diabetes.org)
Calcium/Vitamin D & Incident Diabetes: Calcium plus vitamin D3 supplementation had no significant effect on the risk of incident diabetes in the Women’s Health Initiative, leading investigators to conclude that higher doses of vitamin D may be needed to affect diabetes risk (pp. 701-7). Among 33,951 postmenopausal women without diabetes at study admission, elemental calcium 1,000 mg plus vitamin D3 400 IU daily or placebo produced these results: “Over a median follow-up time of 7 years, 2,291 women were newly diagnosed with diabetes. The hazard ratio for incident diabetes associated with calcium/vitamin D treatment was 1.01 (95% CI 0.94–1.10) based on intention to treat. This null result was robust in subgroup analyses, efficacy analyses accounting for nonadherence, and analyses examining change in laboratory measurements.” (I. H. de Boer, deboer@u.washington.edu)
Inhaled Insulin in Asthma: Pulmonary disease severity and asthma treatment status can alter the metabolic effects of insulin administered using Alkermes’s AIR Insulin System, researchers report (pp. 735-40). In an open-label Phase I crossover euglycemic clamp study in 39 adult nonsmoking nondiabetic participants (13 of whom had mild asthma, and 13 with moderate asthma), AIR insulin exposure was significantly reduced in those with asthma, while metabolic effects were significantly reduced in those with moderate asthma. Among those receiving inhaled insulin, adverse effects (cough, headache, dizziness) were mild or moderate in intensity and were expected based on similar previous trials. Pretreatment with salbutamol improved the bioavailability of insulin delivered by inhalation. The investigators conclude, “In view of the potential interactions between diabetes treatment and pulmonary status, it is prudent to await the results of ongoing clinical trials in diabetic patients with comorbid lung disease before considering the use of inhaled insulin in such patients.” (M. Wolzt, Med. U., Vienna; michael.wolzt@meduniwien.ac.at)

>>>PNN NewsWatch
* “REMS” is a new acronym pharmacists may be hearing as FDA continues implementation of the Food and Drug Administration Amendments Act of 2007. In a Federal Register notice, FDA announced that some manufacturers of new drug and biological products—including some agents already on the U.S. market—must have in place an approved risk evaluation and mitigation strategy, or REMS, that evaluates whether a product’s risks exceed its benefits. Products that must have REMS include those meeting any of these criteria: (1) Health care providers who prescribe the drug have particular training or experience, or are specially certified; (2) pharmacies, practitioners, or health care settings that dispense the drug are specially certified; (3) the drug is dispensed to patients only in certain health care settings, such as hospitals; (4) the drug is dispensed to patients with evidence or other documentation of safe use conditions, such as laboratory test results; (5) each patient using the drug is subject to certain monitoring; or (6) each patient using the drug is enrolled in a registry.
* FDA yesterday provided information about ongoing safety reviews of
montelukast (suicidality/suicide), abacavir/didanosine (myocardial infarction), and becaplermin (cancer/cancer-related mortality).

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 31, 2008 * Vol. 15, No. 62
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Early-release articles from the New England Journal of Medicine (http://content.nejm.org; 2008; 358).
Simvastatin/Ezetimibe in Familial Hypercholesterolemia: A research article, presented this weekend at the American College of Cardiology meeting in Chicago, and three related articles examine the effectiveness of ezetimibe in combination with simvastatin.

In the ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) trial, addition of ezetimibe to simvastatin provided no additional benefit in 720 patients with familial hypercholesterolemia (doi: 10.1056/NEJMoa0800742). Based on 24 months of daily simvastatin 80 mg plus placebo or ezetimibe 10 mg, the investigators found: “The primary outcome, the mean (± SE) change in the carotid-artery intima–media thickness, was 0.0058 ± 0.0037 mm in the simvastatin-only group and 0.0111 ± 0.0038 mm in the simvastatin-plus-ezetimibe (combined-therapy) group (P = 0.29). Secondary outcomes (consisting of other variables regarding the intima–media thickness of the carotid and femoral arteries) did not differ significantly between the two groups. At the end of the study, the mean (± SD) LDL cholesterol level was 192.7 ± 60.3 mg per deciliter (4.98 ± 1.56 mmol per liter) in the simvastatin group and 141.3 ± 52.6 mg per deciliter (3.65 ± 1.36 mmol per liter) in the combined-therapy group (a between-group difference of 16.5%, P <0.01). The differences between the two groups in reductions in levels of triglycerides and C-reactive protein were 6.6% and 25.7%, respectively, with greater reductions in the combined-therapy group (P <0.01 for both comparisons). Side-effect and safety profiles were similar in the two groups.” (J. J. P. Kastelein,
j.j.kastelein@amc.uva.nl)
Commenting on this and another research article that showed marked increases in use of ezetimibe in the U.S. compared with Canada over the 2002–06 period (doi: 10.1056/NEJMsa0801461; C.A. Jackevicius, cjackevicius@westernu.edu),
Journal editors call for this drug to be considered an option of last resort (doi: 10.1056/NEJMe0801842): “Until ... data [on actual coronary events] are available, it seems prudent to encourage patients whose LDL cholesterol levels remain elevated despite treatment with an optimal dose of a statin to redouble their efforts at dietary control and regular exercise. Niacin, fibrates, and resins should be considered when diet, exercise, and a statin have failed to achieve the target, with ezetimibe reserved for patients who cannot tolerate these agents.” (J. M. Drazen)

>>>Lancet Highlights
Source:
Mar. 29 issue of Lancet (www.thelancet.com; 2008; 371).
Insulin Glargine v. Lispro: Once-daily doses of insulin glargine lowered A1C levels just as much as insulin lispro administered three times daily in 418 patients with type 2 diabetes (pp. 1073-84). The basal insulin analogue should be preferred, the researchers conclude it is “more satisfactory to patients than is lispro for early initiation of insulin therapy, since it was associated with a lower risk of hypoglycaemia, fewer injections, less blood glucose self monitoring, and greater patient satisfaction than was insulin lispro.” (T. Linn, Justus-Liebig-Universität, Giessen, Germany; Thomas.linn@innere.med.uni-giessen.de)

>>>PNN JournalWatch
* Treatment of Human Brucellosis: Systematic Review and Meta-analysis of Randomised Controlled Trials, in BMJ, 2008; 336: 701–4. Reprints: M. Paul, Rabin Med. Ctr., Petah Tikva, Israel; pil1pel@zahav.net.il
* Hyperglycemia and Acute Coronary Syndrome: A Scientific Statement From the American Heart Association Diabetes Committee of the Council on Nutrition, Physical Activity, and Metabolism, in
Circulation, 2008; 117: 1610–9. Reprints: No. 71-0437, available by calling 800-242-8721 or contacting AHA, 7272 Greenville Ave, Dallas, TX 75231-4596.
* Macrophage Migration Inhibitory Factor in Cardiovascular Disease, in
Circulation, 2008; 117: 1594–602. Reprints: C. Weber, Institut für Molekulare Herz-Kreislaufforschung, Universitätsklinikum der RWTH, Aachen, Germany; cweber@ukaachen.de
* Lenalidomide for the Treatment of B-Cell Malignancies, in
Journal of Clinical Oncology, 2008; 26: 1544–52. Reprints: A. A. Chanan-Khan, Roswell Park Cancer Inst., Buffalo, N.Y.; asher.chanan-khan@roswellpark.org
* New Evidence Regarding Racial and Ethnic Disparities in Mental Health: Policy Implications, in
Health Affairs, 2008; 27: 393–403. Reprints: T. G. McGuire.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.