Mar 2005

PNN Quarterly File—First Quarter 2005

PNN Pharmacotherapy Line
Jan. 3, 2005 Vol. 12, No. 1
Providing news and information about medications and their proper use

>>>Darifenacin, Pregabalin Approved by FDA
Two more new chemical entities—one for urge incontinence and the other for neuropathic pain—were approved by FDA in the waning days of 2004.

The M3 antagonist darifenacin (Enablex, Novartis) was approved as extended-release tablets (7.5 mg and 15 mg) for treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency. The once-daily medication is expected to launch in the U.S. in early 2005. A similar agent, solifenacin succinate (Vesicare, GlaxoSmithKline; see PNN, Dec. 16), was also recently approved by FDA. In a news release, Novartis quotes urologist David Chaikin, MD, of New York Hosp./Cornell Med. Ctr., as saying that darifenacin’s low incidence of central nervous system and cardiovascular effects makes it unique among the marketed antimuscarinic agents.

Four pivotal studies and safety data from studies involving more than 7,000 patients with a mean age of 58 years provided the basis of FDA’s approval of darifenacin. In these studies, patients taking darifenacin experienced decreased frequency of incontinence and urination episodes, increased bladder capacity, and decreased feelings of urgency. Darifenacin reduced weekly incontinence episodes by up to 83%, and results were seen within 2 weeks of beginning treatment. Efficacy was sustained throughout the 12-week treatment period, and long-term safety was studied only up to 1 year.

The most frequently reported adverse events associated with darifenacin have been dry mouth and constipation. As with other antimuscarinic medications, darifenacin is contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma; in patients who are at risk for these conditions; and in those with known hypersensitivity to the drug or product ingredients.

Pfizer announced on Friday FDA approval of pregabalin (Lyrica) for management of neuropathic pain associated with diabetic peripheral neuropathy and postherpetic neuralgia, but the company failed to get the agency’s approval for another indication, adjunctive treatment of partial seizures in adults. FDA has previously denied an indication for pregabalin for treatment of generalized anxiety disorder. The product will be available after DEA completes a review of pregabalin; the company indicates that it expects DEA to classify the gabapentinoid as a controlled substance.

Six double-blind, placebo-controlled trials, three involving patients with DPN and three involving patients with PHN, indicate that pregabalin provided rapid and clinically meaningful pain reduction in a significant portion of patients, with pain relief beginning as early as the first week of treatment in some patients. Studies lasted up to 12 weeks, with the agent showing sustained analgesic effects. The most common adverse effects associated with pregabalin have included dizziness, somnolence, dry mouth, peripheral edema, blurred vision, weight gain, and difficulty with concentration or attention.

>>>PNN JournalWatch
* Fast-Food Habits, Weight Gain, and Insulin Resistance (The CARDIA Study): 15-Year Prospective Analysis, in Lancet, 2005; 365: 36–42. Reprints: www.thelancet.com; D. S. Ludwig, david.ludwig@childrens.harvard.edu

* FDA To Review “Missing” Drug Company Documents [news], in
BMJ, 2005; 330: 7 ff. Reprints: www.bmj.org

* Prospective Cohort Study of Cannabis Use, Predisposition for Psychosis, and Psychotic Symptoms in Young People, in
BMJ, 2005; 330: 11 ff. Reprints: www.bmj.org; J. van Os, Maastricht U., Maastricht, the Netherlands; j.vanos@sp.unimaas.nl

* Concealment of Drugs in Food and Beverages in Nursing Homes, in
BMJ, 2005; 330: 20 ff. Reprints: www.bmj.org; Ø. Kirkevold, Vestfold Mental Health Care Trust, Tønsberg, Norway; oyvind.kirkevold@nordemens.no

* Switching Prescription Drugs to Over the Counter, in
BMJ, 2005; 330: 39–41. Reprints: www.bmj.org; J. P. Cohen, joshua.cohen@tufts.edu

* Geriatric Content in Medical School Curricula: Results of a National Survey,
in Journal of the American Geriatrics Society, 2005; 53: 136–40. Reprints: www.blackwell-synergy.com; G. P. Eleazer, U. South Carolina, Columbia; pauleleazermd@cs.com

* Psychiatric Genetics: A Methodologic Critique, in
American Journal of Psychiatry, 2005; 162: 3–11. Reprints: ajp.psychiatryonline.org; K. S. Kendler.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 4, 2005 Vol. 12, No. 2
Providing news and information about medications and their proper use

>>>Iloprost Approved for Pulmonary Arterial HTN
FDA last week approved iloprost inhalation solution (Ventavis, CoTherix) for treatment of pulmonary arterial hypertension in patients with New York Heart Association Class III or IV symptoms. This synthetic analogue of prostacyclin PGI2 should be available through specialty pharmacies later this month and has been designated an orphan drug.

Efficacy of iloprost was demonstrated in a randomized, double-blind, multicenter, placebo-controlled trial of 203 adult patients with NYHA Class III or IV pulmonary arterial hypertension or pulmonary hypertension related to chronic thromboembolic disease. The primary clinical endpoint for the trial was a composite of: (1) an improvement in NYHA functional class, (2) an increase in the distance walked in 6 minutes of at least 10%, and (3) no clinical deterioration or death. The response rate for the primary efficacy endpoint among PAH patients was 19% for patients treated with iloprost, significantly more than the 4% for placebo-treated patients, and all three components of the composite endpoint favored iloprost.

The most common adverse effects of iloprost include facial flushing, increased cough, hypotension, headaches, nausea, spasm of the jaw muscles causing trouble opening the mouth, and syncope. Other serious adverse events reported with the use of inhaled iloprost include congestive heart failure, chest pain, supraventricular tachycardia, dyspnea, peripheral edema, and kidney failure.

>>>Internal Medicine Report
Source:
Jan. 4 issue of the Annals of Internal Medicine (www.annals.org; 2005; 142).

Patient Management of Anticoagulation: Patients using a portable coagulometer weekly and self-adjusting their acenocoumarol doses achieved similar levels of anticoagulation control as did a group of hematologist-managed patients—and they did so with fewer major complications and minor bleeding episodes, according to a study of 737 subjects at a Spanish university hospital (pp. 1-10). Comparing the care received in an anticoagulation clinic and self-management, the investigators report, “The median follow-up period was 11.8 months (range, 0.3 to 16.9 months). The unadjusted percentages of in-range INRs were 58.6% in the self-management group and 55.6% in the conventional management group (difference, 3.0 percentage points [95% CI, 0.4 to 5.4 percentage points]). Twenty-seven patients (7.3%) in the conventional management group and 8 (2.2%) in the self-management group had major complications related to anticoagulant treatment. The unadjusted risk difference for major complications between groups was 5.1 percentage points (exact 95% CI, 1.7 to 8.5 percentage points). Fewer patients had minor hemorrhages in the self-management group (14.9%) than in the conventional management group (36.4%). Fifteen patients (4.1%) in the conventional management group and 6 (1.6%) in the self-management group died (unadjusted risk difference, 2.5 percentage points [exact 95% CI, 0.0 to 5.1 percentage points]).” (J. C. Souto, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; jsouto@hsp.santpau.es)

An editorialist supports the idea of patient self-management of anticoagulation as “an idea whose time has come” (pp. 73-4): “With the expansion of clinical indications for the use of oral vitamin K antagonists in thromboembolic conditions, long-term, high-quality management of this therapy will become increasingly important. Responding to this challenge will require improvements not only in biomedical treatment but also in delivery of care. Patient self-management appears to be one such improvement for the delivery of optimal anticoagulation management. As Bodenheimer and colleagues noted [in a 2002 JAMA article], ‘The question is not whether patients with chronic conditions manage their illness, but how they manage them.’ The study by Menéndez-Jándula and colleagues reveals that a patient–professional partnership in the form of self-management of long-term anticoagulation can reduce the risk for thromboembolic disorders.” (R. J. Beyth, RebeccaJ.Beyth@med.va.gov)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 5, 2005 Vol. 12, No. 3
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Early-release article and Jan. 5 issue of JAMA (www.jama.com; 2005; 293).

“House of Coxibs”: In an article scheduled for publication in the Jan. 19 issue of JAMA, Eric J. Topol, MD, of the Cleveland Clinic Foundation continues his criticisms of FDA and the drug industry over their handling of the COX-2–inhibitor situation (early release article). After noting that “seems premature to judge any possible untoward cardiovascular effect of naproxen until the final data from ADAPT become available,” (see PNN, Dec. 21), Topol turns his attention the coxibs: “There are major concerns about how an entire drug class has gone awry with respect to unleashing significant cardiovascular hazard. A ‘house of cards’ is defined as a flimsy situation that is in danger of collapsing or failing. From the outset, the coxib class of medicines seemed destined for potential collapse. These drugs were mass-marketed from the moment they were commercially available in the new world of direct-to-consumer advertising, with unrealistic expectations about pain relief, marked gastrointestinal protection, and safety. Rather than a sufficient waiting period after approval to firmly establish safety in the large, representative ‘real world’ population, the unbridled promotion exacerbated the public health problem. This is so poignantly clear for an indication such as arthritis, which is one of the most common conditions requiring medication. Furthermore, one has to question the wisdom of allowing direct-to-consumer advertising for lifestyle medications that have no capability of preserving life or preventing major events such as MI or stroke. Here the paradox of actually promoting these events is all the more difficult to accept.” (E. J. Topol, Cleveland Clinic Foundation, Cleveland; topole@ccf.org)

Emergency Contraceptives & Pharmacy Availability: Support for less-restrictive provision of emergency contraceptives comes from a research article that seeks to gauge the overall public health impact of clinic, pharmacy, and advance access to these agents (pp. 54-62). At four California family-planning clinics, 2,117 females aged 15–24 years were randomly assigned to pharmacy access to EC, advance provision of EC, or clinic access only (control group). The authors found, “Women in the pharmacy access group were no more likely to use EC (24.2%) than controls (21.0%) (P = .25). Women in the advance provision group (37.4%) were almost twice as likely to use EC than controls (21.0%) (P < .001) even though the frequency of unprotected intercourse was similar (39.8% vs 41.0%, respectively, P = .46). Only half (46.7%) of study participants who had unprotected intercourse used EC over the study period. Eight percent of participants became pregnant and 12% acquired [a sexually transmitted infection]; compared with controls, women in the pharmacy access and advance provision groups did not experience a significant reduction in pregnancy rate (pharmacy access group: adjusted odds ratio [OR], 0.98; 95% confidence interval [CI], 0.58–1.64; P = .93; advance provision group: OR, 1.10; 95% CI, 0.66–1.84, P = .71) or increase in STIs (pharmacy access group: adjusted OR, 1.08, 95% CI, 0.71-1.63, P = .73; advance provision group: OR, 0.94, 95% CI, 0.62-1.44, P = .79). There were no differences in patterns of contraceptive or condom use or sexual behaviors by study group.” The group concludes, “While removing the requirement to go through pharmacists or clinics to obtain EC increases use, the public health impact may be negligible because of high rates of unprotected intercourse and relative underutilization of the method. Given that there is clear evidence that neither pharmacy access nor advance provision compromises contraceptive or sexual behavior, it seems unreasonable to restrict access to EC to clinics.” (T. R. Raine, rainet@obgyn.ucsf.edu)

An editorialist favors “putting emergency contraception in the hands of women” (pp. 98-9): “The finding that women who were provided EC at a clinic visit prior to the time of need were almost twice as likely to use EC than women in the clinic access control group is critically important, even though a reduction in pregnancy was not demonstrated.” (I. F. Litt, iris.litt@stanford.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 6, 2005 Vol. 12, No. 4
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Jan. 6 issue of the New England Journal of Medicine (contents.nejm.org; 2005; 352).

CRP Levels After Statin Therapy in ACS: High levels of C-reactive protein proved detrimental among patients treated with statins for high LDL cholesterol concentrations, ratcheting up the perceived importance of CRP as a marker worth screening on a routine basis (pp. 20-8). In the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT–TIMI 22) trial, investigators evaluated atorvastatin 80 mg or pravastatin 40 mg per day among 3,745 patients with acute coronary syndromes. They found, “Patients in whom statin therapy resulted in LDL cholesterol levels of less than 70 mg per deciliter (1.8 mmol per liter) had lower event rates than those with higher levels (2.7 vs. 4.0 events per 100 person–years, P = 0.008). However, a virtually identical difference was observed between those who had CRP levels of less than 2 mg per liter after statin therapy and those who had higher levels (2.8 vs. 3.9 events per 100 person–years, P = 0.006), an effect present at all levels of LDL cholesterol achieved.... Although atorvastatin was more likely than pravastatin to result in low levels of LDL cholesterol and CRP, meeting these targets was more important in determining the outcomes than was the specific choice of therapy. Patients who had LDL cholesterol levels of less than 70 mg per deciliter and CRP levels of less than 1 mg per liter after statin therapy had the lowest rate of recurrent events (1.9 per 100 person–years).” (P. M. Ridker, pridker@partners.org)

CRP Levels During Statin Therapy in CAD: Reduced rates of atherosclerotic progression were associated with lowering of both LDL cholesterol and C-reactive protein among 502 patients with coronary artery disease who were receiving intensive statin therapy (pp. 29-38). The Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) investigators assessed the impact of moderate and intensive statin therapy (pravastatin 40 mg/day and atorvastatin 80 mg/day, respectively) using intravascular ultrasonography. “In the group as a whole, the mean LDL cholesterol level was reduced from 150.2 mg per deciliter (3.88 mmol per liter) at baseline to 94.5 mg per deciliter (2.44 mmol per liter) at 18 months (P < 0.001), and the geometric mean CRP level decreased from 2.9 to 2.3 mg per liter (P < 0.001),” the author write. “The correlation between the reduction in LDL cholesterol levels and that in CRP levels was weak but significant in the group as a whole (r = 0.13, P = 0.005), but not in either treatment group alone. In univariate analyses, the percent change in the levels of LDL cholesterol, CRP, apolipoprotein B-100, and non–high-density lipoprotein cholesterol were related to the rate of progression of atherosclerosis. After adjustment for the reduction in these lipid levels, the decrease in CRP levels was independently and significantly correlated with the rate of progression. Patients with reductions in both LDL cholesterol and CRP that were greater than the median had significantly slower rates of progression than patients with reductions in both biomarkers that were less than the median (P = 0.001).” (S. E. Nissen, Cleveland Clinic Foundation, Cleveland; nissens@ccf.org)

Are Statins as Good as It Gets?
In an editorial commenting on the above studies, commentators describe potential goals for medical researchers (pp. 73-5): “The notion that the antiinflammatory effects of statins ameliorate cardiovascular disease suggests that it should be possible to create other antiinflammatory agents, perhaps tailored to the specific immunologic abnormalities in atheroma. Determining the mechanisms of action of statins and their relative importance will help to rationalize the design of such therapies.” (M. R. Ehrenstein, U. Coll., London)

HIV-Associated Lipodystrophy: Pathogenesis and treatment of the metabolic complications of highly active antiretroviral therapy are the subjects of a review article (pp. 48-62). It includes discussions of dyslipidemia, insulin resistance, and altered fat distribution. (S. Grinspoon, sgrinspoon@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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 7, 2005 Vol. 12, No. 5
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
Early-release papers from and the Jan. 4 issue of the Journal of the American College of Cardiology (www.cardiosource.com; 2005; 45).

Coronary Events After ASA Discontinuation: Reinforcing the message in an NSAID article published last month (see PNN, Dec. 14), an analysis of 1,236 patients hospitalized for acute coronary syndrome finds that interruption of aspirin therapy increases the risk of new coronary events (early release). “Fifty-one of these ACSs occurred within 1 month after aspirin withdrawal,” the investigators write. “This represents 4.1% of all coronary events but 13.3% of recurrences. Among those patients who relapsed, the incidence of ST-segment elevation ACS was higher in those who stopped aspirin when compared to the 332 patients who did not stop aspirin (39% vs. 18%; p = 0.001). Ten (20%) cases involved a thrombosis of an uncoated stent implanted on average 15.5 ± 6.5 months previously. Mean delay between aspirin withdrawal and the acute coronary event was 10 ± 1.9 days. Reasons for aspirin withdrawal included minor surgery in 7 cases, fibroscopy in 8 cases, dental treatment in 13 cases, bleeding in 3 cases, and patient non-compliance in 20 cases....

“Our results support the hypothesis that aspirin withdrawal in coronary patients may represent a real risk for the occurrence of a new coronary event. Many cases involved late uncoated-stent thrombosis. Assessment of the exact incidence of coronary recurrences after aspirin withdrawal will need prospective studies.” (E. Ferrari, Pasteur Hosp., Nice, France)

Review of Ximelagatran: Despite FDA’s request for more hepatotoxicity data for the oral thrombin inhibitor ximelagatran (see PNN, Sept. 14), an author of a review article maintains that this agent has a more favorable risk– benefit profile than does warfarin (pp. 1-9). “Safe and effective treatment with the [vitamin K antagonists] requires careful monitoring, because they interact with many other drugs and foods, and their anticoagulant action is unpredictable. Besides vitamin K, candidate targets for anticoagulant therapy include thrombin, a key prothrombotic mediator. Ximelagatran, the oral direct thrombin inhibitor at the most advanced stage of clinical development, is rapidly absorbed and bioconverted to its active moiety, melagatran—a potent, competitive inhibitor of both free and clot-bound thrombin. Two large clinical trials have demonstrated that fixed-dose oral ximelagatran, 36 mg twice daily, administered without coagulation monitoring, prevents stroke and systemic embolic events in patients with nonvalvular [atrial fibrillation] as effectively as well-controlled, adjusted-dose warfarin (international normalized ratio 2.0 to 3.0). The overall risk of bleeding was lower with ximelagatran than warfarin, although differences in rates of major hemorrhage were not statistically significant. Elevation of serum alanine aminotransferase levels above 3X the upper limit of normal occurred in approximately 6% of ximelagatran-treated patients but typically returned toward pretreatment levels without associated symptoms.” (J. L. Halperin, Mount Sinai Med. Ctr., New York)

Leu34 Impact on Fibrinolysis: A polymorphism at position 34 of factor XIII can affect patients’ response to fibrinolysis therapy, according to genotypic results on 293 consecutive patients with myocardial infarction (pp. 25-9). “FXIII Val34Leu polymorphism is one of the most relevant functional polymorphisms described in the haemostatic system,” write the researchers. “The common Leu34 allele associates with an increased FXIII-transglutaminase activity, which results in an increased and faster rate of fibrin stabilization....

“Multivariate analysis showed that Leu34 carriers displayed a significantly less efficient fibrinolysis than carriers of Val/Val genotype (p = 0.021; odds ratio [OR] 1.90, 95% confidence interval [CI] 1.10 to 3.28). At 24 h, Leu34 allele carriers had the worst outcome (p = 0.006; OR 2.14, 95% CI 1.25 to 3.68). Interestingly, the combination of the Leu34 allele and nonsmoking status increased the risk of non-reperfusion criteria (p = 0.003, OR 3.77), and worse outcomes at 24 h (p = 0.001, OR 4.55).” (V. Vicente, Centro Regional de Hemodonación, Murcia, Spain)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 10, 2005 Vol. 12, No. 6
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
Jan. 8 issue of Lancet (www.thelancet.com; 2005; 365).

Treatment of Chronic Hepatitis B: In a study of 307 patients with HBeAg-positive chronic hepatitis B infections, pegylated interferon alfa-2b was effective, but addition of lamivudine to the regimen did not further improve responses (pp. 123-9). During the first 32 of 52 weeks of treatment, patients received either combination therapy (pegylated interferon alfa-2b 100 mcg/week and lamivudine 100 mg/day) or monotherapy (pegylated interferon alfa-2b 100 mcg/week and placebo). During weeks 32–52 the pegylated interferon dose was 50 mcg/week in both treatment groups, and patients were followed for 26 weeks after dosing ended. The investigators report: “49 (36%) of 136 patients assigned monotherapy and 46 (35%) of 130 assigned combination therapy had lost HBeAg at the end of follow-up (p = 0.91). More of the combination-therapy than of the monotherapy group had cleared HBeAg at the end of treatment (57 [44%] vs 40 [29%]; p = 0.01) but relapsed during follow-up. Patterns were similar when response was assessed by suppression of serum hepatitis B virus (HBV) DNA or change in concentrations of alanine aminotransferase. Response rates (HBeAg loss) varied by HBV genotype (p = 0.01): A, 42 (47%) patients; B, ten (44%); C, 11 (28%); and D, 26 (25%).” (H. L. A. Janssen, Erasmus Med. Ctr., Rotterdam, the Netherlands; h.janssen@erasmusmc.nl)

>>>BMJ Highlights
Source:
Article published early by BMJ (www.bmj.org; 2005; 330).

Systematic Review of HRT: Combining results of 28 trials involving 39,769 subjects, authors identify a significantly increased risk of ischemic stroke in patients taking hormone-replacement therapy and worse outcomes when strokes occurred (article published early). “Hormone replacement therapy was associated with significant increases in total stroke (odds ratio 1.29 (95% confidence interval 1.13 to 1.47), n = 28), non-fatal stroke (1.23 (1.06 to 1.44), n = 21), stroke leading to death or disability (1.56 (1.11 to 2.20), n = 14), ischaemic stroke (1.29 (1.06 to 1.56), n = 16), and a trend to more fatal stroke (1.28 (0.87 to 1.88), n = 22),” the researchers report. “It was not associated with haemorrhagic stroke (1.07 (0.65 to 1.75), n = 17) or transient ischaemic attack (1.02 (0.78 to 1.34), n = 22). Statistical heterogeneity was not present in any analysis.” The group concludes, “Hormone replacement therapy cannot be recommended for the primary or secondary prevention of stroke.” (P. M. W. Bath, Queen’s Med. Ctr., U. Nottingham, Nottingham, U.K.)

>>>PNN JournalWatch
* Phosphodiesterase-4 Inhibitors for Asthma and Chronic Obstructive Pulmonary Disease, in Lancet, 2005; 365: 167–75. Reprints: www.thelancet.com; B. J. Lipworth, Ninewells Hosp. and Med. Sch., Dundee, U.K.; b.j.lipworth@dundee.ac.uk

* Comparing Estimates of Cost Effectiveness Submitted to the National Institute for Clinical Excellence (NICE) by Different Organisations: Retrospective Study, in
BMJ, 2005; 330: 65 ff. Reprints: www.bmj.org; A. H. Miners, Brunel U., Heslington, York, U.K.; Alec.Miners@nice.nhs.uk

* The Year in Valvular Heart Disease, in
Journal of the American College of Cardiology, 2005; 45: 111–22. Reprints: www.cardiosource.com; S. H. Rahimtoola, U. Southern Calif., Los Angeles.

* Highlights of the Year in
JACC 2004, in Journal of the American College of Cardiology, 2005; 45: 137–53. Reprints: www.cardiosource.com; A. N. DeMaria, ademaria@ucsd.edu

* Adverse Events and Preventable Adverse Events in Children, in
Pediatrics, 2005; 115: 155–60. Reprints: www.pediatrics.org; D. Woods, Inst. for Health Services Research and Policy Studies.

* Recommended Childhood and Adolescent Immunization Schedule: United States, 2005, in
Pediatrics, 2005; 115: 182 ff. Reprints: www.pediatrics.org; American Academy of Pediatrics Committee on Infectious Diseases.

* Gastrointestinal Hormones and Food Intake, in
Gastroenterology, 2005; 128: 175–91. Reprints: www2.gastrojournal.org; S. C. Woods, U. Cincinnati Med. Ctr., Cincinnati; steve.woods@psychiatry.uc.edu

* Community-Associated Methicillin-Resistant
Staphylococcus aureus: A Review, in Pharmacotherapy, 2005; 25: 74–85. Reprints: www.pharmacotherapy.org; M. J. Rybak, Wayne State U., Detroit; m.rybak@wayne.edu

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 11, 2005 Vol. 12, No. 7
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Jan. 10 issue of Archives of Internal Medicine (www.archinternmed.com; 2005; 165).

Clinical Pharmacy Services for Lipid Management: Improved lipid results and lower rates of recidivism were demonstrated among patients with coronary artery disease in a study of clinical pharmacy cardiac risk services combined with a patient-tracking system (pp. 49-54). In the program, patients with CAD are referred to or enrolled by the CPCRS staff, and progress is tracked using a Web-based database that is regularly updated with administrative, laboratory, pharmacy, diagnosis/procedure, vital sign, and demographic data. CPCRS staff members contact patients regularly to review treatment regimens and adherence and make needed changes. Experiences of patients enrolled between 1998 and 2002 yielded these findings: “A total of 8014 patients (mean age, 69.3 years; 69.8% men) met the entry criteria. The mean duration of follow-up was 2.3 years. Most patients (97.3%) had up-to-date lipid screening results at study end compared with 66.9% of patients at baseline. At study end, a total of 72.9% of patients achieved a LDL-C level of less than 100 mg/dL (<2.6 mmol/L) compared with 25.5% at baseline. The mean ± SD LDL-C level for the cohort at study end was 89 ± 24 mg/dL (2.3 ± 0.6 mmol/L). Of patients receiving medication, most (84.8%) were receiving therapy with statins alone, whereas 11.7% were receiving combination therapy.” (K. L. Olson, Kaiser Permanente Colorado Region, Aurora, Colo.; kari.olson@kp.org)

Drug-Related Problems in Elderly Nursing Home Residents: Increased rates of hospitalization and death among nursing home residents are associated with potentially inappropriate prescribing (PIRx) practices, according to an analysis of data from the 1996 Medical Expenditure Panel Survey Nursing Home Component (pp. 68-74). Among 3,372 residents aged 65 and older who were residents of nursing homes for 3 consecutive months or longer, the investigators found these results when drugs on the Beers’ list had been prescribed, “Residents who received any PIRx had greater odds (odds ratio [OR], 1.27; P = .002) of being hospitalized in the following month than those receiving no PIRx. Residents with PIRx exposure for 2 consecutive months were at increased risk (OR, 1.27; P = .004) of hospitalization, as were those receiving PIRx in the second month only (OR, 1.80; P = .001), compared with those receiving no PIRx. Residents who received PIRx were at greater risk of death (OR, 1.28; P = .01) that month or the next. Residents with intermittent PIRx exposures were at greater odds of death (OR, 1.89; P<.001), compared with those with no PIRx exposure.” (D. T. Lau, d-lau@northwestern.edu)

Sleep & Obesity: Reduced amounts of sleep are associated with overweight and obesity, according to a study of 1,001 patients who completed questionnaires (pp. 25-30). The authors note: “Analyzable forms from 924 patients aged between 18 and 91 years indicated that (1) the mean BMI was 30; (2) women slept more than men; (3) overweight and obese patients slept less than patients with a normal BMI (patients reported less sleep in a nearly linear relationship from the normal through the obese group); and (4) this trend of decreasing sleep time was reversed in the extremely obese patients.” (R. D. Vorona, Sentara Norfolk Genl. Hosp., Norfolk, Va.; voronard@evms.edu)

An editorialist comments (pp. 15-6): “A lack of sleep may perturb the homeostatic coordination of [certain] pathways, activating metabolic pathways that trigger energy conservation (increased food intake and decreased expenditure) in excess of the energy cost of increased wakefulness. Indeed, our recent analysis of leptin-deficient animals suggests that leptin per se may be necessary for consolidated sleep, since animals with a genetic absence of leptin display markedly increased sleep fragmentation and experience increased periods of microsleep during the active period.... It may be opportune to ask whether intervention in sleep disorders may ameliorate some of the metabolic deficits associated with overweight and obesity.” (J. Bass, j-bass@northwestern.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 12, 2005 Vol. 12, No. 8
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Jan. 12 issue of JAMA (www.jama.com; 2005; 293).

Drug-Eluting Stents: Placement of drug-eluting stents in a group of patients with in-stent restenosis proved superior to a strategy of balloon angioplasty, with sirolimus outperforming paclitaxel models (pp. 165-71). At two tertiary German centers, 300 patients received pretreatment with clopidogrel 600 mg followed by either sirolimus stent, paclitaxel stent, or balloon angioplasty. At 6-month follow-up, angiographically demonstrated restenosis of at least 50% of the lumen diameter showed these results in 275 patients: “The incidence of angiographic restenosis was 44.6% (41/92) in the balloon angioplasty group, 14.3% (13/91) in the sirolimus stent group (P < .001 vs balloon angioplasty), and 21.7% (20/92) in the paclitaxel stent group (P = .001 vs balloon angioplasty). When compared with balloon angioplasty, receiving a sirolimus stent had a relative risk (RR) of angiographic restenosis of 0.32 (95% confidence interval [CI], 0.18–0.56); a paclitaxel stent had an RR of 0.49 (95% CI, 0.31–0.76). The incidence of target vessel revascularization was 33.0% (33/100) in the balloon angioplasty group, 8.0% (8/100) in the sirolimus stent group (P < .001 vs balloon angioplasty), and 19.0% (19/100) in the paclitaxel stent group (P = .02 vs balloon angioplasty). The secondary analysis showed a trend toward a lower rate of angiographic restenosis (P = .19) and a significantly lower rate of target vessel revascularization (P = .02) among sirolimus stent patients compared with paclitaxel stent patients.” (A. Kastrati, Deutsches Herzzentrum, Munich, Germany; kastrati@dhm.mhn.de)

Preventing Diabetic Foot Ulcers: A review article emphasizes the importance of screening patients with diabetes for foot ulceration, a role pharmacists can assume (pp. 217-28). “Prevention of diabetic foot ulcers begins with screening for loss of protective sensation, which is best accomplished in the primary care setting with a brief history and the Semmes– Weinstein monofilament,” the authors write. “Specialist clinics may quantify neuropathy with biothesiometry, measure plantar foot pressure, and assess lower extremity vascular status with Doppler ultrasound and ankle-brachial blood pressure indices. These measurements, in conjunction with other findings from the history and physical examination, enable clinicians to stratify patients based on risk and to determine the type of intervention. Educating patients about proper foot care and periodic foot examinations are effective interventions to prevent ulceration. Other possibly effective clinical interventions include optimizing glycemic control, smoking cessation, intensive podiatric care, debridement of calluses, and certain types of prophylactic foot surgery. The value of various types of prescription footwear for ulcer prevention is not clear.” (N. Singh, Nalini.Singh2@med.va.gov)

Diet & Cancer: Commenting on two studies—one suggesting an increased risk of colon cancer in people with high consumption of red and processed meats (pp. 172-82) and another that found no relationship between vegetable/fruit intake and breast cancer risk (pp. 183-93)—an editorialist makes these observations about diet and cancer (pp. 233-4): “Although recent findings on fruit and vegetable consumption and cancer may be disappointing, reductions in blood pressure and epidemiological evidence for lower risks of cardiovascular disease provide sufficient reason to consume these foods in abundance.... Prudence would suggest that red meat, and processed meats in particular, should be eaten sparingly to minimize risk.... Replacing red meat with a combination of fish, nuts, poultry, and legumes will also reduce risk of coronary heart disease, in part, because some of these foods have positive benefits. This substitution is an important part of the Mediterranean dietary pattern, which improves blood lipids and other metabolic parameters and has been related to lower rates of total mortality. Thus, keeping red meat consumption low is best viewed, not as an isolated goal, but as part of an overall dietary and lifestyle strategy to optimize health and well-being. Fortunately, substituting pistachio-encrusted salmon and gingered brown basmati pilaf for roast beef with mashed potatoes and gravy is not a culinary sacrifice.” (W. C. Willett, walter.willett@channing.harvard.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 13, 2005 Vol. 12, No. 9
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Jan. 13 issue of the New England Journal of Medicine (content.nejm.org; 2005; 352).

Fracture After Androgen Deprivation: The risk of bone fracture is increased during androgen-deprivation therapy for prostate cancer, according to a study of 50,613 men (pp. 154-64). Using data from 1992 to 1997 in the Surveillance, Epidemiology, and End Results program and Medicare, investigators found these risks of fracture: “Of men surviving at least five years after diagnosis, 19.4 percent of those who received androgen-deprivation therapy had a fracture, as compared with 12.6 percent of those not receiving androgen-deprivation therapy (P < 0.001). In the Cox proportional-hazards analyses, adjusted for characteristics of the patient and the tumor, there was a statistically significant relation between the number of doses of gonadotropin-releasing hormone received during the 12 months after diagnosis and the subsequent risk of fracture.”

The authors make these recommendations based on their study, “Androgen deprivation in the form of orchiectomy or treatment with gonadotropin-releasing hormone agonists is associated with an increased risk of fracture in patients with prostate cancer. This finding underscores the need for caution in the use of these therapies in settings without clear evidence of a benefit. Trials of therapies such as bisphosphonates to lower the risk of fracture are needed in patients for whom gonadotropin-releasing hormone agonists are clearly indicated.” (V. B. Shahinian, U. Texas Med. Branch, Galveston; vbshahin@utmb.edu)

ADHD Treatment: “A single medication is generally all that is needed to treat uncomplicated [attention-deficit/hyperactivity disorder,” writes the author of a clinical practice article (pp. 165-73). “Combinations of psychotropic medications have not been well studied and are reserved for very severe ADHD and coexisting mental health disorders.” In addition to clinical presentation, diagnosis, and nonpharmacologic interventions, the writer reviews major and minor medications used in treatment of ADHD. She recommends: “I begin treatment with methylphenidate, because it is the treatment best supported by research. I prescribe a long-acting preparation, typically a low dose (10 to 18 mg) for a child less than 10 years of age and a midrange dose (20 to 36 mg) for older children or teenagers. A higher starting dose (30 to 54 mg) is reasonable for patients with severe symptoms. If medication is ineffective at the maximal dose or causes intolerable side effects, I try prescribing two to four daily doses of short-acting medication or switching to a long-acting preparation of dextroamphetamine; an alternative is atomoxetine. I see the child and his or her parents every month initially and every three months once a stable dose has been reached, to assess effectiveness and side effects. I recommend behavioral therapy for children and families experiencing conflict with one another and for children with a coexisting mental health condition.” (M. D. Rappley, Michigan State U., East Lansing; rappley@msu.edu)

>>>PNN NewsWatch
* At meetings today and tomorrow in Washington, an FDA advisory committee considers nonprescription sales of statins, and an NIH conference considers effects of dietary supplements in patients who are taking warfarin, aspirin, or other blood thinners.

* With its Liverpool, England, plant out of production until at least April, Chiron is uncertain if it will be able to produce
influenza vaccine for the upcoming season. A series of inspections by the U.K. Medicines and Healthcare products Regulatory Agency—accompanied by FDA observers—will cover critical phases of the manufacture of Fluvirin and affect whether Chiron’s license will be restored.

* FDA has asked for more data on Schering’s
clodronate (Bonefos), a bisphosphonate that was being considered for reducing metastases of breast cancer to bone. The agent has been approved in other countries for as long as 20 years. The type of data requested by FDA has not been revealed, making the impact of the delay uncertain.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 14, 2005 Vol. 12, No. 10
Providing news and information about medications and their proper use

>>>Rheumatology Update
Source:
Jan. issue of Arthritis & Rheumatism (www.rheumatology.org; 2005; 52).

Opioid Use for Chronic Spine Pain: Opioids should be considered for use by patients with chronic nonmalignant pain when caused by well-defined spinal diagnoses, according to results of a retrospective analysis of prescribing records for 230 orthopedic spine clinic patients (pp. 312-21). Based on data on opioid use and the stability of daily doses, combined with information gleaned from patient interviews, the researchers note, “Opioids were prescribed for 152 of the 230 patients, for <3 months (short-term [STO]) in 94, 3 months (long-term [LTO]) in 58, and none in 72 (no opioid [NTO]). Medications prescribed were codeine, oxycodone, propoxyphene, tramadol, morphine, meperidine, fentanyl, or hydroxycodone, either alone or in combination. Interviews were completed in 72 STO, 50 LTO, and 45 NTO patients. Pain severity (0–10 scale) was not different in patients with different spinal pathologies. Opioids significantly reduced the back pain severity score from 8.3 ± 1.5 to 4.5 ± 2.2 (mean ± SD). Mild side effects (most commonly, constipation and sedation) were reported by 58% of the opioid-treated patients but rarely caused them to stop taking the medication. There was no significant increase from the mean ± SD initial opioid dosage of 5.0 ± 12.2 30-mg codeine equivalents per day (30 mg oral codeine = 5 mg oral morphine) to the mean peak dosage of 7.9 ± 12.5 and the mean recent dosage of 4.3 ± 6.3, suggesting that tolerance to opioid analgesia did not appear to occur in these patients. Dosage escalations of >2 30-mg codeine equivalents occurred 19 times in 17 LTO patients and was due to worsening of the underlying painful condition, complications of spine surgery, or unrelated surgical or medical problems in all but 3 of them (5%). These 3 patients also displayed other abuse behaviors. Abuse behaviors were not more frequent in those with or without a history of abuse/addiction.” (M. L. Mahowald, mahow001@umn.edu)

Early Infliximab Treatment of RA: Early treatment of rheumatoid arthritis with 12 months of infliximab plus methotrexate provided significant reductions in synovitis and erosions among 20 patients, and these benefits were sustained during a second year of methotrexate-only treatment (pp. 27-35). “At 1 year, all MRI scores were significantly better, with no new erosions in the infliximab plus MTX group; a greater percentage of infliximab plus MTX-treated patients fulfilled the American College of Rheumatology (ACR) 50% and 70% improvement criteria (78% versus 40% in the placebo plus MTX group and 67% versus 30%, respectively) and had a greater functional benefit (P < 0.05 for all comparisons),” write the researchers. “Importantly, at 1 year after stopping induction therapy, response was sustained in 70% of the patients in the infliximab plus MTX group.” (P. Emery, Leeds Genl. Infirmary, Leeds, U.K.; p.emery@leeds.ac.uk)

>>>PNN NewsWatch
* ASHP yesterday came out in opposition to nonprescription sales of statins; the organization presents today—along with other pharmacy groups—to the FDA advisory committee considering the switch. Supporting the philosophy of the Pharmacy Care OTCs category being advocated by APhA and community pharmacy groups (see PNN, Oct. 29), ASHP said that it “is encouraging the FDA and lawmakers to create an intermediate category of drug products that do not require a prescription but are available only from pharmacists and other licensed health care professionals authorized to prescribe medications.” The APhA Pharmacy Care OTC Task Force, however, has maintained that FDA has authority to approve the switch contingent on a distribution system restricted to pharmacies; by including “lawmakers” in its statement, ASHP apparently believes that new legislation would be required before pharmacy-only requirements could be instituted. Simvastatin has been sold in a pharmacy-only category in the U.K. since last July (see PNN, May 17 and 22).

*
PNN will not be published on Mon., Jan. 17, King Holiday.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 18, 2005 Vol. 12, No. 11
Providing news and information about medications and their proper use

>>>FDA Advisory Panels Turn Down OTC Lovastatin
Despite last Friday’s vote recommending that FDA reject a proposal to transition lovastatin from prescription to pharmacy-only OTC status, two FDA advisory committees may have opened the door to a pharmacist-only class of drugs in the U.S.

Voting 20–3 against the change in lovastatin’s prescription status, members of the Nonprescription Drugs and Endocrinologic & Metabolic Drugs Advisory Committees expressed concern that patients would not be able to self-diagnose and self-treat the chronic, silent disease of hyper-cholesterolemia. Data from simulated consumer purchasing trials showed that substantial numbers of patients incorrectly believed the product was appropriate for them, with percentages reaching 90% in the most stringent analysis.

APhA supported the switch, arguing that the Pharmacy Care OTCs model it developed via a broad-based task force (see PNN, Oct. 29) would enable patients to use the product appropriately. Janet P. Engle, PharmD, past APhA president and faculty member at U. Illinois, presented on behalf of APhA: “Pharmacy Care OTCs are a category of nonprescription medicines available in pharmacies—on the open shelf with other over-the-counter medications. What is different with Pharmacy Care OTCs is the availability of the pharmacist and the marketing, product placement, and pharmacist preparation to support consumer/pharmacist interaction. Pharmacist intervention is not required but strongly supported for Pharmacy Care OTCs—those being used for chronic, asymptomatic conditions or other conditions where consumers would benefit from additional interaction with their pharmacist.”

Despite recommending against such a switch, panel members were quoted in lay media reports as saying they would have voted differently if the proposal had been for a third class of drugs as exists in the U.K. Under this model, interactions with the pharmacist would be required, as the pharmacist would in effect be able to prescribe medications in a category intermediate between Rx and OTC.

FDA is not certain it has the requisite statutory authority to place products in such a category, and the nonprescription drug industry has in the past lobbied against establishment of any intermediate categories. But with the success of emergency contraceptive prescribing in Washington and other states and the need for medications such as statins to be more readily available, the time may have come for establishing a third class of drugs in the U.S.

>>>Circulation Highlights
Source:
Articles released early by Circulation (circ.ahajournals.org; 2005; 111).

COX-2 Inhibitors & Cardiovascular Risks:
In two studies released early on the journal’s Web site, the cardiovascular risks of COX-2 inhibitors are explored in a meta-analysis of people undergoing coronary artery bypass grafts and a mouse study.

The meta-analysis, presented as a 1-page editorial, combines data from two trials. The incidence of coronary and cerebrovascular events in patients on valdecoxib (or in some patients parecoxib followed by valdecoxib) was 3-fold higher than among patients on placebo. The authors conclude that a black-box warning is needed for all COX-2 inhibitors remaining on the U.S. market, as these data combined with recent evidence of problems with celecoxib provide “compelling evidence that these adverse coronary and cerebrovascular events represent a class effect, as originally predicted.” (C. D. Furberg, Wake Forest U., Winston-Salem, N.C.; cfurberg@wfubmc.edu)

>>>PNN JournalWatch
* Global Burden of Hypertension: Analysis of Worldwide Data, in Lancet, 2005; 365: 217–23. Reprints: www.thelancet.com; J. He, jhe@tulane.edu

* Homocysteine and Stroke: Evidence on a Causal Link from Mendelian Randomisation, in
Lancet, 2005; 365: 224–32. Reprints: www.thelancet.com; A. D. Hingorani, Royal Free and U. Coll. Med. Sch., London; a.hingorani@ucl.ac.uk

* Randomised Controlled Trial of Intravenous Antibiotic Treatment for Cellulitis at Home Compared with Hospital, in
BMJ, 2005; 330: 129 ff. Reprints: www.bmj.org; P. Corwin, Christchurch Sch. of Med., Christchurch, New Zealand; paul.corwin@chmeds.ac.nz

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 19, 2005 Vol. 12, No. 12
Providing news and information about medications and their proper use

>>>Meningococcal Conjugate Vaccine Licensed by FDA
The first quadrivalent conjugate vaccine for prevention of meningococcal disease has been licensed by FDA. Menactra (Meningococcal [Groups A, C, Y and W-135] Polysaccharide Diphtheria Toxoid Conjugate Vaccine), a product of Sanofi Pasteur, is approved for adolescents and adults aged 11–55 years.

CDC’s Advisory Committee on Immunization Practices will decide in Feb. whether to update its recommendations for routine vaccinations of young adolescents (11 and 12 year olds) and selected college students based on availability of Menactra. Conjugate vaccines are usually superior to polysaccharide vaccines since they induce boostable memory responses and have longer-lasting immune responses.

The currently approved meningococcal vaccine, Menomune (Sanofi Pasteur), is a polysaccharide vaccine that offers protection from the same four serogroups. The duration of protection against meningococcal disease with Menomune vaccine is approximately 3–5 years, and it is indicated for patients 2 years of age and older. Sanofi Pasteur plans to file a supplemental application with FDA early this year supporting use of Menactra in children younger than 11 years.

>>>JAMA Highlights
Source:
Jan. 19 issue of JAMA (www.jama.com; 2005; 293).

Improving Care of Depression in Adolescents: A quality improvement intervention aimed at increasing access to evidence-based treatments for depression (particularly cognitive-behavior therapy and antidepressant medication) was significantly more effective than usual care in a study of adolescents in diverse primary care practices (pp. 311-9). Over a 6-month period, adolescents with depression received either usual care (n = 207) or care by primary care clinicians who were supported by expert leader teams and care managers who helped with evaluating and managing patients’ depression and providing cognitive-behavior therapy (n = 211). By the end of the study, intervention patients reported significantly fewer depressive symptoms, higher mental health–related quality of life, greater satisfaction with mental health care, and higher rates of mental health care, psychotherapy, or counseling. “Despite increases in youth antidepressant use and primary care clinician prescriptions for antidepressant medications in the past decade,” the authors note, “our results indicate that when both psychotherapy and medication were available options within primary care, psychotherapy (the more difficult option) was generally preferred.” (J. R. Asarnow, jasarnow@mednet.ucla.edu)

Folate Intake & Hypertension in Women: Higher total folate intake is associated with decreased risk of hypertension, particularly in younger women, according to a study that analyzes data from the Nurses’ Health Studies I and II (pp. 320-9). Included were 62,260 older women from the first study and 93,803 younger women from the second study, none of whom initially had hypertension. Based on dietary and supplemental folate intake at baseline and in food questionnaires completed every 4 years, the authors assessed incidence of hypertension during 8 years of follow-up: “Younger women who consumed at least 1000 µg/d of total folate (dietary plus supplemental) had a decreased risk of hypertension (relative risk [RR], 0.54; 95% confidence interval [CI], 0.45–0.66; P for trend <.001) compared with those who consumed less than 200 µg/d. Younger women’s absolute risk reduction (ARR) was approximately 8 cases per 1000 person-years (6.7 vs 14.8 cases). The multivariable RR for the same comparison in older women was 0.82 (95% CI, 0.69– 0.97; P for trend = .05). Older women’s ARR was approximately 6 cases per 1000 person-years (34.7 vs 40.4 cases). When the analysis was restricted to women with low dietary folate intake (<200 µg/d), the multivariable RR for younger women with total folate intake at least 800 µg/d compared with less than 200 µg/d was 0.55 (95% CI, 0.32–0.94; P for trend = .03), and 0.61 (95% CI, 0.34–1.11; P for trend = .05) in the older cohort. Among women who did not take folic acid–containing supplements, dietary folate intake of 400 µg/d or more was not significantly associated with risk of hypertension.” (J. P. Forman, jforman@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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 20, 2005 Vol. 12, No. 13
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Jan. 20 issue of the New England Journal of Medicine (content.nejm.org; 2005; 352).

Preventing Recurrent Ulcer Bleeding: In 320 patients with histories of aspirin-induced gastrointestinal bleeding who needed cardioprotection, combining aspirin therapy with esomeprazole proved preferable to clopidogrel (pp. 238-44). All Helicobacter pylori negative, patients received either aspirin 80 mg once daily plus esomeprazole 20 mg twice daily or clopidogrel 75 mg once daily for 12 months. “Recurrent ulcer bleeding occurred in 13 patients receiving clopidogrel and 1 receiving aspirin plus esomeprazole,” the authors report. “The cumulative incidence of recurrent bleeding during the 12-month period was 8.6 percent (95 percent confidence interval, 4.1 to 13.1 percent) among patients who received clopidogrel and 0.7 percent (95 percent confidence interval, 0 to 2.0 percent) among those who received aspirin plus esomeprazole (difference, 7.9 percentage points; 95 percent confidence interval for the difference, 3.4 to 12.4; P = 0.001).” (F. K. L. Chan, Chinese U., Hong Kong; fklchan@cuhk.edu.hk)

An editorialist comments (pp. 287-9): “The lowest effective dose of aspirin should be used for patients at high risk for gastrointestinal complications who need antiplatelet therapy to prevent thrombotic complications. The more challenging question is what therapy to provide for patients who already have had gastrointestinal complications while taking aspirin or other NSAIDs. The current recommendation for these patients is to replace aspirin with clopidogrel. The study by Chan et al. clearly indicates that this recommendation is harmful and that such patients should be given aspirin plus a proton-pump inhibitor.” (B. Cryer, U. Texas Southwestern Med. Sch., Dallas)

Treatment of CHF: Shock-only implantable cardioverter–defibrillators reduced mortality in a study of 2,521 patients with congestive heart failure, while amiodarone had no effect on deaths (pp. 225-37). “The median LVEF in patients was 25 percent; 70 percent were in NYHA class II, and 30 percent were in class III CHF,” note the authors. “The cause of CHF was ischemic in 52 percent and nonischemic in 48 percent. The median follow-up was 45.5 months. There were 244 deaths (29 percent) in the placebo group, 240 (28 percent) in the amiodarone group, and 182 (22 percent) in the ICD group. As compared with placebo, amiodarone was associated with a similar risk of death (hazard ratio, 1.06; 97.5 percent confidence interval, 0.86 to 1.30; P = 0.53) and ICD therapy was associated with a decreased risk of death of 23 percent (0.77; 97.5 percent confidence interval, 0.62 to 0.96; P = 0.007) and an absolute decrease in mortality of 7.2 percentage points after five years in the overall population. Results did not vary according to either ischemic or nonischemic causes of CHF, but they did vary according to the NYHA class.” (G. H. Bardy, Seattle Institute for Cardiac Research, Seattle; gbardy@sicr.org)

Alcohol & Cognition in Women: Among women in the Nurses’ Health Study, consumption of up to 1 alcoholic beverage per day did not impair cognition and may have decreased the risk of cognitive decline (pp. 245-53). The investigators write: “After multivariate adjustment, moderate drinkers (those who consumed less than 15.0 g of alcohol per day [about one drink]) had better mean cognitive scores than nondrinkers. Among moderate drinkers, as compared with nondrinkers, the relative risk of impairment was 0.77 on our test of general cognition (95 percent confidence interval, 0.67 to 0.88) and 0.81 on the basis of a global cognitive score combining the results of all tests (95 percent confidence interval, 0.70 to 0.93).” (M. J. Stampfer, Brigham and Women’s Hosp., Boston)

Today’s FDA: Communicating drug risks, postmarketing surveillance of medications, and escalating drug product costs are among the topics covered in an assessment of FDA as President Bush begins his second term (pp. 293-7). The writer, a physician, was senior vice president at Merck until 2000 and then an assistant secretary in HHS from 2002 to 2003. (E. E. Slater)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 21, 2005 Vol. 12, No. 14
Providing news and information about medications and their proper use

>>>Pharmacotherapy Update
Source:
Jan. issue of Pharmacotherapy (www.pharmacotherapy.org; 2005; 25).

First-of-the-Month Medication-Related Deaths: Increased pharmacy workloads at the beginning of each month, which presumably produce an increase in medication error rates, may be associated with higher numbers of deaths that occurred during the early parts of months between 1979 and 2000 (pp. 1-9). Investigators examined all U.S. death certificates during this period, totaling more than 47 million. “Medication error deaths for which the decedent was dead on arrival or died in the emergency room or as an outpatient spiked by 25% above normal at the beginning of each month,” the authors write. “This beginning-of-the-month spike (25% ± 4%) was larger than for any other major cause of death. The beginning-of-the-month spike did not vary by socioeconomic status and was not larger for substance abusers than for others. Five explanations for the findings were tested. Evidence suggested that the spike in medication error deaths cannot be solely attributed to a spike in the consumption of alcohol or drugs. An increase in pharmacy error rates might play a role.” (D. P. Phillips, dphillips@ucsd.edu)

Estimating NSAID Potency: Prostaglandin inhibition provides a useful marker for estimating the relative potency of NSAIDs, according to a single-dose, crossover trial conducted in eight healthy volunteers (pp. 18-25). Two different doses of uncoated formulations of indomethacin, diclofenac, and ibuprofen were administered, and serum concentrations of PGEM, a surrogate marker for prostaglandin E2, were measured. The researchers report, “Statistically significant linear correlations were found between the percent reduction in PGEM concentration and the concentrations of diclofenac, indomethacin, and ibuprofen in plasma (R2 = 0.992–0.999). The PGEM plasma concentrations correlated inversely with NSAID plasma concentrations, indicating maximum inhibition when the highest NSAID plasma concentrations were achieved. Statistically significant differences in the percent inhibition of PGEM concentrations were observed between the two doses for each NSAID (p < 0.05), but not between subjects for each NSAID. Doubling the dose (100% increase) of diclofenac and indomethacin produced a 60–65% increase in maximum inhibition of PGEM concentrations, whereas a 50% increase in dose produced a 44% increase in the maximum effect of ibuprofen.” (S. L. Markantonis, U. Athens, Athens, Greece; kyroudi@pharm.uoa.gr)

>>>PNN NewsWatch
* A 28-day course of highly active antiretroviral therapy is now recommended for people who have accidental, nonoccupational exposure to HIV. CDC yesterday released new recommendations for preventing HIV infection following unanticipated sexual or injection-drug-use exposure (www.cdc.gov/mmwr/preview/mmwrhtml/rr5402a1.htm). Within 72 hours after such exposure to blood, genital secretions, or other potentially infectious body fluids of a person known to be HIV-infected, an HAART regimen should be started. The two preferred regimens are efavirenz plus (lamivudine or emtricitabine) plus (zidovudine or tenofovir) (NNRTI-based regimen) or lopinavir/ritonavir plus (lamivudine or emtricitabine) plus zidovudine (PI-based regimen). No recommendations are made for use of prophylaxis when the nonoccupational exposure involves persons of unknown HIV status or when care is sought more than 72 hours after the exposure occurs.

*
Eisai and Cardinal called a truce yesterday, agreeing to a fee-for-service arrangement that will enable continued availability of the drug company’s products through this wholesaler. Large drug wholesalers are in the midst of an effort to shift from their traditional business model to a fee-for-service arrangement. While some pharmaceutical companies have balked at the idea, a financial analyst quoted in this morning’s Wall Street Journal estimates that 85% of the U.S. drug volume will be covered by the new mechanism by the end of 2006.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 24, 2005 Vol. 12, No. 15
Providing news and information about medications and their proper use

>>>CMS Releases Final Medicare Part D Regs
The rules under which the new prescription drug benefit for Medicare beneficiaries will operate were released Friday by the Centers for Medicare & Medicaid Services. Balancing the divergent interests of patients, providers, health plans, and the pharmaceutical industry, the regulations provide for establishment of formularies in the 26 administrative regions of the new program, but the approved drug list will contain at least two agents for nearly all diseases. A regional map is available online at http://www.cms.hhs.gov/medicarereform/mmaregions/

Among the details that pharmacists must learn about in the lead-up to a Jan.1 implementation of Part D are the following:

* Some 6.3 million people whose medications are currently covered under Medicaid can begin choosing their Medicare plan this July. If they do not enroll by mid-December, CMS will automatically assign them to a plan before their Medicaid coverage stops on Jan. 1.

* Other Medicare beneficiaries will choose their plans beginning in Nov. Beneficiaries living in nursing homes will be able to enroll in drug plans; all drug plans must contract with long-term care pharmacies to facilitate access by these residents.

* A new Medicare Advantage program is being established in the 26 Medicare regions, and preferred-provider organizations operating under the program must offer the same services as fee-based Medicare.

* While two drugs will be available for most conditions, plans can choose a single medication if a clearly superior agent is in a category with only one other drug.

* Physicians can certify that a nonformulary agent is medically necessary, and plans must provide the medication.

APhA has set up a resources center with information about Medicare Part D, including continuing education articles on the subject (
http://www.aphanet.org/Content/NavigationMenu/AdvocacyOnYourBehalf/APhAResourcesMedicare/default.htm)

>>>BMJ Highlights
Source:
Online BMJ article (www.bmj.org; 2005; 330).

Home-Based Medication Reviews: Home visits by pharmacists within 2 and 8 weeks of discharge of patients from hospitals in Norfolk and Suffolk resulted in higher hospitalization rates and failed to improve quality of life or mortality (article released early online). The pharmacists educated patients and caregivers about medications, removed out-of-date drugs, informed general practitioners of drug reactions or interactions, and contacted a local pharmacist if the patients needed adherence aids. The researchers noted the “counterintuitive” findings: “By six months 178 readmissions had occurred in the control group and 234 in the intervention group (rate ratio = 1.30, 95% confidence interval 1.07 to 1.58; P = 0.009, Poisson model). 49 deaths occurred in the intervention group compared with 63 in the control group (hazard ratio = 0.75, 0.52 to 1.10; P = 0.14). EQ-5D [quality of life] scores decreased (worsened) by a mean of 0.14 in the control group and 0.13 in the intervention group (difference = 0.01, –0.05 to 0.06; P = 0.84, t test).” (R. Holland, U. East Anglia, Norwich, U.K.; r.holland@uea.ac.uk)

>>>PNN JournalWatch
* Atypical Antipsychotic Drugs and Risk of Ischaemic Stroke: Population Based Retrospective Cohort Study, in BMJ, 2005; early-release article. Reprints: www.bmj.org; S. S. Gill, Inst. for Clinical Evaluative Sciences, Toronto.

* Patient Initiated Outpatient Follow Up in Rheumatoid Arthritis: Six Year Randomised Controlled Trial, in
BMJ, 2005; 330: 171 ff. Reprints: www.bmj.org; S. Hewlett, U. Bristol Academic Rheumatology Unit, Bristol, U.K.; Sarah.Hewlett@bristol.ac.uk

* Isolation of Patients in Single Rooms or Cohorts to Reduce Spread of MRSA in Intensive-Care Units: Prospective Two-Centre Study, in
Lancet, 2005; 365: 295–304. Reprints: www.thelancet.com; A. P. R. Wilson, U. Coll., London; peter.wilson@uclh.nhs.uk

* Recreational Use and Misuse of Phosphodiesterase 5 Inhibitors, in
Journal of the American Pharmacists Association, 2005; 45: 63–75. Reprints: www.japha.org; K. M. Smith, ksmit1@email.uky.edu

* Pharmacists’ and Technicians’ Perceptions and Attitudes Toward Dispensing Buprenorphine/Naloxone to Patients with Opioid Dependence, in
Journal of the American Pharmacists Association, 2005; 45: 63–75. Reprints: www.japha.org; D. W. Raisch, dwraisch@unm.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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 25, 2005 Vol. 12, No. 16
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Jan. 24 issue of Archives of Internal Medicine (www.archinternmed.com; 2005 165).

COX-2 Inhibitors: Four articles and an editorial address various safety issues related to use COX-2 inhibitors.

In the Celecoxib Rofecoxib Efficacy and Safety in Comorbidities Evaluation Trial (CRESCENT), rofecoxib but not celecoxib or naproxen induced a significant increase in 24-hour systolic blood pressures, and the investigators note “destabilization of hypertension control” with all three agents (pp. 161-8). High-risk patients—those with type 2 diabetes and hypertension—were treated for comorbid osteoarthritis with celecoxib 200 mg/day, rofecoxib 25 mg/day, or naproxen 500 mg twice daily for 12 weeks. Ambulatory BP monitoring at baseline, 6 weeks, and 12 weeks showed: “The mean ± SE 24-hour systolic BP following 6 weeks of therapy was increased significantly by rofecoxib (from 130.3 ± 1.2 to 134.5 ± 1.4 mm Hg; P < .001) but not by celecoxib (132.0 ± 1.3 to 131.9 ± 1.3 mm Hg; P = .54) or naproxen (133.7 ± 1.5 to 133.0 ± 1.4 mm Hg; P = .74). The BP difference between rofecoxib and celecoxib was 3.78 mm Hg (95% confidence interval, 1.18-6.38; P = .005); between rofecoxib and naproxen, 3.85 mm Hg (95% confidence interval, 1.15-6.55; P = .005).” (W. B. White, U. Conn., Farmington; wwhite@nso1.uchc.edu)

A second article describes the “nonselective diffusion of a selectively cost-effective innovation” (pp. 171-7). While “the public health benefit of COX-2 inhibitors depends on their use in patients at higher than normal risk from NSAIDs,” these investigators found in national data, “Of the [physician] visits in which either a COX-2 inhibitor or NSAID was prescribed, the frequency of COX-2 inhibitor use increased from 35% (1999) to 55% (2000) to 61% (2001 and 2002). Among patients with the lowest risk for adverse events from NSAIDs, the proportion receiving a COX-2 inhibitor increased from 12% in 1999 to 35% in 2002. Overall, increases in COX-2 inhibitor use among patients in whom NSAIDs could be used accounted for more than 63% of the growth in COX-2 inhibitor use during the period examined.” (G. C. Alexander, galexand@uchicago.edu)

Cardiovascular risks were not elevated among high-risk Maryland Medicaid patients treated with COX-2 inhibitors, according to the third trial (pp. 181-6). Comparing 1,005 patients who received at least a 60-day supply of a COX-2 inhibitor with 5,245 patients treated similarly with nonnaproxen NSAIDs, the researchers found, “Overall, 12% of the patients had at least 1 cardiovascular thrombotic event after treatment within the follow-up period. The propensity-adjusted odds ratio showed no significant effect of COX-2 inhibitor use on this percentage of patients (odds ratio, 1.09; 95% confidence interval, 0.90–1.33).” (F. T. Shaya, fshaya@rx.umaryland.edu)

Gastrointestinal bleeding risks were increased among patients taking COX-2 inhibitors plus warfarin, according the final study (pp. 189-92). “We identified 98,821 elderly patients continuously receiving warfarin,” the authors wrote about their analysis of several databases of Ontario residents. “Of those, 361 (0.3%) were admitted to the hospital with upper GI hemorrhage. After adjusting for other potential confounders, case patients were significantly more likely to be also taking nonselective NSAIDs (OR, 1.9; 95% confidence interval [CI], 1.4–3.7), celecoxib (OR, 1.7; 95% CI, 1.2–3.6), or rofecoxib (OR, 2.4; 95% CI, 1.7–3.6) prior to hospitalization relative to controls.” (M. Battistella, University Health Network–Toronto General Hosp., Toronto; Marisa.battistella@uhn.on.ca)

Commenting on coxibs, science, and the public trust, editorialists note (pp. 158-60): “The dramatic withdrawal of such a widely used and widely promoted drug 5 years after it was introduced to the market raises many questions concerning drug policy, scientific evidence, and treatment alternatives. Several of these questions are raised by articles in this issue of the Archives. A more thoughtful approach to these issues by regulators, industry, clinicians, and researchers could help avoid similar episodes in the future.” (D. H. Solomon, dhsolomon@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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 26, 2005 Vol. 12, No. 17
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Jan. 26 issue of JAMA (www.jama.com; 2005; 293).

Post-MI Treatments: Two reports from the Clinical Trial of Reviparin and Metabolic Modulation in Acute Myocardial Infarction Treatment Evaluation (CREATE) and a related editorial analyze treatments for myocardial infarction.

Reviparin, a low molecular weight heparin, provided the first evidence of reductions in mortality and reinfarction when used to treat 15,570 patients with acute ST-segment elevation or new left bundle-branch block MI (pp. 427-35). Presenting within 12 hours of the onset of symptoms, patients received either reviparin or placebo subcutaneously twice daily for 7 days. The investigators report, “The primary composite outcome [death, myocardial reinfarction, or stroke at 7 and 30 days] was significantly reduced from 854 (11.0%) of 7790 patients in the placebo group to 745 (9.6%) of 7780 in the reviparin group (hazard ratio [HR], 0.87; 95% CI, 0.79–0.96; P = .005). These benefits persisted at 30 days (1056 [13.6%] vs 921 [11.8%] patients; HR, 0.87; 95% CI, 0.79–0.95; P = .001) with significant reductions in 30-day mortality (877 [11.3%] vs 766 [9.8%]; HR, 0.87; 95% CI, 0.79–0.96; P = .005) and reinfarction (199 [2.6%] vs 154 [2.0%]; HR, 0.77; 95% CI, 0.62–0.95; P = .01), and no significant differences in strokes (64 [0.8%] vs 80 [1.0%]; P = .19). Reviparin treatment was significantly better when it was initiated very early after symptom onset at 7 days (<2 hours: HR, 0.70; 95% CI, 0.52–0.96; P = .03; 30/1000 events prevented; 2 to <4 hours: HR, 0.81; 95% CI, 0.67–0.98; P = .03; 21/1000 events prevented; 4 to <8 hours: HR, 0.85; 95% CI, 0.73–0.99; P = .05; 16/1000 events prevented; and 8 hours: HR, 1.06; 95% CI, 0.86–1.30; P = .58; P = .04 for trend). There was an increase in life-threatening bleeding at 7 days with reviparin and placebo (17 [0.2%] vs 7 [0.1%], respectively; P = .07), but the absolute excess was small (1 more per 1000) vs reductions in the primary outcome (18 fewer per 1000) or mortality (15 fewer per 1000).” (S. Yusuf, yusuf@mcmaster.ca)

Glucose–insulin–potassium (GIK) infusions had a neutral effect on mortality, cardiac arrest, cardiogenic shock, and reinfarction at 30 days in 20,201 patients with acute ST-segment elevation MI (pp. 437-46). “At 30 days, 976 control patients (9.7%) and 1004 GIK infusion patients (10.0%) died (hazard ratio [HR], 1.03; 95% confidence interval [CI], 0.95–1.13; P = .45). There were no significant differences in the rates of cardiac arrest (1.5% [151/10,107] in control and 1.4% [139/10,088] in GIK infusion; HR, 0.93; 95% CI, 0.74–1.17; P = .51), cardiogenic shock (6.3% [640/10 107] vs 6.6% [667/10 088]; HR, 1.05; 95% CI, 0.94–1.17; P = .38), or reinfarction (2.4% [246/10,107] vs 2.3% [236/10,088]; HR, 0.98; 95% CI, 0.82–1.17; P = .81). The rates of heart failure at 7 days after randomization were also similar between the groups (16.9% [1711/10 107] vs 17.1% [1721/10 088]; HR, 1.01; 95% CI, 0.95–1.08; P = .72). The lack of benefit of GIK infusion on mortality was consistent in prespecified subgroups, including in those with and without diabetes, in those presenting with and without heart failure, in those presenting early and later after symptom onset, and in those receiving and not receiving reperfusion therapy (thrombolysis or primary percutaneous coronary intervention).” (S. R. Mehta, smehta@mcmaster.ca)

The editorialist, commenting on the factorial design of CREATE that allowed two interventions to be tested simultaneously, wrote (pp. 489-91): “The massive uncertainty about the safety of drugs in Western society stems from a series of revelations that demonstrate the flaw in reasoning when powerful treatments are administered over a long term to large populations based on short-term studies or surrogate measures. A drug simply cannot be declared ‘safe’ without measuring the balance of benefits and risks in a randomized controlled trial over an appropriate period of time in a large population representing those who will use the treatment in practice. Although the specific new knowledge imparted by the CREATE trial is important, its more important lasting legacy may be the demonstration that clear answers to the balance of benefit and risk of therapies can be achieved at a fraction of the current accepted cost of clinical trials.” (R. M. Califf, calif001@mc.duke.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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 27, 2005 Vol. 12, No. 18
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Jan. 27 issue of the New England Journal of Medicine (content.nejm.org; 2005; 352).

Etanercept for Wegener’s Granulomatosis: Added to standard therapy, etanercept proved not useful for treating patients with Wegener’s granulomatosis, with durable remissions observed in few of the 174 patients and serious treatment-related complications common (pp. 351-61). Standard therapy for the multisystem inflammatory illness that most often affects the respiratory tract and kidneys—glucocorticoids plus cyclophosphamide or methotrexate—was provided with either etanercept or placebo, and patients were treated until they achieved sustained remission (score of 0 on an activity instrument for at least 6 months). During 27 months of follow-up, the authors observed: “126 (72.4 percent) had a sustained remission, but only 86 (49.4 percent) remained in remission for the remainder of the trial. There were no significant differences between the etanercept and control groups in the rates of sustained remission (69.7 percent vs. 75.3 percent, P = 0.39), sustained periods of low-level disease activity (86.5 percent vs. 90.6 percent, P = 0.32), or the time required to achieve those measures. Disease flares were common in both groups, with 118 flares in the etanercept group (23 severe and 95 limited) and 134 in the control group (25 severe and 109 limited). There was no significant difference between the etanercept and control groups in the relative risk of disease flares per 100 person–years of follow-up (0.89, P = 0.54). During the study, 56.2 percent of patients in the etanercept group and 57.1 percent of those in the control group had at least one severe or life-threatening adverse event or died (P = 0.90). Solid cancers developed in six patients in the etanercept group, as compared with none in the control group (P = 0.01).” (J. H. Stone, Johns Hopkins Vasculitis Ctr., Baltimore; jstone@jhmi.edu)

In a Perspectives article, an author provides these details about treatment of this rare, primary systemic vasculitis (pp. 330-2)L: “Early data indicate that different subgroups of T cells predominate in localized Wegener's granulomatous and vasculitic lesions—a finding that should be pursued. Uncovering the driving forces behind both the persistence of granulomata and the shift from localized to systemic disease is a major challenge, but fresh approaches are required if the problems with the current therapies are to be solved. Such basic research on the granulomatous aspects of Wegener’s granulomatosis should lead to the identification of new drug targets that may finally make the long-term maintenance of remission as effective as the current regimens for the induction of remission.” (P. A. Bacon, U. Birmingham, Birmingham, U.K.)

Direct-to-Consumer Prescription Drug Advertising: More balanced communication of the risks and benefits of prescription drugs is needed in direct-to-consumer advertising, writes the author of a Perspectives article (pp. 325-8): “Although [proposed] changes in FDA policy are promising, industry must also address the imbalance between risk information and benefit information in its direct-to-consumer advertising. The acting FDA commissioner, Lester Crawford, has argued that such advertising ‘is supposed to get patients who need the medication to know about the drug so they can ask their physician about it. . . . Direct-to-consumer advertising correctly done is a great public health tool.’ But ‘correctly done’ is the operative term; too often, says Crawford, such advertising fails to achieve its highest aim. ‘We now have ads on television that show people walking through meadows as the name is subliminally flashed, and there are birds singing and bees copulating. . . . We’ve got to cut that out, because that is not what direct-to-consumer advertising is supposed to be.’

“As an instrument promoting public health, direct-to-consumer advertising has considerable potential. But industry needs to respond to consumers and physicians, who seek more balanced communication of risks and benefits.” (E. R. Berndt, Mass. Inst. of Technology, Cambridge)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 28, 2005 Vol. 12, No. 19
Providing news and information about medications and their proper use

>>>Oncology Update
Source:
Jan. 20 issue of the Journal of Clinical Oncology (www.jco.org; 2005; 23).

Kinetics, Dynamics, TDM in Cancer Chemotherapy: A pharmacokinetic–pharmacodynamic model proved useful in predicting the white blood cell time course—including nadir day and duration of leukopenia—in 44 patients with advanced breast cancer being treated with epirubicin and docetaxel (pp. 413-21). Initial doses of the drugs were escalated or reduced based on WBC and platelet counts, and a semiphysiological model was developed to describe the time course of leukocyte counts. “In the final pharmacokinetic model, interoccasion variability was estimated to be less than interindividual variability in the clearances for both drugs,” write the authors. “The sum of the individual EPI and DTX areas under concentration–time curve correlated stronger to WBC survival fraction than did the corresponding sum of doses. A pharmacokinetic–pharmacodynamic model with additive effects of EPI and DTX could adequately describe the data.” (M. Sandström, Faculty of Pharmacy, Uppsala U., Uppsala, Sweden; marie.sandstrom@farmbio.uu.se)

An editorialist describes the possibilities of a model that successfully incorporates pharmacokinetic parameters with pharmacodynamic effects of oncolytic drugs (pp. 405-6): “Controlling drug concentrations by therapeutic drug monitoring (TDM) may improve anticancer chemotherapy. However, TDM has rarely been successful in the context of chemotherapy against solid cancers. Successful control of drug concentrations within a target range might still not necessarily result in control of neutropenia. This may be related to the fact that there have been no good pharmacodynamic models that associated pharmacokinetics and pharmacodynamics. By developing good pharmacodynamic models for analyzing the entire time course of neutropenia, we may derive a new platform for TDM in cytotoxic chemotherapy, as Sandström et al. discuss. However, even with Bayesian estimation of neutrophil counts in the pharmacodynamic model in this issue, the correlation between observed neutrophil counts and model-predicted counts was only modest, and poorer than the correlation of pharmacokinetics. Further improvements of the pharmacodynamic model will be necessary before it can be used for TDM. One such approach may be to incorporate characteristics of patients as covariates into the model to reduce residuals. Furthermore, a TDM strategy based on pharmacodynamic models will need to be validated in clinical trials.” (H. Minami, Natl. Cancer Ctr. Hosp. East, Kashiwa, Japan)

Gene Profiling in Predicting Drug Response: Clinical response to docetaxel in patients with breast cancer can be predicted by gene expression patterns of biopsy samples, concludes a study that explored why one half of patients do not respond to this agent (pp. 422-31). Evaluating expression of 2,453 genes in 44 breast tumor tissues and associating patterns with clinical response of patients, the researchers found, “This system predicted the clinical response of 26 previously unanalyzed samples with over 80% accuracy, a level promising for clinical applications. Diagnostic profiles in nonresponders were characterized by elevated expression of genes controlling the cellular redox environment (ie, redox genes, such as thioredoxin, glutathione-S-transferase, and peroxiredoxin). Overexpression of these genes protected cultured mammary tumor cells from docetaxel-induced cell death, suggesting that enhancement of the redox system plays a major role in docetaxel resistance.” (K. Kato, Osaka Med. Ctr. for Cancer and Cardiovascular Diseases, Osaka, Japan; katou-ki@mc.pref.osaka.jp)

>>>PNN NewsWatch
* Goodman & Gilman’s The Pharmacological Basis of Therapeutics is now available online as part of the AccessMedicine.com clinical library, which also includes Harrison’s Principles of Internal Medicine and some 30 other titles. Goodman & Gilman’s features fully integrated links to Gold Standard’s Clinical Pharmacology drug database.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 31, 2005 Vol. 12, No. 20
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
Early-release articles and the Jan. 29 issue of Lancet (www.thelancet.com; 2005; 365).

Mortality with COX-2 Inhibitors: The long-awaited FDA analysis of NSAIDs was finally released last week, and it concluded that rofecoxib increases the risk of serious coronary heart disease, compared with celecoxib, and that naproxen provides no cardioprotection (early-release article). Using data from both the northern and southern California regions of Kaiser Permanente, David Graham, MD, and colleagues used a nested case–control study to assess adult patients treated with an NSAID in 1999 through 2001. They report, “During 2,302,029 person-years of follow-up, 8143 cases of serious coronary heart disease occurred, of which 2210 (27.1%) were fatal. Multivariate adjusted odds ratios versus celecoxib were: for rofecoxib (all doses), 1.59 (95% CI 1.10–2.32, p = 0.015); for rofecoxib 25 mg/day or less, 1.47 (0.99–2.17, p = 0.054); and for rofecoxib greater than 25 mg/day, 3.58 (1.27–10.11, p = 0.016). For naproxen versus remote NSAID use the adjusted odds ratio was 1.14 (1.00–1.30, p = 0.05).” (D. J. Graham, grahamd@cder.fda.gov)

In an accompanying commentary, two writers note that the evidence concerning other COX-2–selective NSAIDs “is not entirely reassuring,” and emphasize the critical nature of the current situation: “It now falls to the manufacturers, under the careful review of the regulatory authorities, to provide the evidence that this class of drugs is safe, if necessary including studies that directly address cardiovascular morbidity as a primary outcome. Indeed, the experience with coxibs underlines the need for full publication of all clinical trial data generated in support of newly licensed drugs.” (S. R. J. Maxwell, U. Edinburgh, Edinburgh; d.j.webb@edac.uk)

Next-Generation Smallpox Vaccine: A new cell-cultured smallpox vaccine (CCSV) provided a safe and immunogenic alternative to calf-lymph–derived vaccine for both vaccinia-naive and -nonnaive people, according to results of a 350-patient study (pp. 398-409). The authors write, “349 (99.7%) of 350 volunteers developed pock lesions; one vaccinia-naive individual who received a 1 in 25 dilution of CCSV did not. The rate of adverse events related to vaccine and the extent of humoral and cellular immune responses did not differ between the vaccine groups in vaccinia-naive or non-naive people. CCSV was immunogenic in vaccine-naive volunteers at a dose 50 times lower than that approved for Dryvax [the currently licensed U.S. product].” (R. N. Greenberg, RNgree01@uky.edu)

>>>BMJ Highlights
Source:
Jan. 29 issue of BMJ (www.bmj.org; 2005; 330).

Adjuvant Chemotherapy of Breast Cancer: Cyclophosphamide, methotrexate, and fluorouracil (CMF), administered to patients with operable breast cancer, reduces the long-term risk of relapse, according to an analysis that followed patients for a median of nearly 30 years (pp. 217 ff). Among patients treated in 1973–80, “Adjuvant CMF was found to reduce the relative risk of relapse significantly (hazard ratio 0.71, 95% confidence interval 0.56 to 0.91, P = 0.005) and death (0.79, 0.63 to 0.98, P = 0.04),” the investigators wrote. “Administration of CMF for 12 cycles does not seem superior to a shorter administration of six cycles. In [a] node negative and oestrogen receptor negative trial, intravenous CMF significantly reduced the relative risk of relapse of disease (0.65, 0.47 to 0.90, P = 0.009) and death (0.65, 0.47 to 0.92, P = 0.01) at a median follow up of 20 years. ” (G. Bonadonna, Istituto Nazionale Tumori, Milan; gianni.bonadonna@istitutotumori.mi.it)

>>>PNN JournalWatch
* Use of Inhaled Corticosteroids During Pregnancy and Risk of Pregnancy Induced Hypertension: Nested Case-Control Study, in BMJ, 2005; 330: 230 ff. Reprints: www.bmj.org; L. Blais, lucie.blais@umontreal.ca

* Recent Developments in Atrial Fibrillation, in
BMJ, 2005; 330: 238-43. Reprints: www.bmj.org; A. K. Taneja, Royal Brompton Hosp., London; a.taneja@rbh.nthames.nhs.uk

* Bayesian Methods for Health-Related Decision Making, in
Statistics in Medicine, 2005; 24: 563–7. Reprints: www3.interscience.wiley.com/cgi-bin/abstract/109882094/ABSTRACT; J. B. Kadane, Carnegie Mellon U., Pittsburgh; kadane@stat.cmu.edu

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 1, 2005 Vol. 12, No. 21
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release articles and Feb. 1 issue of the Annals of Internal Medicine (www.annals.org; 2005; 142).

Rofecoxib & MI: Higher doses of rofecoxib increase the risk of myocardial infarction among older patients with no history of the disease, according to a nested case–control analysis of Quebec administrative health databases (early-release article). Daily doses of aspirin mitigated the risks associated with use of lower drug doses in the 113,927 patients, the authors noted: “Compared with no use of NSAIDs in the year preceding the event, current use of rofecoxib was associated with an increased risk for an acute MI (rate ratio [RR], 1.24 [95% CI, 1.05 to 1.46]) that was more pronounced at higher doses (RR, 1.73 [CI, 1.09 to 2.76]). The concomitant use of aspirin appears to decrease the risk associated with low-dose rofecoxib (RR, 1.00 [CI, 0.77 to 1.28]) but not with high-dose rofecoxib (RR, 2.36 [CI, 1.27 to 4.39]). No increased risks were observed with celecoxib (RR, 0.99 [CI, 0.85 to 1.16]) or the other NSAIDs.” (J. Brophy, james.brophy@mcgill.ca)

Rofecoxib, Celecoxib, & Nonfatal MI: Comparing 1,718 patients with a first, nonfatal myocardial infarction and 6,800 control patients in a 5-county area, researchers found higher odds of MI associated with rofecoxib than with celecoxib (pp. 157-64). “The adjusted odds ratio for MI among celecoxib users, relative to persons who did not use nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs), was 0.43 (95% CI, 0.23 to 0.79) compared with 1.16 (CI, 0.70 to 1.93) among rofecoxib users,” write the researchers. “The use of rofecoxib was associated with a statistically significant higher odds of MI compared with the use of celecoxib (adjusted odds ratio for rofecoxib vs. celecoxib, 2.72 [CI, 1.24 to 5.95]; P = 0.01). Nonselective NSAIDs were associated with a reduced odds of nonfatal MI relative to nonusers. Comparisons of COX-2 inhibitors with nonselective NSAIDs were the following: rofecoxib versus naproxen (odds ratio, 3.39 [CI, 1.37 to 8.40]) and celecoxib versus ibuprofen or diclofenac (odds ratio, 0.77 [CI, 0.40 to 1.48]).” (S. E. Kimmel, U. Penn., Philadelphia)

Assessing current knowledge of the cardiovascular risks of COX-2 inhibitors, editorialists state (pp. 212-4): “We believe that COX-2 inhibitors, in particular at higher dosages and for longer-term use, should not be a first-line therapy for patients who can tolerate alternative therapies.... We urgently need further research to document the safety of long-term use of COX-2 inhibitors and nonselective nonaspirin NSAIDs.” (A. Finckh, Harvard Med. Sch., Boston)

Automated Notification of Rofecoxib Withdrawal: Citing a paper presented at an APhA annual meeting that discussed the legal necessity for institutions to notify health professionals and patients about drug recalls, authors describe how the electronic medical records of the Cleveland Clinic were used for automated notifications following the Sept. 30 market withdrawal of Vioxx (pp. 182-6). Noting that 11,699 patients with a rofecoxib prescription were notified by e-mail or regular mail within 24 hours of withdrawal, the authors explain: “Although we demonstrate the value of this model by using the rofecoxib drug withdrawal, the true value of the model is that it extends beyond the occasional drug withdrawal crisis and can be applied to a variety of patient care emergencies. For example, institutions may wish to notify high-risk patients to present themselves to an influenza vaccine station during an influenza vaccine shortage or an influenza outbreak. The EMR technology should be designed to enable institutions to quickly and easily identify a patient population on the basis of a diagnosis, medication, or laboratory result (that is, the EMR query process should not be the rate-limiting step in the management of a patient care emergency).” (A. Jain, Cleveland Clinic Foundation, Cleveland)

Outpatient CAP Care: Patients with community-acquired pneumonia treated as outpatients with levofloxacin had similar clinical outcomes and greater satisfaction with care as hospitalized patients (pp. 165-72). Among 224 immunocompetent adults without CAP complications, 83.6% had successful clinical outcomes, compared with 80.7% of hospitalized patients. (J. Carratalà, L'Hospitalet de Llobregat, Barcelona; jcarratala@wanadoo.es)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 2, 2005 Vol. 12, No. 22
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Feb. 2 issue of JAMA (www.jama.com; 2005; 293).

Treatment of High-Grade Gliomas: Use of chemotherapy and prophylactic antiepileptic treatment of patients with newly diagnosed grade III or IV malignant gliomas varies from established practice guidelines, according to an analysis of 565 participants in the Glioma Outcomes (GO) Project (pp. 557-64). “Most patients underwent magnetic resonance imaging (n = 518; 92%) and an attempt at tumor resection (n = 425; 75%),” the authors noted after emphasizing the lack of prospective data on care for patients with this diagnosis. “Cortical mapping (n = 107; 19%) and intraoperative image guidance (n = 161; 29%) were uncommon. Most received perioperative corticosteroids (n = 535; 99%) and antiepileptic medications (n = 497; 88%), but few received antidepressants (n = 38; 8%) or prophylactic heparin (n = 42; 7%). Most received adjuvant radiation therapy (n = 479; 87%), but fewer received chemotherapy (n = 300; 54%). Practice patterns varied significantly between academic and community settings.”

The group concludes, “Some common practice patterns are in keeping with published literature (eg, use of radiation therapy), some contradict published guidelines (eg, frequent prophylactic AED administration) or may conflict with published literature (eg, relatively infrequent use of chemotherapy), and still others point out areas for further investigation in this population, including heparin prophylaxis for venous thromboembolism, antidepressant medication, corticosteroid dosing, and use of surgical adjuncts. Variations in patterns of care were associated with differences in survival; establishing further practice guidelines may help reduce this variability. One of the major benefits of the GO Project is that it provides a broad historical cohort that can be used as a comparison for future prospective studies.” (S. M. Chang, changs@neurosurg.ucsf.edu)

Treatment of Neuropsychiatric Symptoms of Dementia: Risperidone and olanzapine have the best evidence for efficacy in treatment of neuropsychiatric symptoms of dementia, but their effects are modest and they increase patients’ risk of stroke, according to a systematic review article in this issue (pp. 596-608). Based on meta-analyses and randomized controlled trials, the authors report: “For typical antipsychotics, 2 meta-analyses and 2 RCTs were included. Generally, no difference among specific agents was found, efficacy was small at best, and adverse effects were common. Six RCTs with atypical antipsychotics were included; results showed modest, statistically significant efficacy of olanzapine and risperidone, with minimal adverse effects at lower doses. Atypical antipsychotics are associated with an increased risk of stroke. There have been no RCTs designed to directly compare the efficacy of typical and atypical antipsychotics. Five trials of antidepressants were included; results showed no efficacy for treating neuropsychiatric symptoms other than depression, with the exception of 1 study of citalopram. For mood stabilizers, 3 RCTs investigating valproate showed no efficacy. Two small RCTs of carbamazepine had conflicting results. Two meta-analyses and 6 RCTs of cholinesterase inhibitors generally showed small, although statistically significant, efficacy. Two RCTs of memantine also had conflicting results for treatment of neuropsychiatric symptoms.” (K. M. Sink, Wake Forest U., Winston- Salem, N.C.; kmsink@wfubmc.edu)

>>>PNN NewsWatch
* Robotic dispensers that provide samples of generic drug products represent one approach being used to increase physicians’ use of these lower-cost agents, reports the Jan. 31 issue of American Medical News (www.ama-assn.org/amednews). MedVantx units were placed in the U. Pittsburgh medical clinics by Highmark BlueCross BlueShield, and each contains about 20 generic medications. Physicians access the products using a passcode and provide the samples to patients with a drug-information sheet. The robot’s manufacturer states that generic prescribing rates have increased 3%–5% in offices supplied with these samples.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 3, 2005 Vol. 12, No. 23
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Feb. 3 issue of the New England Journal of Medicine (content.nejm.org; 2005; 352).

Mortality from Varicella: The varicella mortality rate in the U.S. has declined sharply since universal childhood vaccination programs began in 1995, according to an analysis of National Center for Health Statistics Multiple Cause-of-Death Mortality Data for 1990 through 2001 (pp. 450-8). “The rate of death due to varicella fluctuated from 1990 through 1998 and then declined sharply,” the authors report. “For the interval from 1990 through 1994, the average number of varicella-related deaths was 145 per year (varicella was listed as the underlying cause in 105 deaths and as a contributing cause in 40); it then declined to 66 per year during 1999 through 2001. For deaths for which varicella was listed as the underlying cause, age-adjusted mortality rates dropped by 66 percent, from an average of 0.41 death per 1 million population during 1990 through 1994 to 0.14 during 1999 through 2001 (P < 0.001). This decline was observed in all age groups under 50 years, with the greatest reduction (92 percent) among children 1 to 4 years of age. In addition, by the period from 1999 through 2001, the average rates of mortality due to varicella among all racial and ethnic groups were below 0.15 per 1 million population, as compared with rates ranging from 0.37 per 1 million for whites to 0.66 per 1 million for other races in the period from 1990 through 1994.” (J. F. Seward, jseward@cdc.gov)

In a Perspectives article, writers note that the impact of the vaccine on zoster is not yet clear (pp. 439-40). While some experts believe that immunity to zoster is enhanced by the periodic exposure to varicella afforded by cases of chickenpox, others do not believe this is true. “It is clear that in the short time that it has been in use, varicella vaccine has greatly reduced both morbidity and mortality from varicella,” the authors note. “The vaccine may also have a key role to play in preventing zoster. It is important to continue to monitor closely the epidemiology of both varicella and zoster so that the long-term effects of universal vaccination on both these illnesses can be assessed and so that vaccine policy can be modified, if necessary.” (Marietta Vázquez, Yale U., New Haven, Conn.)

Nuclear Medicine Treatment of Follicular Lymphoma: Prolonged clinical and molecular remissions in patients with advanced follicular lymphoma can be achieved with a single 1-week course of 131I-tositumomab therapy as initial treatment, conclude investigators who studied 76 patients with stage III or IV conditions (pp. 441-9). The therapeutic dose of the radioimmunotherapy delivered a total-body radiation dose of 75 cGy; it was administered 1 week after a dosimetric dose of tositumomab. “Ninety-five percent of the patients had any response, and 75 percent had a complete response,” the authors write. “The use of polymerase chain reaction (PCR) to detect rearrangement of the BCL2 gene showed molecular responses in 80 percent of assessable patients who had a clinical complete response. After a median follow-up of 5.1 years, the actuarial 5-year progression-free survival for all patients was 59 percent, with a median progression-free survival of 6.1 years. The annualized rate of relapse progressively decreased over time: 25 percent, 13 percent, and 12 percent during the first, second, and third years, respectively, and 4.4 percent per year after three years. Of 57 patients who had a complete response, 40 remained in remission for 4.3 to 7.7 years. Hematologic toxicity was moderate, with no patient requiring transfusions or hematopoietic growth factors. No cases of myelodysplastic syndrome have been observed.” (M. S. Kaminski, mkaminsk@umich.edu)

An editorialist notes that radioimmunotherapy is the “hot new treatment” for lymphoma (pp. 496-8): “This article ... takes us one step further in determining the best use of targeted but systemic radiation. As clinicians, we should all support the clinical investigations still needed to define the proper role for radioimmunoconjugates in the management of follicular lymphoma, so that one day an editorial such as this can focus on not just better disease control but the best strategy for cure.” (J. M. Conners, U. British Columbia, Vancouver)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 4, 2005 Vol. 12, No. 24
Providing news and information about medications and their proper use

>>>JAPhA Highlights
Source:
Jan/Feb issue of the Journal of the American Pharmacists Assoc. (www.japha.org; 2005; 45).

Aspirin Use Among Diabetics: A community pharmacy–based intervention program used student pharmacists on rotations to increase aspirin use among patients with diabetes (pp. 17-22). At eight New York state advanced practice experience sites located in supermarket or chain pharmacies, student pharmacists assessed all patients who were having prescriptions filled for antidiabetic medications. Those who met inclusion criteria were approached and recruited for the study. Physicians were contacted by fax as needed, and patients for whom aspirin therapy was appropriate were contacted, informed of the physicians’ decisions, and provided appropriate counseling. Overall, 436 patients with diabetes were evaluated, 322 agreed to participate, 228 were already taking aspirin or other anticlotting agents, 79 patients appeared to be appropriate candidates, and 53 patients were started on aspirin therapy. (J. Cerulli, cerullij@acp.edu)

Diabetes Care in Australia: In New South Wales, community pharmacists trained in medication review and using protocols in collaboration with providers improved adherence in patients with type 2 diabetes, reduced problems patients had in accessing their medications, and recommended medication regimen changes that improved outcomes (pp. 33-40). Comparing patients’ risk of nonadherence with the Brief Medication Questionnaire, the investigators reported these results among 82 control and 106 intervention patients over a 9-month period: “The mean (± SD) number of medications prescribed at follow-up in intervention participants decreased significantly, from 8.2 ± 3.0 to 7.7 ± 2.7. No reduction was observed among the control patients (7.6 ± 2.4 and 7.3 ± 2.4). The overall prevalence of changes to the regimen was also significantly higher in the intervention group (51%) compared with controls (40%).” (I. Krass, U. Sydney, Camperdown, Australia; inesk@pharm.usyd.edu.au)

Community Pharmacists & CAM Use: Pharmacists in the community setting need to be more proactive in identifying and documenting patients’ use of complementary and alternative medicines, according to authors who surveyed 107 Texas pharmacists (pp. 41-7). “A majority (71.0%) of pharmacists had encountered patients who were using CAM, which was defined broadly in the survey to include herbal products, vitamins and minerals, homeopathic products, massage, meditation, and other types of CAM,” the researchers write. “Pharmacists documented CAM use by patients in 11.0% of cases and reported monitoring for drug-related problems in 38.4% of users. Among CAM users, pharmacists most often encouraged CAM use if medically appropriate. Pharmacists were not comfortable with responding to CAM inquiries but believed they needed adequate knowledge about CAM. In general, pharmacists rarely asked patients about their CAM use. Pharmacists’ rate of inquiry about CAM use increased significantly when this information could be documented in patient profiles and when pharmacists had additional training in CAM. Also, in pharmacies that stocked herbal or homeopathic products, pharmacists were significantly more likely to encourage the use of CAM when medically appropriate and to recommend other CAM therapies appropriate for patients’ conditions. When no references were available to research CAM, pharmacists tended to neither encourage nor discourage CAM use based on lack of scientific evidence of their effectiveness.” (C. M. Brown, cmbrown@mail.utexas.edu)

Health Disparities & Language Barriers: Despite availability of clinic-based interpreters and foreign language services in 40 Minneapolis-area pharmacies, adherence problems were significantly more common among non–English-speaking patients (pp. 48-54). During comprehensive drug therapy assessments, adherence problems were identified in 31% of 38 non–English speakers, compared with 12% of 63 English-speaking patients. “Pharmacists committed to providing pharmaceutical care must consider the impact of language barriers when working to optimize drug therapy outcomes,” the authors conclude. (S. M. Westberg, swestber@d.umn.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 7 2005 Vol. 12, No. 25
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
Feb. 5 issue of Lancet (www.thelancet.com; 2005; 365).

Neonatal Withdrawal After Maternal SSRI Use:
Convulsions, irritability, abnormal crying, and tremor may constitute a withdrawal syndrome in neonates whose mothers took selective serotonin reuptake inhibitors during pregnancy, according to a case analysis (pp. 482-7). Data mining of a World Health Organization database indicated a potential problem in Dec. 2001, the authors report, and they then assessed cases reported to WHO through Nov. 2003. “A total of 93 suspected cases of SSRI-induced neonatal withdrawal syndrome had been reported, and were regarded as enough information to confirm a possible causal relation,” wrote the investigators “64 of the cases were associated with paroxetine, 14 with fluoxetine, nine with sertraline, and seven with citalopram.” They conclude, “Paroxetine should not be used in pregnancy or, if used, should be given at the lowest effective dose. With the other SSRIs, especially citalopram and venlafaxine, their use should be carefully monitored and new cases promptly communicated to the pharmacovigilance systems.” (E. J. Sanz, U. La Laguna, La Laguna, Tenerife, Spain; esanz@ull.es)

>>>BMJ Highlights
Source:
Early-release articles and Feb. 5 issue of BMJ (www.bmj.org; 2005; 330).

Depression, Anxiety Following Breast Cancer: Increased levels of depression, anxiety, or both are common among women during the first year following diagnosis of early breast cancer, report researchers who interviewed 170 patients for 5 years after diagnosis or recurrence (article released early online). The group writes: “Nearly 50% of the women with early breast cancer had depression, anxiety, or both in the year after diagnosis, 25% in the second, third, and fourth years, and 15% in the fifth year. Point prevalence was 33% at diagnosis, falling to 15% after one year. 45% of those with recurrence experienced depression, anxiety, or both within three months of the diagnosis. Previous psychological treatment predicted depression, anxiety, or both in the period around diagnosis (one month before diagnosis to four months after diagnosis). Longer term depression and anxiety, were associated with previous psychological treatment, lack of an intimate confiding relationship, younger age, and severely stressful non-cancer life experiences. Clinical factors were not associated with depression and anxiety, at any time. Lack of intimate confiding support also predicted more protracted episodes of depression and anxiety.” (C. Burgess, King’s College, St. Thomas’s Hosp., London)

>>>PNN JournalWatch
*Prediction of Cancer Outcome with Microarrays: A Multiple Random Validation Strategy, in Lancet, 2005; 365: 488–92. Reprints: www.thelancet.com; S. Koscielny, Institut Gustave Roussy, Villejuif, France; koscielny@igr.fr

*Alcohol and Public Health, in
Lancet, 2005; 365: 519–30. Reprints: www.thelancet.com; R. Room, Stockholm U., Stockholm; Robin.Room@sorad.su.se

*Systematic Review and Meta-Analysis of Proton Pump Inhibitor Therapy in Peptic Ulcer Bleeding, in
BMJ, 2005; 330: released early online. Reprints: www.bmj.org; G. I. Leontiadis, U. Hosp. of N. Durham, Durham, U.K.

*Discussions Regarding Reproductive Health for Young Women with Breast Cancer Undergoing Chemotherapy, in
Journal of Clinical Oncology, 2005; 23: 766–73. Reprints: www.jco.org; C. M. Duffy.Christine_Duffy@Brown.edu

*Breast Cancer Treatment Guidelines in Older Women, in
Journal of Clinical Oncology, 2005; 23: 783–91. Reprints: www.jco.org; S. H. Giordano, sgiordan@mdanderson.org

*Multidisciplinary Care in Cancer: The Fellowship of the Ring, in
Journal of Clinical Oncology, 2005; 23: 916–20. Reprints: www.jco.org; F. Boyle, Royal North Shore Hosp., Sydney, Australia; franb@med.usyd.edu.au

*Obstructive Sleep Apnea, in
Annals of Internal Medicine, 2005; 142: 187–97. Reprints: www.annals.org; V. K. Somers, somers.virend@mayo.edu

*Systemic Therapy for Colorectal Cancer, in
New England Journal of Medicine, 2005; 352: 476–87. Reprints: content.nejm.org; J. A. Meyerhardt, Dana–Farber Cancer Institute, 4Boston

*Research in Neonatology for the 21st Century: Executive Summary of the National Institute of Child Health and Human Development–American Academy of Pediatrics Workshop. Part I: Academic Issues; Part II: Training Issues;
Pediatrics, 2005; 115: 468–74; 475–9. Reprints: www.pediatrics.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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 8, 2005 Vol. 12, No. 26
Providing news and information about medications and their proper use

>>>Circulation Highlights
Source:
Feb. 1 and 8 issues of Circulation (circ.ahajournals.org; 2005; 111).

Antidiabetic Agents in HF: Despite strong FDA warnings to the contrary, use of thiazolidinediones and metformin do not seem to be associated with increased mortality in older patients with diabetes and heart failure, report authors of an observational study (pp. 583-90). In a retrospective cohort analysis of 16,417 Medicare beneficiaries with diabetes who were discharged after hospitalization for HF, the authors found, “Crude 1-year mortality rates were lower among the 2226 patients treated with a thiazolidinedione (30.1%) or the 1861 treated with metformin (24.7%) compared with that among the 12,069 treated with neither insulin-sensitizing drug (36.0%, P ≤ 0.0001 for both comparisons). In multivariable models, treatment with the thiazolidinediones (hazard ratio [HR] 0.87, 95% CI 0.80 to 0.94) or metformin (HR=0.87, 95% CI 0.78 to 0.97) was associated with significantly lower risks of death. There was no association with treatment with sulfonylureas (HR = 0.99, 95% CI 0.91 to 1.08) or insulin (HR = 0.96, 95% CI 0.88 to 1.05) and mortality. Admissions for all causes did not differ with either insulin sensitizer. There was a higher risk of readmission for heart failure with thiazolidinedione treatment (HR 1.06, 95% CI 1.00 to 1.09) and a lower risk with metformin treatment (HR 0.92, 95% CI 0.92 to 0.99). ” (F. A. Masoudi, Denver Health Med. Ctr., Denver; fred.masoudi@uchsc.edu)

Tamoxifen & VTE: Among women with conventional risk factors for atherosclerosis, the risk of venous thromboembolism is elevated during adjuvant tamoxifen therapy for breast cancer (pp. 650-6). Among 5,408 women without uteri who were taking tamoxifen 20 mg/day for 5 years, the investigators found, “There were 28 VTEs on placebo and 44 on tamoxifen therapy (hazard ratio [HR]=1.63; 95% confidence interval [CI], 1.02 to 2.63), 80% of which were superficial phlebitis, accounting for all of the excess due to tamoxifen within 18 months from randomization. Compared with placebo, the risk of VTE on tamoxifen was higher in women aged 55 years or older, women with a body mass index ≥25 kg/m2, elevated blood pressure, total cholesterol ≥250 mg/dL, current smoking, and a family history of coronary heart disease (CHD). Of the 685 women with a CHD risk score ≥5 who entered the trial, 1 in the placebo arm and 13 in the tamoxifen arm developed VTE (log-rank P = 0.0013). In multivariate regression analysis, age ≥60 years, height ≥165 cm, and diastolic blood pressure ≥90 mm Hg had independent detrimental effects on VTE risk during tamoxifen therapy, whereas transdermal estrogen therapy concomitant with tamoxifen was not associated with any excess of VTE (HR = 0.64; 95% CI, 0.23 to 1.82). ” (A. Decensi, European Inst. of Oncology, Milan, Italy; andrea.decensi@ieo.it)

Phytoestrogen Intake & Cardiovascular Risks: Other than a small risk reduction for higher lignan intake among smokers, higher intake of phytoestrogens in low doses does not protect against cardiovascular disease, according to researchers who studied 16,165 women aged 49–70 years (pp. 465-71). “Intake of phytoestrogens was estimated using the food frequency questionnaire covering regular dietary intake of 178 food items in the year before enrollment,” the authors write. “Cox regression analysis was used to estimate hazard ratios of cardiovascular disease for quartiles of phytoestrogen intake adjusted for age at intake, body mass index, smoking, physical activity, hypertension, hypercholesterolemia, use of hormone replacement therapy, menopausal status, and intake of total energy, total fiber, vegetables, fruit, and alcohol. In total, 372 women experienced a coronary event (CHD) (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9], 410 to 414, 427.5) and 147 women a cerebrovascular event (ICD-9, 430 to 438) during follow-up. Overall, neither isoflavones nor lignans were associated with decreased cardiovascular disease risk. When stratifying for ever versus never smokers, CHD risk decreased with increasing lignan intake for ever smokers.” (Y. T. van der Schouw, U. Med. Ctr., Utrecht, the Netherlands; y.t.vanderschouw@umcutrecht.nl)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 9, 2005 Vol. 12, No. 27
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Feb. 9 issue of JAMA (www.jama.com; 2005; 293).

Oral Thrombin Inhibition with Ximelagatran: Despite FDA’s rejection of an NDA that would permit its marketing in the U.S. (see PNN, Sept. 14), the oral direct thrombin inhibitor ximelagatran (Exanta, AstraZeneca) continues to generate much interest because of its rapid onset of action and a predictable antithrombotic effect that obviates the need for anticoagulation monitoring. But the drug—which is marketed for short-term use in other countries—may produce hepatotoxicity when used long term, as noted in three studies and an editorial in this issue.

In the Thrombin Inhibitor in Venous Thromboembolism (THRIVE) study, fixed-dose ximelagatran was as effective as enoxaparin/warfarin for treatment of deep vein thrombosis with or without pulmonary embolism and showed similar, low rates of bleeding, but liver-enzyme elevations and serious coronary events occurred more frequently with the new drug (pp. 681-9). During the 6-month study, oral ximelagatran 36 mg twice daily was compared with subcutaneous enoxaparin 1 mg/kg twice daily for 5–20 days followed by warfarin dosed to an international normalized ratio of 2.0 to 3.0. “Venous thromboembolism recurred in 26 of the 1240 patients assigned to receive ximelagatran (estimated cumulative risk, 2.1%) and in 24 of the 1249 patients assigned to receive enoxaparin/warfarin (2.0%),” THRIVE investigators explain. “... Corresponding values for major bleeding were 1.3% and 2.2% (difference, –1.0%; 95% CI, –2.1% to 0.1%), and for mortality were 2.3% and 3.4% (difference, –1.1%; 95% CI, –2.4% to 0.2%). Alanine aminotransferase levels increased to more than 3 times the upper limit of normal in 119 patients (9.6%) and 25 patients (2.0%) receiving ximelagatran and enoxaparin/warfarin, respectively. Increased enzyme levels were mainly asymptomatic. Retrospective analysis of locally reported adverse events showed a higher rate of serious coronary events with ximelagatran (10/1240 patients) compared with enoxaparin/warfarin (1/1249 patients).” (M. V. Huisman, Leiden U. Med. Ctr., Leiden, the Netherlands; m.v.huisman@lumc.nl)

Efficacy was good but hepatotoxicity also evident in the Stroke Prevention using an Oral Thrombin Inhibitor in Atrial Fibrillation (SPORTIF) study (pp. 690-8). After finding equivalent efficacy with warfarin (INR, 2.0–3.0) and fixed-dose ximelagatran, the researchers report, “There was no difference between treatment groups in rates of major bleeding, but total bleeding (major and minor) was lower with ximelagatran (37% vs 47% per year; 95% confidence interval for the difference, –14% to –6.0% per year; P<.001). Serum alanine aminotransferase levels rose to greater than 3 times the upper limit of normal in 6.0% of patients treated with ximelagatran, usually within 6 months and typically declined whether or not treatment continued; however, one case of documented fatal liver disease and one other suggestive case occurred.” (J. L. Halperin, Mount Sinai Med. Ctr., New York; Jonathan.Halperin@msnyuhealth.org)

The third report concludes that “ximelagatran is not likely to be cost-effective in patients with atrial fibrillation unless they have a high risk of intracranial hemorrhage or a low quality of life with warfarin” (pp. 699-706). Comparing ximelagatran, warfarin, and aspirin using a semi-Markov decision model, the authors find that both ximelagatran and warfarin cost more than $50,000 per quality-adjusted life-year, compared with aspirin. (B. F. Gage, Washington U., St. Louis; bgage@im.wustl.edu)

An editorialist notes that only postmarketing surveillance is likely to assess adequately ximelagatran’s long-term adverse effects, as experience with short-term use in Europe and more clinical trials are unlikely to create definitive guidance (pp. 736-9). He then writes: “[FDA], perhaps feeling the effects of recently having to withdraw drugs from the market, has denied approval of ximelagatran because of concerns about hepatotoxicity. However, this precaution concerning the risk of hepatotoxicity from ximelagatran must be balanced against the serious risk of discouraging, if not foreclosing indefinitely, any improvement in oral anticoagulant therapy, which remains an important and growing therapeutic need.” (V. Gurewich, vgurewic@bidmc.harvard.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 10, 2005 Vol. 12, No. 28
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Feb. 10 issue of the New England Journal of Medicine (content.nejm.org; 2005; 352).

Lenalidomide in Myelodysplastic Syndromes: An analogue of thalidomide has shown promise for stimulating blood formation in patients with low-risk myelodysplastic syndromes who do not respond to erythropoietin or who are unlikely to benefit from conventional therapy (pp. 439-57). Among 43 patients with transfusion-dependent or symptomatic anemia who received lenalidomide for 16 weeks, researchers report, “Neutropenia and thrombocytopenia, the most common adverse events, with respective frequencies of 65 percent and 74 percent, necessitated the interruption of treatment or a dose reduction in 25 patients (58 percent). Other adverse events were mild and infrequent. Twenty-four patients had a response (56 percent): 20 had sustained independence from transfusion, 1 had an increase in the hemoglobin level of more than 2 g per deciliter, and 3 had more than a 50 percent reduction in the need for transfusions. The response rate was highest among patients with a clonal interstitial deletion involving chromosome 5q31.1 (83 percent, as compared with 57 percent among those with a normal karyotype and 12 percent among those with other karyotypic abnormalities; P = 0.007) and patients with lower prognostic risk. Of 20 patients with karyotypic abnormalities, 11 had at least a 50 percent reduction in abnormal cells in metaphase, including 10 (50 percent) with a complete cytogenetic remission. After a median follow-up of 81 weeks, the median duration of transfusion independence had not been reached and the median hemoglobin level was 13.2 g per deciliter (range, 11.5 to 15.8).” (A. List, H. Lee Moffitt Cancer Ctr. and Research Inst., Tampa; listaf@moffitt.usf.edu)

Noting that only 21 of the 55 patients treated in this study had a major erythroid response to lenalidomide, authors of a Perspectives article write, “In the past 20 years, several therapeutic meteors have passed through the dark sky of treatment for myelodysplastic syndromes, only to disappear. We look forward to prospective studies that can unequivocally confirm the hematologic activity of lenalidomide in these syndromes, and given the current uncertainties, we recommend the use of this drug only within clinical trials.” (M. Cazzola, U. Pavia Medical School, Pavia, Italy)

Angiotensin II Blockade for Transplant Rejection: In patients with refractory vascular rejection, treatment with angiotensin II type 1 receptor blockers is one option that might be of benefit, according to a study of 33 kidney-transplant recipients (pp. 558-69). “Activating IgG antibodies targeting the AT1 receptor were detected in serum from all 16 patients with malignant hypertension and without anti-HLA antibodies, but in no other patients,” the authors write. “These receptor-activating antibodies are subclass IgG1 and IgG3 antibodies that bind to two different epitopes on the second extracellular loop of the AT1 receptor. Tissue factor expression was increased in renal-biopsy specimens from patients with these antibodies. In vitro stimulation of vascular cells with an AT1-receptor–activating antibody induced phosphorylation of ERK 1/2 kinase and increased the DNA binding activity of the transcription factors activator protein 1 (AP-1) and nuclear factor-B. The AT1 antagonist losartan blocked agonistic AT1-receptor antibody–mediated effects, and passive antibody transfer induced vasculopathy and hypertension in a rat kidney-transplantation model.” (D. Dragun, Charité U. Hosp., Berlin, Germany; duska.dragun@charite.de)

>>>PNN NewsWatch
* Adderall XR (extended-release amphetamine salts, Shire) was removed from the Canadian market yesterday. Health Canada cited 20 cases of sudden unexplained deaths, heart problems, and stroke associated with the use of that product or the immediate-release formulation, Adderall, which is marketed in the U.S. but not Canada. FDA, while posting to its Web site the details on 12 pediatric cases of sudden unexplained death in boys taking Adderall or Adderall XR, said evidence is insufficient to merit market withdrawal (http://www.fda.gov/cder/drug/InfoSheets/HCP/adderalHCP.htm). All but a few cases have involved children with underlying cardiac abnormalities, FDA added.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 11, 2005 Vol. 12, No. 29
Providing news and information about medications and their proper use

>>>Pharmacotherapy Update
Source:
Feb. issue of Pharmacotherapy (www.pharmacotherapy.org; 2005; 25).

Chromogenic Factor X Assay: Among hospitalized patients, a chromogenic factor X level of 45% or less reliably predicts that international normalized ratios will be normal when argatroban is transitioned to warfarin, according to a study of 62 patients (pp. 157-64). “To determine the ability of the chromogenic factor X level to predict the INR free of argatroban influence, we calculated the sensitivity and specificity by using a cutoff chromogenic factor X level of 45% or less, or greater than 45%, which corresponded to an INR of 2 or greater, or less than 2, respectively...” the authors write. “An average of 6 ± 3 doses of warfarin were administered before the confirmatory coagulation studies were obtained. The average time from the chromogenic factor X measurement to obtainment of confirmatory coagulation studies was 9 ± 4 hours. Use of a chromogenic factor X level of 45% or less to predict an INR of 2 or greater absent of argatroban influence had a sensitivity of 93%, a specificity of 78%, and an accuracy of 89%. The area under the receiver operating characteristic curve was 0.91 (95% confidence interval 0.81–0.99, p < 0.0001).” (P. A. Arpino, Mass. Genl. Hosp., Boston; parpino@partners.org.)

Vitamin C–Indinavir Interaction: High doses of vitamin C reduced steady-state plasma indinavir concentrations, conclude investigators who assessed the agents in seven healthy volunteers (pp. 165-70). “Mean steady-state indinavir Cmax was significantly reduced (20%) after 7 days of vitamin C administration (10.3 ± 1.5 vs 8.2 ± 2.9 µg/ml, p = 0.04),” the researchers report based on dosing of vitamin C 1000 mg/day for 7 days and indinavir 800 mg every 8 hours on selected days. “The corresponding mean AUC0–8 was also significantly decreased (14%; 26.4 ± 7.2 vs 22.7 ± 8.1 µghr/ml, p = 0.05). Although not statistically significant, the mean indinavir Cmin was 32% lower in the presence of vitamin C (0.27 ± 0.17 C vs 0.18 ± 0.08 µg/ml, p = 0.09). Indinavir oral clearance and half-life were not significantly different.” (D. Slain, dslain@hsc.wvu.edu)

Natural Treatments for Hyperlipidemia: Ingestion of policosanol reduces LDL levels in patients with hyperlipidemia and approaches the efficacy of medications, according to a systematic review and meta-analysis (pp. 171-83). The authors note: “Weighted estimates of percent change in LDL were –11.0% for plant sterol and stanol esters 3.4 g/day (range 2–9 g/day [893 patients]) versus -2.3% for placebo (769 patients) in 23 eligible studies, compared with -23.7% for policosanol 12 mg/day (range 5–40 mg/day [1528 patients]) versus -0.11% for placebo (1406 patients) in 29 eligible studies. Cumulative p values were significantly different from placebo for both (p < 0.0001). The net LDL reduction in the treatment groups minus that in the placebo groups was greater with policosanol than plant sterols and stanols (-24% versus -10%, p < 0.0001). Policosanol also affected total cholesterol, high-density lipoprotein cholesterol (HDL), and triglyceride levels more favorably than plant sterols and stanols. Policosanol caused a clinically significant decrease in the LDL:HDL ratio. Pooled withdrawal rate due to adverse effects and combined relative risk for patients who withdrew were 0% and 0.84, respectively (95% confidence interval [CI] 0.36–1.95, p = 0.69), for plant sterols and stanols across 20 studies versus 0.86% and 0.31, respectively (95% CI 0.20–0.48, p < 0.0001), for policosanol across 28 studies.” (J. T. Chen, jtchen@pharmacy.purdue.edu)

Reviews: Several interesting review articles are published in this issue of Pharmacotherapy, including the following:

* Tick-borne bacterial, rickettsial, spirochetal, and protozoal infectious diseases (pp. 191-210; J. R. Amsden, U. Arkansas, Little Rock; jramsden@uams.edu)

* Antibiotic lock technique (pp. 211-27; H. L. VandenBussche, Bronson Methodist Hosp.; Kalamazoo, Mich.; vandenbh@bronsonhg.org

* Statins and Osteoporosis (pp. 228-43; M. J. Gonyeau, Northeastern U., Boston; m.gonyeau@neu.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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 14, 2005 Vol. 12, No. 30
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Online articles and Feb. 12 issue of BMJ (www.bmj.org; 2005; 330).

Pharmacogenetics & ADRs: Measurement of the enzyme responsible for metabolizing azathioprine could prevent toxicities such as myelosuppression, according to authors of a case report (pp. 350-1). Thiopurine methyltransferase (TPMT) inactivates azathioprine, and the authors note that information on measurement of erythrocyte TPMT has been available since 1978. In a patient whose pompholyx (dyshidrosis, or vesicopustular eruptions on the hands and feet) was treated with this drug, moderate pancytopenia developed after 10 weeks of therapy. The authors observe: “Monitoring the full blood count during the early stages of treatment with azathioprine is not a satisfactory method for detecting toxicity. The reserve of cells in the bone marrow will sustain cell counts for some time before marrow toxicity is reflected in the peripheral blood. In our case the peripheral blood count was still normal five weeks after starting treatment.

“Prior measurement of erythrocyte TPMT activity will not only identify individuals at risk of myelosuppression, it will also identify patients with high enzyme activity. This is important because such patients may show a suboptimal response to conventional doses of azathioprine.” (M. Konstantopoulou, Ysbyty Gwynedd, Bangor, Gwynedd, U.K.; maria.konstantopoulou@nww-tr.wales.nhs.uk)

Hypericum Extract for Depression: Hypericum extract WS 5570 is at least as effective as and better tolerated than paroxetine in treating moderate to severe depression, according to a study of 251 adult outpatients (online article). Comparing hypericum extract WS 5570 900–1800 mg/day three times a day and paroxetine 20–40 mg once a day for 6 weeks, the investigators report, “The Hamilton depression total score decreased by mean 14.4 (SD 8.8) points, corresponding to 56.6% (SD 34.3%) of the baseline value, in the hypericum group and by 11.4 (SD 8.6) points (44.8% (SD 33.5%) of baseline value) in the paroxetine group (intention to treat analysis; similar results were observed in the per protocol analysis). The intention to treat analysis (lower one sided 97.5% confidence limit 1.5 points for the difference hypericum minus paroxetine) and the per protocol analysis (lower confidence limit 0.7 points) showed non-inferiority of hypericum and statistical superiority over paroxetine. The lower limits in both cases exceeded the pre-specified non-inferiority margin of –2.5 points and the superiority margin of 0. The incidence of adverse events was 0.035 and 0.060 events per day of exposure for hypericum and paroxetine, respectively.” (A. Szegedi, Charité-Universitätsmedizin Berlin, Berlin)

>>>Lancet Report
Source:
Feb. 12 issue of Lancet (www.thelancet.com; 2005; 365).

Peptidoglycan Contamination of Dialysis Solution: Despite testing safe under both European and USP standards, peritoneal dialysis solutions can produce aseptic peritonitis because of the presence of peptidoglycans in the admixtures, conclude researchers who analyzed 186 clinical reports (pp. 588-94). Following extensive testing of recalled dialysate, the group reports, “We identified peptidoglycan from thermophilic acidophilic bacteria (Alicyclobacillus acidocaldarius) as the contaminating proinflammatory substance. In the [peripheral blood mononuclear cells] assay, strong dose-response relations were noted between peptidoglycan concentrations and interleukin 6.... We measured a positive relation between peptidoglycan concentrations in recalled dialysate and reports of aseptic peritonitis. After implementation of corrective actions, the rate of peritonitis returned to baseline.” (W. F. Owen Jr., william_owen@baxter.com)

>>>PNN JournalWatch
* Once Versus Three-Times Daily Regimens of Tobramycin Treatment for Pulmonary Exacerbations of Cystic Fibrosis—The Topic Study: A Randomised Controlled Trial, in Lancet, 2005; 365: 573–8. Reprints: www.thelancet.com; A. Smyth, Nottingham City Hosp., Nottingham, U.K.; alan.smyth@nottingham.ac.uk

* Association Between Hormone Replacement Therapy and Subsequent Stroke: A Meta-analysis, in
BMJ, 2005; 330: 342 ff. Reprints: www.bmj.org; P. M. W. Bath, U. Nottingham, Nottingham, U.K.; philip.bath@nottingham.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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 15, 2005 Vol. 12, No. 31
Providing news and information about medications and their proper use

>>>Internal Medicine Update I
Source:
Feb. 15 issue of the Annals of Internal Medicine (www.annals.org; 2005; 142).

Smoking Cessation & Mortality: Intervention programs aimed at stopping patients from smoking can have a substantial effect on subsequent mortality, even when successful in small proportions of patients, concludes a study of 5,887 middle-aged volunteers with asymptomatic airway obstruction (pp. 233-9). The Lung Health Study assessed special interventions at 10 clinical centers, comparing results in usual-care patients for 14.5 years of monitoring. “At 5 years, 21.7% of special intervention participants had stopped smoking since study entry compared with 5.4% of usual care participants,” the authors report. “After up to 14.5 years of follow-up, 731 patients died: 33% of lung cancer, 22% of cardiovascular disease, 7.8% of respiratory disease other than cancer, and 2.3% of unknown causes. All-cause mortality was significantly lower in the special intervention group than in the usual care group (8.83 per 1000 person-years vs. 10.38 per 1000 person-years; P = 0.03). The hazard ratio for mortality in the usual care group compared with the special intervention group was 1.18 (95% CI, 1.02 to 1.37). Differences in death rates for both lung cancer and cardiovascular disease were greater when death rates were analyzed by smoking habit.” (J. E. Connett, john-c@ccbr.umn.edu)

Mortality & Influenza Vaccination: Differing with CDC estimates of the impact on mortality of influenza vaccine, NIH researchers “conclude that observational studies substantially overestimate vaccination benefit” (pp. 265-72). Noting that observational studies report that vaccination reduces winter mortality risk by 50% among the elderly, the authors share these results from their cyclical regression model: “For people aged 65 to 74 years, excess mortality rates in A(H3N2)-dominated seasons fell between 1968 and the early 1980s but remained approximately constant thereafter. For persons 85 years or older, the mortality rate remained flat throughout. Excess mortality in A(H1N1) and B seasons did not change. All-cause excess mortality for persons 65 years or older never exceeded 10% of all winter deaths.”

The group concludes, “We attribute the decline in influenza-related mortality among people aged 65 to 74 years in the decade after the 1968 pandemic to the acquisition of immunity to the emerging A(H3N2) virus. We could not correlate increasing vaccination coverage after 1980 with declining mortality rates in any age group. Because fewer than 10% of all winter deaths were attributable to influenza in any season, we conclude that observational studies substantially overestimate vaccination benefit.” (L. Simonsen, Lsimonsen@niaid.nih.gov)

>>>Internal Medicine Update II
Source:
Feb. 14 issue of Archives of Internal Medicine (www.archinternmed.com; 2005; 165).

Ginkgo, Acetazolamide for Altitude Sickness: Prophylactic acetazolamide but not Ginkgo biloba protected 57 subjects against acute mountain sickness in a placebo-controlled trial (pp. 296-301). Adults were taken to an elevation of 3,800 meters for 24 hours and symptoms monitored during treatment with acetazolamide 250 mg twice daily, Ginkgo biloba 120 mg vegetarian twice daily (containing a minimum of 24% ginkgoflavonglycosides and 6% terpene lactones), or placebo. The authors report, “The [Lake Louise Acute Mountain Sickness Scoring System] scores were significantly different between groups; the median score of the acetazolamide group was significantly lower than that of the placebo group (P = .01; effect size, 2; and 95% confidence interval [CI], 0 to 3), unlike that of the Ginkgo biloba group (P = .89; effect size, 0; and 95% CI, –2 to 2). Acute mountain sickness occurred less frequently in the acetazolamide group than in the placebo group (effect size, 30%; 95% CI, 61% to –15%), and the frequency of occurrence was similar between the Ginkgo biloba group and the placebo group (effect size, –5%; 95% CI, –37% to 28%).”(T. Chow, Loma Linda U. Med. Ctr., Loma Linda, Calif.; Drtkchow@aol.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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 16, 2005 Vol. 12, No. 32
Providing news and information about medications and their proper use

>>>White House Focuses on FDA, Drug Safety
Plans to name the acting Commissioner of Food and Drugs as the permanent FDA head and establish a Drug Safety Oversight Board have met with criticisms that more fundamental changes are needed in the way the federal agency regulates pharmaceuticals.

The Bush Administration on Monday announced its intention to nominate Lester V. Crawford, DVM, PhD, to become the permanent Commissioner of Food and Drugs. He has served as the acting commissioner for nearly a year, ever since Mark McClellan moved from FDA to CMS. During this time, some politically charged decisions were made—most notably the denial of OTC sales of the postcoital contraceptive Plan B and the subsequent failure to meet a deadline for a second decision about the product—that seem certain to generate questions when Senate hearings are held on Crawford’s nomination.

But drug safety will be the broader area of concern when Crawford makes the trip to Capitol Hill. Pediatric suicidality with antidepressants, the Vioxx market withdrawal and subsequent brouhaha over both nonspecific and COX-2–specific NSAIDs, and the flu-vaccine debacle are areas of concern for both Republicans and Democrats in Congress. To blunt criticisms in this area, Crawford and HHS Secretary Mike Leavitt yesterday unveiled a “a new emboldened vision for FDA,” one in which they “will promote a culture of openness and enhanced oversight within the Agency,” according to a fact sheet posted to the FDA Web site. The centerpiece of this vision is a new independent Drug Safety Oversight Board that will oversee the management of important drug safety issues with the FDA’s Center for Drug Evaluation and Research.

Critics countered quickly that the oversight board—lacking the authority to remove drugs from the market or even to change product labeling—was not an effective solution to the problems uncovered by the events of the past year. The board would comprise 15 members, with most drawn from FDA’s Office of New Drugs and Office of Drug Safety and at least four from outside FDA. In this morning’s Wall Street Journal, U. Pennsylvania professor Brian Strom notes, “If the goal of this is to have autonomy, is it really autonomous? It doesn’t meet the need for an external body. It’s not external.”

>>>JAMA Highlights
Source:
Feb. 16 issue of JAMA, a theme issue on technology (www.jama.com; 2005; 293).

Intermittent HIV Viremia During HAART: “Blips” of HIV-1 viremia in patients on highly active antiretroviral therapy represent biological variation around the 50 copies/mL indicator level rather than clinically important elevations, conclude authors who followed closely 10 asymptomatic, HIV-infected adults for 3 to 4 months (pp. 817-29). Based on intensive blood samples drawn every 2–3 days, the authors report these frequencies of detection of HIV levels of more than 50 copies/mL: “With the intensive sampling, blips were detected in 9 of 10 patients. Statistical analysis was consistent with random assay variation around a mean viral load below 50 copies/mL. Blips were not concordant on independent testing and had a short duration (median, <3 days) and low magnitude (median, 79 copies/mL). Blip frequency was not associated with demographic, clinical, or treatment variables. Blips did not occur in relation to illness, vaccination, or directly measured antiretroviral drug concentrations. Blips were marginally associated (P = .08) with reported episodes of nonadherence. Most importantly, in approximately 1000 independent clones sequenced for both protease and reverse transcriptase, no new resistance mutations were seen before, during, or shortly after blips.”

The group adds, “These conclusions are based on an intensive study of a small group of patients and may not be representative of all patients. The patients studied had started therapy with low CD4 cell counts and high viral load levels, and it will be important to confirm these results in patients who start therapy earlier in the course of infection.” (R. F. Siliciano, Johns Hopkins U., Baltimore; rsiliciano@jhmi.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 17, 2005 Vol. 12, No. 33
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Early-release articles from the New England Journal of Medicine (content.nejm.org; 2005; 352).

Safety of COX-2 Inhibitors: As 3 days of FDA hearings into the safety of COX-2 inhibitors began yesterday, the NEJM released early three research articles and two editorials on the subject.

Further evidence of a COX-2 class effect detrimental to the cardiovascular system comes from a study of 2,035 patients with histories of colorectal neoplasia. Celecoxib 200 mg or 400 mg twice daily was compared with placebo for prevention of colorectal cancer, and 2.8–3.1 years of follow-up data were available for all patients except those who died. The investigators report: “A composite cardiovascular end point of death from cardiovascular causes, myocardial infarction, stroke, or heart failure was reached in 7 of 679 patients in the placebo group (1.0 percent), as compared with 16 of 685 patients receiving 200 mg of celecoxib twice daily (2.3 percent; hazard ratio, 2.3; 95 percent confidence interval, 0.9 to 5.5) and with 23 of 671 patients receiving 400 mg of celecoxib twice daily (3.4 percent; hazard ratio, 3.4; 95 percent confidence interval, 1.4 to 7.8). Similar trends were observed for other composite end points. On the basis of these observations, the data and safety monitoring board recommended early discontinuation of the study drug.” (S. D. Solomon, 10.1056/NEJMoa050405)

Increased rates of cardiovascular events were observed with short-term use of parecoxib and valdecoxib after coronary artery bypass grafts, “arousing serious concern about the use of these drugs in such circumstances,” authors conclude. A total of 1,671 patients received either placebo for 10 days, intravenous parecoxib for at least 3 days followed by oral valdecoxib through day 10, or intravenous placebo followed by oral valdecoxib. “As compared with the group given placebo alone, both the group given parecoxib and valdecoxib and the group given placebo and valdecoxib had a higher proportion of patients with at least one confirmed adverse event (7.4 percent in each of these two groups vs. 4.0 percent in the placebo group; risk ratio for each comparison, 1.9; 95 percent confidence interval, 1.1 to 3.2; P = 0.02 for each comparison with the placebo group),” the researchers report. “In particular, cardiovascular events (including myocardial infarction, cardiac arrest, stroke, and pulmonary embolism) were more frequent among the patients given parecoxib and valdecoxib than among those given placebo (2.0 percent vs. 0.5 percent; risk ratio, 3.7; 95 percent confidence interval, 1.0 to 13.5; P = 0.03).” (N. A. Nussmeier, 10.1056/NEJMoa050330)

In a study of prevention of recurrent neoplastic polyps among 2,586 patients with histories of colorectal adenomas, use of rofecoxib 25 mg daily significantly increased cardiovascular risks but not mortality, compared with placebo. “A total of 46 patients in the rofecoxib group had a confirmed thrombotic event during 3059 patient-years of follow-up (1.50 events per 100 patient-years), as compared with 26 patients in the placebo group during 3327 patient-years of follow-up (0.78 event per 100 patient-years); the corresponding relative risk was 1.92 (95 percent confidence interval, 1.19 to 3.11; P = 0.008),” write the investigators. “The increased relative risk became apparent after 18 months of treatment; during the first 18 months, the event rates were similar in the two groups. The results primarily reflect a greater number of myocardial infarctions and ischemic cerebrovascular events in the rofecoxib group.... Overall and cardiovascular mortality was similar in the two groups.” (R. S. Bresalier, 10.1056/NEJMoa050493)

In the editorials,
NEJM editor Jeffrey M. Drazen, MD, questions whether continued use of COX-2 inhibitors can be justified and reviews the failures of manufacturers and researchers to pursue safety issues with the same zeal they pursue new indications (0.1056/NEJMe058038). Bruce M. Psaty, MD, PhD, and Curt D. Furberg, MD, PhD, write in the second editorial that “the absence of evidence” is “not evidence of safety,” and that if COX-2 inhibitors must be used, the smallest dose should be employed for the shortest possible time (10.1056/NEJMe058042).

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 18, 2005 Vol. 12, No. 34
Providing news and information about medications and their proper use

>>>Chest Highlights
Source:
Feb. issue of Chest (www.chestjournal.org; 2005; 127)

Montelukast in Asthmatic Children: In preschool children with allergic asthma, montelukast exerts beneficial effects on lung function and airway inflammation (pp. 509-14). Levels of exhaled nitric oxide and lung function were measured in 19 girls and 11 boys aged 2–5 years at visits 1 (before a run-in period), 2 (after the 1-week run-in period), and 3 (after 4 weeks of treatment with once-daily montelukast 4 mg). The authors report: “The mean (SD) levels of eNO and the mean (SD) levels of airway resistance after treatment at visit 3 were 11.6 parts per billion (ppb) [9.5 ppb] and 1.15 kPa/L/s (0.26 kPa/L/s), respectively, and were significantly lower compared to values of 33.1 ppb (12.0 ppb) and 1.28 kPa/L/s (0.23 kPa/L/s), respectively, before treatment (p < 0.001) and at visit 2 (p = 0.01). There was no significant change in mean bronchodilator responsiveness between visit 3 (13.2%; SD, 6.8%) and visit 1/visit 2 (13.3%; SD, 7.0%; p = 0.47).” (D. A. Straub, U. Children’s Hosp., Zürich, Switzerland; daniel.straub@kispi.unizh.ch)

Zileuton & Mountain Sickness: Elevated leukotrienes do not appear to be a part of the pathophysiology of acute mountain sickness, according to a study that sought unsuccessfully to test the prophylactic utility of zileuton 600 mg four times daily in 18 participants (pp. 565-70). Baseline urine samples were obtained at sea level, after which the climbers flew to 2,300 meters in the Denali area of Alaska and then trekked to a camp at 4,200 meters over 5–10 days. “Using an enzyme immunoassay, urinary leukotriene E4 was found to decrease after ascent to high altitude in both the zileuton and placebo groups,” the researchers write. “Urinary leukotriene E4 in the zileuton group (n = 9) decreased from 67 ± 35 pg/mg creatinine at sea level to 33 ± 22 pg/mg creatinine at high altitude (p = 0.003) [mean ± SD]. Urinary leukotriene E4 in the placebo group (n = 9) decreased from 97 ± 82 pg/mg creatinine at sea level to 44 ± 21 pg/mg creatinine at high altitude (p = 0.045). One subject in the zileuton group and three subjects in the placebo group met Lake Louise criteria for AMS after arriving at 4,200 m (p = 0.257).” The low incidence of AMS and the small number of study participants prevented making a conclusion about zileuton’s effectiveness for prophylaxis. (C. K. Grissom, LDS Hosp., Salt Lake City; ldcgriss@ihc.com)

Acetaminophen & Asthma: Depletion of pulmonary glutathione and oxidative stress may be involved in a higher prevalence of asthma among frequent users of acetaminophen, according to authors of a review article (pp. 604-12). “Various studies have reported an association between acetaminophen, a widely used analgesic, and diagnosed asthma,” the writers note. “In a prospective cohort study, the rate of newly diagnosed asthma was 63% higher among frequent acetaminophen users than nonusers in multivariate analyses. Studies of patients with asthma suggest that acetaminophen challenge can precipitate a decline in FEV1 > 15% among sensitive individuals. Plausible mechanisms to explain this association include depletion of pulmonary glutathione and oxidative stress.” (I. Eneli, Michigan State U., East Lansing; eneli@msu.edu)

>>>PNN NewsWatch
* On the second day of FDA hearings into the safety of COX-2 inhibitors, Merck upped the ante by stating that it might return rofecoxib (Vioxx) to the U.S. market if FDA concludes that cardiovascular problems represent a manageable risk of this drug class. Company officials maintained that their voluntary market withdrawal was based partially on a concern that increased rates of cardiovascular morbidity and mortality were unique to rofecoxib, but now that numerous studies are showing similar effects with all COX-2–specific NSAIDs, there is no reason for Vioxx not to be available if other agents remain on the market. The 3-day hearings are scheduled to conclude today with a vote by the members of the advisory committees as to whether FDA should remove some or all of the agents from the market, increase the strength of warnings, or take no or other actions.

*
PNN will not be published on Mon., Feb. 21, 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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 22, 2005 Vol. 12, No. 35
Providing news and information about medications and their proper use

>>>Vioxx Redux: FDA Panels Opt for Precautions
Two FDA panels voted on Friday that both nonselective and COX-2–selective NSAIDs should have strengthened warnings and precautions detailing increased cardiovascular risks of the drugs. While FDA could decide differently as it reaches final decisions over the next few weeks, the votes likely mean that the COX-2 inhibitors will remain on the U.S. market and that Merck will seek to resume sales of rofecoxib (Vioxx), an amazing turnaround given that the Sept. 30, 2004, worldwide market withdrawal prompted the largest drug recall in history.

The panels overwhelming supported continued availability of celecoxib, with only 1 of 32 advisors voting negatively. The votes on valdecoxib (Bextra) and rofecoxib were much closer (17–13 and 17–15, respectively), and this deep division among advisors could influence FDA’s ultimate decisions on the latter agents.

In addition, panel members told FDA it should consider black-box warnings in the product labeling for all three agents, as members said the link to thrombotic problems is clear. Noting the emerging evidence that nonselective NSAIDs may also adversely affect cardiovascular function, the panels voted that warnings should be extended to all cyclooxygenase inhibitors. The advisors also called for a moratorium or restrictions on direct-to-consumer advertising of COX-2 inhibitors.

Assuming FDA follows the general direction of these recommendations, physicians would be likely to use COX-2 inhibitors at the lowest possible dose and for the shortest possible time period and primarily in patients at high risk of gastrointestinal problems and low risk of cardiovascular problems. These guidelines would preclude use for most older patients whose primary indication is arthritis and other types of chronic pain, and thus much of the income derived from COX-2 use would be eliminated. The primary benefit of continued COX-2 availability to the pharmaceutical industry would be averted legal liability for adverse events rather than actual income, while patients who respond only to specific agents would benefit.

>>>BMJ Highlights
Source:
Feb. 19 issue of BMJ (www.bmj.org; 2005; 330).

SSRIs & Suicidal Ideation: The relationship between use of selective serotonin reuptake inhibitors and suicidal thoughts and actions remains uncertain, but three articles and an editorial provide new data and insights.

In an editorial assessing the findings of the research articles, writers provide these insights for clinical practice (pp.373-4): “Firstly, current evidence that indicates no clear relation between SSRIs and suicide, together with available robust evidence of efficacy of treatment with antidepressant drugs in the pharmacological management of moderate to severe unipolar depression, should encourage doctors to prescribe effective doses of these drugs in such patients. Doctors should additionally be aware that SSRIs, similarly to tricyclics, may induce or worsen suicidal ideation and suicide attempts during the early phases of treatment, possibly because they cause agitation and activation particularly at that time. During these early phases, doctors should plan frequent follow up visits and also consider a possible supporting role for family members and caregivers. Patients should be advised against withdrawing treatment abruptly, given the risk of reactions to discontinuation. Secondly, the strongest evidence applies to moderate to severe depression only and therefore cannot be extrapolated to mild depression. Thirdly, these indications apply to adults only, whereas in children and adolescents the balance between benefits and harms seems to be negative, with little evidence of efficacy and increasing evidence of an association between exposure to SSRIs and other antidepressant drugs and emergence of suicidal thought and behaviours.” (A. Cipriani, U. Verona, Verona, Italy; andrea.cipriani@medicina.univr.it)

>>>PNN JournalWatch
* Effect of a p210 Multipeptide Vaccine Associated with Imatinib or Interferon in Patients with Chronic Myeloid Leukaemia and Persistent Residual Disease: A Multicentre Observational Trial, in Lancet, 2005; 365: 657–62. Reprints: www.thelancet.com; M. Bocchia, U. Siena, Siena, Italy; Bocchia@unisi.it

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 23, 2005 Vol. 12, No. 36
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Feb. 23 issue of JAMA (www.jama.com; 2005; 293).

HRT & Incontinence: Rather than helping symptoms of urinary incontinence, conjugated equine estrogens with or without medroxyprogesterone acetate increase the risk of UI among continent women and worsen characteristics of the condition among symptomatic women treated for 1 year (pp. 935-48). Data from the Women’s Health Initiative show these correlations: ”Menopausal hormone therapy increased the incidence of all types of UI at 1 year among women who were continent at baseline. The risk was highest for stress UI (CEE + MPA: relative risk [RR], 1.87 [95% confidence interval {CI}, 1.61–2.18]; CEE alone: RR, 2.15 [95% CI, 1.77–2.62]), followed by mixed UI (CEE + MPA: RR, 1.49 [95% CI, 1.10–2.01]; CEE alone: RR, 1.79 [95% CI, 1.26–2.53]). The combination of CEE + MPA had no significant effect on developing urge UI (RR, 1.15; 95% CI, 0.99–1.34), but CEE alone increased the risk (RR, 1.32; 95% CI, 1.10–1.58). Among women experiencing UI at baseline, frequency worsened in both trials (CEE + MPA: RR, 1.38 [95% CI, 1.28–1.49]; CEE alone: RR, 1.47 [95% CI, 1.35–1.61]). Amount of UI worsened at 1 year in both trials (CEE + MPA: RR, 1.20 [95% CI, 1.06–1.36]; CEE alone: RR, 1.59 [95% CI, 1.39–1.82]). Women receiving menopausal hormone therapy were more likely to report that UI limited their daily activities (CEE + MPA: RR, 1.18 [95% CI, 1.06–1.32]; CEE alone: RR, 1.29 [95% CI, 1.15–1.45]) and bothered or disturbed them (CEE + MPA: RR, 1.22 [95% CI, 1.13–1.32]; CEE alone: RR, 1.50 [95% CI, 1.37–1.65]) at 1 year.” (S. L. Hendrix, shendrix@med.wayne.edu)

An editorialist offers this advice about estrogens and UI (pp. 998-1001): “First, clinicians should no longer prescribe long-term oral conjugated equine estrogens for treatment of urge, stress, or mixed UI in postmenopausal women aged 50 years or older.... Second, this trial is not the final word on using estrogens to treat UI. Whether topical estrogens might prove beneficial remains unknown, especially on a short-term basis and/or in combination with other therapies. Finally, both the scientific rigor of the WHI trial and the issues it raises should prompt continuing investigation of the basic science of estrogen in normal and aging detrusor function and pelvic floor composition, and lead to further treatment trials (particularly with topical estrogens) that address head on the methodological issues of unblinding, UI characterization (by patients and by physiological testing such as urodynamics), patient targeting, and comprehensive outcomes assessment.” (C. E. DuBeau, cdubeau@medicine.bsd.uchicago.edu)

Antibiotics for Cystitis: Ciprofloxacin was more effective than a 3-day regimen of amoxicillin–clavulanate in a study of 322 women with acute uncomplicated cystitis (pp. 949-55). During 4 months of follow up, the investigators found, “Clinical cure was observed in 93 (58%) of 160 women treated with amoxicillin–clavulanate compared with 124 (77%) of 162 women treated with ciprofloxacin (P < .001). Amoxicillin–clavulanate was not as effective as ciprofloxacin even among women infected with strains susceptible to amoxicillin–clavulanate (65 [60%] of 109 women in the amoxicillin–clavulanate group vs 114 [77%] of 149 women in the ciprofloxacin group; P = .004). The difference in clinical cure rates occurred almost entirely within the first 2 weeks after therapy. Microbiological cure at 2 weeks was observed in 118 (76%) of 156 women treated with amoxicillin–clavulanate compared with 153 (95%) of 161 women treated with ciprofloxacin (P < .001). At this visit, 45% of women in the amoxicillin–clavulanate group compared with 10% in the ciprofloxacin group had vaginal colonization with E coli (P < .001).” (T. M. Hooton, hooton@u.washington.edu)

Fibrinolytic Support of PCI: The practice in community hospitals of stabilizing patients with myocardial infarction using fibrinolytic agents and then transferring them for percutaneous coronary interventions is a sound one for patients who present early after onset of symptoms, according to authors of a review article (pp. 979-86). However, patients presenting late are more likely to bleed from the drugs than to benefit from them, the group adds. (B. J. Gersh, Mayo Clinic, Rochester, Minn.)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 24, 2005 Vol. 12, No. 37
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Feb. 24 issue of the New England Journal of Medicine (content.nejm.org; 2005; 352).

Factor VIIa for Cerebral Hemorrhage: Administration of recombinant factor VIIa within 4 hours of the onset of intracerebral hemorrhage—a condition for which no treatment currently exists—can limit hematoma growth, reduce mortality, and improve functional outcomes at 90 days with only a slight increase in thromboembolic events, according to a study of 399 patients (pp. 777-85). Based on a dose-ranging study, investigators report: “Hematoma volume increased more in the placebo group than in the rFVIIa groups. The mean increase was 29 percent in the placebo group, as compared with 16 percent, 14 percent, and 11 percent in the groups given 40 µg, 80 µg, and 160 µg of rFVIIa per kilogram, respectively (P = 0.01 for the comparison of the three rFVIIa groups with the placebo group). Growth in the volume of intracerebral hemorrhage was reduced by 3.3 ml, 4.5 ml, and 5.8 ml in the three treatment groups, as compared with that in the placebo group (P = 0.01). Sixty-nine percent of placebo-treated patients died or were severely disabled (as defined by a modified Rankin Scale score of 4 to 6), as compared with 55 percent, 49 percent, and 54 percent of the patients who were given 40, 80, and 160 µg of rFVIIa, respectively (P = 0.004 for the comparison of the three rFVIIa groups with the placebo group). Mortality at 90 days was 29 percent for patients who received placebo, as compared with 18 percent in the three rFVIIa groups combined (P = 0.02). Serious thromboembolic adverse events, mainly myocardial or cerebral infarction, occurred in 7 percent of rFVIIa-treated patients, as compared with 2 percent of those given placebo (P = 0.12).” (S. A. Mayer, sam14@columbia.edu)

Editorialists add these comments about research into treatments for intracerebral hemorrhage (pp. 828-30): “The enthusiasm for collaborative investigation in the treatment of intracerebral hemorrhage is building. The National Institute of Neurological Disorders and Stroke workshop on intracerebral hemorrhage recently outlined future directions for research, including basic-science and imaging endeavors and trials of medical and surgical treatments. Although further study of rFVIIa is warranted, other trials of methods to prevent rebleeding and investigations of blood-pressure lowering, the optimal management of intracranial pressure, and surgical and medical treatments directed at removal or dissolution of clots are also likely to be of great benefit in the treatment of this common and devastating disease.” (D. L. Brown, U. Michigan Health System, Ann Arbor)

Gefitinib Resistance: Repeat biopsies are needed to identify mutations in the epidermal growth factor receptor gene that confer resistance to tyrosine kinase inhibitors, according to investigators who found a second point mutation that emerged in a patient after complete remission of non–small cell lung cancer (pp. 786-72). Relapse occurred 2 years after successful gefitinib treatment, following a point mutation that resulted in amino acid change in tyrosine kinase. (D. G. Tenen, dtenen@bidmc.harvard.edu)

“It will be important to discover at what stage, in the pathogenesis of lung cancer, EGFR mutations occur,” write editorialists (pp. 830-2). “If they are found in preneoplastic lesions, it may be possible to screen for them and, if they are present, to use relatively nontoxic tyrosine kinase inhibitors as chemopreventive agents. Most non–small-cell lung cancers do not have these mutations but, rather, overexpressed and activated phosphorylated EGFR. Clinical trials suggest that some of these tumors are also responsive to tyrosine kinase inhibitors. More intriguing is the possibility that a ‘synthetic lethal’ approach can be developed as a variation on the theme of oncogene addiction. In this scheme, the cancer cell requires not only activated wild-type phosphorylated EGFR-mediated signaling (which can be treated with tyrosine kinase inhibitors) but also a minimum of one other pathway. If these second pathways could be identified and proteins within them ‘drugged,’ perhaps non–small-cell lung cancers could have molecularly targeted therapy.” (J. E. Dowell, U. Texas Southwestern Med. Ctr., Dallas)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 25, 2005 Vol. 12, No. 38
Providing news and information about medications and their proper use

>>>Geriatrics Highlights
Source:
Feb. and Mar. issues of the Journal of the American Geriatrics Society (www.blackwell-synergy.com; 2005; 53).

Suboptimal Medication Therapy Among Seniors: Several articles address potentially inappropriate medication use among elderly patients, including one study that shows that 28.8% of older patients in HMOs receive at least 1 of 33 medications culled from the 1997 version of the Beers’ list (pp. 227-32). Among 157,517 elderly members of 10 HMOs, the researchers found, “Approximately 5% of elderly patients received at least one of the 11 medications classified by an expert panel as ‘always avoid,’ 13% received at least one of the eight medications that would rarely be considered appropriate, and 17% received at least one of the 14 medications that have some indications but are often misused. Overall, rates of use of these medications were greater in women (32.4%) than in men (24.2%). At least 1% of elderly members received belladonna alkaloids (2.3%), dicyclomine (1.1%), or hyoscyamine (1.2%), each of which multiple expert panels have classified as always inappropriate in patients aged 65 years and older. Seven percent of elderly members received propoxyphene, an analgesic medication considered rarely appropriate in the elderly and a drug that has a long history of limited efficacy and potential for toxicity.” (S. R. Simon, steven_simon@hms.harvard.edu)

Targeting drug–drug and drug–disease interactions involving warfarin is a good idea, conclude investigators who analyzed the 1995–2000 National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey (pp. 262-7). “Overall, 0.74% (95% confidence interval (CI)=0.65–0.83) of visits with two or more prescriptions had at least one inappropriate drug-drug combination, and 2.58% (95% CI = 2.44–2.72) of visits with at least one prescription had one or more inappropriate drug-disease combinations. Of visits with a prescription of warfarin, 6.60% (95% CI = 5.46–7.74) were prescribed a drug with potentially harmful interaction. Of patients with benign prostatic hypertrophy, 4.06% (95% CI = 3.06–5.06) had at least one of six drugs that should be avoided. The number of drugs prescribed is most predictive of inappropriate drug–drug and drug–disease combinations.” (C. Zhan, czhan@ahrq.gov)

Racial Differences in Antidepressant Use: Caregivers with depressive symptoms—especially those of African descent—are unlikely to be taking antidepressants, according to a study of 2,032 women caring for male relatives with probable Alzheimer’s disease or vascular dementia (pp. 397-404). The group reports, “Of caregivers with depressive symptoms, 19% used antidepressants, 23% antianxiety agents, and 2% sedative/hypnotics. African-American caregivers with depressive symptoms were significantly less likely than whites with depressive symptoms to be using antidepressants and antianxiety medications. Caregivers who reported higher levels of social support and more physician visits during the previous 6 months were significantly more likely than others to be taking antidepressants.” (B. Sleath, bsleath@email.unc.edu)

Nursing Home Medication Prescribing: Using data from the 1997 Medicare Current Beneficiary Survey and the 1996 Medical Expenditure Panel Survey–Nursing Home Component, researchers quantify medication use among nursing home residents (pp. 438-43): “NH residents received, on average, seven to eight medications each month.... About one-third of residents had monthly drug regimens of nine or more medications (31.8% MCBS, 32.4% MEPS-NHC). The most commonly used medications in NHs, in descending order, were analgesics and antipyretics, gastrointestinal agents, electrolytic and caloric preparations, central nervous system agents, anti-infective agents, and cardiovascular agents.” (J. Doshi, jdoshi@mail.med.upenn.edu)

>>>PNN NewsWatch
* Sodium phenylacetate–sodium benzoate is returning to the U.S. market, this time as an injectable product (Ammonul, Medicis). Approved as adjunctive therapy for acute hyperammonemia and associated encephalopathy in patients with urea cycle disorder, this combination was marketed several years ago as an oral product (Ucephan, Braun).

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 28, 2005 Vol. 12, No. 39
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
Feb. 26 issue of Lancet (www.thelancet.com; 2005; 365).

Influenza Vaccine for Infants and Young Children: Data on effectiveness of influenza vaccines in children younger than 2 years are sparse, according to a systematic review (pp. 773-80). “We included 14 randomised controlled trials, eight cohort studies, one case-control study, and one randomised controlled trial of intraepidemic use of the vaccines,” the authors write. “Live attenuated influenza vaccines had 79% efficacy and 38% effectiveness in children older than 2 years compared with placebo or no immunisation. Inactivated vaccines had lower efficacy (65%) than live attenuated vaccines, and in children aged 2 years or younger they had similar effects to placebo. Effectiveness of inactivated vaccines was about 28% in children older than 2 years. Vaccines were effective in reducing long school absences (relative risk 0.14 [95% CI 0.07–0.27]). Studies assessing the effects of vaccines against secondary cases, lower-respiratory tract disease, acute otitis media, and hospital stay suggested no difference with placebo or standard care, but lacked statistical power.” (T. Jefferson, Cochrane Vaccines Field, Alessandria, Italy; toj1@aol.com)

Nutritional Supplements for Patients with Stroke: Two articles address the controversial use of routine oral nutritional supplements in patients with stroke.

Routine use of nutritional supplements is not supported by results of a study of 4,023 patients in 125 hospitals in 15 countries (pp. 755-63). In the Food or Ordinary Diet (FOOD) trials, only 314 (8%) patients were malnourished at baseline, and use of supplements was associated with an absolute mortality risk reduction of 0.7% and an increased risk of death or poor outcome of 0.7%.

In a subanalysis of FOOD data on use of percutaneous endoscopic gastrostomy in 859 patients with dysphagic stroke, investigators conclude, “Early tube feeding might reduce case fatality, but at the expense of increasing the proportion surviving with poor outcome. Our data do not support a policy of early initiation of PEG feeding in dysphagic stroke patients.” Results of the study show, “Early tube feeding was associated with an absolute reduction in risk of death of 5.8% (95% CI –0.8 to 12.5, p = 0.09) and a reduction in death or poor outcome of 1.2% (–4.2 to 6.6, p = 0.7). In the PEG versus nasogastric tube trial, 321 patients were enrolled by 47 hospitals in 11 countries. PEG feeding was associated with an absolute increase in risk of death of 1.0% (–10.0 to 11.9, p = 0.9) and an increased risk of death or poor outcome of 7.8% (0.0 to 15.5, p = 0.05).” (M. Dennis, Western General Hosp., Edinburgh; martin.dennis@ed.ac.uk)

>>>BMJ Highlights
Source:
Feb. 26 issue of BMJ (www.bmj.org; 2005; 330).

Atypical Antipsychotics & Stroke Risk: The risk of ischemic stroke is no higher in patients taking second-generation antipsychotic agents than among those on older agents, conclude investigators who conducted a population-based retrospective cohort study among 32,710 older adults with dementia (pp. 445 ff). “After adjustment for potential confounders, participants receiving atypical antipsychotics showed no significant increase in risk of ischaemic stroke compared with those receiving typical antipsychotics (adjusted hazard ratio 1.01, 95% confidence interval 0.81 to 1.26),” write the researchers. “This finding was consistent in a series of subgroup analyses, including ones of individual atypical antipsychotic drugs (risperidone, olanzapine, and quetiapine) and selected subpopulations of the main cohorts.” (S. S. Gill, St. Mary’s of the Lake Hosp., Kingston, Ont., Canada; gills@pccchealth.org)

>>>PNN JournalWatch
* Nonsteroidal Anti-inflammatory Drugs and Risk of ARF in the General Population in American Journal of Kidney Diseases, 2005; published early online. Reprints: www2.ajkd.org; C. Huerta Alvarez, Centro Español de Investigación Farmacoepidemiológica, Madrid, Spain; chuerta@ceife.es

* Moderate Alcohol Consumption Lowers the Risk of Type 2 Diabetes: A Meta-analysis of Prospective Observational Studies, in
Diabetes Care, 2005; 28: 719–25. Reprints: care.diabetesjournals.org; L. L. J. Koppes, U. Med. Ctr., Amsterdam, Netherlands; l.koppes@vumc.nl

* A Systematic Review of Drug Therapy to Delay or Prevent Type 2 Diabetes, in
Diabetes Care, 2005; 28: 736–44. Reprints: care.diabetesjournals.org; R. Padwal, rpadwal@ualberta.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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 28, 2005 Special Alert
Providing news and information about medications and their proper use

>>>PNN Special Alert
Marketing and distribution of the multiple sclerosis agent natalizumab (Tysabri) have been voluntarily suspended by Biogen Idec and Elan. In a news release (http://www.elan.com/News/full.asp?ID=679361), the companies cited the death of one patient and progressive multifocal leukoencephalopathy (a demyelinating CNS condition) in a second after 2 years of therapy with natalizumab in combination with interferon beta-1a. The companies are advising physicians to switch patients on natalizumab to other drugs and are stopping clinical trials of the agent. More details will be in tomorrow’s PNN.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 1, 2005 Vol. 12, No. 40
Providing news and information about medications and their proper use

>>>Natalizumab Distribution Suspended for Now
Biogen Idec and Elan yesterday announced a suspension in distribution and testing of natalizumab (Tysabri), citing two cases of progressive multifocal leukoencephalopathy, a rare and frequently fatal demyelinating disease of the CNS. The companies emphasized that this is not a withdrawal, even though they are advising physicians to suspend administration of the drug until further notice.

Natalizumab was only recently approved for treatment of relapsing multiple sclerosis (see PNN, Nov. 24). PML occurred in two patients in clinical trials in which the drug is used in combination with interferon beta-1a (Avonex, Biogen Idec) for treatment of MS. One of the patients died. No other cases of the disorder have been observed among some 3,000 patients in clinical trials.

Biogen Idec and Elan indicated that they will review these cases with experts and work with FDA before deciding on an appropriate course of action. The drug’s mechanism of action—interfering with movement of leukocytes from peripheral blood into the CNS—will be examined as a possible factor in development of PML, as will pathophysiologic events that occur in MS that might contribute to the problem.

>>>Internal Medicine Update
Source:
Mar. 1 issue of the Annals of Internal Medicine (www.annals.org; 2005; 142).

Diabetes Prevention: Lifestyle modifications trumped metformin in a diabetes-prevention simulation that used a Markov model to analyze data from the Diabetes Prevention Program (pp. 323-32). Analyzing members of the cohort who were 25 years or older and who had impaired glucose tolerance, the authors assessed the cost-effectiveness of intensive lifestyle, metformin, and placebo interventions. “Compared with the placebo intervention, the lifestyle and metformin interventions were estimated to delay the development of type 2 diabetes by 11 and 3 years, respectively, and to reduce the absolute incidence of diabetes by 20% and 8%, respectively,” the authors note of their analysis conducted from health system and societal perspectives. “The cumulative incidence of microvascular, neuropathic, and cardiovascular complications were reduced and survival was improved by 0.5 and 0.2 years. Compared with the placebo intervention, the cost per QALY was approximately $1100 for the lifestyle intervention and $31,300 for the metformin intervention. From a societal perspective, the interventions cost approximately $8800 and $29,900 per QALY, respectively. From both perspectives, the lifestyle intervention dominated the metformin intervention.” (Diabetes Prevention Program Coordinating Center, dppmail@biostat.bsc.gwu.edu)

Writing about this study and another report in this issue on the impact of lifestyle interventions in the Multiple Risk Factor Intervention Trial (MRFIT; pp. 313-22), an editorialist notes (pp. 381-3): “Randomized trials have now unequivocally proven that preventing type 2 diabetes is possible. New RCTs may be needed to answer some specific questions, but the time is right to implement community-wide diabetes prevention programs. Finland has launched a nationwide program, and many other communities are making plans.... We must remember that a large proportion of the human population, including all ethnic groups, carries genes that permit type 2 diabetes to develop if a person’s environment and lifestyle is conducive. During the history of public health, many large public health problems and epidemics have been overcome by acting on much less evidence than we have today for preventing type 2 diabetes. Therefore, we should act as if vigorous measures could control the emerging epidemic of diabetes, even though we may not eradicate this disease in those with a strong genetic background. In the 1970s, Dr. Jeremiah Stamler, one of the founders of the MRFIT, stated that mass diseases require mass prevention. [These] results ... now suggest that the return on investment in diabetes prevention is similar to that for other preventive health interventions. Preventing diabetes would require major investment of resources, but the cost of this investment should probably be less than that needed to treat the disease and its complications.” (J. Tuomilehto, National Public Health Inst., Helsinki, Finland; jaakko.tuomilehto@ktl.fi)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 2, 2005 Vol. 12, No. 41
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Mar. 2 issue of JAMA (www.jama.com; 2005; 293).

Chemotherapy in Older Women with Breast Cancer: General health rather than age alone should be a determinant when decisions are made about adjuvant chemotherapy among older women with breast cancer, according to a retrospective review of four randomized trials (pp. 1073-81). Among 6,487 women with lymph node–positive breast cancer (including 542 patients 65 years or older and 159 who were 70 years or older), the authors found: “Multivariate analysis showed that smaller tumor size, fewer positive lymph nodes, more chemotherapy, and tamoxifen use were all significantly (P < .001) related to longer disease-free and overall survival. There was no association between age and disease-free survival. Overall survival was significantly (P < .001) worse for patients aged 65 or older because of death from causes other than breast cancer. Thirty-three deaths (0.5% of all patients) were attributed to treatment, and older women had higher treatment-related mortality. Older women and younger women derived similar reductions in breast cancer mortality and recurrence from regimens containing more chemotherapy.” (H. B. Muss, Vermont Cancer Ctr., Burlington; hyman.muss@uvm.edu)

Asking whether “one size fits all” when it comes to adjuvant therapy of breast cancer, editorialists provide this assessment (pp. 1118-20): “Clinical trials are under way in the United States and Europe in an effort to identify adjuvant treatment regimens that may offer equal efficacy to established chemotherapy regimens but with better tolerability in an older patient population. In the United States, capecitabine, an oral prodrug of fluorouracil, is being compared with doxorubicin/cyclophosphamide or cyclophosphamide/methotrexate/fluorouracil in patients aged at least 65 years. Outside the United States, the use of a bisphosphonate with or without capecitabine is under evaluation. The International Breast Cancer Study Group has proposed evaluating liposomal doxorubicin as a single agent compared with cyclophosphamide/methotrexate in elderly patients who are deemed to be candidates for adjuvant chemotherapy. These trials may identify a more patient-friendly approach to reduce risk of disease recurrence in elderly patients who are considered candidates for chemotherapy. Ultimately, it will be incumbent on the physician, in consultation with the patient and family, to carefully articulate the potential benefits and adverse effects of adjuvant therapy in a patient population for whom both the length and quality of life can be threatened by a variety of other issues.” (W. J. Gradishar, w-gradishar@northwestern.edu)

Homocysteine, B12, Folate, & Hip Fracture: Daily supplements of vitamin B12 and folate reduce the risk of hip fractures among patients with hyperhomocysteinemia and history of ischemic stroke, concludes a study of 559 Japanese patients (pp. 1082-8). Observing the elevations in homocysteine can produce both stroke and osteoporosis, the investigators used a placebo-controlled design to test the effects of folate 5 mg and mecobalamin 1,500 mcg daily for 2 years: “Plasma homocysteine levels decreased by 38% in the treatment group and increased by 31% in the placebo group (P < .001). The number of hip fractures per 1000 patient-years was 10 and 43 for the treatment and placebo groups, respectively (P < .001). The adjusted relative risk, absolute risk reduction, and the number needed to treat for hip fractures in the treatment vs placebo groups were 0.20 (95% confidence interval [CI], 0.08–0.50), 7.1% (95% CI, 3.6%–10.8%), and 14 (95% CI, 9–28), respectively. No significant adverse effects were reported.” (Y. Sato, Mitate Hosp., Tagawa, Japan; y-sato@ktarn.or.jp

Editorialists applaud this line of investigation and call for further study in other patient groups (pp. 1121-2): “After the initial observation of association between circulating homocysteine levels and fracture risk less than 1 year ago, these results now support a causal link. However, final proof of causality will have to come from elucidation of the biological mechanism underlying this relationship.” (J. B. J. van Meurs, Erasmus Med. Ctr., Rotterdam, the Netherlands; j.vanmeurs@erasmusmc.nl)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 3, 2005 Vol. 12, No. 42
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Mar. 3 issue of the New England Journal of Medicine (content.nejm.org; 2005; 352).

Intrapleural Streptokinase for Pleural Infection: Intrapleural administration of streptokinase failed to improve mortality, rates of surgery, or lengths of hospital stay among patients with pleural infection, according to results from the First Multicenter Intrapleural Sepsis Trial (MIST1) group (pp. 865-74). Among 427 patients with pleural infection (presence of purulent pleural fluid or pleural fluid with a pH below 7.2 with signs of infection or by proven bacterial invasion of the pleural space) who received either intrapleural streptokinase 250,000 IU twice daily for 3 days or placebo, the investigators found, “There was no significant difference between the groups in the proportion of patients who died or needed surgery (with streptokinase: 64 of 206 patients [31 percent]; with placebo: 60 of 221 [27 percent]; relative risk, 1.14 [95 percent confidence interval, 0.85 to 1.54; P = 0.43), a result that excluded a clinically significant benefit of streptokinase. There was no benefit to streptokinase in terms of mortality, rate of surgery, radiographic outcomes, or length of the hospital stay. Serious adverse events (chest pain, fever, or allergy) were more common with streptokinase (7 percent, vs. 3 percent with placebo; relative risk, 2.49 [95 percent confidence interval, 0.98 to 6.36]; P = 0.08).” (R. J. O. Davies, Oxford Radcliffe Hosp., Oxford, U.K.; robert.davies@ndm.ox.ac.uk)

Noting the need to “do no harm,” an editorialist calls for more research but restraint in routine use of fibrinolytic drugs in treating empyema outside clinical trials (pp. 926-8): “Considering the frequency of pleural infections and the high associated morbidity, funding is needed for additional trials that will enroll specific populations with the potential to benefit from fibrinolytic therapy, apply structured protocols, include a group treated by video-assisted thoracoscopy, adjust outcomes for the severity of infection, and use computed tomography to determine the stage of empyema before treatment. As more selective fibrinolytic drugs become available for study, they can be used in combination with agents that reduce the viscosity of pleural pus and promote its drainage. Meanwhile, the results of this study should dampen the ardor for the routine use of fibrinolytic agents in all patients with pleural infections, regardless of stage. Existing data favor early use of video-assisted thoracoscopy for patients with fibrinopurulent empyemas that cannot be managed by chest-tube drainage, with fibrinolytic therapy reserved for patients who are poor surgical candidates or for health care settings in which surgical interventions are unavailable. Hippocrates’s primary recommendation remains the same: whatever the approach, drain infected pleural fluid as rapidly as possible.” (J. E. Heffner, Medical U. of South Carolina, Charleston)

New TB Drug: R207910 is a new antibiotic with antitubercular activity, notes an author of a brief review (pp. 933-4; E. J. Rubin, Harvard U., Boston).

>>>PNN NewsWatch
* Asian patients not requiring aggressive cholesterol reductions have been added to the list of individuals who should begin rosuvastatin doses at 5 mg daily, FDA announced yesterday. The revised Crestor labeling states that patients taking cyclosporine, Asian patients, and patients with severe renal insufficiency are candidates for the 5-mg starting doses. All patients on statins should be counseled to report promptly to a health care professional any signs or symptoms of muscle pain and weakness (malaise, fever, dark urine, nausea or vomiting).

* An extremely important milestone: That is how FDA described yesterday’s announcement that the British Medicines and Healthcare products Regulatory Agency is lifting the suspension of Chiron’s license to produce
influenza vaccine at its Liverpool plant. “FDA and MHRA will continue to closely monitor Chiron’s progress as manufacturing proceeds,” FDA noted in a statement to the media. “When all critical stages of manufacturing are in full swing, and needed corrective actions can be fully evaluated, FDA plans to conduct a comprehensive inspection of Chiron’s Liverpool facility to assure that Chiron can produce a safe and effective vaccine.”

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 4, 2005 Vol. 12, No. 43
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Mar. issue of Diabetes Care (care.diabetesjournals.org; 2005; 28).

Treatment Gap with Hypertension, Hypercholesterolemia: While the public’s awareness of hypertension and hypercholesterolemia improved over the first decade of the Pittsburgh Epidemiology of Diabetes Complications Study, a gaping treatment gap remains (pp. 521-6). Among patients with childhood-onset type 1 diabetes diagnosed between 1950 and 1980 and followed since 1986, investigators report, “Awareness of both conditions has improved; however, control is not optimal (e.g., only 32.1 and 28% of those with hypertension in 1986–1988 and 1996–1998 were controlled, while for hypercholesterolemia, the rates were 0 and 5.5%, respectively). Stratified by age-group (18–29, 30–39, and >40 years), the youngest subjects with hypercholesterolemia were least likely to be treated and controlled to goal levels. Older age and physician contact were correlates of awareness and treatment of hypertension at baseline, while presence of renal or coronary complications was also associated with awareness and treatment of both hypertension and hypercholesterolemia at the 10-year follow-up.” (J. C. Zgibor, edcjan@pitt.edu)

Statin Adherence: Could pharmacists who focus on adherence to statin therapy make a difference in patients’ lives? The answer is yes, according to an analysis of 653 patients showing that adherence is closely associated with attainment of LDL cholesterol goals (pp. 595-9). Using medication possession ratios as determined from pharmacy records, researchers show, “The average MPR was significantly higher for men than for women (0.75 vs. 0.66, P < 0.05). Overall, 44% (n = 290) of the patients achieved an LDL cholesterol level <100 mg/dl (52% of men and 37% of women, P < 0.05). A significant correlation emerged between MPR and plasma LDL cholesterol (P < 0.001), and MPR was significantly higher in patients who achieved the LDL cholesterol target than in those who did not (0.82 vs. 0.61, P < 0.05).” The group concludes, “The probability of goal achievement appears to increase substantially when the MPR is >0.80. Pharmacy records can be used to identify patients who are poorly compliant with statin therapy and at high risk for failure to attain LDL cholesterol goals. Because outcomes are directly related to patients’ medication-taking behavior, when clinical goals (such as serum cholesterol levels) are not being reached, adherence should be the first item assessed by the clinician.” (D. B. Lawrence, Bart.Lawrence@pfizer.com)

Measuring Doses of Diabetes Education: A “dosage effect” is evident among patients with diabetes, with greater improvement in glycemic control resulting from more exposure to educational sessions (pp. 527-32). In the Starr County Border Health Initiative, researchers compared “extended” (24 hours of education, 28 hours of support groups) with "compressed" (16 hours of education, 6 hours of support groups) among 216 Mexican Americans aged 35–70 years with type 2 diabetes. “The interventions were not statistically different in reducing HbA1c; however, both were effective,” the researchers write. “A ‘dosage effect’ of attendance was detected with the largest HbA1c reductions achieved by those who attended more of the extended intervention. For individuals who attended 50% of the intervention, baseline to 12-month HbA1c change was –0.6 percentage points for the compressed group and –1.7 percentage points for the extended group.” (S. A. Brown, sabrown@mail.utexas.edu)

Insulin Aspart in CSII: Among 100 patients with type 1 diabetes, continuous subcutaneous insulin infusions with insulin aspart provided better glycemic results than did multiple daily injections with insulin aspart and glargine (pp. 533-8). Mean serum fructosamine levels, area under the 80 mg/dL level on a glucose curve, and AUC glucose 140 mg/dL were all significantly improved with CSII, while hypoglycemic episodes occurred in similar numbers of patients in the two groups. (I. B. Hirsch, ihirsch@u.washington.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 7, 2005 Vol. 12, No. 44
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
Mar. 5 issue of Lancet (www.thelancet.com; 2005; 365).

Macrolide Resistance & Pneumococcal Vaccine: Introduction of childhood pneumococcal vaccine produced a decline in macrolide-resistant Streptococcus pneumoniae among adults, according to an analysis from Atlanta (pp. 855-63). Pathologic isolates were obtained and cumulative incidence rates for invasive pneumococcal disease analyzed from 1994 to 2002, a time period that includes the Feb. 2000 licensing of the heptavalent pneumococcal conjugate vaccine for young children. “The incidence of invasive pneumococcal disease in Atlanta fell from 30.2 per 100,000 population (mean annual incidence 1994–99) to 13.1 per 100,000 in 2002 (p < 0.0001). Striking reductions were seen in children younger than 2 years (82% decrease) and in those 2–4 years (71% decrease), age-groups targeted to receive pneumococcal conjugate vaccine. Significant declines were also noted in adults aged 20–39 (54%), 40–64 (25%), and 65 years and older (39%). Macrolide resistance in invasive S pneumoniae disease in Atlanta, after increasing steadily from 4.5 per 100000 in 1994 to 9.3 per 100,000 in 1999, fell to 2.9 per 100000 by 2002. Reductions in disease caused by mefE-mediated and erm-mediated macrolide-resistant isolates of conjugate-vaccine serotypes 6B, 9V, 19F, and 23F, and the vaccine-associated serotype 6A were also recorded.” (D. S. Stephens, dstep01@emory.edu)

Neonatal Survival Series: The journal features in this issue numerous articles on challenges related to worldwide neonatal survival. Noting that 99% of neonatal deaths occur in developing countries yet nearly all published research focuses on the 1% of such deaths in developed countries, the journal editors described their effort to reduce neonatal mortality as the “most important public-health campaign we have taken part in for a generation.”

>>>BMJ Highlights
Source:
Early-release article from BMJ (www.bmj.org; 2005; 330).

Treatment Exhaustion with HAART: Substantial proportions of U.K. patients are in danger of exhausting their highly active antiretroviral treatment options, according to a multicenter cohort study (early-release article). “Information is available on 16,593 individuals (13,378 (80.6%) male patients, 10,340 (62.3%) infected via homosexual or bisexual sex, 4426 (26.7%) infected via heterosexual sex, median age 34 years). Overall, 10 207 of the 16,593 patients (61.5%) have been exposed to any antiretroviral therapy. This proportion increased from 41.2% of patients under follow up at the end of 1996 to 71.3% of those under follow up in 2002. The median CD4 count and HIV RNA burden of patients under follow up in each year changed from 270 cells/mm3 and 4.34 log10 copies/ml in 1996 to 408 cells/mm3 and 1.89 log10 copies/ml, respectively, in 2002. By 2002, 3060 (38%) of patients who had ever been treated with antiretroviral therapy had experienced all three main classes. Of these, around one quarter had evidence of ‘viral load failure’ with all these three classes. Patients with three class failure were more likely to have an HIV RNA burden >2.7 log10 copies/ml and a CD4 count <200 cells/mm3.” (C. A. Sabin, Royal Free and UC Medical School, London)

>>>PNN NewsWatch
* FDA and federal marshals on Friday seized millions of Paxil CR and Avandamet tablets at three GlaxoSmithKline facilities, citing the company’s failure to recall all affected lots of the products with quality problems. FDA said the products could deliver inaccurate doses of active ingredients, but advised consumers to continue taking tablets they already have until they can talk with prescribers about switching to alternative agents. What pharmacists should do with product in the supply chain is currently unclear.

>>>PNN JournalWatch
* Tobacco, Alcohol, and Other Drugs: The Role of the Pediatrician in Prevention, Identification, and Management of Substance Abuse, in Pediatrics, 2005; 115: 816–21. Reprints: www.pediatrics.org; American Academy of Pediatrics.

* Evaluation and Management of Pain in Patients with Klippel–Trenaunay Syndrome: A Review, in
Pediatrics, 2005; 115: 744–9. Reprints: www.pediatrics.org; A.. Lee, Mayo Clinic, Rochester, Minn.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 8, 2005 Vol. 12, No. 45
Providing news and information about medications and their proper use

>>>ACC Highlights
The 54th Annual Scientific Session of the American College of Cardiology opened over the weekend in Orlando. Here are highlights of sessions held thus far:

* In terms of cardioprotection, aspirin affects women differently than men, according to results from the Women’s Health Study. Reporting research that was simultaneously released on the Web site of the
New England Journal of Medicine (content.nejm.org), Paul Ridker, MD, Brigham and Women’s Hospital in Boston, presented data on 39,876 initially healthy women who were followed for 10 years. Study participants were randomized to receive aspirin 100 mg every other day and/or vitamin E 600 IU every other day. Writing in the NEJM about the aspirin results, the investigators reported that the agent was of benefit primarily in elderly women: “During follow-up, 477 major cardiovascular events were confirmed in the aspirin group, as compared with 522 in the placebo group, for a nonsignificant reduction in risk with aspirin of 9 percent (relative risk, 0.91; 95 percent confidence interval, 0.80 to 1.03; P = 0.13). With regard to individual end points, there was a 17 percent reduction in the risk of stroke in the aspirin group, as compared with the placebo group (relative risk, 0.83; 95 percent confidence interval, 0.69 to 0.99; P = 0.04), owing to a 24 percent reduction in the risk of ischemic stroke (relative risk, 0.76; 95 percent confidence interval, 0.63 to 0.93; P = 0.009) and a nonsignificant increase in the risk of hemorrhagic stroke (relative risk, 1.24; 95 percent confidence interval, 0.82 to 1.87; P = 0.31). As compared with placebo, aspirin had no significant effect on the risk of fatal or nonfatal myocardial infarction (relative risk, 1.02; 95 percent confidence interval, 0.84 to 1.25; P = 0.83) or death from cardiovascular causes (relative risk, 0.95; 95 percent confidence interval, 0.74 to 1.22; P = 0.68). Gastrointestinal bleeding requiring transfusion was more frequent in the aspirin group than in the placebo group (relative risk, 1.40; 95 percent confidence interval, 1.07 to 1.83; P = 0.02). Subgroup analyses showed that aspirin significantly reduced the risk of major cardiovascular events, ischemic stroke, and myocardial infarction among women 65 years of age or older.”

* Vitamin E failed to affect cardiovascular end points in this Women’s Health Study, added Julie Burring, ScD, also of Boston’ s Brigham and Women’s Hospital.

* Reviewing the rate versus rhythm control for atrial fibrillation debate, panelists noted that one half of AF patients are now 75 years or older, and this proportion is expected to increase to two thirds as the baby boomers age. For these patients, maintenance of the INR at 2 to 3 with warfarin is a reasonable option, providing a favorable risk–benefit ratio despite the possibility of strokes.

* While more data on COX-2 inhibitors are slated for release today, Andrew Whelton, MD, of Johns Hopkins U. in Baltimore concluded yesterday that while parecoxib/valdecoxib is inappropriate in patients after cardiac surgery, they provide certain advantages following general surgery. In contrast to the negative results in the coronary artery bypass surgery patients published online last month by the
NEJM (see PNN, Feb. 17), the general surgery patients used significantly less morphine than study participants who received standard care and also reported significantly better postoperative analgesia.

* In the Optimal Pharmacological Therapy in Implantable Cardioverter Defibrillator Patients (OPTIC) trial, amiodarone plus a beta-blocker significantly reduced the need for cardioversion shocks among 412 patients implanted with a St. Jude Medical dual chamber implantable cardioverter defibrillator. Comparing beta blockers alone, sotalol, or amiodarone plus a beta blocker, Stuart J. Connolly, MD, of McMaster U. in Hamilton, Ont., said that patients who received the amiodarone combination had an annual risk of shock of 10%, compared with 24% for sotalol and 39% for beta blocker alone.

* Clopidogrel 600 mg, twice the usual loading dose, given 6 hours before percutaneous coronary intervention, significantly reduced the percentage of patients with creatine kinase-MB elevations, according to Germano Di Sciascio, MD, of Campus Bio-Medico in Rome.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 9, 2005 Vol. 12, No. 46
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Early-release article from the New England Journal of Medicine (content.nejm.org; 2005; 352).

Intensive Statin Therapy: In a study released yesterday to coincide with presentation at the American College of Cardiology meeting, researchers described intensive therapy with atorvastatin 80 mg daily and identified “significant clinical benefit beyond that afforded by treatment with 10 mg of atorvastatin per day” among 10,001 patients with coronary heart disease and LDL cholesterol levels of less than 130 mg/dL. Conducted to assess the efficacy and safety of lowering LDL-C levels below 100 mg/dL, the Treating to New Targets (TNT) investigators randomly assigned patients to one of the two atorvastatin doses and followed them for a median of 4.9 years. “The mean LDL cholesterol levels were 77 mg per deciliter (2.0 mmol per liter) during treatment with 80 mg of atorvastatin and 101 mg per deciliter (2.6 mmol per liter) during treatment with 10 mg of atorvastatin,” the authors write. “The incidence of persistent elevations in liver aminotransferase levels was 0.2 percent in the group given 10 mg of atorvastatin and 1.2 percent in the group given 80 mg of atorvastatin (P < 0.001). A primary event occurred in 434 patients (8.7 percent) receiving 80 mg of atorvastatin, as compared with 548 patients (10.9 percent) receiving 10 mg of atorvastatin, representing an absolute reduction in the rate of major cardiovascular events of 2.2 percent and a 22 percent relative reduction in risk (hazard ratio, 0.78; 95 percent confidence interval, 0.69 to 0.89; P < 0.001). There was no difference between the two treatment groups in overall mortality.” (J. C. LaRosa, SUNY Brooklyn; jclarosa@downstate.edu)

Commenting on these findings, an editorialist cautions, “Until the safety and effectiveness of an 80-mg daily dose of atorvastatin have been established, patients and their physicians will need to carefully weigh the benefits of a reduction in the risk of cardiovascular events, including myocardial infarction and stroke, with their attendant disability, against the uncertainty of an increase in the risk of death from noncardiovascular causes. We need further reassurance as to the safety of this approach before we can advocate a major shift in our current goals for LDL cholesterol levels in patients with stable CHD.” (B. Pitt, U. Michigan, Ann Arbor)

>>>JAMA Highlights
Source:
Mar. 9 issue of JAMA (www.jama.com; 2005; 293).

Computer Challenges: Three articles explore experiences with computerized physician order entry systems and clinical decision support systems.

When widely implemented, a CPOE system “facilitated 22 types of medication error risks,” note researchers who gathered data using house staff focus groups and interviews (pp. 1197-203). “Examples include fragmented CPOE displays that prevent a coherent view of patients’ medications, pharmacy inventory displays mistaken for dosage guidelines, ignored antibiotic renewal notices placed on paper charts rather than in the CPOE system, separation of functions that facilitate double dosing and incompatible orders, and inflexible ordering formats generating wrong orders. Three quarters of the house staff reported observing each of these error risks, indicating that they occur weekly or more often.” (R. Koppel, rkoppel@sas.upenn.edu)

Based on data in 100 studies of CDSSs, authors find that these systems “improve practitioner performance,” but their “effects on patient outcomes remain understudied and, when studied, inconsistent” (pp. 1223-38). “Improved practitioner performance was associated with CDSSs that automatically prompted users compared with requiring users to activate the system (success in 73% of trials vs 47%; P = .02) and studies in which the authors also developed the CDSS software compared with studies in which the authors were not the developers (74% success vs 28%; respectively, P = .001).” (R. B. Haynes, bhaynes@mcmaster.ca)

“Information technology in and of itself cannot do anything, and when the patterns of its use are not tailored to the workers and their environment to yield high-quality care, the technological interventions will not be productive,” an editorialist adds (pp. 1261-3; R. L. Wears, wears@ufl.edu).

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 10, 2005 Vol. 12, No. 47
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Early-release articles and Mar. 10 issue of the New England Journal of Medicine (content.
nejm.org; 2005; 352).

Clopidogrel for MI with ST Elevation: Patency of the infarct-affected artery was improved by addition of clopidogrel to aspirin and standard fibrinolytic therapy among 3,491 patients younger than 76 who had myocardial infarction with ST-segment elevation (article released early in conjunction with presentation at the American College of Cardiology meeting). Study participants were those who presented within 12 hours of the onset of MI, and they received placebo or a loading dose clopidogrel 300 mg followed by 75 mg once daily. Based on a composite primary efficacy end point of an occluded infarct-related artery on angiography, death, or recurrent myocardial infarction before angiography, the authors report: “The rates of the primary efficacy end point were 21.7 percent in the placebo group and 15.0 percent in the clopidogrel group, representing an absolute reduction of 6.7 percentage points in the rate and a 36 percent reduction in the odds of the end point with clopidogrel therapy (95 percent confidence interval, 24 to 47 percent; P < 0.001). By 30 days, clopidogrel therapy reduced the odds of the composite end point of death from cardiovascular causes, recurrent myocardial infarction, or recurrent ischemia leading to the need for urgent revascularization by 20 percent (from 14.1 to 11.6 percent, P = 0.03). The rates of major bleeding and intracranial hemorrhage were similar in the two groups.” (M. S. Sabatine, msabatine@partners.org)

Editorialist note the advantages of using agents from various drug classes: “Because many patients are resistant to the effects of a single oral antiplatelet agent, therapy with multiple agents with different mechanisms of action is conceptually attractive, provided that it can be administered without an increased risk of bleeding. For patients who are receiving fibrinolytic therapy, a combination of clopidogrel and aspirin appears, in fact, to be effective and safe.” (R. A. Lange, Johns Hopkins Medical Institution, Baltimore)

Temozolomide for Glioblastoma: The oral alkylating agent temozolomide provided meaningful extensions in survival in patients with glioblastoma, but positive results were limited to those with tumors containing a methylated promoter gene for the MGMT (O6-methylguanine–DNA methyltransferase) DNA-repair gene, according to two research studies.

At 85 centers, 573 patients with newly diagnosed glioblastoma received either radiotherapy alone or radiotherapy plus continuous daily temozolomide (75 mg/sq m/day on 7 days per week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150–200 mg/sq m for 5 days during each 28-day cycle; pp. 987-96). “The median age was 56 years, and 84 percent of patients had undergone debulking surgery,” report the investigators. “At a median follow-up of 28 months, the median survival was 14.6 months with radiotherapy plus temozolomide and 12.1 months with radiotherapy alone. The unadjusted hazard ratio for death in the radiotherapy-plus-temozolomide group was 0.63 (95 percent confidence interval, 0.52 to 0.75; P < 0.001 by the log-rank test). The two-year survival rate was 26.5 percent with radiotherapy plus temozolomide and 10.4 percent with radiotherapy alone. Concomitant treatment with radiotherapy plus temozolomide resulted in grade 3 or 4 hematologic toxic effects in 7 percent of patients.” (R. Stupp, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; roger.stupp@chuv.hospvd.ch)

In the gene study, median survival of patients with a methylated MGMT promoter was 21.7 months, significantly longer than in other patients, whose median survival was 15.3 months (pp. 997-1003). “Irrespective of treatment, MGMT promoter methylation was an independent favorable prognostic factor (P < 0.001 by the log-rank test; hazard ratio, 0.45; 95 percent confidence interval, 0.32 to 0.61),” the authors explain. “Among patients whose tumor contained a methylated MGMT promoter, a survival benefit was observed in patients treated with temozolomide and radiotherapy.” (M. E. Hegi, U. Hosp., Lausanne, Switzerland; monika.hegi@chuv.hospvd.ch)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 11, 2005 Vol. 12, No. 48
Providing news and information about medications and their proper use

>>>Pharmacotherapy Update
Source:
Mar. issue of Pharmacotherapy (www.pharmacotherapy.org; 2005; 25).

Atorvastatin Therapy & Emerging Risk Factors: Among 19 patients with LDL cholesterol levels greater than 100 mg/dL and at least two cardiovascular risk factors, atorvastatin 10 mg/day for 20 weeks produced sizable but nonsignificant decreases in levels of C-reactive protein and no change in LDL particle size (pp. 335-44). Comparing treated patients with a control group receiving no treatment, the authors found, “Atorvastatin therapy was associated with no change in mean LDL particle size (p = 0.23) and with a 90% decrease in mean CRP level (p = 0.52). When evaluated by standard chemical analysis, atorvastatin therapy reduced total cholesterol levels by 29% (p = 0.025) and resulted in nonsignificant reductions in LDL, high-density lipoprotein cholesterol, and triglyceride levels. Treatment with atorvastatin was not associated with significant changes in lipoprotein profile as determined by nuclear magnetic resonance (NMR) spectroscopy.” (K. A. Dornbrook-Lavender, Medical Communications, Durham, N.C.)

Myopathy Rates in Patients Taking Statins and Fibrates: While the risk of myopathy is increased when statins are used with agents such as fibrates that inhibit cytochrome P-450 3A4, a retrospective chart review found no clinically important increase in myopathy among members of a health-maintenance organization during concomitant therapy with such drugs (pp. 345-51). “Medical records were reviewed to confirm myopathy cases associated with statin therapy,” the investigators write. “Of the 468 patients [with a diagnosis of myopathy during a 4-year period], 61 had received statin therapy before their diagnosis, and 41 (67%) of these patients had confirmed myopathy (documented creatine kinase level ≥ 1000 IU/L). The prevalence of myopathy was 0.12% with statin monotherapy and 0.22% with statins in combination with interacting drugs. Only 17 of the 41 (41%) patients had confirmed myopathy with no other plausible clinical explanation, such as a muscle injury. Increased risk of myopathy associated with statin therapy in combination with interacting drugs approached statistical significance (p = 0.052) but was of minimal clinical significance.” (R. Shanahan, Kaiser Permanente Colorado Region, Denver; roberta.shanahan@kp.org)

Collaboration in Lipids Care: Implementation of physician-approved care plans by clinical pharmacists enabled 481 patients with coronary heart disease to achieve target LDL cholesterol goals more often, according to a study conducted in a managed care setting (pp. 360-71). At 2 of 19 clinics in the Twin Cities area, clinical pharmacists were involved in managing lipid-lowering drug therapy and educating patients on cardiovascular risk reduction. Patients in two of the other clinics served as controls. “Primary outcomes were changes in LDL level and the proportion of patients achieving goal LDL in the intervention versus the usual care (control) group,” explain the researchers. “Secondary outcomes were the sustainability of the impact observed up to 18 months after discontinuation of the intervention. Mean ± SD baseline LDL levels were 131 ± 28 and 131 ± 26 mg/dl (p = NS) for the intervention and control groups, respectively. After a mean of 6.5 months follow-up, 107 (72%) patients in the intervention group and 61 (18%) patients in the control group had attained their LDL goal (p < 0.001). Mean LDL levels were reduced by 35.6 mg/dl (27.5%) and 6.7 mg/dl (4.6%) in the intervention and control groups, respectively (p < 0.001). When the active program was discontinued, results of the 18-month follow-up indicated that 85 (65%) intervention patients remained at goal compared with 96 (42%) controls (p < 0.001).” The authors conclude, “This trial provides quantitative evidence to support the effectiveness of the collaborative approach as an intervention to optimize management of patients with CHD whose LDL levels are not at goal; this approach is specifically called for in the executive summary of the National Cholesterol Education Program Adult Treatment Panel III. Furthermore, this study documents both the magnitude and sustainability of the impact collaborative care models can have in managed care environments.” (R. J. Straka, strak001@umn.edu.)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 14, 2005 Vol. 12, No. 49
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
Mar. 12 issue of Lancet (www.thelancet.com; 2005; 365).

Rasagiline for PD: In a study of 687 patients with Parkinson’s disease who had motor fluctuations despite levodopa therapy, addition of the monoamine oxidase B inhibitor rasagiline reduced mean daily off-time and improved symptoms (pp. 947-54). The 18-week trial assigned patients to oral rasagiline 1 mg once daily, entacapone 200 mg with every levodopa dose, or placebo. Considering scores on the clinical global improvement scale and unified Parkinson’s disease rating scale, the investigators found, “88 (13%) patients who were assigned treatment did not complete the study (23 rasagiline, 30 entacapone, 35 placebo), mainly because of withdrawal of consent (n = 34) and adverse events (n = 34). Both rasagiline and entacapone reduced mean daily off-time (–1.18 h rasagiline and –1.2 h entacapone vs placebo –0.4 h; p = 0.0001, p < 0.0001, respectively) and increased daily on-time without troublesome dyskinesia (0.85 h vs placebo 0.03 h; p = 0.0005 for both). We recorded significant mean improvements in CGI scores (–0.86 rasagiline and –0.72 entacapone vs –0.37 placebo; p < 0.0001, p = 0.0002, respectively). Changes in UPDRS scores also significantly improved for activities of daily living during off-time (–1.71 and –1.38 vs placebo; p < 0.0001, p = 0.0006, respectively) and motor function during on-time (–2.94 and –2.73 vs placebo; both p < 0.0001). Frequency of adverse events was similar for all treatments.” (O. Rascol, U. Hosp., Toulouse, France; rascol@cict.fr)

>>>BMJ Highlights
Source:
Mar. 12 issue of BMJ (www.bmj.org; 2005; 330).

Neural Tube Defects & Folate Recommendations: Issuance of recommendations for pregnant women concerning the need for folate supplements had no identifiable impact on the incidence of neural tube defects among babies born in 1988–98 in 10 European countries and Israel, report authors who conducted a retrospective cohort study (pp. 571 ff). Trends in the incidence of these birth defects were similar before and after the recommendations were issued in 1992. Noting that the rate of use of folate supplements in Europe remains 10% or less, the authors conclude, “New cases of neural tube defects preventable by folic acid continue to accumulate. A reasonable strategy would be to quickly integrate food fortification with fuller implementation of recommendations on supplements.” (L. D. Botto, CDC, Atlanta; icbd@icbd.org)

>>>PNN JournalWatch
* Transmission of Infectious Diseases During Commercial Air Travel, in Lancet, 2005; 365: 989–96. Reprints: www.thelancet.com; M. Gendreau, Lahey Clinic Med. Ctr., Burlington, Mass.; mark.a.gendreau@lahey.org

* Systematic Review and Meta-analysis of Proton Pump Inhibitor Therapy in Peptic Ulcer Bleeding, in
BMJ, 2005; 330: 568 ff. Reprints: www.bmj.org; C. W. Howden; c-howden@northwestern.edu

* Recent Developments in Asthma Management, in
BMJ, 2005; 330: 585–9. Reprints: www.bmj.org; G. P. Currie Aberdeen Royal Infirmary, Aberdeen, U.K.; graeme.currie@nhs.net

* Tactics for Vascular Protection After Acute Ischemic Stroke, in
Pharmacotherapy, 2005; 25: 387–95. Reprints: www.pharmacotherapy.org; S. C. Fagan, Med. Coll. of Ga., Augusta; sfagan@mail.mcg.edu

* Duloxetine: A Dual Serotonin-Norepinephrine Reuptake Inhibitor for Treatment of Major Depressive Disorder, in
Pharmacotherapy, 2005; 25: 396–410. Reprints: www.pharmacotherapy.org; J. L. Goren, jgoren@mclean.harvard.edu

* The Use of Tricyclic Antidepressants and Selective Serotonin Reuptake Inhibitors in Women Who Are Breastfeeding, in
Pharmacotherapy, 2005; 25: 396–410. Reprints: www.pharmacotherapy.org; K. M. Smith, U. Kentucky, Lexington.

* Nonsteroidal Antiinflammatory Drug Use and Lung Cancer: A Meta-analysis, in
Chest, 2005; 127: 748–54. Reprints: www.chestjournal.org; S. A. Khuder, Medical College of Ohio, Toledo; skhuder@mco.edu

* Serious Infections in Elderly Patients with Diabetes Mellitus, in
Clinical Infectious Diseases, 2005; 40: 990–6. Reprints: www.journals.uchicago.edu/CID; S. Rajagopalan, King-Drew Med. Ctr., Los Angeles

* Unique Aspects of Antimicrobial Use in Older Adults, in
Clinical Infectious Diseases, 2005; 40: 990–6. Reprints: www.journals.uchicago.edu/CID; C. M. Faulkner, Wake Forest U. Baptist Med. Ctr., Winston-Salem, N.C.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 15, 2005 Vol. 12, No. 50
Providing news and information about medications and their proper use

>>>Internal Medicine I
Source:
Mar. 14 issue of Archives of Internal Medicine (www.archinternmed.com; 2005; 165).

COX-2 Inhibitors & BP: Compared with placebo and nonselective NSAIDs, COX-2 inhibitors induce an increase in patient blood pressure that may be clinically important in increasing cardiovascular risk, according to results of a meta-analysis of 19 randomized controlled trials (pp. 490-6). Considering the weighted mean difference in point estimates of BP, the investigators report, “Among the trials analyzed, coxibs caused a WMD point estimate increase in systolic and diastolic BP compared with placebo (3.85/1.06 mm Hg) and nonselective NSAIDs (2.83/1.34 mm Hg). Cyclooxygenase-2 inhibitors were associated with a nonsignificantly higher RR of causing hypertension compared with placebo (RR, 1.61; 95% confidence interval [CI], 0.91–2.84; P = .10) and non-selective NSAIDs (RR, 1.25; 95% CI, 0.87–1.78; P = .23). Rofecoxib induced a WMD point estimate increase in systolic BP (2.83 mm Hg) and a nonsignificantly higher risk of developing clinically important systolic BP elevation (RR, 1.50; 95% CI, 1.00–2.26; P = .05) compared with celecoxib.” (H. Krum, Monash U., Melbourne, Victoria, Australia; Henry.Krum@med.monash.edu.au

Thiazides & Gallbladder Surgery: The risk of cholecystectomy is increased among women taking thiazide diuretics, a finding consistent with prior studies but possibly related to confounding factors such as the effects of hypertension, according to researchers who followed a cohort of 81,351 women in the U.S. for 20 years (pp. 567-73). “During follow-up, 8607 women reported undergoing a cholecystectomy,” the group explains. “A modest positive relation between the use of thiazide diuretics and cholecystectomy was observed. Compared with never users of thiazide diuretics, the multivariate relative risk of cholecystectomy for past users was 1.16 (95% confidence interval,1.08–1.24) and the multivariate relative risk for current users was 1.39 (95% confidence interval, 1.29–1.50).” (M. F. Leitzmann, leitzmann@.mail.nih.gov)

>>>Internal Medicine II
Source:
Mar. 15 issue of the Annals of Internal Medicine (www.annals.org; 2005; 142).

Treatment of Hypothyroidism: Replacement of part of the l-thyroxine dose with small but supraphysiologic doses of liothyronine provides no clinical advantage but is preferred by patients, report investigators who studied 28 women (pp. 412-24). Patients received l-thyroxine 100 mcg/day (standard treatment) or l-thyroxine 75 mcg/day plus liothyronine 5 mcg/day (combination treatment) for 8 weeks. All patients also received l-thyroxine 87.5 mcg/day plus liothyronine 7.5 mcg/day (add-on combination treatment) for a final 8-week add-on period. The authors write, “Compared with standard treatment, combination treatment led to lower free thyroxine levels (decrease, 3.9 pmol/L [95% CI, 2.5 to 5.3 pmol/L]), slightly higher serum levels of thyroid-stimulating hormone (increase, 0.62 mU/L [CI, 0.01 to 1.23 mU/L]), and unchanged free triiodothyronine levels.... The add-on combination treatment resulted in overreplacement.... Twelve patients preferred combination treatment, 6 patients preferred the add-on combination treatment, 2 patients preferred standard treatment, and 6 patients had no preference (P = 0.015).” (H. F. Escobar-Morreale, Hospital Ramón y Cajal, Madrid, Spain; hescobarm.hrc@salud.madrid.org)

>>>PNN NewsWatch
* Pfizer’s intentions of marketing its HDL-raising drug torcetrapib only in a combination tablet with atorvastatin are criticized in an editorial in this morning’s edition of the New York Times.

* Used in previously untreated patients with nonsquamous, non–small-cell lung cancer,
bevacizumab (Avastin, Genentech) increased survival, compared with standard chemotherapy using six cycles of paclitaxel and carboplatin. In announcing preliminary results in 878 patients, NIH reported a higher incidence of life-threatening or fatal pulmonary bleeding among patients treated with bevacizumab. Full results will be presented in May at the American Society of Clinical Oncology meeting.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 16, 2005 Vol. 12, No. 51
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Mar. 16 issue of JAMA (www.jama.com; 2005; 293).

Long-term Vitamin E Supplementation: Daily use of vitamin E 400 IU for a median of 7.0 years resulted in no cancer or cardiovascular benefits, reported investigators who conducted the HOPE (Heart Outcomes Prevention Evaluation) and HOPE-TOO (HOPE–The Ongoing Outcomes) trials (pp. 1338-47). In fact, the only significant differences among the nearly 10,000 patients were increases in the incidence of heart failure and rates of hospitalization for heart failure among those taking vitamin E, the authors report: “Among all HOPE patients, there were no significant differences in the primary analysis: for cancer incidence, there were 552 patients (11.6%) in the vitamin E group vs 586 (12.3%) in the placebo group (relative risk [RR], 0.94; 95% confidence interval [CI], 0.84–1.06; P = .30); for cancer deaths, 156 (3.3%) vs 178 (3.7%), respectively (RR, 0.88; 95% CI, 0.71–1.09; P = .24); and for major cardiovascular events, 1022 (21.5%) vs 985 (20.6%), respectively (RR, 1.04; 95% CI, 0.96–1.14; P = .34). Patients in the vitamin E group had a higher risk of heart failure (RR, 1.13; 95% CI, 1.01–1.26; P = .03) and hospitalization for heart failure (RR, 1.21; 95% CI, 1.00–1.47; P = .045). Similarly, among patients enrolled at the centers participating in the HOPE-TOO trial, there were no differences in cancer incidence, cancer deaths, and major cardiovascular events, but higher rates of heart failure and hospitalizations for heart failure.” (E. Lonn, lonnem@mcmaster.ca)

Asking “is there any hope for vitamin E,” editorialists write (pp. 1387-90): “The hopes for vitamin E alone or in combination with vitamin C and beta carotene have been diminished by a compelling body of clinical trial evidence and by certain adverse effects with plausible biological explanation. These hopes are now confined to modest expectations for specific disorders and there are concerns about adverse effects. While there is solid evidence linking oxidative processes to human disease (as well as to normal biological function), the details of these processes and of proposed therapeutic or preventive interventions appear to need considerable rethinking.” (B. G. Brown, bgbrown@u.washington.edu)

Inappropriate Medication Use Among Elderly Europeans: Interesting differences between countries are uncovered in a study of 2,707 European elderly patients receiving home care in metropolitan areas of 8 countries (pp. 1348-58). Assessing patients in Sept. 2001 through Jan. 2002 using the Minimum Data Set in Home Care instrument, the investigators report, “We found that 19.8% of patients in the total sample used at least 1 inappropriate medication; using older 1997 criteria it was 9.8% to 10.9%. Substantial differences were documented between Eastern Europe (41.1% in the Czech Republic) and Western Europe (mean 15.8%, ranging from 5.8% in Denmark to 26.5% in Italy). Potentially inappropriate medication use was associated with patient’s poor economic situation (adjusted relative risk [RR], 1.96; 95% confidence interval [CI], 1.58–2.36), polypharmacy (RR, 1.91; 95% CI, 1.62–2.22), anxiolytic drug use (RR, 1.82; 95% CI, 1.51–2.15), and depression (RR, 1.29; 95% CI, 1.06–1.55). Negatively associated factors were age 85 years and older (RR, 0.78; 95% CI, 0.65–0.92) and living alone (RR, 0.76; 95% CI, 0.64–0.89). The odds of potentially inappropriate medication use significantly increased with the number of associated factors (P < .001).” (D. Fialová, Charles U., Prague, Czech Republic; fickova@faf.cuni.cz)

Error-Reporting Systems: Hospital executives believe mandatory reporting of patient safety incidents to government agencies would produce more lawsuits while failing to improve patient safety, according to a survey of 203 chief executive or operating officers from six states with varying requirements (pp. 1359-66): “More than 80% felt that the names of both the hospital and the involved professionals should be kept confidential, although respondents from states with mandatory public disclosure systems were more willing than respondents from the other states to release the hospital name (22% vs 4%–6%, P = .005).” (J. S. Weissman, jweissman@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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 17, 2005 Vol. 12, No. 52
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Mar. 17 issue of the New England Journal of Medicine (content.nejm.org; 2005; 352).

COX-2 Inhibitors: Published in this issue are the three research articles and two editorials released just before last month’s FDA hearings into the safety of these drugs (see PNN, Feb. 17). The articles assess the cardiovascular risk of celecoxib or rofecoxib among participants in colorectal adenoma prevention trials (pp. 1071-80 and 1092-102) and detail complications of parecoxib and valdecoxib treatment of patients who had undergone cardiac surgery (pp. 1081-91).

Describing the COX-2 inhibitor events of the past few months as “a lesson in unexpected problems,”
Journal editor J. M. Drazen writes in the first editorial (pp. 1131-2), “When the CLASS and VIGOR trials were started, the cardiovascular adverse events were not foreseen. However, when these clinical trials showed an increased risk of myocardial infarction, rather than consider this finding a major danger signal, the manufacturers designed trials to show efficacy for other indications and enhanced the cardiovascular safety monitoring in these subsequent trials. It is a sobering thought that although the number of deaths and cardiovascular events attributable to COX-2 inhibitors remains in dispute, had trials designed to test the question of cardiovascular toxicity directly been launched in 1999 and executed with urgency, substantial morbidity and perhaps a substantial number of deaths could have been prevented. As we apply new science to develop new medicines, we must not forget that our first job is to do no harm.”

Turning to the “lesson in drug safety” afforded by the COX-2 controversy, authors of the second editorial note (pp. 1133-5): “Without the efficacy results from the colorectal-polyp prevention studies, it is not possible to assess the balance of risk and benefit. Although the cardiovascular risks of COX-2 inhibitors are now more clearly documented, they have not been adequately evaluated in long-term studies in low-risk populations or high-risk populations. The absence of evidence here is not evidence of safety. In clinical trials, NSAIDs, aspirin, and acetaminophen are just as effective in relieving pain as the COX-2 inhibitors. If a COX-2 inhibitor were necessary, patients would have to be informed of the potential risks, and the lowest possible dose should be used for the shortest possible time.” (B. M. Psaty, U. Washington, Seattle)

Potential Decline in U.S. Life Expectancy: The impact on obesity is being ignored in Social Security Administration calculations that project a continued climb in life expectancy among Americans, argue authors of a special report (pp. 1138-45). Their conclusion reads, “Unless effective population-level interventions to reduce obesity are developed, the steady rise in life expectancy observed in the modern era may soon come to an end and the youth of today may, on average, live less healthy and possibly even shorter lives than their parents. The health and life expectancy of minority populations may be hit hardest by obesity, because within these subgroups, access to health care is limited and childhood and adult obesity has increased the fastest. In fact, if the negative effect of obesity on life expectancy continues to worsen, and current trends in prevalence suggest it will, then gains in health and longevity that have taken decades to achieve may be quickly reversed. The optimism of scientists and of policymaking bodies about the future course of life expectancy should be tempered by a realistic acknowledgment that major threats to the health and longevity of younger generations today are already visible.” (S. J. Olshansky, sjayo@uic.edu)

>>>PNN NewsWatch
* The product labeling for interferon beta-1a (Avonex, Biogen) has been updated to warn of the possibility of severe hepatic injury, hepatic failure, and asymptomatic increases in serum transaminases during drug use.

*
Temozolomide (Temodar, Schering) has been approved for extending lives of adult patients newly diagnosed with glioblastoma multiforme when used concurrently with radiotherapy and as maintenance therapy after radiotherapy.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 18, 2005 Vol. 12, No. 53
Providing news and information about medications and their proper use

>>>Pramlintide Approved
Patients with diabetes will soon have a new short-acting option for improving glycemic control. FDA yesterday announced approval of pramlintide acetate (Symlin, Amylin) for adjunctive treatment of adult patients with type 1 or type 2 diabetes. The injectable synthetic analogue of the human hormone amylin is approved for use at mealtimes in conjunction with insulin for treating type 1 diabetes and a sulfonylurea and/or metformin in treating type 2 diabetes.

In clinical trials of more than 5,300 patients, pramlintide improved blood glucose control and weight loss. It is generally administered with meals and helps to lower blood glucose for about 3 hours. FDA has approved a Medication Guide for patients using the agent and a risk-minimization plan for the product.

Pramlintide is contraindicated in patients who cannot tell when their blood glucose is low, have gastroparesis, or allergic to the drug, metacresol, d-mannitol, acetic acid, or sodium acetate. Adverse effects include nausea, vomiting, abdominal pain, headache, fatigue, and dizziness.

>>>Pediatrics Highlights
Source:
Mar. issue of Pediatrics (www.pediatrics.org; 2005; 115).

Vitamin A Supplements for Premies: Use of vitamin A for reduction of bronchopulmonary dysplasia did not increase mortality or impair neurologic development at 18–22 months, report authors of a study that assessed developmental progress among extremely low birth weight infants (e249-e254). In the study, vitamin A supplements reduced the relative risk of BPD by 11% when administered during the first month of life. “The primary outcome of [neurodevelopmental impairment] or death could be determined for 687 of 807 randomized infants (85%),” the authors write. “Baseline characteristics and predischarge and postdischarge mortality were comparable in both study groups. NDI or death by 18 to 22 months occurred in 190 of 345 (55%) infants in the vitamin A group and in 204 of 342 (60%) of the control group (RR: 0.94; 95% confidence interval: 0.80–1.07). RRs for low [Bayley Mental Index], low [Psychomotor Index], and [cerebral palsy] were also <1.0. We found no evidence that neonatal vitamin A supplementation reduces hospitalizations or pulmonary problems after discharge.” (N. Ambalavanan, U. Alabama, Birmingham)

Use of Folk Remedies Among Caregivers of Black Children:
Knowledge and use of folk remedies was ubiquitous among 107 caregivers of healthy black children younger than 2 years of age in Detroit (e297-e304). “All participants were familiar with the use of folk remedies,” the participants reported during structured interviews. “Most caregivers learned of these remedies from their mothers or grandmothers. Older parents were more likely to use folk remedies, but there was no difference in remedy use among different levels of maternal education.” (L. C. Smitherman, Children’s Hospital of Michigan, Detroit)

Legal Perspective on Complementary Therapies: Medical malpractice and/or professional discipline could result from pediatricians’ recommendations that unproven complementary and alternative medicine be used for pediatric patients, according to a legal review article (pp. 774-80). The authors note: “Pediatricians can incorporate these considerations into advising and clinical decision-making about CAM therapies to address the best interest of the pediatric patient while helping to manage potential liability risk. This article provides a suggested framework, including asking the following questions: (1) Do parents elect to abandon effective care when the child’s condition is serious or life-threatening? (2) Will use of the CAM therapy otherwise divert the child from imminently necessary conventional treatment? (3) Are the CAM therapies selected known to be unsafe and/or ineffective? (4) Have the proper parties consented to the use of the CAM therapy? (5) Is the risk-benefit ratio of the proposed CAM therapy acceptable to a reasonable, similarly situated clinician, and does the therapy have at least minority acceptance or support in the medical literature? Such an approach ideally can help guide the pediatrician toward clinical conduct that is clinically responsible, ethically appropriate, and legally defensible.” (M. H. Cohen, Harvard Med. Sch., 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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 21, 2005 Vol. 12, No. 54
Providing news and information about medications and their proper use

>>>Lancet Report
Source:
Online articles and the Mar. 19 issue of Lancet (www.thelancet.com; 2005; 365).

Injection Facilities for IDUs: Reduced syringe sharing was evident among injection drug users following opening of a new injection facility in Vancouver (published online): “Safer injection facilities provide medical supervision for illicit drug injections. We aimed to examine factors associated with syringe sharing in a community-recruited cohort of illicit injection drug users in a setting where such a facility had recently opened. Between Dec 1, 2003, and June 1, 2004, of 431 active injection drug users 49 (11.4%, 95% CI 8.5–14.3) reported syringe sharing in the past 6 months. In logistic regression analyses, use of the facility was independently associated with reduced syringe sharing (adjusted odds ratio 0.30, 0·11–0.82, p = 0.02) after adjustment for relevant sociodemographic and drug-use characteristics. These findings could help inform discussions about the merits of such facilities.” (T. Kerr, tkerr@cfenet.ubc.ca)

Multidrug-Resistant HIV: A case report of transmission of multidrug-resistant HIV and rapid progression to AIDS is reported, and the authors express concern about the patient’s high-risk sexual contacts and use of methamphetamine (pp. 1031-8). “Our patient seems to have been recently infected by a viral variant of HIV-1 resistant to multiple classes of antiretroviral drugs,” the authors note. “Furthermore, his virus population is dual tropic for cells that express CCR5 or CXCR4 coreceptor. The infection has resulted in progression to symptomatic AIDS in 4–20 months.” The researchers add, “Another concern is this man's history of a large number of high-risk sexual contacts and [methamphetamine] use. Convergence of his sexual history with the multidrug resistant and rapidly-progressing nature of his illness led us to bring this case to the special attention of the New York City Department of Health and Mental Hygiene. Because of the public-health ramifications, they issued a health alert to physicians in the area on Feb 11, 2005.” (M. Markowitz, Rockefeller U., New York; mmarkowitz@adarc.org)

>>>BMJ Highlights
Source:
Mar. 19 issue of BMJ (www.bmj.org; 2005; 330).

BNP Utility: B-type natriuretic peptide “is a strong prognostic indicator for both asymptomatic patients and for patients with heart failure at all stages of disease,” according to a systematic review of 19 studies (pp. 625). Despite difficulties inherent in prognostic studies and the possibility of publication bias, the authors note, “In heart failure patients, each 100 pg/ml increase was associated with a 35% increase in the relative risk of death. BNP was used in 35 multivariable models of prognosis. In nine of the models, it was the only variable to reach significance—that is, other variables contained no prognostic information beyond that of BNP. Even allowing for the scale of the variables, it seems to be a strong indicator of risk.” (J. Doust, U. Queensland, Herston, Australia; j.doust@sph.uq.edu.au)

>>>PNN NewsWatch
* Late Friday, FDA issued a nationwide alert against the use of PharMEDium Services Magnesium Sulfate 1 gram in 50mL D5W IV solution, lot number 100504900049 and expiration date 4/4/05. This product is manufactured by PharMEDium Services of Houston and may be contaminated with Serratia marcescens. Hospitals with questions may contact the company at 847-457-2300, and problems can be reported to FDA’s MedWatch office at 800-FDA-1088.

>>>PNN JournalWatch
* Acquired Mutation of the Tyrosine Kinase JAK2 in Human Myeloproliferative Disorders, in Lancet, 2005; 365: 1054–61. Reprints: www.thelancet.com; A. R. Green, U. Cambridge, Cambridge, U.K.; arg1000@cam.ac.uk

* Improving Clinical Practice Using Clinical Decision Support Systems: A Systematic Review of Trials to Identify Features Critical to Success, in
BMJ, 2005 (published online). Reprints: www.bmj.org; K. Kawamoto, Duke U. Med. Ctr., Durham, N.C.

* The Serotonin Syndrome, in
New England Journal of Medicine, 2005; 352: 1112–20. Reprints: contents.nejm.org; E. W. Boyer, edward.boyer@tch.harvard.edu

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 22, 2005 Vol. 12, No. 55
Providing news and information about medications and their proper use

>>>Chest Highlights
Source:
Mar. issue of Chest (www.chestjournal.org; 2005; 127).

Warfarin in High-Risk Surgical Patients: In 100 consecutive patients considered at high risk of bleeding but for whom warfarin was nonetheless continued perioperatively using a lower target INR (1.5–2), few bleeding events occurred, and investigators conclude that the practice is reasonable (pp. 922-7). Most patients were considered at high risk because of thromboembolic events within the past 6 months (62%) or prior postoperative venous thromboembolism (11%). “Two patients had major bleeding, and four patients had minor bleeding” report the researchers. “One patient developed deep venous thrombosis. Several weeks after surgery, one patient with a prosthetic heart valve died from an embolic stroke, which was associated with a failure to increase his anticoagulation to therapeutic levels.” (C. S. Kitchens, craig.kitchens@med.va.gov)

Pulmonary Rehabilitation & Tiotropium in COPD: Improved endurance, less dyspnea, and improved health status were evident among patients with chronic obstructive pulmonary disorder who were treated with tiotropium (pp. 809-17). Comparing 47 patients taking the study drug and 44 patients receiving placebo, the investigators found, “Mean endurance time differences (tiotropium minus placebo) prior to [pulmonary rehabilitation], at the end of PR, and 12 weeks after PR were 1.65 min (p = 0.183), 5.35 min (p = 0.025), and 6.60 min (p = 0.018), respectively. Mean [transition dyspnea index] focal scores at the end of PR were 1.75 for tiotropium and 0.91 for placebo (p > 0.05). At 12 weeks after PR, [transition dyspnea index] focal scores were 1.75 for tiotropium and 0.08 for placebo (p < 0.05). Relative to placebo, tiotropium improved [St. George’s respiratory questionnaire] total scores by 3.86 at the end of PR and 4.44 at 12 weeks after PR (p > 0.05). Mean albuterol use declined following PR plus tiotropium, compared to PR alone (p ≤ 0.05 for 17 of 25 weeks).” (R. Casaburi, casaburi@ucla.edu)

Beta-Blockers in COPD: Selectivity of beta-blockers influences the drugs’ pulmonary effects, conclude authors who found potential problems with nonselective agents such as propranolol (pp. 818-24). The study included 15 patients who received propranolol 80 mg, the cardioselective agents metoprolol 100 mg or celiprolol 200 mg, or placebo for 4 days, followed by a washout period of at least 3 days. “On day 4 of treatment, FEV1 and [the provocative concentration of methacholine causing a 20% fall in FEV1 (PC20)] were assessed,” the researchers report. “Immediately hereafter, formoterol 12 mcg was administered and FEV1 was measured for up to 30 min.... PC20 was significantly lower (p < 0.01) with propranolol and metoprolol treatment (geometric means, 2.06 mg/mL and 2.02 mg/mL, respectively) than with placebo (3.16 mg/mL) or celiprolol (3.41 mg/mL). FEV1 deteriorated only after propranolol treatment (2.08 ± 0.31 L) [mean ± SD] compared with placebo (2.24 ± 0.37 L). The fast bronchodilating effect of formoterol was hampered by propranolol (mean increase in FEV1 at 3 min, 6.7 ± 8.9%) but was unaffected by the other beta-blockers (16.9 ± 9.8%, 22 ± 11.6%, and 16.9 ± 9.0% for placebo, metoprolol, and celiprolol, respectively).” (H. J. van der Woude, Martini Hosp., Groningen, the Netherlands; jvbhw@home.nl)

Infliximab Treatment of Sarcoidosis: Infliximab improved symptoms in 9 of 10 patients with refractory sarcoidosis and decreased the doses of corticosteroids required by 5 of 6 patients taking these agents when infliximab therapy was begun, note authors of a case series (pp. 1064-71). The investigators conclude: “Infliximab appears to be an effective, safe treatment for patients with refractory sarcoidosis, including such manifestations as lupus pernio, uveitis, hepatic sarcoidosis, and neurosarcoidosis. Infliximab appears to be steroid sparing. Patients receiving the drug should be screened for latent tuberculosis and lymphoproliferative disorders.” (M. A. Judson, judsonma@musc.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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 23, 2005 Vol. 12, No. 56
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Mar. 23/30 issue of JAMA (www.jama.com; 2005; 293).

Risk Factors with Health Professional Substance Use: Use of a major opioid, coexisting psychiatric illness, and a family history of a substance use disorder increase the risk of relapse for substance use among health professionals, according to a study of 292 individuals (pp. 1453-60). Analysis of retrospective cohort data on professionals enrolled in the Washington Physicians Health Program shows: “Twenty-five percent (74 of 292 individuals) had at least 1 relapse. A family history of a substance use disorder increased the risk of relapse (hazard ratio [HR], 2.29; 95% confidence interval [CI], 1.44–3.64). The use of a major opioid increased the risk of relapse significantly in the presence of a coexisting psychiatric disorder (HR, 5.79; 95% CI, 2.89–11.42) but not in the absence of a coexisting psychiatric disorder (HR, 0.85; 95% CI, 0.33–2.17). The presence of all 3 factors—major opioid use, dual diagnosis, and family history—markedly increased the risk of relapse (HR, 13.25; 95% CI, 5.22–33.59). The risk of subsequent relapses increased after the first relapse (HR, 1.69; 95% CI, 1.13–2.53).” (K. B. Domino, kdomino@u.washington.edu)

Asking what these results mean for physicians and everyone else, an editorialist writes (pp. 1513-5): “Individualized monitoring plans and treatment contracts that take into account various risk loadings should improve outcomes for patients with substance use disorders. Success from substance use disorder treatment should be sought and expected not just for physicians but for every patient—but only if the conditions available for physician recovery can be provided to all. These ‘ifs’ are pivotal: if intervention occurs early, if structure is provided as well as support, if treatment resources are provided as if a life and career matter, and if close monitoring and treatment matching are provided with active treatment intervention and escalation to meet the clinical need. Surely this type of care is costly. Why should such high-quality care be provided? Because a brain disease that subverts self-preservation is a disease nonetheless, and helping patients recover from this disease can save lives, families, and productive careers.” (D. R. Gastfriend, Alkermes Inc., Cambridge, Mass., david.gastfriend@alkermes.com)

Mercaptopurine in Childhood ALL: Thiopurine methyltransferase genotype has an important impact on residual disease following mercaptopurine treatment of children with acute lymphoblastic leukemia, conclude researchers who assessed 814 patients in Germany (pp. 1485-9). “Patients (n = 55) heterozygous for allelic variants of TPMT conferring lower enzyme activity had a significantly lower rate of minimal residual disease positivity (9.1%) compared with patients (n = 755) with homozygous wild-type alleles (22.8%) on day 78 (P = .02,” the authors explain. “This translated into a 2.9-fold reduction in risk for patients with wild-type heterozygous alleles (relative risk, 0.34; 95% confidence interval, 0.13–0.86).” The group concludes, “TPMT genotype has a substantial impact on minimal residual disease after administration of mercaptopurine in the early course of childhood ALL, most likely through modulation of mercaptopurine dose intensity. Our findings support a role for minimal residual disease analyses in the assessment of genotype-phenotype associations in multiagent chemotherapeutic trials.” (M. Stanulla, Hannover Med. Sch., Hannover, Germany; Stanulla.Martin@MH-Hannover.de)

Diabetes & Coronary Revascularization: “There is a relative lack of data from [randomized controlled trials] specifically comparing CABG surgery and PCI as currently practiced in diabetic patients,” conclude authors of a review article on coronary revascularization procedures in patients with diabetes (pp. 1501-8).. “The mortality advantage and decreased rates of revascularization seen with CABG in subgroups from early trials may not be applicable in the era of drug-eluting stents, glycoprotein IIb/IIIa inhibitors, and the latest medical therapies.” (C. J. Davidson, Northwestern Mem. Hosp., Chicago; cdavidso@nmh.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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 24, 2005 Vol. 12, No. 57
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Mar. 24 issue of the New England Journal of Medicine (content.nejm.org; 2005; 352).

Clopidogrel for MI with ST Elevation: The early-release research article (pp. 1179-89) and related editorial (pp. 1248-50) on addition of clopidogrel to standard therapy for myocardial infarction with ST-segment elevation are published in this issue (see PNN, Mar. 10).

Chemotherapy Options for Localized Aggressive Lymphoma: The Groupe d’Etude des Lymphomes de l’Adulte (GELA) finds three cycles of intensified doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP) superior to three cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus involved-field radiotherapy among 647 previously untreated patients with localized stage I or II lymphoma (pp. 1197-205). “With a median follow-up of 7.7 years, event-free and overall survival rates were significantly higher in the group given chemotherapy alone than in the group given CHOP plus radiotherapy (P < 0.001 and P = 0.001, respectively),” the authors write. “The five-year estimates of event-free survival were 82 percent (95 percent confidence interval, 78 to 87 percent) for patients receiving chemotherapy alone and 74 percent (95 percent confidence interval, 69 to 78 percent) for those receiving chemoradiotherapy. The respective five-year estimates of overall survival were 90 percent (95 percent confidence interval, 87 to 93 percent) and 81 percent (95 percent confidence interval, 77 to 86 percent). In a multivariate analysis, event-free and overall survival rates were affected by treatment group, independently of tumor stage and the presence or absence of bulky disease.” (F. Reyes, Hôpital Henri Mondor, Créteil, France; felix.reyes@hmn.ap-hop-paris.fr)

An editorialist, commenting on this study, calls for better identification of patient subgroups who could benefit from various lymphoma regimens (pp. 1250-2): “As the concept of staging continues to evolve, multiple factors other than the Ann Arbor stage will be important in predicting prognosis and choosing treatment for patients with aggressive non-Hodgkin’s lymphoma. In addition to the factors considered in the [International Prognostic Index], the specific type of non-Hodgkin’s lymphoma, the specific extranodal primary sites, and the patterns of gene and protein expression are likely eventually to be incorporated into staging systems. Correlating these observations with specific treatments might allow the identification of subgroups of patients most likely to benefit from a particular intensive regimen, such as ACVBP, or those for whom a simpler and less toxic treatment would be equally efficacious. For example, ACVBP may not have been the best treatment for all patients in the study by Reyes et al. Physicians who treat patients with lymphomas hope that we will continue to move away from the ‘one-size-fits-all’ approach to the management of aggressive lymphomas.” (J. O. Armitage, U. Nebraska, Omaha)

FDA & Drug Safety: In a Perspectives, a Journal contributing editor identifies the problems and pitfalls in FDA’s efforts to improve its oversight of safety of marketed drugs (pp. 1173-6). "’The preapproval system is really designed and powered to detect efficacy’ rather than safety, according to Alastair J. J. Wood, a professor of medicine and pharmacology at Vanderbilt University School of Medicine, who chaired the recent FDA advisory committee hearing on the safety of cyclooxygenase-2 (COX-2) inhibitors,” the author notes, based on one of several interviews conducted for the article. “‘That’s probably not an inappropriate balance,’ Wood said in an interview, ‘but we’d be more comfortable if we had a better postapproval monitoring system.’ Wood suggests allowing new medications to be marketed with limited FDA approval and then requiring the manufacturer, as a condition of retaining its patent exclusivity, to collect extensive additional data on safety for several years. He favors such an approach over one that severely delays access to new drugs by forcing companies to conduct studies involving tens of thousands of users before approval.” (S. Okie)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 25, 2005 Vol. 12, No. 58
Providing news and information about medications and their proper use

>>>Infectious Disease Update
Source:
Apr. 1 and Apr. 15 issues of Clinical Infectious Diseases (www.journals.uchicago.edu/CID; 2005; 40).

Treatment of Multidrug-Resistant TB: In a study of multidrug-resistant tuberculosis in patients in San Francisco, treatment of HIV-seronegative patients was feasible at costs lower than previously reported, but those “with underlying HIV infections had very poor outcomes,” researchers reported (pp. 968-75). Based on billing charges and genotyping results of clinical isolates of Mycobacterium tuberculosis, the investigators showed, “Forty-eight cases were identified with resistance to a median of 3 drugs (range, 29 drugs). The median age of the patients was 49.5 years (range, 2278 years); 36 (75%) of 48 patients were foreign born, 11 (23%) were human immunodeficiency virus (HIV) seropositive, and 45 (94%) had pulmonary tuberculosis. Thirty-two (97%) of the 33 HIV-seronegative patients were cured, with only 1 relapse occurring 5 years after treatment. All 11 HIV-seropositive patients died during observation. Twenty-one patients (44%) required hospitalization, with a median duration of stay of 14 days (range, 374 days). The estimated inpatient and outpatient aggregate cost for the 11 patients treated after 1994 was $519,928, with a median cost of $27,752 per patient. No secondary cases of multidrug-resistant tuberculosis were identified through population-based genotyping.” (M. Burgos, mburgos@salud.unm.edu)

Levofloxacin Prophylaxis During Neutropenia: Increasing rates of fluoroquinolone resistance are problematic, but patients with neutropenia during treatment of hematologic malignancies can still benefit from levofloxacin prophylaxis, according to results of a study of 310 patients (pp. 1087-93). However, monitoring for gram-negative bacteremia must continue during prophylaxis to detect loss of efficacy of fluoroquinolones, the group concludes based on these results: “After a 12-month baseline period of levofloxacin prophylaxis, a period of discontinuation of fluoroquinolone prophylaxis was planned but was stopped prematurely after 9 neutropenic episodes over 3 weeks, because the mortality rate (33.3%) was higher than that with routine fluoroquinolone prophylaxis (2.9%) (odds ratio [OR], 16.6; 95% confidence interval [CI], 3.6–77.2). Fewer patients had gram-negative bacteremia during the baseline period (4.8%; n = 15) than during the discontinuation period (44.4%; n = 4) (OR, 16.9; 95% CI, 4.1–70.0). After levofloxacin therapy was reintroduced, the incidence of gram-negative bacteremia and the mortality rate were comparable to those during the first period. Escherichia coli isolated during the discontinuation period was susceptible to levofloxacin in vitro, whereas all E. coli isolates isolated during both prophylaxis periods were resistant. Bloodstream infections were caused by a single agent when the patient had received levofloxacin prophylaxis, whereas most cases of gram-negative bacteremia were polymicrobial after discontinuation.” (S. Reuter, U. Hosp., Ulm, Germany; stefan.reuter@medizin.uni-ulm.de)

An editorialist adds (pp. 1094-5): “The entire issue of fluoroquinolone prophylaxis for patients with neutropenia and cancer leads to the question of the efficacy of outpatient oral therapy for fever in low-risk patients. The Ulm group's finding of high rates of infection and colonization with fluoroquinolone-resistant gram-negative rods raises concern about the future efficacy of oral fluoroquinolone regimens in this population.” (S. H. Zinner, szinner@caregroup.harvard.edu)

>>>PNN NewsWatch
* In an article released early by the Journal of the American College of Cardiology, a pharmacodynamic interaction between naproxen and aspirin is reported in which naproxen interferes with aspirin’s cardioprotective effects on platelet COX-1 (www.cardiosource.com).

*
FDA yesterday released three final risk-management guidance documents: Premarketing Risk Assessment, Development and Use of Risk Minimization Action Plans, and Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment. These describe pre-market risk assessment; development, implementation, and evaluation of risk minimization action plans; and good pharmacovigilance practices.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 28, 2005 Vol. 12, No. 59
Providing news and information about medications and their proper use

>>>Ibandronate Approved
The first once-monthly prevention and treatment for postmenopausal osteoporosis gained FDA approval on Friday. Monthly ibandronate sodium (Boniva, Roche and GlaxoSmithKline) will be marketed in 150-mg tablets, providing dosing with 1 tablet, and packaged in boxes of 3 blister packs with 1 tablet each.

Ibandronate was originally approved by FDA in May 2003 as a daily treatment of 2.5 mg, but the companies delayed marketing until this once-monthly strength was approved. Both strengths will be available to pharmacies during April.

The agent carries the same dosing precautions as other bisphosphonates (take with plain water first thing in the morning on an empty stomach, remain upright and avoid food, drink, and other medications after ingestion, for 60 minutes in the case of ibandronate), but the regimen will be less onerous since it will be only once monthly with the higher dosage. Patients will need to set their “Boniva Day,” as the drug should be taken on the same day each month. A patient package insert provides advice on appropriate recommendations if a monthly dose is missed.

>>>BMJ Highlights
Source:
Articles published online by BMJ (www.bmj.org; 2005; 330).

Statins & Secondary Prevention in Primary Care: For patient groups that were not well represented in clinical trials of statins, efficacy results are similar to those established in randomized studies, according to an analysis of 4,892 patients discharged from Scottish hospitals in 1993 through 2001 (doi:10.1136/bmj.
38398.408032.8F). “319 deaths occurred in the statin treated group (age adjusted rate 4.1 per 100 person years, 95% confidence interval 3.2 to 4.9), and 1200 in the statin untreated group (12.7 per 100 person years, 11.1 to 14.3). More older people and women were represented in the population of patients treated with statins than among those recruited into clinical trials (mean age 67.8 v 59.8; women 39.6% v 16.9%, respectively). The effects of statins in routine clinical practice were consistent with, and similar to, those reported in clinical trials (adjusted hazard ratio for all cause mortality 0.69, 95% confidence interval 0.59 to 0.80; adjusted hazard ratio for cardiovascular recurrence 0.82, 0.71 to 0.95).” (L. Wei, Ninewells Hospital and Medical School, Dundee, U.K.)

Tamoxifen & Nonalcoholic Steatohepatitis: While tamoxifen was associated with development of nonalcoholic steatohepatitis among overweight and obese women with normal baseline liver function, the disease appeared indolent during 10 years of follow-up (doi:10.1136/bmj.38391.663287.E0). Among 5,408 women in an Italian chemoprevention trial, researchers identified 64 with nonalcoholic steatohepatitis, including 12 who were hepatitis C positive: “Factors associated with the development of non-alcoholic fatty liver disease included overweight (2.4, 1.2 to 4.8), obesity (3.6, 1.7 to 7.6), hypercholesterolaemia (3.4, 1.4 to 7.8), and arterial hypertension (2.0, 1.0 to 3.8). Twenty women had liver biopsies: 15 were diagnosed as having mild to moderate steatohepatitis (12 tamoxifen, 3 placebo), and five had fatty liver alone (1 tamoxifen, 4 placebo). No clinical, biochemical, ultrasonic, or histological signs suggestive of progression to cirrhosis were observed after a median follow up of 8.7 years.” (S. Bruno, Azienda Ospedaliera Fatebenefratelli e Oftalmico, Milan, Italy)

>>>PNN JournalWatch
* New Considerations in Infectious Disease Outbreaks: The Threat of Genetically Modified Microbes, in Clinical Infectious Diseases, 2005; 40: 1160–5. Reprints: www.journals.uchicago.edu/CID; J. R. Gilsdorf, gilsdorf@umich.edu

* Recent Hypertension Trials: Implications and Controversies, in
Journal of the American College of Cardiology, 2005; 45: 813–27. Reprints: www.cardiosource.com; B. Williams, Leicester Royal Infirmary, Leicester, U.K.

* Hemodynamic and Autonomic Effects of Smokeless Tobacco in Healthy Young Men, in
Journal of the American College of Cardiology, 2005; 45: 910–4. Reprints: www.cardiosource.com; V. K. Somers, Mayo Clinic, Rochester, Minn.

* Deep Vein Thrombosis, in
Lancet, 2005; 365: 1163–74. Reprints: www.thelancet.com; P. A. Kyrle, Med. U., Vienna, Austria; paul.kyrle@meduniwien.ac.at

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 29, 2005 Vol. 12, No. 60
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Mar. 29 issue of Archives of Internal Medicine, a special issue on professionalism and professional ethics in medicine (www.archinternmed.com; 2005; 165).

Physicians’ Efforts to Reduce Prescription Costs: In an effort to limit patients’ out-of-pocket payments for prescription drugs, generalist and specialist physicians use a variety of strategies, but barriers to patient–physician communications limit their effectiveness, report researchers who conducted a national 1–5 scale survey of cardiologists and general internists (pp. 633-6). “Overall, 519 (39.1%) of 1328 eligible physicians responded to the survey,” the authors write. “The most common barriers were lack of habit, insufficient time, and concern over patient discomfort. The most common strategies used to assist patients were switching to a generic drug (mean, 4.34; SD, 0.86), using office samples (mean, 4.16; SD, 1.22), and discontinuing nonessential medicines (mean, 4.03; SD, 0.99). There were no statistically significant differences between cardiologists and general internists in barriers or strategies examined (P < .05).” (G. C. Alexander, galexand@uchicago.edu)

Physician Attitudes Toward HIV-Infected IDUs: Education and experience-based exercises are suggested as ways of improving physicians’ largely negative attitudes toward HIV-infected injection drug users, along with ensuring that clinicians have enough time to deal with complex problems (pp. 618-23). Based on a cross-sectional surveys of noninstitutionalized HIV-infected individuals and their main HIV care physicians, researchers report: “Nationally, 23.2% of HIV-infected patients had physicians with negative attitudes toward IDUs. Seeing more IDUs, having higher HIV treatment knowledge scores, and treating fewer patients per week were independently associated with more positive attitudes toward IDUs. Injection drug users who were cared for by physicians with negative attitudes had a significantly lower adjusted rate of exposure to highly active antiretroviral therapy by December 1996 (13.5%) than non-IDUs who were cared for by such physicians (36.1%) or IDUs who were cared for by physicians with positive attitudes (32.3%). Physician attitudes were not associated with other problems with care, satisfaction with care, unmet needs, or perceived access to care.” (P. D. Cleary, cleary@hcp.med.harvard.edu)

Disclosure of Physicians’ Financial Incentives: In health plans, what do patients want to know about financial incentives provided to their physicians, and how do they react to the information? Those questions are addressed in a survey of 2,765 U.S. households (pp. 625-30). “Nearly half (48.8%) of respondents had previously heard of financial incentives to limit test ordering,” report the researchers. “Of the respondents, 94.8% wanted to be told about incentives, at the time of enrollment in a health plan (80.5%), by a health plan representative (44.8%), their physician (17.1%), or both (38.1%). Of the 6 different disclosure strategies, ‘addressing emotions’ and ‘negotiation’ were associated with the best outcomes, while ‘common enemy’ and ‘denying influences’ were most negatively perceived. Black and Hispanic subjects were less likely to express satisfaction or trust and more likely to disenroll or seek a second opinion.” (W. Levinson, wendy.levinson@utoronto.ca)

An editorialist reflects on professionalism and his own experiences in the care provided to his mother (pp. 607-8): “As Peabody wrote in 1927, ‘The good physician knows his patients through and through, and his knowledge is bought dearly. Time, sympathy, and understanding must be lavishly dispensed, but reward is to be found in that personal bond which forms the greatest satisfaction of the practice of medicine. One of the essential qualities of the clinician is interest in humanity, for the secret of the care of the patient is in caring for the patient.’

“I believe strongly that we can address our share of the crisis in health care today by returning and holding fast to these long-held values. I can now say from personal experience that anything less will not satisfy us when our own relatives are sick. Why should we be willing to settle for less when someone else’s mother, father, husband, wife, son, or daughter is the patient?” (P. Greenland, p-greenland@northwestern.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 30, 2005 Vol. 12, No. 61
Providing news and information about medications and their proper use

>>>FDA Approves Two Drugs
Two new medications have been approved by FDA, one a nucleoside analogue indicated for chronic hepatitis B infection and the other an ophthalmic NSAID for patients with ocular inflammation following cataract surgery.

Entecavir (Baraclude, Bristol-Myers Squibb) was approved for treatment of chronic hepatitis B infection in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease. The agent was superior to lamivudine in a 48-week trial, with statistically greater improvements in liver histology, HBV viral load reductions to undetectable levels (defined as less than 300 copies/mL), and normalization of ALT levels.

The most common adverse effects of entecavir have been headache, tiredness, dizziness, and nausea. Cross resistance has been observed among HBV nucleoside analogues. Lamivudine-resistant patients may not respond as well as nucleoside-naive patients to entecavir therapy, BMS cautioned in a news release.

Because of the risk of lactic acidosis and severe hepatomegaly in patients taking nucleoside analogues, patients should be advised to contact a health professional promptly if they feel very weak or tired, have unusual muscle pain, have trouble breathing, have stomach pain with nausea and vomiting, feel cold (especially in their arms and legs), feel dizzy or lightheaded, or have a fast or irregular heartbeat.

Bromfenac ophthalmic solution 0.09% (Xibrom, ISTA Pharmaceuticals) is the new drug indicated for post-cataract-surgery ocular inflammation, and it has the advantage of being dosed twice daily, rather than the four-times-daily schedule of previously approved products. In pivotal studies of 527 patients, a statistically significant proportion of patients treated with bromfenac achieved treatment success, defined as the complete absence of ocular inflammation, compared with those who received placebo. This effect was evident in the bromfenac group by the third day of treatment.

Adverse effects of bromfenac have commonly been abnormal sensation in the eye, conjunctival hyperemia, eye irritation, eye pain, eye pruritus, eye redness, headache, and iritis.

>>>Diabetes Highlights
Source:
Apr. issue of Diabetes Care (care.diabetesjournals.org.; 2005; 28).

Impact of Pharmaceutical Care: Pharmaceutical care “could prove a valuable component of community-based multidisciplinary diabetes care,” conclude researchers who conducted a 12-month intervention with 198 community-based patients with type 2 diabetes (pp. 771-6). “PC patients had face-to-face goal-directed medication and lifestyle counseling at baseline and at 6 and 12 months plus 6-weekly telephone assessments and provision of other educational material,” note the investigators. “At total of 180 patients (91%) completed the study. Mean (95% CI) reductions were greater in PC case subjects (n = 92) than control subjects (n = 88) for HbA1c (–0.5% [95% CI –0.7 to –0.3] vs. 0 [–0.2 to 0.2]) and systolic (–14 mmHg [–19 to –9] vs. –7 [–11 to –2]) and diastolic (–5 mmHg [–8 to –3] vs. –2 [–4 to 1]) blood pressure (P ≤ 0.043). The improvement in HbA1c persisted after adjustment for baseline value and demographic and treatment-specific variables. The median (interquartile range) 10-year estimated risk of a first CHD event decreased in the PC case subjects (25.1% [15.6–36.2] to 20.3 [14.6–30.2]; n = 42, P = 0.002) but not in the control subjects (26.1% [17.2–39.4] vs. 26.4 [16.7–38.0]; n = 52, P = 0.17).” (T. M. E. Davis, Fremantle Hosp., Fremantle, Western Australia, Australia; tdavis@cyllene.uwa.edu.au)

Impact of Self-Management: Reinforcing the kind of diabetes care pharmacists can provide, investigators show that patients with diabetes who knew their A1C values “reported better diabetes care understanding and assessment of their glycemic control than those who did not” (pp. 816-22). Other behavioral strategies must supplement such efforts, however, as information alone did not translate into self-efficacy and self-management behaviors (M. Heisler, mheisler@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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 31, 2005 Vol. 12, No. 62
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Mar. 31 issue of the New England Journal of Medicine (content.nejm.org; 2005; 352).

ASA for Primary Prevention in Women: The study described in PNN on Mar. 8 about use of aspirin for primary cardioprotection in women is published in this issue of NEJM (pp. 1293-304) along with a related editorial (pp. 1366-8).

Warfarin & ASA for Intracranial Stenosis: For patients with symptomatic intracranial arterial stenosis, aspirin should be favored over warfarin, based on the significantly higher rate of adverse events observed with the anticoagulant in the Warfarin–Aspirin Symptomatic Intracranial Disease Trial (pp. 1305-16). Warfarin was dosed to an INR of 2.0 to 3,0, while aspirin was given in doses of 1,300 mg/day, with these results: “After 569 patients had undergone randomization, enrollment was stopped because of concerns about the safety of the patients who had been assigned to receive warfarin. During a mean follow-up period of 1.8 years, adverse events in the two groups included death (4.3 percent in the aspirin group vs. 9.7 percent in the warfarin group; hazard ratio for aspirin relative to warfarin, 0.46; 95 percent confidence interval, 0.23 to 0.90; P = 0.02), major hemorrhage (3.2 percent vs. 8.3 percent, respectively; hazard ratio, 0.39; 95 percent confidence interval, 0.18 to 0.84; P = 0.01), and myocardial infarction or sudden death (2.9 percent vs. 7.3 percent, respectively; hazard ratio, 0.40; 95 percent confidence interval, 0.18 to 0.91; P = 0.02). The rate of death from vascular causes was 3.2 percent in the aspirin group and 5.9 percent in the warfarin group (P = 0.16); the rate of death from nonvascular causes was 1.1 percent and 3.8 percent, respectively (P = 0.05). The primary end point [of ischemic stroke, brain hemorrhage, or death from vascular causes other than stroke] occurred in 22.1 percent of the patients in the aspirin group and 21.8 percent of those in the warfarin group (hazard ratio, 1.04; 95 percent confidence interval, 0.73 to 1.48; P = 0.83).” (M. I. Chimowitz, mchimow@emory.edu)

Sirolimus & Kaposi’s Sarcoma: Sirolimus reduced the progression of dermal Kaposi’s sarcoma among 15 patients who had undergone kidney transplantation while also providing effective immunosuppression, according to investigators who analyzed biopsy specimens for vascular endothelial growth factor, Flk-1/KDR protein, and phosphorylated Akt and p70S6 kinase (pp. 1317-23). “Three months after sirolimus therapy was begun, all cutaneous Kaposi's sarcoma lesions had disappeared in all patients,” the authors report. “Remission was confirmed histologically in all patients six months after sirolimus therapy was begun. There were no acute episodes of rejection or changes in kidney-graft function. Levels of Flk-1/KDR and phosphorylated Akt and p70S6 kinase were increased in Kaposi's sarcoma cells. The expression of VEGF was increased in Kaposi's sarcoma cells and even more so in normal skin cells around the Kaposi's sarcoma lesions.” (G. Grandaliano, U.Bari, Bari, Italy; g.grandaliano@nephro.uniba.it)

Relief of Neuropathic Pain: Combination therapy with morphine plus gabapentin provides better analgesia for neuropathic pain than does either agent alone, conclude authors who compared the agents with placebo (lorazepam) therapy in a 5-week trial (pp. 1324-34): “Of 57 patients who underwent randomization (35 with diabetic neuropathy and 22 with postherpetic neuralgia), 41 completed the trial. Mean daily pain (on a scale from 0 to 10, with higher numbers indicating more severe pain) at a maximal tolerated dose of the study drug was as follows: 5.72 at baseline, 4.49 with placebo, 4.15 with gabapentin, 3.70 with morphine, and 3.06 with the gabapentin–morphine combination (P < 0.05 for the combination vs. placebo, gabapentin, and morphine). Total scores on the Short-Form McGill Pain Questionnaire (on a scale from 0 to 45, with higher numbers indicating more severe pain) at a maximal tolerated dose were 14.4 with placebo, 10.7 with gabapentin, 10.7 with morphine, and 7.5 with the gabapentin–morphine combination (P < 0.05 for the combination vs. placebo, gabapentin, and morphine).” (I. Gilron, Queen's U., Kingston, Ont., Canada; gilroni@post.queensu.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 © 2005, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail lmposey@mac.com or call 800/211-4223 to request missing copies of PNN.