Mar 2007

PNN Quarterly File—First Quarter 2007

PNN Pharmacotherapy Line
Jan. 2, 2007 * Vol. 14, No. 1
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Jan. 2 issue of Annals of Internal Medicine (www.annals.org; 2007; 146).
Alcohol Use & CVD Events in Men with Hypertension: According to a news release issued by Annals, men with high blood pressure can have one or two drinks a day without increasing their risk for heart attack or stroke (pp. 10 ff). A prospective cohort study of nearly 12,000 men with hypertension found that men who drank moderately had reduced risk of myocardial infarction. Moderate alcohol consumption was defined as one to two drinks (glass of beer, a glass of wine or a shot of liquor count) a day.
An accompanying editorial discusses measurement error in nutritional epidemiology studies (p. 65). Current limitations of procedures and reference instruments mean that “we cannot assume that corrected estimates of diet–disease associations in any single study are definitive.”
Folate Intake & Hearing Loss in the Elderly: In a 3-year study, 728 older men and women in the Netherlands with high blood homocysteine levels and no hearing loss were given either daily oral folic acid or a placebo supplement (pp. 1 ff). Daily folic acid supplementation slowed decline in hearing of low frequencies by 0.7 dB after 3 years. Folic acid did not affect hearing thresholds of the high frequencies.
At the time this study was conducted in the Netherlands, folic acid fortification of food was not allowed, so participants’ baseline folate levels were about one-half those found in the U.S. population. The authors note: “Considering that the folate status of older adults is generally low in countries without folic acid fortification programs, our findings suggest a possible way to diminish the public health burden of hearing loss in those countries.”
A related editorial is on p. 63.

>>>BMJ Highlights
Source:
Dec. 23 issue of BMJ (www.bmj.org; 2006; 333).
Mistletoe Extract Injection: In the annual holiday issue of BMJ, authors report a case of subcutaneous inflammation mimicking metastatic malignancy induced by injection of mistletoe extract (pp. 1293-4). Two months following excision of tubular carcinoma of the breast, a 61-year-old woman complained of an abdominal wall mass. After much testing, the patient shared with her surgeon that at the site of the inflammation, she had been self-injecting a whole-plant extract of mistletoe grown on ash trees subcutaneously three times weekly. She was using the complementary therapy as treatment for a lymphoma for 12 months before presentation for the inflammation. Since other causes of the inflammation were ruled out, the authors conclude that “the microscopic features [appear] to be a direct inflammatory response to mistletoe extract.” (A. Finall, U. Hosp. of Wales, Cardiff; Alison.Finall@CardiffandVale.wales.nhs.uk)
>>>PNN JournalWatch
* 2007 Clinical Practice Recommendations, in Diabetes Care, 2007; 30 (suppl 1). Reprints: http://care.diabetesjournals.org/content/vol30/suppl_1/
* Primary Prevention of Cardiovascular Diseases in People with Diabetes Mellitus: A Scientific Statement from the American Heart Association and the American Diabetes Association, in
Diabetes Care, 2007; 30: 162–72 (also published in Circulation). Reprints: http://care.diabetesjournals.org/cgi/content/abstract/30/1/162; H. N. Ginsberg, College of Physicians and Surgeons, New York; hng1@columbia.edu
* Generic Drugs [position statement], in
Diabetes Care, 2007; 30: 173 ff. Reprints: http://care.diabetesjournals.org/cgi/content/extract/30/1/173; American Diabetes Assoc.
* Heart Disease and Stroke Statistics—2007 Update. A Report From the American Heart Association Statistics Committee and Stroke Statistics Subcommittee, in
Circulation, 2007; doi: 10.1161/CIRCULATIONAHA.106.179918. Reprints: http://circ.ahajournals.org/cgi/content/abstract/CIRCULATIONAHA.106.179918v1
* Triglycerides and the Risk of Coronary Heart Disease. 10,158 Incident Cases Among 262,525 Participants in 29 Western Prospective Studies, in
Circulation, 2007; doi:10.1161/CIRCULATIONAHA.106.637793. Reprints: http://circ.ahajournals.org/cgi/content/abstract/CIRCULATIONAHA.106.637793v1; J. Danesh, U. Cambridge, Cambridge, U.K.; john.danesh@phpc.cam.ac.uk
* Pertussis Resurgence: Diagnosis, Treatment, Prevention, and Beyond, in
Pharmacotherapy, 2007; 27: 41–52. Reprints: www.pharmacotherapy.org; S. Raguckas, SarahRaguckas@ferris.edu
* Micafungin: A New Echinocandin Antifungal, in
Pharmacotherapy, 2007; 27: 53–67. Reprints: www.pharmacotherapy.org; R. Jain, rupali@uic.edu

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 3, 2007 * Vol. 14, No. 2
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Jan. 3 issue of JAMA (www.jama.com; 2007; 297).
Pexelizumab During PCI for STEMI: Mortality was “low and unaffected by administration of pexelizumab,” a humanized monoclonal antibody that binds the C5 component of complement, in a group of 5,745 patients with acute ST-elevation myocardial infarction undergoing percutaneous coronary intervention (pp. 43-51). Within 6 hours of symptom onset, patients were randomized to either placebo or pexelizumab 2 mg/kg intravenous bolus before PCI followed by 0.05 mg/kg/hr infusion over the subsequent 24 hours. Results of this Phase III study, the Assessment of Pexelizumab in Acute Myocardial Infarction (APEX AMI) trial, showed the following: “No difference in mortality through day 30 was observed between the pexelizumab and placebo treatment groups, with 116 patients (4.06%) and 113 patients (3.92%) who died in the respective groups (hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.80–1.35; log-rank P = .78). The composite end points of death, shock, or heart failure were also similar with 257 patients (8.99%) receiving pexelizumab and 265 patients (9.19%) receiving placebo at 30 days (HR, 0.98; 95% CI, 0.83–1.16; P = .81) and 293 patients (10.24%) receiving pexelizumab and 293 patients (10.16%) receiving placebo at 90 days (HR, 1.01; 95% CI, 0.86–1.19; P = .91).” (P. W. Armstrong, paul.armstrong@ualberta.ca)
In an editorial, writers describe the quandary for pexelizumab created by an early termination of the APEX AMI trial (pp. 91-2): “Despite the promising results of the early pexelizumab trials, it seems unlikely that this drug provides any major benefit in preventing reperfusion injury when it is used as an adjunct to primary PCI in patients with STEMI. Furthermore, commercial realities make it unlikely that additional trials will be conducted with this drug in the future. The revised statistical analysis plan for the APEX AMI trial, developed in consultation with the US Food and Drug Administration, details plans for a meta-analysis of all 6 completed pexelizumab studies. Even if the meta-analysis reports a significant benefit of pexelizumab, it is unclear whether the Food and Drug Administration will approve the drug or require an additional study. Despite the disappointing results of the pexelizumab trials, the central hypothesis, that modulating inflammatory mediators may improve clinical outcomes by reducing reperfusion injury, remains worthy of further study. Anti-inflammatory therapies that target other aspects of the complement pathway and that target leukocytes, inflammatory mediators (eg, leukotriene B4), and C-reactive protein are currently under investigation.” (J. W. Eikelboom,
eikelb@mcmaster.ca)
Performance Measures for HF: Discharge prescription of an ACE inhibitor or angiotensin II receptor blocker at discharge proved the only currently recommended performance measure that significantly affected 60- to 90-day rates of postdischarge mortality and rehospitalization among 5,791 patients with heart failure, but data support addition of beta-blockers as a new measure (pp. 61-70). Analyzing a 10% sample of patients being discharged following hospitalization for heart failure at 91 U.S. hospitals, researchers found no impact of other recommended interventions, including smoking cessation counseling and anticoagulation for those with atrial fibrillation: “Mortality during follow-up was 8.6% and mortality/rehospitalization was 36.2%. None of the 5 ACC/AHA heart failure performance measures was significantly associated with reduced early mortality risk, and only angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use at discharge was associated with 60- to 90-day postdischarge mortality or rehospitalization. Beta-blockade at the time of hospital discharge, currently not a heart failure performance measure, was strongly associated with reduced risk of mortality (hazard ratio, 0.48; 95% confidence interval, 0.30-0.79; P = .004) and mortality/rehospitalization during follow-up.” (G. C. Fonarow, gfonarow@mednet.ucla.edu)
Making Obesity Illegal: The use of legal interventions such as tort liability, taxes, zoning, and food prohibitions in fighting the obesity epidemic is explored in a commentary (pp. 87-90; L. O. Gostin, Georgetown U., Washington, D.C.).

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 4, 2007 * Vol. 14, No. 3
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Jan. 4 issue of the New England Journal of Medicine (content.nejm.org; 2007; 356).
Dopamine Agonists & Valvular Regurgitation: Two articles and a Perspectives article examine the relationship between use of dopamine agonists and incident cardiac-valve regurgitation.
Newly diagnosed cardiac-valve regurgitation was more common among those using pergolide or cabergoline in an analysis of the U.K. General Practice Research Database for 1988–2005 (pp. 29-38). Among 11,417 participants aged 40–80 years of age who were prescribed antiparkinsonian agents, a nested case–control analysis showed: “Of 31 case patients with newly diagnosed cardiac-valve regurgitation, 6 were currently exposed to pergolide, 6 were currently exposed to cabergoline, and 19 had not been exposed to any dopamine agonist within the previous year. The rate of cardiac-valve regurgitation was increased with current use of pergolide (incidence-rate ratio, 7.1; 95% confidence interval [CI], 2.3 to 22.3) and cabergoline (incidence-rate ratio, 4.9; 95% CI, 1.5 to 15.6), but not with current use of other dopamine agonists.” (R. Schade, Charité-Universitätsmedizin Berlin, Berlin)
Pergolide and cabergoline were linked to an increased frequency of clinically important valve regurgitation in the second study, a problem not found in those taking non–ergot-derived dopamine agonists (pp. 39-46). Performing echocardiographic studies on a convenience sample of 155 patients taking dopamine agonists for Parkinson’s disease, and 90 medical staff, relatives of patients, and other volunteers, the researchers found: “Clinically important regurgitation (moderate to severe, grade 3 to 4) in any valve was found with significantly greater frequency in patients taking pergolide (23.4%) or cabergoline (28.6%) but not in patients taking non–ergot-derived dopamine agonists (0%), as compared with control subjects (5.6%). The relative risk for moderate or severe valve regurgitation in the pergolide group was 6.3 for mitral regurgitation (P = 0.008), 4.2 for aortic regurgitation (P = 0.01), and 5.6 for tricuspid regurgitation (P = 0.16); corresponding relative risks in the cabergoline group were 4.6 (P = 0.09), 7.3 (P < 0.001), and 5.5 (P = 0.12). The mean mitral tenting area was significantly greater in ergot-treated patients and showed a linear relationship with the severity of mitral regurgitation. Patients treated with ergot derivatives who had grade 3 to 4 regurgitation of any valve had received a significantly higher mean cumulative dose of pergolide or cabergoline than had patients with lower grades.” (R. Zanettini, Istituti Clinici di Perfezionamento, Milan, Italy;
cardriab@icp.mi.it)
“These two studies reinforce the notion of a causal association between 5-HT
2B agonism and valvular heart disease,” adds the Perspectives author (pp. 6-9). “Such an association has now been seen with drugs for diverse indications, including anorectic agents (fenfluramine), antimigraine drugs (dihydroergotamine, methysergide, and ergotamine), and antiparkinsonian agents (pergolide and cabergoline). On the basis of these findings, my colleagues and I have urged pharmaceutical companies and regulatory agencies to screen candidate drugs and their major metabolites at 5-HT2B receptors comprehensively before launching clinical trials, in order to prevent ‘fen–phen’-type disasters. Clearly, practitioners should avoid prescribing drugs that are potent 5-HT2B–receptor agonists — a growing list of medications that now includes ergot derivatives (ergotamine, methysergide, and dihydroergotamine), dopamine agonists (pergolide and cabergoline), and amphetamine derivatives (fenfluramine and methylenedioxymethamphetamine [MDMA, or ‘ecstasy’]).” (B. L. Roth, U. North Carolina, Chapel Hill)
Congressional Health Care Agenda: The Democrats today assume control of both the Senate and the House of Representatives, and a writer reviews the health care agenda the party is planning for the 110th Congress (pp. 1-4): “Empowering Medicare to negotiate prices of prescription drugs directly with manufacturers rather than through private health plans and expanding federal support for embryonic stem-cell research” are two of the Democrats’ “Six for ’06” agenda, and the new FDA commissioner “will be spending many hours in front of at least three congressional committees.” (J. K. Iglehart)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 5, 2007 * Vol. 14, No. 4
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Jan. issue of Diabetes Care (care.diabetesjournals.org; 2007; 30).
Rosiglitazone in Hemodialysis Patients: Rosiglitazone may be safely used for diabetes control in patients with chronic viral hepatitis infections who are undergoing regular hemodialysis, but clinicians need to monitor for deterioration in cardiovascular reserve, according to a prospective cohort study (pp. 3-7). “A total of 78 patients [with type 2 diabetes and A1C levels of more than 8%], including 15.4% (n = 12) hepatitis B surface antigen–positive and 16.7% (n = 13) anti–hepatitis C virus (HCV)-positive patients, were enrolled,” the authors write. “The mean follow-up period was 15.4 ± 3.8 months. The diabetic response rate (A1C < 7%) to rosiglitazone was 86.1%. The serum triglyceride level was reduced (194 ± 112.5 to 168 ± 88 mg/dl, P = 0.037) more significantly than the total cholesterol level (178 ± 42.1 to 174 ± 46.5 mg/dl, P = 0.13). High-dose rosiglitazone (8 mg/day) reduced the serum level of C-reactive protein and increased the serum adiponectin level significantly. After rosiglitazone, interdialysis weight gain (2.07 ± 1.6 to 3.2 ± 1.2 kg, P < 0.01) and mean CTR (48.2 ± 5.6 to 50.4 ± 6.2%, P = 0.0213) of individuals increased significantly. Nevertheless, liver aminotransferase (aspartate aminotransferase and alanine aminotransferase) levels did not show a tendency to increase in patients (n = 25) with viral hepatitis B or C infections.” (K-Y Hung, Natl. Taiwan U. Hosp., Taipei; d820612@ha.mc.ntu.edu.tw)
Effects of Duloxetine on Glycemic Control: Pooling data from three clinical trials, researchers determine that duloxetine produces modest increases in fasting plasma glucose when used for treatment of diabetic peripheral neuropathic pain (pp. 21-6). The studies included adults with diabetes and DPNP (n = 1,024) who were randomized to duloxetine 60 mg once or twice daily or placebo for 12 weeks. Following this, 867 participants were re-randomized to duloxetine 60 mg twice daily or routine care for an additional 52 weeks, with these results: “Duloxetine treatment resulted in modest increases in fasting plasma glucose in short- and long-term studies (0.50 and 0.67 mmol/l, respectively). A1C did not increase in placebo-controlled studies; however, a greater increase was seen relative to routine care in long-term studies (0.52 vs. 0.19%). Short-term duloxetine treatment resulted in mean weight loss (–1.03 kg; P < 0.001 vs. placebo), whereas slight, nonsignificant weight gain was seen in both duloxetine and routine care groups with longer treatment. Between-group differences were seen for some lipid parameters, but these changes were generally small. Metabolic changes did not appear to impact improvement in pain severity seen with duloxetine, and nerve conduction was also not significantly impacted by treatment.” (T. Hardy, hardyta@lilly.com)

>>>PNN NewsWatch
* An error in a dosing chart for oseltamivir distributed with a Nov. 13 letter to health professionals is corrected in a Dec. 26 notice from Roche, manufacturer of Tamiflu. According to information posted on FDA’s MedWatch site, the original letter referenced changes to the Precautions Section of prescribing information for Tamiflu about postmarketing reports of self-injury and delirium with the use of Tamiflu in patients with influenza. The prescribing information that accompanied the letter contained an incorrect dosing chart for the Standard Dosage of Tamiflu Oral Suspension for prophylaxis of influenza in pediatric patients. The chart incorrectly specified twice daily instead of once daily dosing under “Recommended Dose” for 10 days. The company asks that pediatric and primary care health professionals discard the original letter and refer to the corrected dosing chart provided in the Dec. 26 communication.
* The
Federal Trade Commission yesterday said that it has filed complaints in four separate cases alleging that weight-loss and weight-control claims were not supported by competent and reliable scientific evidence. Marketers of the four products–Xenadrine EFX, CortiSlim, TrimSpa, and One-A-Day WeightSmart–have settled with the FTC, surrendered cash and other assets worth at least $25 million, and agreed to limit their future advertising claims, the agency stated in a news release.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 8, 2007 * Vol. 14, No. 5
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Jan. 6 issue of Lancet (www.thelancet.com; 2007; 369).
Trastuzumab & Survival After Breast Cancer: In the Herceptin Adjuvant (HERA) study of women with HER2-positive node-positive or high-risk node-negative breast cancer, 1,703 women treated with trastuzumab for 1 year had significantly higher survival than did 1,698 control patients over a median follow-up of 23.5 months (pp. 29-36). “97 (5.7%) patients randomised to observation alone and 58 (3.4%) patients randomised to 1 year of treatment with trastuzumab were lost to follow-up,” the authors explain. “172 women stopped trastuzumab prematurely. 59 deaths were reported for trastuzumab and 90 in the control group. The unadjusted hazard ratio (HR) for the risk of death with trastuzumab compared with observation alone was 0.66 (95% CI 0.47–0.91; p = 0.0115). 218 disease-free survival events were reported with trastuzumab compared with 321 in the control group. The unadjusted HR for the risk of an event with trastuzumab compared with observation alone was 0.64 (0.54–0.76; p < 0.0001).” (I. Smith, Royal Marsden Hosp., London; ian.smith@rmh.nhs.uk)

>>>BMJ Highlights
Source:
Jan. 6 issue of BMJ (www.bmj.org; 2007; 334).
Case Management of Frail Elderly: Hospital admissions were not reduced by case management of frail elderly patients in nine U.K. primary care trusts (pp. 31 ff). “Employment of community matrons is now a key feature of case management policy in the [National Health Service] in England,” the authors write, adding this cautionary note, “Without more radical system redesign this policy is unlikely to reduce hospital admissions.” During pilot tests of case management of elderly patients from Apr. 2001 to Mar. 2005, these results were recorded for the Evercare program: “The intervention had no significant effect on rates of emergency admission (increase 16.5%, (95% confidence interval –5.7% to 38.7%), emergency bed days (increase 19.0%, –5.3% to 43.2%), and mortality (increase 34.4%, –1.7% to 70.3%) for a high risk population aged >65 with a history of two or more emergency admissions in the preceding 13 months. For the general population aged 65 effects on the rates of emergency admission (increase 2.5%, –2.1% to 7.0%), emergency bed days (decrease –4.9%, –10.8% to 1.0%), and mortality (increase 5.5%, –3.5% to 14.5%) were also non-significant.” (M. Roland, U. Manchester, Manchester, U.K.; m.roland@manchester.ac.uk)
Patient Self-Management for LUTS: Among 140 men with uncomplicated lower urinary tract symptoms, a self-management program reduced the frequency of treatment failures and reduced urinary symptoms, compared with usual care (pp. 25 ff). The interventions were educational sessions and advice about modification of lifestyle (e.g., fluid management, caffeine avoidance, and alcohol use) and specific changes in behavior (e.g., bladder retraining, double voiding, and urethral milking) along with training in problem solving and goal setting. Treatment failures were significantly reduced at 3, 6, and 12 months among the intervention group, as were symptom scores. (J. van der Meulen, Royal College of Surgeons of England, London; Jan.vanderMeulen@LSHTM.ac.uk)

>>>PNN JournalWatch
* Medium Intensity Oral Anticoagulants Versus Aspirin After Cerebral Ischaemia of Arterial Origin (ESPRIT): A Randomised Controlled Trial, in Lancet Neurology, 2007; doi: 10.1016/S1474-4422(06)70685-8. Reprints: www.thelancet.com/journals/laneur/article/PIIS1474442206706858; A. Algra, U. Med. Ctr., Utrecht, the Netherlands; a.algra@umcutrecht.nl
* Systematic Review: Efficacy and Safety of Rituximab for Adults with Idiopathic Thrombocytopenic Purpura, in
Annals of Internal Medicine, 2007; 146: 25–33. Reprints: www.annals.org/cgi/content/abstract/146/1/25; D. M. Arnold, arnold@mcmaster.ca
* Prevention of Rotavirus Disease: Guidelines for Use of Rotavirus Vaccine, in
Pediatrics, 2007; 119: 171–82. Reprints: http://pediatrics.aappublications.org/cgi/content/abstract/119/1/171; American Academy of Pediatrics Committee on Infectious Diseases.
* Recommended Immunization Schedules for Children and Adolescents—United States, 2007, in
Pediatrics, 2007; 119: 171–82. Reprints: http://pediatrics.aappublications.org/cgi/content/abstract/119/1/207; American Academy of Pediatrics Committee on Infectious Diseases.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 9, 2007 * Vol. 14, No. 6
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Jan. 8 issue of the Archives of Internal Medicine (www.archinternmed.com; 2007; 167).
B Vitamins, Folate, & Cognitive Function: Evidence is inadequate to support supplementation with vitamins B6 and B12 and folic acid as a means of maintaining or enhancing cognitive function in those with normal or impaired baseline function, according to a review article (pp. 21-30). “Fourteen trials met our criteria; most were of low quality and limited applicability,” write the researchers. “Approximately 50 different cognitive function tests were assessed. Three trials of vitamin B6 and 6 of vitamin B12 found no effect overall in a variety of doses, routes of administration, and populations. One of 3 trials of folic acid found a benefit in cognitive function in people with cognitive impairment and low baseline serum folate levels. Six trials of combinations of the B vitamins all concluded that the interventions had no effect on cognitive function. Among 3 trials, those in the placebo arm had greater improvements in a small number of cognitive tests than participants receiving either folic acid or combination B-vitamin supplements. The evidence was limited by a sparsity of studies, small sample size, heterogeneity in outcomes, and a lack of studies that evaluated symptoms or clinical outcomes.” (E. M. Balk, ebalk@tufts-nemc.org)
Flu Vaccine & CAP Outcomes: Significantly fewer patients with community-acquired pneumonia died during hospitalization when they had been immunized against influenza in the current or past season, report investigators who analyzed a database of Tenet Healthcare (pp. 53-9). At 109 hospitals in that system, patients hospitalized with CAP during Nov. to Apr. of 1999 through 2003 were reviewed, with these results: “Among 17,393 adults hospitalized with CAP during the study period, 1,590 (19% of those with recorded vaccine status) had a history of influenza vaccination in the current or most recent influenza season. Vaccine recipients were less likely to die in hospital of any cause than individuals without vaccination (odds ratio, 0.30; 95% confidence interval, 0.22–0.41). These effects remained significant after adjustment for the presence of comorbid illnesses and pneumococcal vaccination (adjusted odds ratio for death, 0.61; 95% confidence interval, 0.43–0.87) and under widely varying assumptions about individuals with missing vaccination status.” (D. N. Fisman, Hosp. for Sick Children, Toronto; david.fisman@sickkids.ca)
Thrombolysis in Submassive PE: In a cost-effectiveness analysis, use of thrombolysis in patients with submassive pulmonary embolism is not supported (pp. 74-80). Using a Markov model and taking a societal perspective, the authors assessed treatment of hemodynamically stable patients with PE and right ventricular dysfunction with alteplase plus heparin sodium versus heparin alone, with these results: “Based on data from a recent randomized trial, we assumed that the risk of clinical deterioration requiring treatment escalation was almost 3 times higher in patients who received heparin alone (23.2% vs 7.6%) but that the risk of death was equal in the 2 cohorts (2.7%). Based on registry data, we assumed that the risk of intracranial hemorrhage was approximately 3 times higher in patients who received alteplase plus heparin (1.2% vs 0.4%). Under these and other assumptions, thrombolysis resulted in marginally higher total lifetime health care costs ($43,900 vs $43,300) and was slightly less effective (10.52 vs 10.57 quality-adjusted life–years) than treatment with heparin alone. Thrombolysis was more effective and cost less than $50,000 per quality-adjusted life–year gained when we assumed that the baseline risk of death in the heparin group was 3 times the base-case value (8.1%) and that alteplase reduced the relative risk of death by at least 10%.” (M. K. Gould, gould@stanford.edu)

>>>PNN NewsWatch
* Cold adapted influenza vaccine–trivalent has been licensed by FDA. The new formulation of MedImmune’s FluMist can be stored under standard refrigeration rather than frozen, increasing its utility in schools, pharmacies, and grocery stores with limited capacity for frozen storage. The CAIT product will be available for the 2007–08 season and is administered intranasally.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 10, 2007 * Vol. 14, No. 7
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Jan. 10 issue of JAMA (www.jama.com; 2007; 297).
Evidence-Based Pharmacotherapy After AMI: Benefits seen with medication adherence following acute myocardial infarction result from class-specific effects of pharmacotherapeutic agents and are not just the products of “healthy adherer” behavioral attributes, according to a longitudinal study of 31,455 elderly AMI survivors in Ontario (pp. 177-86). Looking at data for patients obtaining certain medications in 1999–2003, the researchers found these differences between those adhering to evidence-based medications (statins and beta-blockers) compared with unproven therapies (calcium-channel blockers): “Among statin users, compared with their high-adherence counterparts, the risk of mortality was greatest for low adherers (deaths in 261/1,071 (24%) vs 2310/14,345 (16%); adjusted hazard ratio, 1.25; 95% confidence interval, 1.09–1.42; P = .001) and was intermediary for intermediate adherers (deaths in 472/2,407 (20%); adjusted hazard ratio, 1.12; 95% confidence interval, 1.01–1.25; P = .03). A similar but less pronounced dose-response–type adherence-mortality association was observed for beta-blockers. Mortality was not associated with adherence to calcium channel blockers. Moreover, sensitivity analyses demonstrated no relationships between drug adherence and cancer-related admissions, outcomes for which biological plausibility do not exist.” (D. A. Alter, Inst. for Clinical Evaluative Sciences, Toronto; david.alter@ices.on.ca)
‘New Era of Unapproved Drugs’: A three-judge U.S. Court of Appeals decision that is now under review by the full court could “[threaten] the ability of the FDA to protect public health” if upheld, write authors of a commentary (pp. 205-8). In the case, Abigail Alliance for Better Access to Developmental Drugs v Von Eschenbach, the court ruled “that terminally ill patients have a constitutional right to purchase unapproved drugs that have successfully completed phase 1 testing,” the authors explain, adding, “Despite the appealing rhetoric of choice and the belief that there is a medical cure for every illness—even at the end of life—public policy must balance the harms and benefits of pharmaceuticals and determine the optimal level of regulation. No one wants to deprive dying patients of access to drugs that may extend their lives. But no one should understate the potential scientific and clinical consequences of removing the FDA’s role in monitoring drug safety and effectiveness.” (P. D. Jacobson, pdj@umich.edu)

>>>Diabetes Report
Source:
Suppl. 1 to Diabetes Care (care.diabetesjournals.org; 2007; 30).
2007 Clinical Practice Recommendations: Rather than only implementing lifestyle modifications at the time of diagnosis of type 2 diabetes, the new clinical practice recommendations of the American Diabetes Assoc. are to start metformin therapy on day 1 and to consider adding basal insulin therapy if A1C levels remain elevated after 3 months (p. S3; S4-41). Published as a supplement to the Jan. issue of Diabetes Care, the revised recommendations make the following changes in the advice offered to clinicians:
* An algorithm added to the standards of medical care monograph advises 3 months of lifestyle intervention plus metformin at the time of diagnosis of type 2 diabetes. For those with A1Cs of 7% or more at 3 months, three options are recommended. Basal insulin is the most effective intervention, the guidelines note; addition of a sulfonylurea is the least expensive; and addition of a glitazone provides the least risk of hypoglycemia. Third-level interventions include insulin intensification or addition of a glitazone or a sulfonylurea, depending on the actions taken earlier. For those whose A1C levels remain at 7% or more, triple pharmacotherapy should be considered (intensive insulin plus metformin with or without a glitazone).
* A new table of drugs for treating distal symmetric polyneuropathy lists these options: tricyclic drugs, anticonvulsants, duloxetine, and capsaicin cream.
* In the hospital, use of correction doses or “supplemental” insulin is recommended for handle premeal hyperglycemia.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 11, 2007 * Vol. 14, No. 8
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Jan. 11 issue of the New England Journal of Medicine (content.nejm.org; 2006; 356).
Viral Resistance After Single-Dose ART: Higher rates of virologic failure were evident among women with HIV-1 who received single doses of nevirapine for perinatal prophylaxis (pp. 135-47). In a trial in Botswana, 218 women received either peripartum nevirapine or placebo along with antenatal zidovudine; they later received nevirapine-based antiretroviral treatment. Results showed: “By the 6-month visit after the initiation of antiretroviral treatment, 5.0% of the women who had received placebo had virologic failure, as compared with 18.4% of those who had received a single dose of nevirapine (P = 0.002). Among 60 women starting antiretroviral treatment within 6 months after receiving placebo or a single dose of nevirapine, no women in the placebo group and 41.7% in the nevirapine group had virologic failure (P < 0.001). In contrast, virologic failure rates did not differ significantly between the placebo group and the nevirapine group among 158 women starting antiretroviral treatment 6 months or more post partum (7.8% and 12.0%, respectively; P = 0.39). Thirty infants also began antiretroviral treatment (15 in the placebo group and 15 in the nevirapine group). Virologic failure by the 6-month visit occurred in significantly more infants who had received a single dose of nevirapine than in infants who had received placebo (P < 0.001). Maternal and infant findings did not change qualitatively by 12 and 24 months after the initiation of antiretroviral treatment.” (S. Lockman, slockman@hsph.harvard.edu)
Microsomal Triglyceride Transfer Protein Inhibition: BMS-201038 was effective in a dose-escalation study of six patients with homozygous familial hypercholesterolemia, but the inhibitor of the microsomal triglyceride transfer protein was associated with increased liver aminotransferase levels and hepatic fat accumulation (pp. 148-56). “All patients tolerated titration to the highest dose, 1.0 mg per kilogram per day,” report the researchers. “Treatment at this dose decreased low-density lipoprotein (LDL) cholesterol levels by 50.9% and apolipoprotein B levels by 55.6% from baseline (P < 0.001 for both comparisons). Kinetic studies showed a marked reduction in the production of apolipoprotein B. The most serious adverse events were elevation of liver aminotransferase levels and accumulation of hepatic fat, which at the highest dose ranged from less than 10% to more than 40%.” (D. J. Rader, rader@mail.med.upenn.edu)
Treating Renal-Cell Carcinoma: Commenting on two Phase III trials of agents for treating renal-cell carcinoma (sunitinib versus interferon-alfa for metastatic RCC, pp. 115-24, R. J. Motzer, Memorial Sloan-Kettering Cancer Ctr, New York, motzerr@mskcc.org; and sorafenib versus placebo for advanced clear-cell RCC, pp. 125-34, B. Escudier, Institut Gustave Roussy, Villejuif, France, escudier@igr.fr), editorialists make these comments about “molecular pathways and therapies “ (pp. 185-7). “Clinical trials of sunitinib, sorafenib, and temsirolimus in patients with advanced renal-cell carcinoma show how promising treatments can emerge from an understanding of the molecular genetics and biology of tumors. Improvements in current treatments will arise from a greater understanding of how these three drugs affect tumors. Sunitinib and sorafenib interact with a region of kinases with shared structural features, the ATP-binding domain, and consequently inhibit multiple kinases. In contrast, sirolimus (which largely mediates the effects of temsirolimus) binds to an intracellular protein, FK506-binding protein 12 kD (FKBP12), and as a sirolimus–FKBP12 complex, it specifically interacts with the mTOR complex 1. Sunitinib, sorafenib, and temsirolimus down-regulate angiogenesis, but they also affect other processes and can inhibit cell proliferation in vitro, where angiogenesis is not required. Hence, these agents probably act through more than one mechanism — they do not specifically target the VEGF and PDGF-beta pathways.” (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 © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 12, 2007 * Vol. 14, No. 9
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Jan. issue of Pharmacotherapy (www.pharmacotherapy.org; 2007; 27).
MRSA Antibiotic Susceptibility: Inducible resistance to clindamycin is significantly more common among hospital isolates of methicillin-resistant Staphylococcus aureus than among MRSA strains found in the community, according to an ongoing study in a Detroit level 1 trauma center (pp. 3-10). Based on testing of 130 community-associated and 178 hospital-associated MRSA strains, the researchers report: “All tested MRSA isolates were susceptible to daptomycin, linezolid, and vancomycin. In addition, community-associated MRSA isolates were significantly (all p ≤ 0.05) more susceptible to trimethoprim–sulfamethoxazole (99%), clindamycin (96%), and a fluoroquinolone (76%) than hospital-associated MRSA isolates. Inducible resistance to clindamycin was demonstrated in 8.4% of community-associated MRSA isolates versus 50% of hospital-associated MRSA isolates (p ≤ 0.001). Of interest, 35% of the MRSA isolates collected from hospitalized patients (> 48 hrs after admission and according to the CDC definition) possessed [staphylococcal chromosomal cassette mec] type IV.” (M. J. Rybak, m.rybak@wayne.edu)
Statins & Sepsis: A retrospective evaluation indicates a potential role for statins in reducing the risk of sepsis-induced hypotension (pp. 20-6). Among 53 patients with sepsis, 16 cases were receiving statins, and they were compared with 37 controls: “Preadmission statin therapy, compared with no statin therapy, was associated with a 30% lower rate of severe sepsis (56% vs 86%, p < 0.02). In-hospital mortality was not significantly different between groups (38% vs 49%, p = 0.33); however, the rate of cardiovascular dysfunction, defined as hypotension requiring vasopressor therapy, was significantly lower in the statin group (38% vs 73%, p < 0.02). No significant differences in the other organ dysfunction categories were noted between groups.” (C. P. Martin, U. Oklahoma, Tulsa; Christopher-Martin@ouhsc.edu)
Carbapenem–Penicillin Cross-Sensitivity: “Patients whose history of penicillin allergy is self-reported and is not type 1 may be at moderate risk for hypersensitivity when treated with a carbapenem antibiotic,” concludes a minireview (pp. 137-42). “The risk of hypersensitivity appears to be higher in patients whose penicillin allergy was documented by a health care provider, those with several antibiotic allergies, and those with a positive penicillin skin test result or a history of type 1 penicillin hypersensitivity.” (W. A. Prescott, Jr., prescott@buffalo.edu)

>>>PNN NewsWatch
* As part of this year’s reauthorization of the Prescription Drug User Fee program, FDA is proposing significantly broadening and upgrading the agency’s drug safety program, increasing its resources for review of television drug advertising, and facilitating more efficient development of safe and effective new medications. The agency proposed that annual user fee collections be increased to $392.8 million, an $87.4 million increase over the current baseline. The user fee program, first authorized by the Prescription Drug Use Fee Act (PDUFA) in Nov. 1992, enables FDA to increase its staff for review of new drug applications in return for making decisions within established timelines. The program must be reauthorized by Congress every 5 years.
*
FDA has proposed allowing several new claims for foods and dietary supplements containing calcium and vitamin D with regard to their potential to reduce the risk of osteoporosis, including adding a claim for concomitant use of calcium and vitamin D; dropping the reference in product labeling to gender, race, and age; dropping the need to identify the mechanism by which calcium reduces the risk of osteoporosis; and dropping the requirement to state limits to benefit of calcium intakes above 200% of the established Daily Value.
*
FDA has recommended that certain pharmaceutical companies reevaluate pharmacokinetic studies conducted for them by MDS Pharma Services from 2000 through 2004. The contract company performs pharmacokinetic testing services, and this action resulted from inspections of two MDS Pharma Canadian facilities that raised questions about the validity and accuracy of results from studies of brand-name and generic drugs.
*
PNN will not be published on Mon., Jan. 15, M. L. King Day.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 16, 2007 * Vol. 14, No. 10
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Early-release articles from and Jan. 13 issue of Lancet (www.thelancet.com; 2007; 369).
Chemotherapy Intensification in ALL: No benefit was noted in 3,109 children with intermediate-risk acute lymphoblastic leukemia treated with intensification of the continuation-therapy phase with a schedule of pulses of vincristine and dexamethasone (pp. 132-31). In addition to the conventional mercaptopurine and methotrexate chemotherapy given to control patients, those in the treatment arm received pulses of vincristine (1.5 mg/m2 weekly for 2 weeks) and dexamethasone (6 mg/m2 daily for 7 days) every 10 weeks for six cycles plus pulses of vincristine (1.5 mg/m2 weekly for 2 weeks) and dexamethasone (6 mg/m2 daily for 7 days) every 10 weeks for six cycles. The authors report these results: “174 patients (5.6%) relapsed or died in complete remission before randomisation. Of the remaining 2,935 patients, 2,618 (89.2%) were randomly assigned: 1,325 to the treatment group and 1,293 to the control group. With median follow-up of 4.8 years, 240 children in the treatment group and 241 in the control group had relapses; 15 in the treatment group and 14 controls died in complete remission or developed second malignant neoplasms. The 5-year and 7-year disease-free survival estimates were 79.8% (SE 1.2) and 77.5% (1.5) in the treatment group and 79.2% (1.2) and 78.4% (1.3) in the control group, respectively. Treatment with pulses of vincristine and dexamethasone was associated with a non-significant 3% relative-risk reduction (hazard ratio 0.97; 95% CI 0.81–1.15; p = 0.70).” (V. Conter, U. Milano-Bicocca, Monza, Italy; valentino.conter@pediatriamonza.it)

>>>Internal Medicine Report
Source:
Jan. 16 issue of the Annals of Internal Medicine (www.annals.org; 2007; 146).
Back Pain & Opioids: While efficacious during short-term use for chronic back pain, opioids are associated with substance-use disorders, and up to 24% of patients have resulting and/or aberrant medication-taking behaviors, according to a systematic review (pp. 116-27). Many of the studies found were of poor quality, and none evaluated relief of pain lasting 16 weeks or longer, the authors report, adding these details: “Opioid prescribing varied by treatment setting (range, 3% to 66%). Meta-analysis of the 4 studies assessing the efficacy of opioids compared with placebo or a nonopioid control did not show reduced pain with opioids (g, –0.199 composite standardized mean difference, [95% CI, –0.49 to 0.11]; P = 0.136). Meta-analysis of the 5 studies directly comparing the efficacy of different opioids demonstrated a nonsignificant reduction in pain from baseline (g, –0.93 composite standardized mean difference [CI, –1.89 to –0.03]; P = 0.055). The prevalence of lifetime substance use disorders ranged from 36% to 56%, and the estimates of the prevalence of current substance use disorders were as high as 54%. Aberrant medication-taking behaviors ranged from 5% to 24%.” (D. A. Fiellin, david.fiellin@yale.edu)
Growth Hormone in the Elderly: Use of human growth hormone by healthy elderly people found that the synthetic hormone was associated with small changes in body composition but not in body weight or other clinically important outcomes, conclude authors of a review article (pp. 104 ff). People who took GH had increased rates of unhealthy adverse effects such as soft tissue swelling, joint pain, and carpal tunnel syndrome, and some men developed abnormally large mammary glands and were also somewhat more likely to develop diabetes. The authors write: “Although GH has been widely publicized as an anti-aging therapy …scant clinical experience of GH in the healthy elderly suggests that although GH may minimally alter body composition, it does not improve other clinically relevant outcomes … [and] is associated with high rates of adverse events. On the basis of available evidence, GH cannot be recommended for use among the healthy elderly.”

>>>PNN JournalWatch
* Telomere Length, Risk of Coronary Heart Disease, and Statin Treatment in the West of Scotland Primary Prevention Study: A Nested Case–Control Study, in Lancet, 2007; 369: 107–14. Reprints: www.thelancet.com/journals/lancet/article/PIIS0140673607600713/abstract; N. J. Samani, U. Leicester, Leicester, U.K.; njs@le.ac.uk
* Survival of Patients With and Without HIV Infection in Denmark, in
Annals of Internal Medicine, 2007; 146: 87–95. Reprints: www.annals.org; N. Lohse, Odense U. Hosp., Odense, Denmark; nl@dce.au.dk

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 17, 2007 * Vol. 14, No. 11
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Jan. 17 issue of JAMA (www.jama.com; 2007; 297).
Gemcitabine for Pancreatic Cancer: Use of gemcitabine as adjuvant chemotherapy in resectable carcinoma of the pancreas is supported by results of the Phase 3 CONKO-001 (Charité Onkologie) study (pp. 267-77). Six cycles of gemcitabine were administered on days 1, 8, and 15 every 4 weeks to 179 patients following gross complete (R0 or R1) resection. Comparing their results with those in 175 patients who received no chemotherapy after resection, the researchers found: “More than 80% of patients had R0 resection. The median number of chemotherapy cycles in the gemcitabine group was 6 (range, 0–6). Grade 3 or 4 toxicities rarely occurred with no difference in quality of life (by Spitzer index) between groups. During median follow-up of 53 months, 133 patients (74%) in the gemcitabine group and 161 patients (92%) in the control group developed recurrent disease. Median disease-free survival was 13.4 months in the gemcitabine group (95% confidence interval, 11.4–15.3) and 6.9 months in the control group (95% confidence interval, 6.1–7.8; P < .001, log-rank). Estimated disease-free survival at 3 and 5 years was 23.5% and 16.5% in the gemcitabine group, and 7.5% and 5.5% in the control group, respectively. Subgroup analyses showed that the effect of gemcitabine on disease-free survival was significant in patients with either R0 or R1 resection. There was no difference in overall survival between the gemcitabine group (median, 22.1 months; 95% confidence interval, 18.4–25.8; estimated survival, 34% at 3 years and 22.5% at 5 years) and the control group (median, 20.2 months; 95% confidence interval, 17–23.4; estimated survival, 20.5% at 3 years and 11.5% at 5 years; P = .06, log-rank).” (H. Oettle, Charité Sch. of Med., Berlin, Germany; helmut.oettle@charite.de)
An editorialist describes CONKO-001 as promising but only a “small step forward” (pp. 311-3): “Empirical clinical research design has certainly resulted in the introduction of new agents to improve the outcome for cancer patients. Empiricism, however, often results in failure to detect statistical significance, leaving many patients with a poorly understood lack of benefit from an intervention. As new agents emerge, particularly the biologics, integration of research disciplines (eg, molecular biology, experimental imaging, and clinical trials) is imperative. Worldwide, there is a need to move away from the question of current chemotherapy agents vs chemoradiation to a research focus based on enhancing understanding of biologic principles. Given the rapid lethality of pancreatic cancer, this is no easy task. Whether it is possible to build on the small steps taken with CONKO-001 results remains to be seen. It is unlikely, however, that these small steps alone will provide the necessary enhancement of benefit beyond the improvements in surgery to profoundly alter the course of this most challenging of cancers.” (A. B. Benson III,
a-benson@northwestern.edu)
Fatigue at the Close of Life: In a Clinician’s Corner article on palliative management of fatigue at the close of life, pharmacologic treatment is proposed and possible drug-related contributors reviewed (pp. 295-304). Corticosteroids, methylphenidate, megestrol acetate, modafinil, and l-carnitine are among the agents with “some evidence” supporting their use for symptomatic treatment of fatigue at the end of life, the writers note. Treatment of pain and opioid-induced neurotoxicity, depression, delirium and cognitive dysfunction, weight loss, and anemia can also lessen symptoms of fatigue. The authors conclude, “Continued access to the physician on short notice, continued assessment of symptoms, and emphasis on comfort and maximizing function are essential. Excellent patient–physician communication, including expressive supportive therapy and empathic listening, is critical particularly at the end of life. This is particularly so when changes to care setting are necessary so that the patient and family have a sense of stability and continuity. Finally, simply being present can provide patients and families great comfort, even with progressive illness and severe symptoms.” (E. Bruera, ebruera@mdanderson.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 © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 18, 2007 * Vol. 14, No. 12
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Jan. 18 issue of the New England Journal of Medicine (content.nejm.org; 2007; 356).
Breast Cancer ‘Gene Signatures’: In a study of four different types of tumors, a 186-gene “invasiveness” signature (IGS) was strongly associated with metastasis-free survival and overall survival, and the relationship was especially strong for tumorigenic breast-cancer cells (pp. 217-26). Assessing the gene-expression profile of CD44+CD24–/low tumorigenic breast-cancer cells with that of normal breast epithelium, the researchers found: “There was a significant association between the IGS and both overall and metastasis-free survival (P < 0.001, for both) in patients with breast cancer, which was independent of established clinical and pathological variables. When combined with the prognostic criteria of the National Institutes of Health, the IGS was used to stratify patients with high-risk early breast cancer into prognostic categories (good or poor); among patients with a good prognosis, the 10-year rate of metastasis-free survival was 81%, and among those with a poor prognosis, it was 57%. The IGS was also associated with the prognosis in medulloblastoma (P = 0.004), lung cancer (P = 0.03), and prostate cancer (P = 0.01). The prognostic power of the IGS was increased when combined with the wound-response signature.” (R. Lui, U. Michigan, Ann Arbor)
An editorialist explains how these results could be linked to a search for new medications and chemotherapy regimens (pp. 294-7): “The power of combined signatures might be improved with the use of decision-tree analysis methods or the integration of new signatures.... For example, the performance of the IGS was better in predicting the clinical outcome when it was combined with the wound-response signature. Much work remains to be done to settle the questions discussed here. Cancer gene-expression signatures are beginning to be tested in the clinic. Predictions of a good prognosis have been proposed as criteria for limiting the use of unnecessary adjuvant therapy. It remains to be seen whether such criteria would provide a sufficient incentive for the widespread use of prognostic signatures. Further incentives may be on the horizon: as pharmacologic inhibitors for specific pathways become available, the signatures that define tumors according to their vital pathways may provide crucial guidance for designing drug combinations of choice.” (J. Massagué, Memorial Sloan-Kettering Cancer Ctr., New York)

Cardiology Report
Source:
Jan. 23 issue of the Journal of the American College of Cardiology (content.onlinejacc.org; 2007; 49).
Anti-inflammatory Effects of Pioglitazone vs. Simvastatin: Probably by reducing insulin resistance, pioglitazone exerts additive anti-inflammatory effects when used with simvastatin in nondiabetic patients with elevated high-sensitivity C-reactive protein levels (pp. 290-7). In the 12-week, 125-patient trial, participants received simvastatin, pioglitazone, or both, with these results: “Pioglitazone and simvastatin monotherapies significantly reduced hs-CRP (3.64 ± 2.42 mg/l to 2.48 ± 1.77 mg/l and 3.26 ± 2.02 mg/l to 2.81 ± 2.11 mg/l) and the combination regimen had an additive effect (from 3.49 ± 1.97 mg/l to 2.06 ± 1.42 mg/l, p < 0.001). For subgroups, the difference between monotherapy and combination therapy was only significant for simvastatin versus simvastatin plus pioglitazone in patients without [metabolic syndrome].” (M. Hanefeld, Zentrum für Klinische Studien, Dresden, Germany; hanefeld@gwtonline-zks.de)
Intensive Insulin Therapy in ACS: Aggressive glycemic control reduced the levels of deleterious markers that are induced by hyperglycemia in patients with acute coronary syndromes (pp. 304-10). Among 76 patients with diabetes who were admitted with ACS, the investigators found an inverse correlation between admission blood glucose levels and both inhibition of platelet aggregation by the NO donor sodium nitroprusside and the endogenous inhibitor of NO synthase asymmetric dimethylarginine. Intravenous insulin infusion reduced glucose levels, improved platelet responsiveness to nitroprusside, and decreased superoxide and dimethylarginine levels. (J. D. Horowitz, U. Adelaide, Woodville South, South Australia, Australia; john.horowitz@adelaide.edu.au)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 19, 2007 * Vol. 14, No. 13
Providing news and information about medications and their proper use

>>>Allergy/Immunology Report
Source:
Jan. issue of the Journal of the Allergy and Clinical Immunology (www.jacionline.org; 2007; 119).
Early Steroids for Preventing Asthma: The author of a review article comments on three recent studies that showed a lack of effectiveness with early inhaled corticosteroids in infants and young children at high risk for asthma (pp. 30-3): “These findings challenge the concept that the inflammatory processes that cause asthma symptoms and are responsive to inhaled corticosteroids are also responsible for the chronic changes in airway structure and function that are believed to predispose to the development of persistent asthma. This conclusion is supported by studies showing that bronchial hyperresponsiveness, independent of current asthma symptoms, is associated with subsequent deficits in airway function growth during childhood. Successful strategies for the prevention of asthma will require a better understanding of the genetic, environmental, and developmental factors that predispose toward inappropriate responses to airway injury. Abnormal airway remodeling and persistent dysregulation of airway tone might be the final common pathway for different disease mechanisms, and this might explain the heterogeneity of clinical phenotypic syndromes that go under the common label of ‘asthma.’” (F. D. Martinez, fernando@arc.arizona.edu)
Controller Regimens in Childhood Asthma: Overall, fluticasone monotherapy proved to be the preferred controller regimen in children with mild to moderate persistent asthma, a confirmation of current guidelines (pp. 64072). Included in the Pediatric Asthma Controller Trial (PACT) were 285 children aged 8–14 years with FEV1 values of 80% or more of predicted, and they received either fluticasone 100 mcg twice daily; montelukast 5 mg once daily in the evening; or a combination PACT regimen consisting of fluticasone 100 mcg/salmeterol 50 mcg in the morning and salmeterol 50 mcg in the evening. Investigators report these results: “Fluticasone monotherapy and PACT combination were comparable in many patient-measured outcomes, including percent of asthma control days, but fluticasone monotherapy was superior for clinic-measured FEV1/forced vital capacity (P = .015), maximum bronchodilator response (P = .009), exhaled nitric oxide (P < .001), and [methacholine FEV1] PC20 (P < .001). Fluticasone monotherapy was superior to montelukast for asthma control days (64.2% vs 52.5%; P = .004) and for all other control outcomes. Growth over 48 weeks was not statistically different (fluticasone, 5.3 cm; PACT combination, 5.3 cm; montelukast, 5.7 cm).” The group concludes, “Both fluticasone monotherapy and PACT combination achieved greater improvements in asthma control days than montelukast. However, fluticasone monotherapy was superior to PACT combination in achieving other dimensions of asthma control.” (C. A. Sorkness, Sorkness@facstaff.wisc.edu)
Aspirin Doses Following Desensitization: Aspirin 650 mg twice daily followed by decreases to the lowest effective dose is recommended for patients with aspirin-exacerbated respiratory disease who have successfully completed desensitization (pp. 157-64). In a 137-patient study, the researchers identified these results with initial randomization to either aspirin 325 or 650 mg twice daily for 1 month followed by dose titrations based on symptom control for the remainder of the 1-year trial: “Patients taking either 650 mg twice daily or 325 mg twice daily showed significant improvements in number of sinus infections, sinus operations, and hospitalizations for asthma (all P < .0001). Anosmia, nasal/sinus symptoms, and asthma symptoms also improved in both groups (all P < .03). Systemic corticosteroid dosages decreased by 3- and 4-fold in the 325 mg twice daily and 650 mg twice daily groups, respectively. Of the 137 patients, 32 had adverse effects from or discontinued aspirin therapy: 14 (44%) of 32 from the group randomized to taking 650 mg twice daily and 18 (56%) of 32 from the group randomized to 325 mg twice daily. The most common adverse effect was dyspepsia.” (D. D. Stevenson, Scripps Res. Inst., La Jolla, Calif.; Stevenson.donald@Scrippshealth.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 © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 22, 2007 * Vol. 14, No. 14
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Jan. 20 issue of Lancet (www.thelancet.com; 2007; 369).
Antihypertensives & New-Onset Diabetes: According to a systematic review of 22 clinical trials with 143,153 participants, angiotensin II receptor blockers and ACE inhibitors are the antihypertensive agents that are least associated with incident diabetes mellitus, followed by calcium-channel blockers, placebo, beta-blockers, and diuretics (pp. 201-7). Assessing the proportion of patients who developed diabetes in the studies, the researchers found: “Initial drug therapy used in the trials (and the number of patients with diabetes of the total number at risk) included: an ARB (1,189 of 14,185, or 8.38%), ACE inhibitor (1,618 of 22,941, or 7.05%), calcium-channel blocker (CCB, 2,791 of 38,607, or 7.23%), placebo (1,686 of 24,767, or 6.81%), beta-blocker (2,705 of 35,745, or 7.57%), or diuretic (998 of 18,699, or 5.34%). With an initial diuretic as the standard of comparison (eight groups), the degree of incoherence (a measure of how closely the entire network fits together) was small (omega=0.000017, eight degrees of freedom). The odds ratios were: ARB (five groups) 0.57 (95% CI 0.46–0.72, p < 0.0001); ACE inhibitor (eight groups) 0.67 (0.56–0.80, p < 0.0001); CCB (nine groups): 0.75 (0.62–0.90, p = 0.002); placebo (nine groups) 0.77 (0.63-0.94, p = 0.009); beta-blocker (nine groups) 0.90 (0.75-1.09, p = 0.30). These estimates changed little in many sensitivity analyses.” (W. J. Elliott, welliott@rush.edu)

>>>Health Affairs Report
Source:
Jan/Feb issue of Health Affairs (content.healthaffairs.org; 2007; 26).
Value of Antihypertensives: Improved use of antihypertensive medications could save as many lives as eliminating all deaths from medical errors or accidents, concludes a review article (pp. 97-110). Authors write: “Using national survey data and risk equations from the Framingham Heart Study, we quantify the impact of antihypertensive therapy changes on blood pressures and the number and cost of heart attacks, strokes, and deaths. Antihypertensive therapy has had a major impact on health. Without it, 1999–2000 average blood pressures (at age 40+) would have been 10–13 percent higher, and 86,000 excess premature deaths from cardiovascular disease would have occurred in 2001. Treatment has generated a benefit-to-cost ratio of at least 6:1, but much more can be achieved.” (D. M. Cutler)
Cardiovascular Disease Burden : Cardiovascular disease is the leading cause of death worldwide, investigators report, and a leading cause of disability around the globe (pp. 38-48): “In the United States, CVD accounted for 34.4 percent of the 2.4 million deaths in 2003 and remain a major cause of health disparities and rising health care costs. In 2006, health care spending and lost productivity from CVD exceeded $400 billion. The aging population, obesity epidemic, underuse of prevention strategies, and suboptimal control of risk factors could exacerbate the future CVD burden. Increased adherence to clinical and community-level guidelines and renewed emphasis on policy, environmental, and lifestyle changes will be crucial for its effective prevention and control.” (G. A. Mensah)

>>>PNN JournalWatch
* Effect of Isoniazid Prophylaxis on Mortality and Incidence of Tuberculosis in Children with HIV: Randomised Controlled Trial, in BMJ, 2007; 334: 136 ff. Reprints: www.bmj.com/cgi/content/full/334/7585/136; H. Zar, U. Cape Town, South Africa; hzar@ich.uct.ac.za
* Antibiotic Treatment of Exacerbations of COPD: A Randomized, Controlled Trial Comparing Procalcitonin-Guidance with Standard Therapy, in
Chest, 2007; 131: 9–19. Reprints: www.chestjournal.org/cgi/content/abstract/131/1/9; D. Stolz, U. Massachusetts Med. Sch., Worcester; dstolz@uhbs.ch
* Continuous Bronchodilator Therapy, in
Chest, 2007; 131:296–9. Reprints: www.chestjournal.org/cgi/content/abstract/131/1/286; S. G. Peters, peters.steve@mayo.edu
* Going Beyond “ABC” to Include “GEM”: Critical Reflections on Progress in the HIV/AIDS Epidemic, in
American Journal of Public Health, 2007; 97: 13–8. Reprints: www.ajph.org/cgi/content/abstract/97/1/13; S. L. Dworkin, sld2011@columbia.edu
* Explaining Recent Declines in Adolescent Pregnancy in the United States: The Contribution of Abstinence and Improved Contraceptive Use, in
American Journal of Public Health, 2007; 97: 150–6. Reprints: www.ajph.org/cgi/content/abstract/97/1/150; J. S. Santelli, js2637@columbia.edu

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 23, 2007 * Vol. 14, No. 15
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Jan. 22 issue of and early-release article from the Archives of Internal Medicine (www.archinternmed.com; 2007; 167).
Rapid Flu Tests & Hospital Antibiotic Use: Among 166 hospitalized adults, rapid influenza testing reduced antibiotic use, and many patients placed on anti-infective agents were frail elderly individuals or had other concomitant conditions that placed them at risk for bacterial infections (doi: 10.1001/archinte.167.4.ioi60207). Investigators concluded that “better tools to rule out concomitant bacterial infection are needed to optimize the impact of viral testing,” based on these comparisons of those with positive (Ag+) and negative (Ag0) rapid influenza antigen test results: “Of 166 patients with available records, 86 were Ag+ and 80 were Ag0. Antibiotic use (74 [86%] of 86 patients vs 79 [99%] of 80 patients; P = .002) was less and antibiotic discontinuance (12 [14%] of 86 patients vs 2 [2%] of 80 patients; P = .01) was greater in Ag+ compared with Ag0 patients. No significant differences in antibiotic days, length of hospital stay, or antibiotic complications were noted. Antiviral use (63 [73%] of 86 patients vs 6 [8%] of 80 patients; P < .001) was greater in Ag+ than Ag0 patients. Antigen status was independently associated with withholding or discontinuing antibiotics in multivariate analysis. Of 44 Ag+ patients deemed low risk for bacterial infection, 27 continued to receive antibiotics despite positive influenza test results. These patients more commonly had pulmonary disease and had significantly more abnormal lung examination results (P = .005) compared with those in whom antibiotics were withheld or discontinued.” (A. R. Falsey, Rochester Genl. Hosp., Rochester, N.Y.; ann.falsey@viahealth.org)
Aspirin as Adjunct to Oral Anticoagulation: Other than in patients with mechanical heart valves, the current practice of adding aspirin to regimens in patients on oral anticoagulation is questionable, based on findings of a meta-analysis of 10 randomized trials of 4,180 patients (pp. 117-24). Benefits were questionable, the researchers reported, and the risk of major bleeding was significantly elevated: “The risk for arterial thromboembolism was lower in patients receiving combined aspirin–OAC therapy compared with OAC therapy alone (OR, 0.66; 95% CI, 0.52–0.84). However, these benefits were limited to patients with a mechanical heart valve (OR, 0.27; 95% CI, 0.15–0.49). There was no difference in the risk for arterial thromboembolism with these treatments in patients with atrial fibrillation (OR, 0.99; 95% CI, 0.47–2.07) or coronary artery disease (OR, 0.69; 95% CI, 0.35–1.36). There was no difference in all-cause mortality with either treatment (OR, 0.98; 95% CI, 0.77–1.25). The risk for major bleeding was higher in patients receiving aspirin–OAC therapy compared with OAC therapy alone (OR, 1.43; 95% CI, 1.00–2.02).” (J. D. Douketis, jdouket@mcmaster.ca)
Hypertension Treatment Among Countries: More aggressive use of antihypertensive agents is one factor contributing to better control of elevated blood pressures among Americans than among Europeans, according to a cross-sectional analysis of data from the CardioMonitor 2004 survey (pp. 141-7). Initial pretreatment blood pressures were lowest in the U.S., and use of two or more antihypertensive agents concomitantly was highest on this side of the Atlantic. The authors add: “Compared with US patients, European patients had higher latest systolic BP levels (by 5.3–10.2 mm Hg across countries examined) and diastolic BP levels (by 1.9–5.3 mm Hg), a smaller likelihood of hypertension control (odds ratios, 0.27–0.50), and a smaller likelihood of medication increase for inadequately controlled hypertension (odds ratios, 0.29–0.65) (all P < .001).” (Y. R. Wang, yize.wang@tuhs.temple.edu)
Aging Injection Drug Users: The mean age of American adolescents and adults who report injection drug use within the past year has increased from 21 years in 1979 to 36 years in 2002, reports an investigator who analyzed data from the National Household Survey on Drug Abuse (pp. 166-73). “Clinicians should understand that injection drug users are a heterogeneous group and that, on average, they are no longer young,” the author writes, adding that “heroin [is] not the only recreational drug used by injection.” (G. L. Armstrong, GArmstrong@cdc.gov)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 24, 2007 * Vol. 14, No. 16
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Jan. 24/31 issue of JAMA (www.jama.com; 2007; 297).
Citalopram in Cardiac Patients: Among 284 patients with coronary artery disease, citalopram improved symptoms of major depression in a 12-week trial, but concomitant interpersonal psychotherapy failed to add any benefit to the drug therapy (pp. 367-79). Looking at scores on the Hamilton Depression Rating Scale and the Beck Depression Inventory II, the researchers found: “Citalopram was superior to placebo in reducing 12-week HAM-D scores (mean difference, 3.3 points; 96.7% confidence interval [CI], 0.80–5.85; P = .005), with a small to medium effect size of 0.33. Mean HAM-D response (52.8% vs 40.1%; P = .03) and remission rates (35.9% vs 22.5%; P = .01) and the reduction in BDI-II scores (difference, 3.6 points; 98.3% CI, 0.58–6.64; P = .005; effect size = 0.33) also favored citalopram. There was no evidence of a benefit of IPT over clinical management, with the mean HAM-D difference favoring clinical management (–2.26 points; 96.7% CI, –4.78 to 0.27; P = .06; effect size, 0.23). The difference on the BDI-II did not favor clinical management (1.13 points; 98.3% CI, –1.90 to 4.16; P = .37; effect size = 0.11).” Combining these results with those of a prior trial, the investigators conclude that citalopram or sertraline plus clinical management “should be considered as a first-step treatment for patients with CAD and major depression.” (F. Lespérance, francois.lesperance@umontreal.ca)
While acknowledging that this Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE) trial adds to the literature, editorialists question whether SSRIs save lives among patients with acute coronary syndromes (pp. 411-2): “[Citalopram and sertraline] are ... the SSRIs least likely to produce drug interactions, an important issue for patients with ACS. However, safety data on heart failure remain limited. Because SSRIs have antiplatelet properties, when large numbers of ACS patients are treated with SSRIs combined with other antiplatelet agents bleeding problems could occur, but this has not been apparent so far and therefore is not likely to occur frequently. Surveillance for SSRI–clopidogrel interactions should be planned for in studies in which patients with drug-eluting stents require treatment for depression. Benefit in terms of reduced stent thrombosis as well as bleeding problems might be found.” (A. H. Glassman,
ahg1@columbia.edu)
Adherence with TB Drugs: In a resource-poor African country, use of a multipronged intervention strategy improved outcomes among patients with newly diagnosed pulmonary tuberculosis (pp. 380-6). “The intervention strategy included reinforced counseling through improved communication between health personnel and patients, decentralization of treatment, choice of directly observed therapy (DOT) supporter by the patient, and reinforcement of supervision activities,” the authors report. “A total of 1,522 patients were recruited into the study. Treatment was successful for 682 (88%) of 778 patients recruited in the intervention group, and for 563 (76%) of 744 patients recruited in the control group (adjusted risk ratio [RR], 1.18; 95% confidence interval [CI], 1.03–1.34). The proportion of patients defaulting was reduced in the intervention group to 5.5% (n = 43) compared with 16.8% (n = 125) in the control group (adjusted RR, 0.43; 95% CI, 0.21–0.89).” (C. Lienhardt, Intl. Union Against Tuberculosis and Lung Diseases, Paris; clienhardt@iuatld.org)

>>>PNN NewsWatch
* Following a day of hearings at an advisory committee meeting, FDA last night sought to correct reports in the lay media concerning effectiveness of newer hormonal oral contraceptives. “[Recent wire service stories] inaccurately report that the products are significantly less effective at preventing pregnancy than those approved decades ago,” FDA explained. “In fact, the newer generation products are highly effective in preventing pregnancy. The stories also mistakenly state that FDA called the meeting to discuss the need for higher standards of efficacy for the newer products.”
*
CDC last week described three deaths in U.S. infants associated with use of cough and cold medications. These products should be administered with caution to children aged younger than 2 years, the agency 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 © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 25, 2007 * Vol. 14, No. 17
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Jan. 25 issue of the New England Journal of Medicine (content.nejm.org; 2007; 356).
Posaconazole Prophylaxis: Two research studies and an editorial examine the prophylactic utility of the recently approved antifungal agent posaconazole.
While similar overall to fluconazole in a Phase III study of patients with severe graft-versus-host disease who were receiving immunosuppressive therapy after allogeneic hematopoietic stem-cell transplantation, posaconazole proved significantly more effective for preventing invasive aspergillosis and reducing the rate of deaths related to fungal infections (pp. 335-47). “Of a total of 600 patients, 301 were assigned to posaconazole and 299 to fluconazole,” the authors write. “At the end of the fixed 112-day treatment period, posaconazole was found to be as effective as fluconazole in preventing all invasive fungal infections (incidence, 5.3% and 9.0%, respectively; odds ratio, 0.56; 95 percent confidence interval [CI], 0.30 to 1.07; P = 0.07) and was superior to fluconazole in preventing proven or probable invasive aspergillosis (2.3% vs. 7.0%; odds ratio, 0.31; 95% CI, 0.13 to 0.75; P = 0.006). While patients were receiving study medications (exposure period), in the posaconazole group, as compared with the fluconazole group, there were fewer breakthrough invasive fungal infections (2.4% vs. 7.6%, P = 0.004), particularly invasive aspergillosis (1.0% vs. 5.9%, P = 0.001). Overall mortality was similar in the two groups, but the number of deaths from invasive fungal infections was lower in the posaconazole group (1%, vs. 4% in the fluconazole group; P = 0.046). The incidence of treatment-related adverse events was similar in the two groups (36% in the posaconazole group and 38% in the fluconazole group), and the rates of treatment-related serious adverse events were 13% and 10%, respectively.” (A. J. Ullmann, Johannes Gutenberg U., Mainz, Germany;
ullmann@uni-mainz.de)
Compared with fluconazole or itraconazole in patients undergoing chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome, posaconazole was more effective—even increasing survival—but it also produced more adverse effects (pp. 348-59). In the unblinded, non–placebo-controlled study, patients received prophylaxis with each cycle of chemotherapy until recovery from neutropenia and complete remission, until occurrence of an invasive fungal infection, or for up to 12 weeks. Results showed: “A total of 304 patients were randomly assigned to receive posaconazole, and 298 patients were randomly assigned to receive fluconazole (240) or itraconazole (58). Proven or probable invasive fungal infections were reported in 7 patients (2%) in the posaconazole group and 25 patients (8%) in the fluconazole or itraconazole group (absolute reduction in the posaconazole group, –6%; 95% confidence interval, –9.7 to –2.5%; P < 0.001), fulfilling statistical criteria for superiority. Significantly fewer patients in the posaconazole group had invasive aspergillosis (2 [1%] vs. 20 [7%], P<0.001). Survival was significantly longer among recipients of posaconazole than among recipients of fluconazole or itraconazole (P = 0.04). Serious adverse events possibly or probably related to treatment were reported by 19 patients (6%) in the posaconazole group and 6 patients (2%) in the fluconazole or itraconazole group (P = 0.01). The most common treatment-related adverse events in both groups were gastrointestinal tract disturbances.” (O. A. Cornely, Klinikum der Universität zu Köln, Cologne, Germany;
liver.cornely@uni-koeln.de">oliver.cornely@uni-koeln.de)
Describing a mixed bag of study results, editorialists note that they do not use primary antifungal prophylaxis for all patients with GVHD or prolonged neutropenia (pp. 409-11). Four questions should be considered in this matter, they note, providing their own answers: Would invasive fungal disease be difficult to treat if it occurred (no), is invasive fungal disease a serious event (yes), is prophylaxis safe and tolerated well enough (yes), and is the prophylaxis effective as reflected in a small number needed to treat (for their center, no). They add that clinicians will have to ponder study dichotomies that suggest one drug as first-line therapy for prophylaxis for invasive aspergillosis (posaconazole) but another for treatment (voriconazole). (B. E. De Pauw, U. Med. Ctr. St. Radboud, Nijmegen, the Netherlands)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 26, 2007 * Vol. 14, No. 18
Providing news and information about medications and their proper use

>>>Neurology Highlights
Source:
Jan. 23 issue of Neurology (www.neurology.org; 2007; 68).
Transdermal Rotigotine in Early Parkinson Disease: In a study of 277 patients with early-stage Parkinson’s disease, transdermal rotigotine relieved symptoms and produced adverse effects similar to those of other transdermal systems and dopamine agonists (pp. 272-6). Looking at changes in scores on parts II and III of the Unified Parkinson’s Disease Rating Scale and the proportions of patients with at least a 20% improvement in symptoms, the researchers report: “Patients receiving rotigotine had a mean absolute difference of 5.28 (± 1.18) points lower in UPDRS subtotal scores compared with those receiving placebo (p < 0.0001). The mean change in part III motor scores was –3.50 (± 7.26) (n = 177) and was the greatest contributor to UPDRS improvement. The rotigotine group had more responders (48 vs 19%; p < 0.0001). The most commonly reported adverse events were application site reactions (44% rotigotine vs 12% placebo), nausea (41 vs 17%), somnolence (33 vs 20%), and dizziness (19 vs 13%), and most were mild or moderate in intensity.” (R. L. Watts, U. Alabama, Birmingham; rlwatts@uab.edu)
Stroke Treatment with tPA in Rural Settings: Tissue plasminogen activator can be used safely for strokes being treated outside major medical centers, conclude authors of a brief report (pp. 292-4). “We reviewed charts from 1998 to 2004 of 493 patients admitted with TIA or stroke to our small rural hospital,” the investigators write. “There was a 4% tPA treatment rate with no symptomatic intracranial hemorrhage and zero mortality. IV tPA can be safe and effective in the treatment of acute stroke despite the size of the institution.” (L. L. Edwards, Central Nebraska Neurology, Hastings; centralnn@alltel.net)
Pathologic Gambling with Dopamine Agonists: Pathologic gambling, previously reported in patients taking dopamine agonists for Parkinson’s disease, also occurs when these agents are used to treat restless legs syndrome, according to a brief report (pp. 301-3). The authors describe the cases of three patients treated in a sleep disorders clinic for RLS. (M. Tippmann-Peikert, tippmannpeikert.maja@mayo.edu)
Conversion from Mild Cognitive Impairment to AD: Nearly one-half of patients who had amnestic mild cognitive impairment at age 75 developed Alzheimer’s disease within 2.5 years, investigators report (pp. 288-91). Analyzing data from the Vienna Trans-Danube Aging Study, the researchers found: “The 141 patients with MCI at baseline were classified into two subtypes. At follow-up, 41 of these patients with MCI were diagnosed with AD. Conversion rates to AD were 48.7% (CI: 32.4 to 65.2) for amnestic MCI and 26.8% (CI: 17.6 to 37.8) for nonamnestic MCI. Another 49 AD cases originated from cognitive health at baseline (12.6%; CI: 9.4 to 16.3).” (P. Fischer, Psychiatrische Klinik AKH, Vienna; Peter.Fischer@meduniwien.ac.at)

>>>PNN NewsWatch
* FDA and Ebek, Inc., yesterday announced a voluntary nationwide recall of the company’s dietary supplement, Liviro 3, because the product contains the erectile dysfunction drug tadalafil. Liviro3 is not approved by FDA to treat this condition. Tadalafil may interact with nitrates found in some prescription drugs and may lower blood pressure to dangerous levels, the announcement warns. Consumers who have Liviro3 should stop using it immediately and contact their physician if they experience any problems that may be related to taking this product.
*
Pentacel, a five-component Sanofi Pasteur vaccine, was endorsed yesterday by an FDA advisory panel. The product targets diphtheria, tetanus, pertussis, polio, and Haemophilus influenzae type b. If approved by the agency, Pentacel would eliminate 7 of the 23 vaccine injections that infants and young children currently receive by the time they reach 18 months of age. Already licensed in nine countries, Pentacel has been studied in more than 5,000 children in the U.S. and Canada, Sanofi Pasteur noted in a news release.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 29, 2007 * Vol. 14, No. 19
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Early-release articles from Lancet Oncology and Jan. 27 issue of Lancet (www.thelancet.com; 2007; 369).
Skeletal Health with Exemestane: Survival improved in women with breast cancer by the switch from tamoxifen to exemestane is achieved at some expense to bone mineral density, according to an analysis of 206 evaluable patients in the Intergroup Exemestane Study (Lancet Oncology; doi:10.1016/S1470-2045(07)70003-7). “Within 6 months of switching to exemestane, BMD was lowered by 0.051 g/cm3 (2.7%; 95% CI 2.0–3.4; p < 0.0001) at the lumbar spine and 0.025 g/cm3 (1.4%; 0.8–1.9; p < 0.0001) at the hip compared with baseline,” the investigators report. “BMD decreases were only 1.0% (0.4–1.7; p = 0.002) and 0.8% (0.3–1.4; p = 0.003) in year 2 at the lumbar spine and hip, respectively. No patient with BMD in the normal range at trial entry developed osteoporosis. Bone resorption and formation markers increased at all time points in women receiving exemestane (p < 0.001). With a median follow-up in all IES participants (n = 4274) of 58 months, 162 (7%) and 115 (5%) patients in the exemestane and tamoxifen groups, respectively, had fractures (odds ratio 1.45 [1.13–1.87]; p = 0.003). (R. E. Coleman, Weston Park Hosp., Sheffield, U.K.; R.E.Coleman@sheffield.ac.uk)
Alteplase for Stroke: Used within 3 hours of stroke onset, alteplase was safe and effective in “routine clinical use” among 6,483 patients at 285 centers, including some with little prior experience in use of thrombolytic therapy for stroke (pp. 275-82). In the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST), patients received alteplase in open, observational fashion, and results were compared with pooled data from randomized controlled trials. Results showed: “Baseline characteristics of patients in SITS-MOST were much the same as those in the pooled randomised controlled trials. At 24 h, the proportion of patients with symptomatic intracerebral haemorrhage (per the SITS-MOST protocol) was 1.7% (107/6444; 95% CI 1.4–2.0); at 7 days, the proportion with the same condition as per the Cochrane definition was 7.3% (468/6438; 6.7–7.9) compared with 8.6% (40/465; 6.3–11.6) in the pooled randomised controlled trials. The mortality rate at 3 months in SITS-MOST was 11.3% (701/6218; 10.5–12.1) compared with 17.3% (83/479; 14.1–21.1) in the pooled randomised controlled trials.” (N. Wahlgren, Karolinska U. Hosp., Stockholm, Sweden; nils.wahlgren@karolinska.se)

>>>BMJ Highlights
Source:
Early-release articles from BMJ (www.bmj.org; 2007; 334).
Folate Supplements & Facial Clefts: In a population-based case–control study that used data from Norway for 1996–2001, use of folic acid supplements during early pregnancy reduced the risk of isolated cleft lip with or without cleft palate by about one-third (doi: 10.1136/bmj.39079.618doi:10.1136/bmj.39079.618287.0Bdoi:10.1136/bmj.39079.618287.0B). “Folic acid supplementation during early pregnancy (≥400 µg/day) was associated with a reduced risk of isolated cleft lip with or without cleft palate after adjustment for multivitamins, smoking, and other potential confounding factors (adjusted odds ratio 0.61, 95% confidence interval 0.39 to 0.96),” write the authors. “Independent of supplements, diets rich in fruits, vegetables, and other high folate containing foods reduced the risk somewhat (adjusted odds ratio 0.75, 0.50 to 1.11). The lowest risk of cleft lip was among women with folate rich diets who also took folic acid supplements and multivitamins (0.36, 0.17 to 0.77). Folic acid provided no protection against cleft palate alone (1.07, 0.56 to 2.03).” (A. J. Wilcox, wilcox@niehs.nih.gov)

>>>PNN JournalWatch
* Pharmacotherapy of Childhood Obesity: An Evidence-Based, Conceptual Approach, in Diabetes Care, 2007; 30: 395–402. Reprints: http://care.diabetesjournals.org/cgi/content/extract/30/2/395; M. Freemark, freem001@mc.duke.edu
* Thiazolidinediones and Risk of Repeat Target Vessel Revascularization Following Percutaneous Coronary Intervention: A Meta-analysis, in
Diabetes Care, 2007; 30: 384–8. Reprints: http://care.diabetesjournals.org/cgi/content/extract/30/2/384; N. N. Henyan, nhenyan@sop.umsmed.edu
* A Systematic Review and Meta-Analysis of Hypoglycemia and Cardiovascular Events: A Comparison of Glyburide with Other Secretagogues and with Insulin, in
Diabetes Care, 2007; 30: 389–94. Reprints: http://care.diabetesjournals.org/cgi/content/extract/30/2/389; C. M. Clase, clase@mcmaster.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 © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 30, 2007 * Vol. 14, No. 20
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; 2007; 47).
Patient Recall of Diabetes ABCs: Patients with diabetes presenting in 35 community and clinic pharmacies during a 1-year period generally recalled their blood pressures but were not able to remember their A1C and cholesterol levels, according to a study in which 132 student pharmacists administered questionnaires (pp. 29-34). Among 816 patients in this convenience sample, these results were identified: “The greatest number of patients were able to recall their personal blood pressure level (68%), followed by A1C (53%) and LDL-C (23%). Of those who knew their levels, one-half or fewer were within ADA targets for one or more ABCs. Only 1% of patients who were able to provide ABC levels were below all three ADA target values. Patients were most likely to provide an A1C target (43%), followed by blood pressure (35%) and LDL-C (21%).” (L. M. Guirguis, lmguirguis@pharmacy.ualberta.ca)
Acetaminophen Knowledge: While 80% of patients in an adult internal medicine clinic reported recent use of acetaminophen, knowledge of maximum daily acetaminophen doses and potential toxicities associated with higher doses was poor and independent of education level, age, and race (pp. 35-41). Concluding that “this indicates a need for educational efforts to all patients receiving acetaminophen-containing products, especially since the ability to recognize multi-ingredient products containing acetaminophen was likewise poor,” the author report: “A large percentage of participants (68.3%) reported pain on a daily or weekly basis, and 78.9% reported use of acetaminophen in the past 6 months. Only 2 patients correctly identified the maximum daily dose of regular acetaminophen, and just 3 correctly identified the maximum dose of extra-strength acetaminophen. Furthermore, 28 patients were unsure of the maximum dose of either product. Approximately 63% of participants either had not received or were unsure whether information on the possible danger of high doses of acetaminophen had been previously provided to them. When asked to identify potential problems associated with high doses of acetaminophen, 43.3% of patients noted the liver would be affected. The majority of the patients (71.2%) recognized Tylenol as containing acetaminophen, but fewer than 15% correctly identified Vicodin, Darvocet, Tylox, Percocet, and Lorcet as containing acetaminophen.” (J. L. Stumpf, jlstumpf@umich.edu)
Pharmacy & Health Food Store Knowledge of Drug–Supplement Interaction: Training and education, more comprehensive product labeling, and policies to refer consumers to drug information centers are needed, based on results of a study of 99 community pharmacists and 184 health food store clerks who were posed this question by telephone, “Is there a problem with taking St. John’s wort with birth control pills?” (pp. 42-7). “Community pharmacists were more likely than health food store clerks to correctly identify the drug interaction (50.5% versus 10.9%; chi square(1 df) = 54.32, P < 0.001),” the researchers write. “Overall, 31.8% of respondents provided inappropriate advice that implied the absence of a drug interaction (26.3% of 99 pharmacists and 34.8% of 184 health food store clerks; chi square(1 df) = 2.15, P = 0.14). Appropriateness of advice varied significantly among the three pharmacy chains (P < 0.001) and the three health food store chains (P < 0.05). Responses did not differ by gender of respondents (P = 0.18).” (P. J. Ambrose, U. California, San Francisco; pambrose@memorialcare.org)
Texas Pharmacists & Emergency Contraception: In a late 2004 survey of 153 Texas community pharmacists, the majority of respondents were not previously familiar with pharmacist-initiated emergency contraception, and most were not interested in becoming involved with such projects (pp. 48-57). Using a 1–5 response scale, the investigators found: “Although pharmacists agreed (3.42 ± 1.38) that PIEC would enhance the role of community pharmacists, they were unwilling (2.71 ± 1.54) to participate in PIEC. Significant predictors of willingness to participate in PIEC included background characteristics, experience with EC, as well as benefits and barriers associated with PIEC.” (S. K. Griggs, scottkgriggs@mail.utexas.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 © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Jan. 31, 2007 * Vol. 14, No. 21
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Feb. issue of Diabetes Care (http://care.diabetesjournals.org; 2007; 30).
Pramlintide & Treatment Satisfaction: Among 266 patients with type 1 diabetes who participated in a noninferiority trial, pramlintide produced significantly greater satisfaction with treatment, compared with placebo (pp. 210-6). Study participants were receiving intensive insulin therapy via either multiple daily injections or continuous subcutaneous insulin infusion pump therapy. After pramlintide or placebo was added for 29 weeks, these results were measured: “Pramlintide-treated patients reported greater treatment satisfaction in most questionnaire responses. Treatment satisfaction was similar for pramlintide-treated patients regardless of intensive insulin regimens (MDI versus CSII). Mean A1C was reduced to a similar degree in both pramlintide- (–0.39 ± 0.07%) and placebo-treated (–0.45 ± 0.07%) patients. However, pramlintide treatment was associated with reductions in mean body weight (–1.50 ± 0.33 kg; P < 0.0001) and mealtime insulin use (–19.05 ± 5.17%; P < 0.005) over 29 weeks, while placebo treatment resulted in weight gain (1.28 ± 0.25 kg) and a smaller reduction in mealtime insulin use (–2.20 ± 3.33%).” (D. Marrero, Indiana U., Indianapolis; dgmarrer@iupui.edu)
Vildagliptin v. Rosiglitazone Monotherapy: Vildagliptin, a DPP-4 inhibitor whose approval is pending at FDA, provided glycemic reductions similar to those of rosiglitazone but without weight gain among 786 drug-naive patients with type 2 diabetes (pp. 217-23). Comparing vildagliptin 100 mg in equally divided doses with rosiglitazone 8 mg once daily over 24 weeks, the investigators report: “Monotherapy with vildagliptin and rosiglitazone decreased A1C (baseline = 8.7%) to a similar extent during the 24-week treatment, with most of the A1C reduction achieved by weeks 12 and 16, respectively. At end point, vildagliptin was as effective as rosiglitazone, improving A1C by –1.1 ± 0.1% (P < 0.001) and –1.3 ± 0.1% (P < 0.001), respectively, meeting the statistical criterion for noninferiority (upper-limit 95% CI for between-treatment difference 0.4%). Fasting plasma glucose decreased more with rosiglitazone (–2.3 mmol/l) than with vildagliptin (–1.3 mmol/l). Body weight did not change in vildagliptin-treated patients (–0.3 ± 0.2 kg) but increased in rosiglitazone-treated patients (+1.6 ± 0.3 kg, P < 0.001 vs. vildagliptin). Relative to rosiglitazone, vildagliptin significantly decreased triglycerides, total cholesterol, and LDL, non-HDL, and total-to-HDL cholesterol (–9 to –16%, all P ≤ 0.01) but produced a smaller increase in HDL cholesterol (+4 vs. +9%, P = 0.003). The proportion of patients experiencing an adverse event was 61.4 vs. 64.0% in patients receiving vildagliptin and rosiglitazone, respectively. Only one mild hypoglycemic episode was experienced by one patient in each treatment group, while the incidence of edema was greater with rosiglitazone (4.1%) than vildagliptin (2.1%).” (J. Rosenstock, Dallas Diabetes and Endocrine Ctr. at Medical City, Dallas; juliorosenstock@dallasdiabetes.com)
Nurse-Directed Diabetes Care: Significantly fewer urgent care and emergency department visits were required by 331 patients with diabetes in a county public health center when a specially trained nurse used treatment algorithms to provide diabetes care (pp. 224-7). Comparing prior-year values with experiences during the 1-year Diabetes Managed Care Program, researchers found: “There were 94 total urgent care/emergency room visits and hospitalizations in the year before entering the DMCP and 46 during the DMCP year, a 51% reduction.... Total charges for urgent care/emergency room visits and hospitalizations only (not other charges related to diabetes care) during the year before entering the DMCP were $129,176 compared with $24,630 during the DMCP year.” (M. B. Davidson, Charles R. Drew U., Los Angeles; mayerdavidson@cdrewu.edu)

>>>PNN NewsWatch
* Responding to last year’s Institute of Medicine report on drug safety, FDA yesterday detailed three initial steps aimed at ensuring the safety of the nation’s medication. FDA also announced that it has signed a memorandum of understanding with the U.S. Department of Veterans Affairs to “share information and expertise related to the review and use of FDA-regulated drugs, biologics, and medical devices.”

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 1, 2007 * Vol. 14, No. 22
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Feb. 1 issue of the New England Journal of Medicine (http://content.nejm.org; 2007; 356).
New Treatments for Diabetes: “Ensuring the effective and cost-effective use of the medications that have already been established by high-quality clinical trials to control glycemia or prevent diabetes should be a higher priority than flooding the market with ever more medications,” writes the author of a Perspective article (pp. 437-40). Questioning the rush to market of the gliptins, the writer provides this analysis of the current situation: “Results indicate that sitagliptin is one of the less effective glycemia-lowering drugs introduced in recent years. Moreover, the drug has no obvious extraglycemic benefits. The GLP analogues, for example, are associated with some weight loss, whereas sitagliptin does not appear to affect weight. Although sitagliptin seems relatively safe, causing no increase in severe adverse events, the published data reflect testing in only a limited number of patients for a limited period (641 patient–years in total). Since nearly 20 million people in the United States have type 2 diabetes, there is potential for extensive use of new diabetes medications. For example, within 1 year after the approval of troglitazone in 1997, an estimated 600,000 U.S. patients were receiving it. Although severe hepatotoxicity had not been identified in preliminary testing in about 5,000 people, cases of severe idiosyncratic liver disease began to appear within 6 months after approval, ultimately reaching a prevalence of approximately 1 in 15,000 patients who were receiving the drug. In the first 6 weeks after the approval of sitagliptin, business reports suggested that it accounted for 14% of new prescriptions for antidiabetes medications.” (D. M. Nathan, Harvard Med. Sch., Boston)
Inhaled Insulin: Avoiding the injections needed for insulin therapy through use of inhaled insulin is not always a good idea, according to authors of a Clinical Therapeutics article (pp. 497-502). After presenting the case of a 52-year-old man with an 8-year history of type 2 diabetes, the physicians translate their advice to patients in general: “The patient described in the vignette presents with circumstances that are typical of many persons for whom insulin therapy is recommended. Although the concept of inhaled insulin is likely to be attractive to many such patients, we would first target the fasting glucose before introducing a preprandial insulin. After appropriate education and with the necessary support in place, we would begin treatment with a basal insulin given before sleep, adjusting the dose to achieve a mean fasting glucose level of approximately 100 mg per deciliter. Thus, we do not recommend the use of inhaled insulin in this patient. Should the patient later require preprandial insulin, the freedom from subcutaneous injection offered by inhaled insulin should be weighed against the necessity for multiple inhalations (sometimes at each dose), added cost, limited portability, risk of hypoglycemia, and unknown long-term adverse effects of this form of therapy.” (G. T. McMahon, gmcmahon@partners.org)
Gynecomastia & Lavender/Tea Tree Oils: Topical application of products containing lavender and tea tree oils was associated with male prepubertal gynecomastia in three boys (pp. 479-85). Breast enlargement was temporally related to use of the products—a healing balm in a 4-year-old, styling gel for the hair of a 10-year-old, and soap and skin lotions in a 7-year-old—and the problems resolved upon discontinuation. Noting that studies in human cell lines show that the oils have estrogenic and antiandrogenic properties, the investigators add: “This report raises an issue of concern, since lavender oil and tea tree oil are sold over the counter in their ‘pure’ form and are present in an increasing number of commercial products, including shampoos, hair gels, soaps, and body lotions.... Until epidemiologic studies are performed to determine the prevalence of gynecomastia associated with exposure to lavender oil and tea tree oil, we suggest that the medical community should be aware of the possibility of endocrine disruption and should caution patients about repeated exposure to any products containing these oils.” (K. S. Korach, korach@niehs.nih.gov)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 2, 2007 * Vol. 14, No. 23
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Feb. issue of Pharmacotherapy (www.pharmacotherapy.org; 2007; 27).
QT Intervals in Patients on Haloperidol: In 46 critically ill patients receiving intravenous haloperidol for sedation, QT intervals that were uncorrected or adjusted using the Framingham method best predicted patients’ risk of developing torsades de pointes (pp., 175-82). Retrospectively comparing those approaches with the methods of Bazett and Fridericia and measurement of RR intervals during treatment, the investigators report: “The QTu was associated with the highest R2 compared with QTFram, QTFrid, QTB, and RR interval (0.77, 0.73, 0.68, 0.53, and 0.30, respectively). No significant differences in areas under the ROC curves were found between any of the QT-interval methods. Areas under the ROC curves for QTu and QTFram trended toward being greater than that associated with the RR interval. All QT-interval methods were highly sensitive (100% for each), whereas the RR interval was less sensitive (86%); QTu and QTFram were most specific (82%) compared with the QTFrid (72%), QTB (64%), and RR interval (36%).” (J. E. Tisdale, Purdue U., Indianapolis; jtisdale@iupui.edu)
Atorvastatin & Cognitive Function: No decrements in cognitive function were identified among a group of 57 participants in the Lipid Lowering and Onset of Renal Disease (LORD) trial (pp. 183-90). “Performance was measured using three standard neuropsychological tests: Digit Symbol Coding subtest, Trail Making Test, and Stroop Color-Word Reading Test. Patients received atorvastatin for a mean of 72.93 weeks and placebo for a mean of 68.85 weeks,” the authors explain. “Repeated-measures multivariate analysis of variance failed to identify any significant differences between the two groups on any of the three cognitive measures. Multiple regression analyses identified no single factor or combination of plasma cholesterol levels, renal function, liver function, or age that predicted cognitive performance in either the atorvastatin or placebo group on the three measures at either testing session.” (M. J. Summers, U. Tasmania, Tasmania, Australia; Mathew.Summers@utas.edu.au)
Cardiovascular Events & Contraceptive Patches: Use of contraceptive patches by girls and women aged 15 to 45 years was not associated with increased risk of ischemic stroke or acute myocardial infarction in a retrospective, population-based, epidemiologic analysis of the PharMetrics database (pp. 218-20). Reporting summaries of data for those receiving Ortho EVRA or a norgestimate oral contraceptive in 2002 to 2005, the researchers report: “Crude incidence rates of ischemic stroke among users of the patch and users of norgestimate OCs were 13.6/100,000 woman–years (95% CI 5.9–26.8) and 11.3/100,000 woman–years (95% CI 5.4–20.8), respectively. The crude incidence rate of acute myocardial infarction was 1.7/100,000 woman–years (95% CI 0.04–9.5) in current patch users and 7.9/100,000 woman–years (95% CI 3.2–16.3) in current users of norgestimate OCs. Incidence rate ratios (IRRs) were estimated for the outcomes by comparing data for users of the patch and users of a norgestimate OC. The IRR for stroke was 1.2 (95% CI 0.41–3.4) and for acute myocardial infarction was 0.2 (95% CI 0.004–1.7).” (S. S. Jick, Boston Collaborative Drug Surveillance Program, Lexington, Mass.; sjick@bu.edu)
Emergency Contraception: Pharmacists and other clinicians should understand the evidence underlying the use of levonorgestrel for emergency contraception, write authors of a mini-review article (pp. 278-84). “Evidence supports the safety and efficacy of a single dose of levonorgestrel 1.5 mg for emergency contraception,” they explain. “Furthermore, when two doses of levonorgestrel 0.75 mg are administered, the second dose can confidently be taken 12–24 hours after the first without compromising efficacy.” (L. B. Hansen, U. Colorado, Denver)

>>>PNN NewsWatch
* The battle over FDA and the way it approves and monitors medications has been engaged on Capitol Hill. As reported in today’s Wall Street Journal, bipartisan bills have been introduced this week that would have far-reaching effects on the agency, the drug industry, and both premarketing testing and postmarketing oversight of medications. Drug safety in the wake of the Vioxx debacle is driving much of the discussion, but also on the table are user fees, approval of follow-on versions of biotechnology drugs, and reimportation of medications.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 5, 2007 * Vol. 14, No. 24
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Feb. 3 issue of Lancet (www.thelancet.com; 2007; 369).
Erythropoietin & Upper Limit for Hemoglobin: Mortality rates are higher among patients with anemia of chronic kidney disease when higher hemoglobin concentrations are targeted during erythropoietin therapy, report authors of a meta-analysis (pp. 381-8). Considering randomized controlled trials of at least 100 patients that had a minimum follow-up period of 12 weeks, the investigators found: “We analysed nine randomised controlled trials that enrolled 5,143 patients. There was a significantly higher risk of all-cause mortality (risk ratio 1.17, 95% CI 1.01–1.35; p = 0.031) and arteriovenous access thrombosis (1.34, 1.16–1.54; p = 0.0001) in the higher haemoglobin target group than in the lower haemoglobin target group in the fixed effects model without heterogeneity between studies. There was a significantly higher risk of poorly controlled blood pressure (1.27, 1.08–1.50; p = 0.004) in the higher haemoglobin target group than in the lower target haemoglobin group with the fixed effects model; however, this was not significant in the random effects model (1.31, 0.97–1.78; p = 0.075). The incidence of myocardial infarction was much the same in the two groups.” (H. Krum, Monash U., Melbourne, Australia; henry.krum@med.monash.edu.au)
Cost-effectiveness of Pneumococcal Vaccine: Vaccination of infants against Streptococcus pneumoniae would “substantially reduce childhood mortality and to be highly cost-effective” in most of the world’s poorest countries at a vaccine cost of $1 to $5 per dose, report authors of an economic analysis (pp. 389-96). Using a decision analysis model that compared a three-dose series with no vaccination, the investigators determined: “Pneumococcal vaccination at the rate of diphtheria–tetanus–pertussis vaccine coverage was projected to prevent 262,000 deaths per year (7%) in children aged 3–29 months in the 72 developing countries studied, thus averting 8.34 million disability-adjusted life years (DALYs) yearly. If every child could be reached, up to 407,000 deaths per year would be prevented. At a vaccine cost of International $5 per dose, vaccination would have a net cost of $838 million, a cost of $100 per DALY averted. Vaccination at this price was projected to be highly cost-effective in 68 of 72 countries when each country’s per head gross domestic product per DALY averted was used as a benchmark.” (A. Sinha, sinhaan1@umdnj.edu)

>>>BMJ Highlights
Source:
Feb. 3 issue of BMJ (www.bmj.org; 2007; 334).
Antidepressants & Suicide: In an analysis of the U.K. General Practice Research Database, use of venlafaxine “was consistently associated with higher risk of suicide compared with citalopram, fluoxetine, and dothiepin” (pp. 242 ff). “Venlafaxine users had a higher burden of risk factors for suicide, including previous suicide attempts and proxies for severe depression or depression that was difficult to treat,” the authors note of the 219,088 patients included in the report. “In the analysis for completed suicides, unadjusted and adjusted hazard ratios for venlafaxine compared with citalopram were 2.44 (95% confidence interval 1.12 to 5.31) and 1.70 (0.76 to 3.80), for venlafaxine compared with fluoxetine were 2.85 (1.37 to 5.94) and 1.63 (0.74 to 3.59), and for venlafaxine compared with dothiepin were 2.54 (1.07 to 6.02) and 1.31 (0.53 to 3.25). Compared with other study drugs, venlafaxine was also associated with an increased risk of attempted suicide, but adjustment for measured confounders substantially reduced the hazard ratios.” (A Rubino, RTI Health Solutions, Manchester, U.K.; arubino@rti.org)

>>>PNN JournalWatch
* Successful Tobacco Dependence Treatment in Schizophrenia, in American Journal of Psychiatry, 2007; 164: 222–7. Reprints: http://ajp.psychiatryonline.org/cgi/content/full/164/2/222; J. M. Williams.
* Alcohol Use and Anxiety: Diagnostic and Management Issues, in
American Journal of Psychiatry, 2007; 164: 217:–21. Reprints: http://ajp.psychiatryonline.org/cgi/content/full/164/2/217; K. T. Brady.
* The Use of Statins in Pediatrics: Knowledge Base, Limitations, and Future Directions, in
Pediatrics, 2007; 119: 370–80. Reprints: http://pediatrics.aappublications.org/cgi/content/abstract/119/2/370; B. Belay, Temple U., Philadelphia.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 6, 2007 * Vol. 14, No. 25
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Feb. 6 issue of the Annals of Internal Medicine (www.annals.org; 2007; 146).
Brief Intervention for Alcohol Misuse: On the medical service of an urban hospital, brief interventions for patients with unhealthy alcohol use were insufficient to change behaviors, report authors of a 341-patient study (pp. 167-76). In the randomized controlled trial, those drinking risky amounts of alcohol—defined as more than 14 drinks/week or 4 drinks/occasion for men or more than 11 drinks/week or 3 drinks/occasion for women and the elderly—received either a 30-minute motivational counseling session or usual care. Results showed: “The intervention was not significantly associated with receipt of alcohol assistance by 3 months among alcohol-dependent patients (adjusted proportions receiving assistance, 49% for the intervention group and 44% for the control group; intervention–control difference, 5% [95% CI, –8% to 19%]) or with drinks per day at 12 months among all patients (adjusted mean decreases, 1.5 for patients who received the intervention and 3.1 for patients who received usual care; adjusted mean group difference, –1.5 [CI, –3.7 to 0.6]). There was no significant interaction between the intervention and alcohol dependence in statistical models predicting drinks per day (P = 0.24).” (R. Saitz, Boston Med. Ctr., Boston; rsaitz@bu.edu)
An editorialist writes that this study provides “a missing piece of the intervention puzzle” and calls for better coordination between inpatient and outpatient care (pp. 223-5): “What should clinicians do when one of their inpatients is a problem drinker? The key principle is to link inpatient treatment in a continuous manner to ongoing outpatient treatment—either brief interventions for nondependent drinkers or more specialized treatment for patients with alcohol dependence. Medical hospitalization can be a hook with which to engage the problem drinker. We have proven outpatient treatments for both nondependent and dependent drinkers. As with other medical problems, we need to work hard at making smooth handoffs from inpatient care to outpatient care for alcohol disorders.” (P. G. O’Connor,
patrick.oconnor@yale.edu)
Preoperative Bridging of Warfarin–LMWH Therapy: Often used when warfarin therapy is interrupted for surgery, a commonly used low molecular weight heparin schedule produces “markedly elevated anti-Xa heparin levels shortly before surgery was scheduled to begin,” according to a study conducted at a single university hospital (pp. 184-7). Based on results obtained with enoxaparin 1 mg/kg twice daily with the last dose given the evening before surgery, the researchers found: “Preoperative anti-Xa heparin levels were obtained in 80 patients at an average of 14 hours after the last dose of enoxaparin was administered. The average anti-Xa heparin level was 0.6 U/mL. The anti-Xa heparin level, measured shortly before surgery, was 0.5 U/mL or greater in 54 (68%) patients and 1.0 U/mL or greater in 13 (16%) patients. A shorter interval since the last dose (P < 0.001) and a higher body mass index (P = 0.001) were associated with higher preoperative anti-Xa heparin levels.” (M. J. O’Donnell, donnm@mcmaster.ca">odonnm@mcmaster.ca)
IVIG in Sepsis: While needing confirmation in a large trial that avoids the methodological limitations of past studies, intravenous immunoglobulin provides a survival benefit among critically ill adult patients with sepsis, according to a meta-analysis of 20 articles (pp. 193-203). “Polyclonal intravenous immunoglobulin therapy was associated with an overall survival benefit (risk ratio, 0.74 [95% CI, 0.62 to 0.89]) compared with placebo or no intervention,” the authors note. “In sensitivity analyses, documented survival improved when the analysis was limited to published, peer-reviewed trials (risk ratio, 0.72 [CI, 0.58 to 0.89]) (17 trials [n = 1,865]) and blinded trials (risk ratio, 0.61 [CI, 0.40 to 0.93) (7 trials [n = 896]).” (A. F. Turgeon, Ottawa Health Research Inst., Ottawa, Ont., Canada; alexisturgeon@yahoo.ca)
VTE Management: Clinical guidelines (pp. 204-10; A. Qaseem, Am. College of Physicians, Philadelphia) and a supporting systematic review (pp. 211-22; J. Segal, Johns Hopkins U., Baltimore; jsegal@jhmi.edu) detail management strategies for use in patients with venous thromboembolism. For those with unprovoked VTE, more than 12 months of conventional-intensity oral anticoagulation is advised.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 7, 2007 * Vol. 14, No. 26
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Feb. 7 issue of JAMA (www.jama.com; 2007; 297).
Aprotinin & Long-term Mortality After CABG: In addition to previously reported problems with acute renal and vascular problems, aprotinin has now been linked to increased mortality rates for 5 years following its use in conjunction with coronary artery bypass graft surgery (pp. 471-9). Noting that “safer and less expensive alternatives (ie, aminocaproic acid and tranexamic acid) are available,” the researchers provide these details on 3,876 patients who underwent CABG surgery at 62 medical centers: “Aprotinin treatment (223 deaths among 1,072 patients [20.8% 5-year mortality]) was associated with significantly increased mortality compared with control (128 deaths among 1,009 patients [12.7%]; covariate adjusted hazard ratio for death, 1.48; 95% confidence interval, 1.19–1.85), whereas neither aminocaproic acid (132 deaths among 834 patients [15.8%]; adjusted hazard ratio for death, 1.03; 95% confidence interval, 0.80–1.33) nor tranexamic acid (65 deaths among 442 patients [14.7%]; adjusted hazard ratio for death, 1.07; 95% confidence interval, 0.80-1.45) was associated with increased mortality. In multivariable logistic regression, either with propensity adjustment or without, aprotinin was independently predictive of 5-year mortality (adjusted odds ratio with propensity adjustment, 1.48; 95% confidence interval, 1.13–1.93; P = .005) among patients with diverse risk profiles, as well as among those surviving their index hospitalization. Neither aminocaproic nor tranexamic acid was associated with increased risk of death.” (D. T. Mangano, Ischemia Res. and Educ. Found., San Bruno, Calif.; dtb@iref.org)
Asking about lessons learned from aprotinin, an editorial writes (pp. 527-9): “The controversy surrounding these studies on aprotinin risks centers on the degree to which the robust statistical analyses can account for the unmeasured biases in this registry. The concept that observational data sets and analyses can play a substantial role in postmarket surveillance and safety evaluation for drugs and devices has enormous merit and, many believe, feasibility. With regard to aprotinin use, the US Food and Drug Administration issued a relabeling of aprotinin on December 15, 2006, once again confining it to use in high-risk coronary artery bypass graft patients. While the admonition to ‘First, do no harm’ certainly applies to ongoing use of aprotinin, an equally important consideration is when and where, at the drug/device safety evaluation level, the issue of first, do no harm actually could have been initially identified. Ultimately, going forward, the most important lesson learned from the aprotinin story is determining better ways to ensure drug safety and to eliminate and prevent these harms.” (T. B. Ferguson, Jr., East Carolina U., Greenville;
Fergusont@ecu.edu)
Statins & Regression of Atherosclerosis: The benefits of statins as derived from regression of coronary atherosclerosis depends both the drugs’ reductions in LDL cholesterol and increases of HDL cholesterol, according to a post-hoc analysis from four prospective randomized trials involving 1,455 patients with angiographic coronary disease (pp. 499-508). “During statin therapy ... the ratio of LDL-C to HDL-C was reduced from a mean (SD) of 3.0 (1.1) to 2.1 (0.9) (a 26.7% decrease; P < .001). These changes were accompanied by a mean (SD) increase in percent atheroma volume from 39.7% (9.8%) to 40.1% (9.7%) (a 0.5% [3.9%] increase; P = .001) and a mean (SD) decrease in total atheroma volume of 2.4 (23.6) mm3 (P < .001). In univariate analysis, mean levels and treatment-mediated changes in LDL-C, total cholesterol, non–HDL cholesterol, apolipoprotein B, and ratio of apolipoprotein B to apolipoprotein A-I were significantly correlated with the rate of atherosclerotic progression, whereas treatment-mediated changes in HDL-C were inversely correlated with atheroma progression. In multivariate analysis, mean levels of LDL-C ( coefficient, 0.11 [95% confidence interval, 0.07–0.15]) and increases in HDL-C ( coefficient, –0.26 [95% confidence interval, –0.41 to –0.10]) remained independent predictors of atheroma regression. Substantial atheroma regression (5% reduction in atheroma volume) was observed in patients with levels of LDL-C less than the mean (87.5 mg/dL) during treatment and percentage increases of HDL-C greater than the mean (7.5%; P < .001).” (S. J. Nicholls, Cleveland Clinic, Cleveland; nichols1@ccf.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 © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 8, 2007 * Vol. 14, No. 27
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Feb. 8 issue of the New England Journal of Medicine (http://content.nejm.org; 2007; 356).
Treatment of Polycystic Ovary Syndrome: Among 626 infertile women with polycystic ovary syndrome, clomiphene proved superior to metformin for achieving live births but with an increased risk of multiple births (pp. 551-66). In a 6-month trial, participants received either clomiphene citrate, extended-release metformin, or both, with these results: “The live-birth rate was 22.5% (47 of 209 subjects) in the clomiphene group, 7.2% (15 of 208) in the metformin group, and 26.8% (56 of 209) in the combination-therapy group (P < 0.001 for metformin vs. both clomiphene and combination therapy; P = 0.31 for clomiphene vs. combination therapy). Among pregnancies, the rate of multiple pregnancy was 6.0% in the clomiphene group, 0% in the metformin group, and 3.1% in the combination-therapy group. The rates of first-trimester pregnancy loss did not differ significantly among the groups. However, the conception rate among subjects who ovulated was significantly lower in the metformin group (21.7%) than in either the clomiphene group (39.5%, P = 0.002) or the combination-therapy group (46.0%, P < 0.001). With the exception of pregnancy complications, adverse-event rates were similar in all groups, though gastrointestinal side effects were more frequent, and vasomotor and ovulatory symptoms less frequent, in the metformin group than in the clomiphene group.” (R. S. Legro, Penn. State U., Hershey; rsl1@psu.edu)
An editorialist adds (pp. 622-4): “Legro et al. [provide] strong evidence that the metabolic benefits of metformin do not translate into live-birth rates that are as high as those with the old-fashioned standard, clomiphene citrate. Aside from the low but ever-present risk of multiple pregnancy, the use of clomiphene citrate to treat infertility in women with the polycystic ovary syndrome is simple, inexpensive, generally safe, and—as demonstrated by Legro et al.—more efficacious than the use of metformin.” (D. S. Guzick, U. Rochester, Rochester, N.Y.)
Interleukin Monoclonal Antibody for Psoriasis: An interleukin-12/23 monoclonal antibody was effective for reducing symptoms of psoriasis among 320 patients with moderate or severe cases (pp. 580-92). These findings provide “further evidence of a role of the interleukin-12/23 p40 cytokines in the pathophysiology of psoriasis,” the group concludes, adding: “There was at least 75% improvement in the psoriasis area-and-severity index at week 12 (the primary end point) in 52% of patients who received 45 mg of the interleukin-12/23 monoclonal antibody, in 59% of those who received 90 mg, in 67% of those who received four weekly 45-mg doses, and in 81% of those who received four weekly 90-mg doses, as compared with 2% of those who received placebo (P < 0.001 for each comparison), and there was at least 90% improvement in 23%, 30%, 44%, and 52%, respectively, of patients who received the monoclonal antibody as compared with 2% of patients who received placebo (P < 0.001 for each comparison). Adverse events occurred in 79% of patients treated with the interleukin-12/23 monoclonal antibody as compared with 72% of patients in the placebo group (P = 0.19). Serious adverse events occurred in 4% of patients who received the monoclonal antibody and in 1% of those who received placebo (P = 0.69).” (G. G. Krueger, gerald.krueger@derm.med.utah.edu)
Conscience & Care: In a survey of 1,144 physicians, 63% believed that explaining to patients their moral objections to controversial clinical practices was acceptable, 86% thought physicians were obligated to present all options to patients, and 71% indicated that physicians should refer patients to another clinician without objections to a requested procedure (pp. 593-600; F. A. Curlin, fcurlin@medicine.bsd.uchicago.edu)

>>>PNN NewsWatch
* FDA yesterday approved a 60-mg dose of the lipase inhibitor orlistat for nonprescription sales. GlaxoSmithKline Consumer Healthcare will market the product—indicated for overweight patients who are also on reduced-calorie, low-fat diets and exercise programs—under the trade name alli beginning this summer, and higher doses of Xenical (Roche) will remain prescription only.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 9, 2007 * Vol. 14, No. 28
Providing news and information about medications and their proper use

>>>Geriatrics Highlights
Source:
Feb. issue of the Journal of the American Geriatrics Society (www.blackwell-synergy.com; 2007; 55).
Initiating Insulin Therapy in Type 2 Diabetes: Addition of once-daily insulin glargine provided a simple and effective adjunct to oral antidiabetic drug (OAD) therapy in a group of 364 poorly controlled elderly patients with type 2 diabetes mellitus (pp. 182 ff). In a subgroup analysis involving 130 insulin-naive patients with fasting blood glucose levels greater than 120 mg/dL and glycosylated hemoglobin (A1C) levels between 7.5% and 10.5% while taking glimeperide plus metformin, twice-daily 70/30 insulin was compared with once-daily morning insulin glargine, with these results: “A1C decreased from baseline to endpoint for both glargine + OAD (from 8.8% to 7.0%) and 70/30 (from 8.9% to 7.4%); adjusted mean A1C decrease for glargine + OAD and 70/30 was −1.9% and −1.4%, respectively (P = .003). More patients reached A1C of 7.0% or less without confirmed nocturnal hypoglycemia with glargine + OAD (n = 37, 55.2%) than with 70/30 (n = 19, 30.2%) (P = .006). FBG decreased significantly more with glargine + OAD (−57 mg/dL (−3.2 mmol/L)) than with 70/30 (−40 mg/dL (−2.2 mmol/L)) (P = .002). Patients treated with glargine + OAD experienced fewer episodes of any hypoglycemia (3.68/patient–year) than did those treated with 70/30 (9.09/patient–year) (P = .008).” (H. U. Janka, Medizinische Abteilung, Bremen, Germany; Hans.Janka@klinikum-bremen-nord.de)
Pain in Patients with Depression: Pain reduces patients’ recovery from depression, researchers note, adding that in elderly patients, “multiple domains of functioning (e.g., physical and social disability) and the degree to which pain and other forms of physical comorbidity may hinder or minimize treatment-related improvements in depressive symptoms” should be addressed (pp. 202). The Primary Care Research in Substance Abuse and Mental Health for the Elderly Study included 524 adults aged 60 or older who received either integrated care or enhanced specialty referral care. Results showed: “Intention-to-treat analyses revealed that both treatment groups showed reduced depressive symptoms over time, although self-reported pain moderated reductions in depressive symptoms. At higher levels of pain severity and interference with work activities, improvements in depressive symptoms were blunted. Furthermore, pain interference appeared to have a greater effect on depressive symptoms than did pain severity; in individuals with major depression, pain interference fully accounted for the moderating effects of pain severity on changes in depressive symptoms over time.” (S. Mavandadi, smavanda@mail.med.upenn.edu)
Alcohol Use & Physical Performance: Among 5,962 older men, consumption of 7 to 20 drinks/week was associated with “modestly better physical performance and lower odds of reporting a functional limitation” (pp. 212 ff). Alcohol consumption was categorized as abstainers, intermittent (< 1 drink/wk), light (1–6), low-moderate (7–13), high-moderate(14–20), or heavy (≥21). “After age adjustment, men with low-moderate or high-moderate intake generally performed 3% to 5% better on physical performance tests than abstainers; heavy drinkers performed similarly to abstainers,” the authors report. “These associations lessened yet tended to remain significant after multivariate adjustment. Men with low-moderate alcohol intake had the lowest odds of reporting a limitation in instrumental activities of daily living (multivariate-adjusted odds ratio (OR) = 0.52, 95% confidence interval (CI) = 0.39–0.69) compared to abstainers; similar odds were seen for high-moderate and heavy use. The association between alcohol intake and self-reported physical limitation was U-shaped, with the highest odds of physical limitation in abstainers (OR = 1.0, referent) and heavy users (OR = 0.88, 95% CI = 0.58–1.36) and the lowest odds in low-moderate users (OR = 0.62, 95% CI = 0.46–0.95).(P. M. Cawthon, Calif. Pacific Med. Ctr., San Francisco; pcawthon@sfcc-cpmc.net)
High-Dose Vitamin D: Falls were reduced among nursing home residents on high doses of vitamin D, according to a study of 725 patients (pp. 234 ff). Over 5 months, the incidence of falls was 72% lower among those on 800 IU daily, compared with placebo, and the proportion of patients with falls was lower in that group than in patients on 200, 400, or 600 IU daily doses. (K. E. Broe, broe@hrca.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 © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 12, 2007 * Vol. 14, No. 29
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Early-release articles from and Feb. 10 issue of Lancet (www.thelancet.com; 2007; 369).
GI Events with Etoricoxib: Providing more results from the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) trial (see PNN, Nov. 20, 2006), investigators report “significantly fewer upper gastrointestinal clinical events with the COX-2 selective inhibitor etoricoxib than with the traditional NSAID diclofenac due to a decrease in uncomplicated events, but not in the more serious complicated events” (pp. 465-73). The MEDAL trial included 34,701 patients with osteoarthritis or rheumatoid arthritis, and they received either etoricoxib 60 or 90 mg daily or diclofenac 150 mg daily, with these results: “Overall upper gastrointestinal clinical events were significantly less common with etoricoxib than with diclofenac (hazard ratio [HR] 0.69, 95% CI 0.57–0.83; p = 0.0001). There were significantly fewer uncomplicated gastrointestinal events with etoricoxib than there were with diclofenac (0.57, 0.45–0.74; p < 0.0001); there was no difference in complicated events (0.91, 0.67–1.24; p = 0.561). PPIs were used concomitantly for at least 75% of the study period by 13,862 (40%) and low-dose aspirin by 11,418 (33%) patients; treatment effects did not differ significantly in these individuals.” (L. Laine, llaine@usc.edu)
Antibiotic Resistance Caused by Antibiotic Use: In a study of macrolide resistance, macrolide use is shown to be the “single most important driver” of resistance (pp. 482-90). In a study of 224 volunteers who received either azithromycin, clarithromycin, or placebo, pharyngeal swabs were obtained before and for 180 days after drug administration, with these results: “Both macrolides significantly increased the proportion of macrolide-resistant streptococci compared with the placebo at all points studied, peaking at day 8 in the clarithromycin group (mean increase 50.0%, 95% CI 41.7–58.2; p < 0.0001) and at day 4 in the azithromycin group (53.4%, 43.4–63.5; p < 0.0001). The proportion of macrolide-resistant streptococci was higher after azithromycin treatment than after clarithromycin use, with the largest difference between the two groups at day 28 (17.4% difference, 9.2–25.6; p < 0.0001). Use of clarithromycin, but not of azithromycin, selected for the erm(B) gene, which confers high-level macrolide resistance.” (H. Goossens, U. Hosp., Edegem-Antwerp, Belgium; herman.goossens@uza.be)

>>>BMJ Highlights
Source:
Early-release article from BMJ (www.bmj.org; 2007; 334).
Length of Anticoagulation After VTE/PE: Based on data from 46 U.K. hospitals, increasing the duration of anticoagulation following deep-vein thrombosis or pulmonary embolism from 3 to 6 months provides “little, if any, advantage,” investigators conclude (doi:10.1136/bmj.39098.583356.55). “During treatment deep vein thrombosis or pulmonary embolism failed to resolve, extended, or recurred in six patients in the three month group without fatal consequences, compared with 10 in the six month group,” the group writes. “After treatment there were 23 non-fatal recurrences in the three month group and 16 in the six month group. Fatal and non-fatal deep vein thrombosis or pulmonary embolism during treatment, and after treatment thus occurred in 31(8%) of those who had received three months’ anticoagulation compared with 29 (8%) of those who had received six months’ (P = 0.80, 95% confidence interval for difference –3.1% to 4.7%). There were no fatal haemorrhages during treatment but there were eight major haemorrhages in those treated for six months and none in those treated for three months (P = 0.008, –3.5% to –0.7%). Thus 31 (8%) of the patients receiving three months’ anticoagulation experienced adverse outcomes as a result of deep vein thrombosis or pulmonary embolism or its treatment compared with 35 (9%) of those receiving six months’ (P = 0.79, –4.9% to 3.2%).” (I. A. Campbell, Llandough Hosp., Llandough, Cardiff, U.K.; ian.campbell@cardiffandvale.wales.nhs.uk)

>>>PNN JournalWatch
* Prolonged QT Interval and Torsades de Pointes Associated with Atazanavir Therapy, in Clinical Infectious Diseases, 2007; 44. Reprints: www.journals.uchicago.edu/CID/journal/issues/v44n6/41427/brief/41427.abstract.html; T. Ly, Washington Hosp. Ctr., Washington, D.C.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 13, 2007 * Vol. 14, No. 30
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Feb. 12 issue of the Archives of Internal Medicine (www.archinternmed.com; 2007; 167).
Pulmonary Effects of Marijuana Smoking: Short-term exposure to marijuana is associated with bronchodilation, but long-term marijuana smoking is associated with symptoms suggestive of obstructive lung disease, according to a review of 34 published studies (pp. 221-8). “Eleven of 12 challenge studies found an association between short-term marijuana administration and bronchodilation (eg, increases of 0.15–0.25 L in forced expiratory volume in 1 second),” the authors write. “No consistent association was found between long-term marijuana smoking and airflow obstruction measures. All 14 studies that assessed long-term marijuana smoking and respiratory complications noted an association with increased respiratory symptoms, including cough, phlegm, and wheeze (eg, odds ratio, 2.00; 95% confidence interval, 1.32–3.01, for the association between marijuana smoking and cough). Studies were variable in their overall quality (eg, controlling for confounders, including tobacco smoking).” (J. M. Tetrault, jeanette.tetrault@yale.edu)
Adherence & Anticoagulation: Warfarin therapy presents adherence challenges to patients, yet undercoagulation and overcoagulation can be linked to too few and too many prescription bottle openings, according to a study of patients at three anticoagulation clinics (pp. 229-35). “Among 136 participants observed for a mean of 32 weeks, 92% had at least 1 missed or extra bottle opening; 36% missed more than 20% of their bottle openings; and 4% had more than 10% extra bottle openings,” report researchers. “In multivariable analyses, there was a significant association between underadherence and underanticoagulation. For each 10% increase in missed pill bottle openings, there was a 14% increase in the odds of underanticoagulation (P < .001); participants with more than 20% missed bottle openings (1–2 missed days each week) had more than a 2-fold increase in the odds of underanticoagulation (adjusted odds ratio, 2.10; 95% confidence interval, 1.48–2.96). Participants who had extra pill bottle openings on more than 10% of days had a statistically significant increase in overanticoagulation (adjusted odds ratio, 1.73; 95% confidence interval, 1.09–2.74).” (S. E. Kimmel, skimmel@cceb.med.upenn.edu)
INR Control & AF Events: The risks of death, myocardial infarction, major bleeding, and stroke or systemic embolism events are related to INR control, report investigators with the SPORTIF (Stroke Prevention Using an Oral Thrombin Inhibitor in Atrial Fibrillation) III and V trials (pp. 239-45). Among 3,587 patients with AF randomized to receive warfarin in the trials, those who achieved good (>75% of time in INR ranges of 2.0 to 3.0), moderate (60%–75%), and poor (<60%) control were analyzed: “The poor control group had higher rates of annual mortality (4.20%) and major bleeding (3.85%) compared with the moderate control group (1.84% and 1.96%, respectively) and the good control group (1.69% and 1.58%, respectively) (P < .01 for all). Compared with the good control group, the poor control group had higher rates of MI (1.38% vs 0.62%, P = .04) and of stroke or SEE (2.10% vs 1.07%, P = .02).” (H. D. White, Auckland City Hosp., Auckland, New Zealand; harveyw@adhb.govt.nz)

>>>PNN NewsWatch
* FDA yesterday announced revisions to the labeling for telithromycin (Ketek, Sanofi Aventis) that the agency said were designed to improve the safe use of this antibiotic by patients. The changes include the removal of two of the three previously approved indications—acute bacterial sinusitis and acute bacterial exacerbations of chronic bronchitis—from the drug’s label; updating a boxed warning that the drug is contraindicated in patients with myasthenia gravis; and introduction of a Patient Medication Guide for dispensing to patients with telithromycin prescriptions. FDA’s actions are consistent with the risk–benefit conclusions of advisory committees that met jointly in December 2006. Telithromycin remains indicated only for treatment of community-acquired pneumonia of mild to moderate severity.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 14, 2007 * Vol. 14, No. 31
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Feb. 14 issue of JAMA (www.jama.com; 2007; 297).
Gp IIb/IIIa Inhibitors in ACS: Benefits of use of glycoprotein IIb/IIIa inhibitors in the cardiac catheterization laboratory should be weighed carefully against risks such as major and minor bleeding and the need for blood transfusions, according to researchers in the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) Timing trial (pp. 591-602). Current guidelines recommend use of Gp IIb/IIIa inhibitors in patients with ACS undergoing an invasive strategy, the authors explain, “either administered upstream prior to angiography in all patients or initiated in the catheterization laboratory selectively to patients undergoing PCI.” Testing these two strategies in 9,207 patients with moderate- or high-risk ACS who were undergoing invasive interventions, the ACUITY investigators report: “Glycoprotein IIb/IIIa inhibitors were used more frequently (98.3% vs 55.7%, respectively) and for a significantly longer duration (median, 18.3 vs 13.1 hours; P<.001) in patients in the upstream group compared with the deferred group. Composite ischemia at 30 days occurred in 7.9% of patients assigned to deferred use compared with 7.1% of patients assigned to upstream administration (relative risk, 1.12; 95% confidence interval, 0.97-1.29; P = .044 for noninferiority; P = .13 for superiority); as such, the criterion for noninferiority was not met. Deferred use compared with upstream use resulted in reduced 30-day rates of major bleeding (4.9% vs 6.1%, respectively; P < .001 for noninferiority; P = .009 for superiority) and similar rates of net clinical outcomes (11.7% vs 11.7%; P < .001 for noninferiority; P = .93 for superiority).” (G. W. Stone, gs2184@columbia.edu)
Editorialists add (pp. 636-9): “Even though the results from the ACUITY Timing Trial should not fundamentally change the use of Gp IIb/IIIa inhibitors in clinical practice, the ACUITY investigators have addressed an important question within the framework of a large clinical trial. Because of varying results from SYNERGY (enoxaparin vs unfractionated heparin), ACUITY (bivalirudin vs unfractionated heparin/low-molecular-weight heparin), OASIS (fondaparinux vs enoxaparin), and other trials, clinicians currently struggle with what constitutes the optimum antithrombin/antiplatelet strategy for patients with ACS. The ACUITY Timing Trial was not designed to allow comparisons among agents, and these considerations are appropriately absent from this report. Much remains to be learned about optimum care of patients with ACS, and the findings from the ACUITY Timing Trial provide valuable insights for future investigators seeking answers to critical questions of clinical practice.” (K. W. Mahaffey,
mahaf002@mc.duke.edu)
Iron Stores in PAD: Reduction of iron stores through phlebotomy did not reduce all-cause mortality or secondary end points among 1,277 patients with symptomatic peripheral arterial disease (pp. 603-10). Comparing control patients with those who underwent removal of defined volumes of blood at 6-month intervals, investigators found: “All-cause deaths occurred in 148 patients (23%) in the control group and in 125 (20%) in the iron-reduction group (hazard ratio (HR), 0.85; 95% confidence interval (CI), 0.67–1.08; P = .17). Death plus nonfatal myocardial infarction and stroke occurred in 205 patients (32%) in the control group and in 180 (28%) in the iron-reduction group (HR, 0.88; 95% CI, 0.72–1.07; P = .20).” (L. R. Zacharski, leo.r.zacharski@dartmouth.edu)

>>>PNN NewsWatch
* The controversy over the efficacy of oral phenylephrine in currently recommended dosages of 10 mg every 4 hours is intensifying. A citizen’s petition has been filed with FDA by U. Fla. pharmacy professors Leslie Hendeles, PharmD, Randy C. Hatton, PharmD, and Almut G. Winterstein, PhD, calling for the agency to increase the maximum dose of this drug in product labeling for patients aged 12 years and older and to withdraw approval for use of oral phenylephrine in patients younger than 12. The petition suggests a dosage of 25 mg every 4 hours but notes that additional studies are needed to determine the efficacy and safety of this dosage. The Consumer Healthcare Products Association has countered with a meta-analysis conducted by its staff that concludes that phenylephrine is more effective than placebo for relieving congestion in the first 30, 60, and 90 minutes after a dose.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 15, 2007 * Vol. 14, No. 32
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Feb. 15 issue of the New England Journal of Medicine (http://content.nejm.org; 2007; 356).
Treatment of Kawasaki Disease: A single pulsed dose of intravenous methylprednisolone provided no benefit when added to the standard i.v. immune globulin regimen, according to a study of 199 North American patients treated within the first 10 days of initial fever (pp. 663-75). Therapy with those agents plus aspirin 80–100 mg/kg/day until afebrile for 48 hours and 3–5 mg/kg/day thereafter produced these results: “At week 1 and week 5 after randomization, patients in the two study groups had similar coronary dimensions, expressed as z scores adjusted for body-surface area, absolute dimensions, and changes in dimensions. As compared with patients receiving placebo, patients receiving intravenous methylprednisolone had a somewhat shorter initial period of hospitalization (P = 0.05) and, at week 1, a lower erythrocyte sedimentation rate (P = 0.02) and a tendency toward a lower C-reactive protein level (P = 0.07). However, the two groups had similar numbers of days spent in the hospital, numbers of days of fever, rates of retreatment with intravenous immune globulin, and numbers of adverse events.” (J. W. Newburger, Children’s Hosp., Boston; jane.newburger@cardio.chboston.org)
In a Perspectives article, a writer discusses “the riddle of Kawasaki disease” (pp. 659-61): “Now, 40 years after the original description of the clinical signs of this illness by Japanese pediatrician Tomisaku Kawasaki, we understand that this self-limited vasculitis affords a unique opportunity to study acute endothelial-cell injury, aneurysm formation, and vascular-wall remodeling in young children in whom the cumulative effects of aging and environmental insults have not yet taken their toll. The lessons to be learned from Kawasaki disease are likely to have relevance for the study of chronic conditions involving vascular injury, including atherosclerosis and abdominal aortic aneurysm. Progress toward understanding genetic influences, refining treatment, developing diagnostic tests, and understanding the best management practices for children with coronary-artery damage can come only through adequately powered, multicenter, collaborative studies such as the clinical trial by Newburger et al.” (J. C. Burns, U. Calif., San Diego)
Flu Vaccines in Young Children: In infants and young children aged 6–59 months, live attenuated influenza vaccine was significantly more efficacious than inactivated vaccine, and safety results showed the two vaccine types to be equivalent among children aged 12–59 months of age (pp. 685-96). Comparing the cold-adapted trivalent live attenuated influenza vaccine (FluMist, MedImmune) with trivalent inactivated product (Fluzone or Vaxigrip [depending on the geographic location of the study site], Aventis Pasteur) during the 2004–05 season, investigators report: “Safety data were available for 8,352 children, and 7,852 children completed the study according to the protocol. There were 54.9% fewer cases of cultured-confirmed influenza in the group that received live attenuated vaccine than in the group that received inactivated vaccine (153 vs. 338 cases, P < 0.001). The superior efficacy of live attenuated vaccine, as compared with inactivated vaccine, was observed for both antigenically well-matched and drifted viruses. Among previously unvaccinated children, wheezing within 42 days after the administration of dose 1 was more common with live attenuated vaccine than with inactivated vaccine, primarily among children 6 to 11 months of age; in this age group, 12 more episodes of wheezing were noted within 42 days after receipt of dose 1 among recipients of live attenuated vaccine (3.8%) than among recipients of inactivated vaccine (2.1%, P = 0.076). Rates of hospitalization for any cause during the 180 days after vaccination were higher among the recipients of live attenuated vaccine who were 6 to 11 months of age (6.1%) than among the recipients of inactivated vaccine in this age group (2.6%, P = 0.002).” (R. B. Belshe, Saint Louis U., St. Louis, Mo.; belsherb@slu.edu)
Editorialists find these data “encouraging” but caution (pp. 729-31): “Further discussion and careful review of the safety data for cold-adapted trivalent live attenuated vaccine by the FDA and others are needed before developing guidance on the use of this vaccine versus trivalent inactivated vaccine in young children.” (N. J. Cox, CDC)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 16, 2007 * Vol. 14, No. 33
Providing news and information about medications and their proper use

>>>Infectious Disease Report
Source:
March 1 supplement to and March 15 issue of Clinical Infectious Diseases (www.journals.uchicago.edu/CID; 2007; 44).
CAP Treatment Guidelines: Antibiotic therapy remains largely unchanged in updated consensus guidelines for management of community-acquired pneumonia in adults, with the two main changes being addition of ertapenem to the choices for hospitalized patients with risk factors for infection with gram-negative pathogens other than Pseudomonas aeruginosa and strengthening of the evidence supporting combination therapy for patients with severe CAP (pp. S27-S72). In guidelines that for the first time are endorsed by both the Infectious Diseases Society of America and the American Thoracic Society, macrolides are supported as first-line outpatient treatment for previously healthy patients who have no risk factors for drug-resistant Streptococcus pneumoniae (e.g., chronic heart, lung, liver, or renal disease, diabetes, alcoholism, malignancies). In such patients, respiratory quinolones such as moxifloxacin, gemifloxacin, and levofloxacin have the best supporting evidence, the guidelines explain. (L. A. Mandell, lmandell@mcmaster.ca)
Nonadherence to UTI Prescribing Guidelines: U.S. physicians did not transition to prescribing of trimethoprim–sulfamethoxazole as first-line therapy for uncomplicated urinary tract infections, as recommended by the Infectious Diseases Society of America in 1999 (pp. 769-74). Analyzing data on ambulatory medical care in 1996–2001, researchers report: “We identified 2,339 cases of uncomplicated UTI. Trimethoprim–sulfamethoxazole and ciprofloxacin were the most commonly prescribed drugs. Despite the Infectious Diseases Society of America guidelines, the use of trimethoprim–sulfamethoxazole did not change significantly (odds ratio, 0.89; 95% confidence interval, 0.60–1.30; P = .53), whereas the use of ciprofloxacin increased significantly (odds ratio, 1.75; 95% confidence interval, 1.11–2.75; P ≤ .016). Similar results were obtained after adjusting for age, geographic region, race, physician specialty, payment method, and whether the visit was by a new or returning patient.” (Y. Taur, Long Island Jewish Med. Ctr., New Hyde Park, N.Y.)
Treatment of Community-Onset MRSA Skin Infections: Treatment with an appropriate antibiotic is the key determinant of outcomes among patients with community-onset skin and soft-tissue infections caused by methicillin-resistant Staphylococcus aureus, according to a retrospective cohort study of 492 adult patients (pp. 777-84). During 531 episodes of abscesses, furuncles/carbuncles, and cellulitis, researchers noted: “An incision and drainage procedure was performed for the majority of patients. Treatment failure occurred in 45 (8%) of 531 episodes of community-onset MRSA SSTI. Therapy was successful for 296 (95%) of 312 patients who received an active antibiotic, compared with 190 (87%) of 219 of those who did not (P = .001 in bivariate analysis). Use of an inactive antimicrobial agent was an independent predictor of treatment failure on logistic regression analysis (adjusted odds ratio, 2.80; 95% confidence interval, 1.26–6.22; P = .01).” (J. J. Ruhe, U. Ark. for Med. Sci., Little Rock)
Cumulative Antibiograms: Specific recommendations for analysis and presentation of cumulative antibiograms are presented in an invited review article (pp. 867-73). “Critical issues include the recommended frequency of reporting, the number of isolates to include in a statistic, and a mechanism for eliminating multiple isolates of a given bacterial species obtained from an individual patient,” the authors write. (J. F. Hindler, U. Calif., Los Angeles)

>>>PNN NewsWatch
* FDA has launched podcasts on its Web site at www.fda.gov/cder/drug/podcast/default.htm. Subscribers can be alerted to new audio advisories as they are posted on the site at the same time the media receives notifications of problems, FDA Commissioner Andrew von Eschenbach explained in the inaugural podcast on Feb. 6. The first substantive podcast covered potential hazards of using topical anesthetics for cosmetic procedures. Podcasts can be viewed on a computer or downloaded for viewing on personal devices such as iPods.
*
PNN will not be published on Mon., Feb. 19, 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 © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 20, 2007 * Vol. 14, No. 34
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Early-release article from and Feb. 17 issue of Lancet (www.thelancet.com; 2007; 369).
Preventing HIV Infection: Microbicidal drugs could play an important role in preventing HIV infections if developed and tested appropriately and used effectively, write authors of a review article (doi: 10.1016/S0140-6736(07)60202-5). “A combination of several drugs, preferentially targeting different steps in the viral infection process, will probably ensure the most effective protection,” the writers explain. “It will be a continuous challenge to decide which of the wide array of candidate drugs are likely to be most effective. The epidemic is continuing to spread, especially in developing countries but also in large areas of Eastern Europe and Asia, and from specific population groups such as drug users and sex workers to the general population. Thus, microbicide research and development and increasing public awareness of the pandemic should be one of the highest priorities in health policy. The academic world, pharmaceutical companies, and governments have a tremendous responsibility to speed-up microbicide research to find efficient microbicide formulations that are affordable, and accessible. Although it is highly advisable to develop only those drugs that give the best preventive results, mathematical models have shown that the use of a microbicide that is only moderately effective could have a substantial effect in tackling the epidemic and improving human health.” (J. Balzarini, Rega Inst. for Med. Res., Leuven, Belgium; jan.balzarini@rega.kuleuven.be)

>>>Internal Medicine Report
Source:
Early-release article from and Feb. 20 issue of the Annals of Internal Medicine (www.annals.org; 2007; 146).
Tiotropium in COPD: In 449 patients with moderate or severe chronic obstructive pulmonary disease, addition of fluticasone–salmeterol to tiotropium therapy had several benefits but did not reduce rates of exacerbations (early release). Researchers report these findings from this 1-year study: “The proportion of patients in the tiotropium plus placebo group who experienced an exacerbation (62.8%) did not differ from that in the tiotropium plus salmeterol group (64.8%; difference, –2.0 percentage points [95% CI, –12.8 to 8.8 percentage points]) or the tiotropium plus fluticasone–salmeterol group (60.0%; difference, 2.8 percentage points [CI, –8.2 to 13.8 percentage points]. In sensitivity analyses, the point estimates and 95% confidence bounds shifted in the direction favoring tiotropium plus salmeterol and tiotropium plus fluticasone–salmeterol. Tiotropium plus fluticasone–salmeterol improved lung function (P = 0.049) and disease-specific quality of life (P = 0.01) and reduced the number of hospitalizations for COPD exacerbation (incidence rate ratio, 0.53 [CI, 0.33 to 0.86]) and all-cause hospitalizations (incidence rate ratio, 0.67 [CI, 0.45 to 0.99]) compared with tiotropium plus placebo. In contrast, tiotropium plus salmeterol did not statistically improve lung function or hospitalization rates compared with tiotropium plus placebo.” (S. Aaron, Ottawa Hosp., Ottawa, Ont., Canada; saaron@ohri.ca)
Glucose Management During Cardiac Surgery: Cardiac deaths and events were increased among patients provided with intensive insulin therapy during cardiac surgery, compared with conventional glucose management (pp. 233-43). During on-pump cardiac surgery in 400 patients, these results were recorded: “Eighty-two of 185 patients (44%) in the intensive treatment group and 86 of 186 patients (46%) in the conventional treatment group had an event (risk ratio, 1.0 [CI, 0.8 to 1.2]). More deaths (4 deaths vs. 0 deaths; P = 0.061) and strokes (8 strokes vs. 1 strokes; P = 0.020) occurred in the intensive treatment group. Length of stay in the intensive care unit (mean, 2 days [SD, 2] vs. 2 days [SD, 3]; difference, 0 days [CI, –1 to 1 days]) and in the hospital (mean, 8 days [SD, 4] vs. 8 days [SD, 5]; difference, 0 days [CI, –1 to 0 days]) was similar for both groups.” (G. Y. Gandhi, gandhi.gunjan@mayo.edu)

>>>PNN JournalWatch
* Sinusitis and Its Management, in BMJ, 2007; 334: 358–61. Reprints: www.bmj.com/cgi/content/extract/334/7589/358; K. W. Ah-See, Aberdeen Royal Infirmary, Aberdeen, U.K.; kim.ah-see@nhs.net
* Effects of Antithyroid Drugs on Radioiodine Treatment, in
BMJ, 2007; doi: 10.1136/bmj.39114.670150.BE. Reprints: www.bmj.com/cgi/content/short/bmj.39114.670150.BEv1; M. A. Walter; U. Hosp., Basel, Switzerland; m.a.walter@gmx.net

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 21, 2007 * Vol. 14, No. 35
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Feb. 21 issue of JAMA (www.jama.com; 2007; 297)
Pay-for-Performance Programs: Describing pay-for-performance programs as “now firmly ensconced in the payment systems of US public and private insurers across the spectrum,” authors of a Commentary provide this perspective on the latest trend in health care financing (pp. 740-4): “The current enthusiasm for pay-for-performance could reasonably be dismissed as the latest health care fad, but it may also represent a rare opportunity for physicians and payers to engage cooperatively in meaningful reform of an arcane payment system that for decades has held back efforts to improve care. Although most pay-for-performance programs currently fall short of such lofty goals, we highlight several key ways to increase the fidelity of payment incentives to the goal of improving care for all patients. The public discourse on the use of incentives need not be limited to direct payment issues, because many pay-for-performance programs have also involved other approaches to providing support for clinical improvement. These have included public reporting of performance or ‘honor roll’ programs, grants or in-kind support from payers to community quality improvement initiatives, and administrative simplification programs. The exact design of pay-for-performance and its admixture with these other initiatives is likely to be a local decision and we cannot offer a single best prescription. Rather, the key is for providers, purchasers, and policy makers to understand both the potential benefits and the limitations of pay-for-performance and to consider how it can best be designed to improve care for patients.” (M. B. Rosenthal, mrosenth@hsph.harvard.edu)
Off-Label Drug Use: In a news article, the challenges to physicians of determining what constitutes appropriate off-label use of prescription drugs are catalogued (pp. 683-4). After noting that one study showed that 73% of prescriptions for off-label uses “lacked evidence of clinical efficacy” and reviewing the off-label promotions permitted under the Food and Drug Administration Modernization Act of 1997, the news reporter wrote: “Physicians also feel pressure from patient advocacy groups and others who are pushing for more off-label prescribing and loosening of reimbursement rules that restrict access to off-label therapies. Such restrictions often exist for patients with rare diseases, which may have no effective approved therapies. The use of off-label drugs for these conditions may be considered ‘experimental’ by payers, sometimes despite clinical evidence of effectiveness, according to the nonprofit National Organization for Rare Diseases (NORD), in Washington, DC. ‘Sometimes it’s difficult to get reimbursed for these drugs, and patients have to go through a lot of hoops and appeals, which is problematic,’ said Diane Dorman, NORD’s vice president for public policy.” (T. Hampton)

>>>PNN NewsWatch
* Pay-for-performance programs are being implemented for pharmacies, but the depth of those programs and the data elements needed for some measures of quality present challenges. Those were central messages of six speakers and an expert panel at a conference sponsored by the National Council for Prescription Drug Programs held yesterday in Atlanta. Among the metrics being used in pharmacy programs are simple dispensing-oriented measures such as the rate of half tablets being dispensed for statin prescriptions and the rate of generic drug substitution and more complex measures such as medication overuse and suboptimal treatment regimens, speakers said. Measures of performance—such as patient adherence to therapy—are shared among providers, presenters agreed, making it difficult to hold pharmacists and physicians accountable.
* In a large clinical trial evaluating use of an erythropoiesis-stimulating agent (ESA) for treatment of anemia in cancer patients not receiving chemotherapy, patients treated with
darbepoetin alfa (Aranesp, Amgen) had a higher death rate and no reduction in the need for transfusions, compared with those treated with placebo, FDA noted in a warning to health professionals. The agency added that the findings in this darbepoetin study may apply to other ESAs. Additionally, the findings show that treating anemic cancer patients not currently on chemotherapy with an ESA may offer no benefit and may cause serious harm.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 22, 2007 * Vol. 14, No. 36
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Feb. 22 issue of the New England Journal of Medicine (http://content.nejm.org; 2007; 356).
COPD Treatment: Mortality was unchanged but other benefits apparent with combination treatment of patients with chronic obstructive pulmonary disease (pp. 775-89). Using the inhaled corticosteroid fluticasone and the long-acting beta-agonist salmeterol, researchers report these results from the Towards a Revolution in COPD Health (TORCH) trial: “Of 6,112 patients in the efficacy population, 875 died within 3 years after the start of the study treatment. All-cause mortality rates were 12.6% in the combination-therapy group, 15.2% in the placebo group, 13.5% in the salmeterol group, and 16.0% in the fluticasone group. The hazard ratio for death in the combination-therapy group, as compared with the placebo group, was 0.825 (95% confidence interval [CI], 0.681 to 1.002; P = 0.052, adjusted for the interim analyses), corresponding to a difference of 2.6 percentage points or a reduction in the risk of death of 17.5%. The mortality rate for salmeterol alone or fluticasone propionate alone did not differ significantly from that for placebo. As compared with placebo, the combination regimen reduced the annual rate of exacerbations from 1.13 to 0.85 and improved health status and spirometric values (P < 0.001 for all comparisons with placebo). There was no difference in the incidence of ocular or bone side effects. The probability of having pneumonia reported as an adverse event was higher among patients receiving medications containing fluticasone propionate (19.6% in the combination-therapy group and 18.3% in the fluticasone group) than in the placebo group (12.3%, P < 0.001 for comparisons between these treatments and placebo).” (P. M. A. Calverley, U. Hosp. Aintree, Liverpool, U.K.; pmacal@liverpool.ac.uk)
Valacyclovir for HIV Suppression: In 136 women who were dually infected with HIV-1 and herpes simplex virus type 2 but ineligible for highly active antiretroviral therapy, valacyclovir therapy significantly suppressed genital and plasma HIV-1 RNA levels (pp. 790-9). “At enrollment, the median CD4 cell count was 446 cells per cubic millimeter, and the mean plasma viral load was 4.44 log10 copies per milliliter,” write the authors. “With the use of summary-measures analysis, valacyclovir therapy was found to be associated with a significant decrease in the frequency of genital HIV-1 RNA (odds ratio, 0.41; 95% confidence interval [CI], 0.21 to 0.80) and in the mean quantity of the virus (log10 copies per milliliter, –0.29; 95% CI, –0.44 to –0.15). However, there was no significant decrease in detection of HIV (risk ratio, 0.93; 95% CI, 0.81 to 1.07). HSV suppressive therapy also reduced the mean plasma HIV-1 RNA level by 0.53 log10 copy per milliliter (95% CI, –0.72 to –0.35). Repeated-measures analysis showed that these effects became significantly stronger during the 3 months of follow-up.” (N. Nagot, London Sch. of Hygiene and Tropical Med., London, U.K.; n_nagot@hotmail.com)
In-Pharmacy Clinics: Well-educated health care consumers, rise of the Internet, and patients’ ability to recognize acute self-limiting conditions such as urinary tract infections are among the forces driving the success of in-pharmacy clinics staffed by nurse practitioners, writes the author of a Perspectives article (pp. 765-8): “Whether or not this model becomes a permanent feature of the health care landscape, the thinking behind it—in terms of operating-system alignment, alternative approaches to stratification and capacity creation, and the patient’s role—may well influence the design of future delivery systems. If these clinics are to complement existing services, they will have to ensure continuity of care by building effective relationships with local primary care physicians and by developing systems to track patients who have multiple appointments in order to identify patterns suggestive of underlying illnesses. However, concern about the quality of care is not a reason to reject such models out of hand. Given the stresses expected to bear upon delivery of services in the future, such models deserve consideration as one potential mechanism for managing a particular class of medical problems, serving a particular patient need, and maximizing patient benefit with limited resources.” (R. Bohmer, Harvard Business 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 © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 23, 2007 * Vol. 14, No. 37
Providing news and information about medications and their proper use

>>>Pediatrics Highlights
Source:
Feb. issue of Pediatrics (www.pediatrics.org; 2007; 119).
Second Doses of Varicella Vaccine: A 2005 national survey of 550 pediatricians and 550 family physicians reflects the need for the second dose of varicella vaccine that was later recommended by the CDC’s Advisory Committee on Immunization Practices (pp. 258-64). “Surveys were returned by 727 respondents, for a response rate of 69%; 610 physicians were eligible,” the authors report. “Most respondents (94%) recommend routine 1-dose varicella vaccination, and 79% have seen breakthrough disease in the past 5 years (95% of pediatricians and 58% of family physicians). The majority (68%) agreed or strongly agreed that the current burden of breakthrough disease is acceptable. Only 38% (46% of pediatricians and 28% of family physicians) agreed or strongly agreed that a second dose of varicella vaccine is needed to address the burden of breakthrough disease, whereas 40% were neutral. However, if the Advisory Committee on Immunization Practices were to recommend a second dose of varicella vaccine, then 65% of pediatricians and 39% of family physicians would likely follow the recommendation. Most respondents (78%) would be more willing to recommend a second dose if a combination measles-mumps-rubella-varicella vaccine was available.” (M. M. Davis, U. Mich., Ann Arbor)
Eczema/Wheezing & Vaccination Status: In a study of infant vaccinations, risks of eczema or recurrent wheeze were no different among those vaccinated or unvaccinated against diphtheria, pertussis, poliomyelitis, tetanus, or Haemophilus influenzae type b (e367-73). The KOALA Birth Cohort Study reports: “During the first year of life, the incidence of eczema was 23% (584 of 2,537 infants) and of recurrent wheeze, the incidence was 8.5% (203 of 2402 infants). At age 6 months, 1,969 (77%) of 2,545 infants had been vaccinated according to a standard schedule, 393 (15%) vaccinated according to an incomplete schedule, and 182 (7%) never vaccinated. Compared with infants with standard vaccination schedules, infants with incomplete schedules did not differ significantly in eczema risk or recurrent wheeze. This was also true for infants who had never been vaccinated.” (I. Kummeling, Maastricht U., Maastricht, the Netherlands)
Use of Statins in Pediatrics: Authors of a review article present the cholesterol hypothesis and knowledge base for use of statins in adults and children (pp. 370-80): “We pay particular attention to the known effects of statins in primary and secondary prevention of cardiovascular events. The toxicities of statins and their limitations in pediatrics are then considered. The use of statins in conjunction with noninvasive modalities of assessing atherosclerotic burden are also reviewed. Finally, we suggest methods to advance the use of statins in childhood that introduce their potential benefits to those individuals at highest risk for future events.” (B. Belay, Temple U., Philadelphia)
Steroids in Duchenne Muscular Dystrophy: In 35 patients with Duchenne muscular dystrophy, long-term steroid therapy improved peak cough flow and respiratory muscle strength (e320-4). The case–control study compared 10 steroid-treated and 25 untreated patients, with these results: “The linear model that had the highest adjusted r2 value included only 2 variables: maximum voluntary ventilation and steroid treatment, demonstrating that steroid-treated patients had peak cough flow values that were 27 L/min higher than the untreated patients. The interaction between maximum voluntary ventilation and steroid was not statistically significant, suggesting that the steroid-associated increase in peak cough flow was approximately constant over the observed range of maximum voluntary ventilation values. The effects of maximum voluntary ventilation and treatment group on peak cough flow were not confounded with the patient age.” (A. S. Daftary, Children’s Hosp. Med. Ctr., Cincinnati)

>>>PNN NewsWatch
* The New York Times this week continued its coverage of pharmacists’ medication therapy management services. Focusing on the elimination of drug copayments in Asheville Project–like efforts, a Feb. 21 article discussed activities of pharmacists Charles Posey (brother of PNN’s editor/publisher) at a Mohawk carpet plant in East Dublin, Ga., and Liz Berndt, with Polk County, Ga., beneficiaries.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 26, 2007 * Vol. 14, No. 38
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from and Feb. 24 issue of BMJ (www.bmj.org; 2007; 334).
Safe Medication Practices for Oral Chemotherapy: At U. S. cancer centers, no consensus exists regarding the appropriate precautions to take in prescribing, preparing, dispensing, and administering oral chemotherapy, according to a survey of 42 pharmacy directors (pp. 407 ff). While infusion chemotherapy is handled using many safeguards, the pharmacists told surveyors: “Clinicians at 29 centres used handwritten prescriptions, two used preprinted paper prescriptions, and six used electronic systems for most oral chemotherapy prescribing. For six commonly used oral chemotherapies, on average 10 centres required a diagnosis on the prescription, 11 required the protocol number, four required the cycle number, nine required double checking by a second clinician, 14 required a calculation of body surface area, and 14 required a calculation of dose per square metre of body surface area. Only a third of centres requested patients’ written informed consent when oral chemotherapy was given off protocol. Nearly a quarter (10) of centres had no formal process for monitoring patients’ adherence. In the past year respondents at 10 centres reported at least one serious adverse drug event related to oral chemotherapy, and respondents at 13 centres reported a serious near miss.” (S N Weingart, Dana-Farber Cancer Inst., Boston; saul_weingart@dfci.harvard.edu)
Pharmacist-Only Sildenafil Pilot Project: Pharmacists at three Boots units in Manchester, England, are dispensing sildenafil to men with erectile dysfunction without a prescription under a pilot project that began earlier this month (pp. 387 ff). An initial screening is performed by the pharmacist, and long-term follow-up is provided for patients who wish to continue use long-term, a news report notes. The project will be evaluated for extension across the U.K. later this year. The reporter writes: “The new programme is the fourth of its kind for Boots, which offers similar pharmacy programmes for weight loss (including a supply of orlistat), hair retention (with a supply of finasteride (Propecia)), and chlamydia (including provision of free azithromycin or doxycycline). They all make use of private patient group directions, in which health professionals other than doctors can prescribe medicines for a defined group of people under waivers signed off by local health managers.” Patients in the program must be registered with a physician, and they pay $98 for the initial screening with the pharmacist and a supply of four tablets. (S. Mayor)

>>>Lancet Highlights
Source:
Early-release article from Lancet (www.thelancet.com; 2007; 369).
ACE Inhibition: Blockade of the renin–angiotensin system “will remain a cornerstone of our strategies to reduce cardiovascular risk,” conclude authors of a review article (doi: 10.1016/S0140-6736(07)60242-6): “Renin–angiotensin system blockade exerts potent antiatherosclerotic effects, which are mediated by their antihypertensive, anti-inflammatory, antiproliferative, and oxidative stress lowering properties. Inhibitors of the system—ie, angiotensin converting enzyme inhibitors and angiotensin receptor blockers, are now first-line treatments for hypertensive target organ damage and progressive renal disease. Their effects are greater than expected by their ability to lower blood pressure alone. Angiotensin receptor blockers reduce the frequency of atrial fibrillation and stroke. Renin-angiotensin system blockade delays or avoids the onset of type 2 diabetes and prevents cardiovascular and renal events in diabetic patients.” (R. E. Schmieder, U. Erlangen-Nuremberg, Erlangen, Germany; roland.schmieder@rzmail.uni-erlangen.de)

>>>PNN JournalWatch
* Clinical Review: Dog Bites, in BMJ, 2007; 334: 413–7. Reprints: www.bmj.com/cgi/content/short/334/7590/413; M. Morgan, Royal Devon and Exeter Foundation Trust, Exeter, U.K.; mailto:marina.morgan@rdeft.nhs.uk
* Evidence-Based Guidelines for Cardiovascular Disease Prevention in Women: 2007 Update, in
Circulation, 2007; doi: 10.1161/CIRCULATIONAHA.107.181546. Reprints: http://circ.ahajournals.org/cgi/reprint/CIRCULATIONAHA.107.181546v1; L. Mosca; single reprints (71-0401) available by calling 800-242-8721 (U.S. only) or writing AHA Public Information, 7272 Greenville Ave, Dallas, TX 75231-4596.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 27, 2007 * Vol. 14, No. 39
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Feb. 26 issue of Archives of Internal Medicine (www.archinternmed.com; 2007; 167).
Garlic Ineffective for Lipid Disorders: In 192 adults with hypercholesterolemia, neither raw garlic nor commercially available garlic supplements had statistically or clinically significant effects on LDL cholesterol levels in a 6-month study (pp. 346-53). Compared were raw garlic, powdered garlic supplement, aged garlic extract supplement, and placebo; products were taken 6 days per week in servings approximating a 4-g clove per day, with these results: “Retention was 87% to 90% in all 4 treatment arms, and chemical stability of study materials was high throughout the trial. There were no statistically significant effects of the 3 forms of garlic on LDL-C concentrations. The 6-month mean (SD) changes in LDL-C concentrations were +0.4 (19.3) mg/dL (+0.01 [0.50] mmol/L), +3.2 (17.2) mg/dL (+0.08 [0.44] mmol/L), +0.2 (17.8) mg/dL (+0.005 [0.46] mmol/L), and –3.9 (16.5) mg/dL (–0.10 [0.43] mmol/L) for raw garlic, powdered supplement, aged extract supplement, and placebo, respectively. There were no statistically significant effects on high-density lipoprotein cholesterol, triglyceride levels, or total cholesterol–high-density lipoprotein cholesterol ratio.” (C. D. Gardner, cgardner@stanford.edu)
Concluding that the “jury is still out” on the efficacy of garlic for patients with elevated LDL cholesterol levels, editorialists note these difficulties in studying garlic preparations (pp. 325-6): “Allicin is generally believed to be an important bioactive compound in garlic, and it is the single compound on which most supplements are standardized. It is a nonprotein sulfur amino acid that is derived from the odorless compound alliin through action of the enzyme allinase. The mechanical action of crushing or cutting brings the enzyme allinase into contact with alliin, yielding the unstable pungent principal allicin. Other bioactive compounds in garlic include ajoene, allixin, erubosides,
S-allyl cysteine, and N-acetyl S-allyl cysteine, among a host of other compounds. Many of these compounds have antithrombotic and antiplatelet effects, reduce LDL oxidation, and affect expression of endothelial adhesion molecules during simulated endothelial injury. The pharmacologic mechanisms are multiple, and the chemicals responsible are believed to act synergistically. The selection of a single compound for the purpose of standardization when exact mechanisms of action are unknown continues to hinder our ability to evaluate the health effects of natural products. Although one must be certain that the dosages of products used in clinical trials are sufficiently similar and that these dosages can be achieved reproducibly, standardization of one or even a few compounds may provide a misleading sense that products are the same when biologically they are not. Innovation is required to move away from the single active principal method.” (M. Charlson, Weill Cornell Med. College, New York)
Analgesic Use & Hypertension in Men: Among 16,031 men health professionals, use of nonnarcotic analgesics was independently associated with a moderate increase in risk of new-onset hypertension (pp. 394-9). Looking at acetaminophen, NSAID, and aspirin use, the researchers found: “We identified 1,968 incident cases of hypertension. After adjusting for multiple potential confounders, men who used acetaminophen 6 to 7 days per week compared with nonusers had a relative risk for incident hypertension of 1.34 (95% confidence interval, 1.00–1.79; P = .01 for trend). This same comparison resulted in relative risks of 1.38 (95% confidence interval, 1.09–1.75; P = .002 for trend) for nonsteroidal anti-inflammatory drugs and 1.26 (95% confidence interval, 1.14–1.40; P < .001 for trend) for aspirin. We observed similar results when the number of pills per week was analyzed rather than frequency of use in days per week.” (J. P. Forman, Channing Laboratory, Boston; jforman@partners.org)

>>PNN NewsWatch
* FDA has approved for marketing the prodrug lisdexamfetamine dimesylate (Vyvanse, Shire/New River) for once-daily treatment of attention-deficit/hyperactivity disorder. A study of abuse potential showed lower responses with this lysine-linked prodrug than with d-amphetamine, but the product is likely to be placed in Schedule II by DEA. Three dosage strengths will be marketed: 30, 50, and 70 mg.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Feb. 28, 2007 * Vol. 14, No. 40
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Feb. 28 issue of JAMA (www.jama.com; 2007; 297).
Mortality with Antioxidant Vitamins Used for Primary, Secondary Prevention: Supplements of beta-carotene and vitamins A and E may increase mortality, and use of vitamin C and selenium products requires more study, according to a systematic review and meta-analysis of 68 randomized trials of 232,606 participants (pp. 842-57). “When all low- and high-bias risk trials of antioxidant supplements were pooled together there was no significant effect on mortality (RR, 1.02; 95% CI, 0.98-1.06),” report the authors. “Multivariate meta-regression analyses showed that low-bias risk trials (RR, 1.16; 95% CI, 1.05-1.29) and selenium (RR, 0.998; 95% CI, 0.997-0.9995) were significantly associated with mortality. In 47 low-bias trials with 180,938 participants, the antioxidant supplements significantly increased mortality (RR, 1.05; 95% CI, 1.02-1.08). In low-bias risk trials, after exclusion of selenium trials, beta carotene (RR, 1.07; 95% CI, 1.02-1.11), vitamin A (RR, 1.16; 95% CI, 1.10-1.24), and vitamin E (RR, 1.04; 95% CI, 1.01-1.07), singly or combined, significantly increased mortality. Vitamin C and selenium had no significant effect on mortality.” (G. Bjelakovic, U. Nis, Nis, Serbia; goranb@junis.ni.ac.yu)
HPV Infections: Human papillomavirus infection is very common among girls and women in the United States, a study shows, with age, marital status, and increasing numbers of lifetime and recent sex partners proving to be independent risk factors (pp. 813-9). However, examinations of female participants in the 2003 National Health and Nutrition Examination Survey (NHANES) show that the recently approved HPV vaccine against types 6, 11, 16, and 18 will not prevent infection with many of the strains prevalent in the U.S. The authors report: “The overall HPV prevalence was 26.8% (95% confidence interval [CI], 23.3%-30.9%) among US females aged 14 to 59 years (n = 1,921). HPV prevalence was 24.5% (95% CI, 19.6%-30.5%) among females aged 14 to 19 years, 44.8% (95% CI, 36.3%-55.3%) among women aged 20 to 24 years, 27.4% (95% CI, 21.9%-34.2%) among women aged 25 to 29 years, 27.5% (95% CI, 20.8%-36.4%) among women aged 30 to 39 years, 25.2% (95% CI, 19.7%-32.2%) among women aged 40 to 49 years, and 19.6% (95% CI, 14.3%-26.8%) among women aged 50 to 59 years. There was a statistically significant trend for increasing HPV prevalence with each year of age from 14 to 24 years (P < .001), followed by a gradual decline in prevalence through 59 years (P = .06). HPV vaccine types 6 and 11 (low-risk types) and 16 and 18 (high-risk types) were detected in 3.4% of female participants; HPV-6 was detected in 1.3% (95% CI, 0.8%-2.3%), HPV-11 in 0.1% (95% CI, 0.03%-0.3%), HPV-16 in 1.5% (95% CI, 0.9%-2.6%), and HPV-18 in 0.8% (95% CI, 0.4%-1.5%) of female participants.” (E. F. Dunne, dde9@cdc.gov)
Information Discharge Gap: Poor communication and information transfer between hospital- and primary care physicians at hospital discharge is “common and may adversely affect patient care,” researchers write (pp. 831-41). Medication reconciliation is just one component of the problem, along with lack of information on lab tests, the hospital course, counseling, and plans for follow-up. (S. Kripalani, skripal@emory.edu)
Medicare Doughnut Hole: Ways of helping patients who must spend $3,850 for medications in the Medicare Part D “doughnut hole” are explored in a Commentary (pp. 868-70). The authors advise physicians to eliminate medications for conditions that have resolved, use higher doses of a single medication rather than small doses of two drugs, review the need for medications for conditions that are minor inconveniences or primarily affect quality of life, and consider generic alternatives. Tablet splitting is also suggested, with this guidance: “Although certain tablets can be safely split by a pharmacist, it is generally not recommended that patients perform this themselves. This approach will not be helpful if the patient is already taking the highest dose or if the desired dose is not half of an existing formulation. Nonscored tablets and other medication forms usually are not designed to be split. Patients should be advised that it is preferable to have a pharmacist split even properly scored tablets.” (G. F. Anderson, Johns Hopkins Bloomberg Sch. of Public Health, Baltimore; ganderso@jhsph.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 © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 1, 2007 * Vol. 14, No. 41
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Mar. 1 issue of New England Journal of Medicine (http://content.nejm.org; 2007; 356).
Hepatitis E Vaccine: A recombinant protein vaccine against hepatitis E virus proved effective in a study of 2,000 high-risk individuals in Nepal (pp. 895-903). Study participants, members of the Nepalese army and nearly all men, received three doses of rHEV vaccine or placebo at months 0, 1, and 6, with these results: “A total of 1,794 subjects (898 in the vaccine group and 896 in the placebo group) received three vaccine doses; the total vaccinated cohort was followed for a median of 804 days. After three vaccine doses, hepatitis E developed in 69 subjects, of whom 66 were in the placebo group. The vaccine efficacy was 95.5% (95% confidence interval [CI], 85.6 to 98.6). In an intention-to-treat analysis that included all 87 subjects in whom hepatitis E developed after the first vaccine dose, 9 subjects were in the vaccine group, with a vaccine efficacy of 88.5% (95% CI, 77.1 to 94.2). Among subjects in a subgroup randomly selected for analysis of injection-site findings and general symptoms (reactogenicity subgroup) during the 8-day period after the administration of any dose, the proportion of subjects with adverse events was similar in the two study groups, except that injection-site pain was increased in the vaccine group (P = 0.03).” (B. L. Innis, bruce.2.innis@gsk.com)
An editorialist proposes potential uses of this vaccine (pp. 949-51): “HEV vaccine may be useful for people traveling from the developed world to hepatitis E–endemic regions. Since HEV infection may cause fatal disease in pregnant women, determining the safety and efficacy of HEV vaccine in this group should be a high priority. As long as questions remain with respect to the length of the protective efficacy of the vaccine, its use in children and adolescents in hepatitis E–endemic countries requires further study. The cost of the vaccine will be an important factor in determining its availability in the developing world, where it is most needed.” (K. Krawczynski, CDC, Atlanta)
Vancomycin-Induced Immune Thrombocytopenia: Severe bleeding occurs in about one-third of patients who develop immune thrombocytopenia during vancomycin therapy, according to a study of patients referred for testing over a 5-year period (pp. 904-10). Development of antiplatelet antibodies is the apparent mechanism of this adverse effect, researchers report, adding: “Drug-dependent, platelet-reactive antibodies of the IgG class, the IgM class, or both were identified in 34 patients, and clinical follow-up information was obtained from 29 of these patients. The mean nadir platelet count in these patients was 13,600 per cubic millimeter, and severe bleeding occurred in 10 patients (34%). Platelet levels returned to baseline in all 26 surviving patients after vancomycin was stopped. In 15 patients, the drug was continued for 1 to 14 days while other possible causes of thrombocytopenia were investigated. Vancomycin-dependent antibodies were not found in 25 patients who had been given vancomycin and in whom thrombocytopenia did not develop.” (R. H. Aster, Blood Ctr. of Wisconsin, Milwaukee; richard.aster@bcw.edu)
Amiodarone for Atrial Fibrillation: Amiodarone is useful for maintenance of sinus rhythm in patients with atrial fibrillation, an off-label use, according to an author of a clinical vignette involving a 73-year-old man (pp. 935-41). “Recently published guidelines of the American Heart Association, the American College of Cardiology, and the European Society of Cardiology recommend reserving amiodarone as an alternative agent for most patients with atrial fibrillation, the exceptions being those who have clinical heart failure or hypertension with substantial left ventricular hypertrophy,” writes the author. “For patients at very high risk for recurrence of atrial fibrillation (e.g., those with severe mitral regurgitation), amiodarone may be the best choice of a first-line agent, given the low likelihood that treatment with other antiarrhythmic agents will be successful.” Several areas of uncertainty remain, the writer adds, including adverse effects of low-dose therapy (200 mg daily) when administered for more than 5 years, the place of amiodarone in cardiac surgery of patients at risk for or having atrial fibrillation, and use of this drug in combination with other antiarrhythmic agents. (P. Zimetbaum, Beth Israel Deaconess Med. Ctr., 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 © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 2, 2007 * Vol. 14, No. 42
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Mar. issue of Diabetes Care (http://care.diabetesjournals.org; 2007; 30).
Exercise & Diabetes Avoidance: Moderate-intensity physical activities decrease patients’ risk of developing type 2 diabetes, reports a systematic review (pp. 744-52). “We identified 10 prospective cohort studies of physical activity of moderate intensity and type 2 diabetes, including a total of 301,221 participants and 9,367 incident cases,” write the researchers. “Five of these studies specifically investigated the role of walking. The summary RR of type 2 diabetes was 0.69 (95% CI 0.58–0.83) for regular participation in physical activity of moderate intensity as compared with being sedentary. Similarly, the RR was 0.70 (0.58–0.84) for regular walking (typically 2.5 h/week brisk walking) as compared with almost no walking. The associations remained significant after adjustment for BMI. Similar associations were observed in men and women and in the U.S. and Europe.” (R. M. van Dam, rvandam@hsph.harvard.edu)
Long-term Safety of Inhaled Insulin: Based on findings in 580 patients with type 1 diabetes, investigators conclude that differences in lung function between those on inhaled versus subcutaneous insulin “are small, develop early, and are nonprogressive for up to 2 years of therapy” (pp. 579-85). Considering changes in forced expiratory volume in 1 second and carbon monoxide diffusing capacity, the group found significant declines in pulmonary function over the 24-month study, but the mean annual rates of change between months 3 and 24 were not significantly different between the groups. “Adverse event profiles were similar except for a higher incidence of cough (usually mild and unproductive) in patients receiving [inhaled insulin] (37.6 vs. 13.1%) that decreased to 1.3% by month 24,” continue the authors. “Glycemic control was sustained in both groups (adjusted mean treatment difference in change from baseline A1C at month 24 0.25 ± 0.07% [0.13–0.37]). Although the overall hypoglycemic events were comparable between groups (4.0 vs. 3.8 events/subject–month), the incidence of severe hypoglycemic events was lower with [inhaled insulin] than with SC insulin (2.8 vs. 4.1 events/100 subject–months, risk ratio 0.67 [0.57–0.79]). Body weight increased to a significantly lesser extent with [inhaled insulin] (adjusted mean treatment difference –1.25 ± 0.36 kg [–1.85 to –0.66]).” (J. S. Skyler, jskyler@miami.edu)
Psychosocial Factors & Insulin Pumps: Thirty patients with type 1 diabetes who were using insulin pumps had better glycemic control when they were active participants in self-care, had realistic expectations of pump use, and were emotional in their recall of the diabetes diagnosis, reports a group of researchers who conducted focus groups (pp. 549-54). “Low A1C groups reported that starting the insulin pump reminded them of feelings they experienced at their initial diabetes diagnosis, whereas the high A1C groups did not report these feelings,” the investigators note. “Women were more concerned than men about body image and social acceptance with pump use.” (K. Weinger, katie.weinger@joslin.harvard.edu)

>>>PNN NewsWatch
* FDA yesterday told 20 companies to cease marketing unapproved drug products containing ergotamine tartrate. As part of the FDA’s continued efforts to combat the marketing of unapproved drugs, the agency sent warning letters to 8 manufacturers and 12 distributors warning them that they are subject to further enforcement action if they do not stop manufacturing and distributing these products. Companies have 15 days to respond to the FDA with a discontinuation plan for their products. Manufacturers have 60 days to cease manufacturing of new product, and distributors have 180 days to cease further shipment of existing products. Previously manufactured unapproved ergotamine products may remain on pharmacy shelves for a short period of time.
* The
New York Times reports this morning that FDA is reviewing the safety of pediatric cough-and-cold products. The agency was responding to a “petition filed on Thursday by a group of prominent pediatricians and public health officials demanding that the agency stop drug makers from marketing cold and cough medicines for children under age 6,” the newspaper notes. “The petition says that the medicines do not work and that in rare cases they can cause serious injury.”

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 5, 2007 * Vol. 14, No. 43
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Mar. 3 issue of Lancet (www.thelancet.com; 2007; 369).
Diabetes Burden: By 2005, the prevalence of diabetes in the province of Ontario had already exceeded the global rate that had been predicted for 2030 by the World Health Organization, according to a population-based study, owing to increased incidence of the disease coupled with declining mortality (pp. 750-6). Examining trends in diabetes prevalence and mortality among adults aged 20 years and older from 1995 to 2005 and incidence from 1997 to 2003, the investigators found: “Age-adjusted and sex-adjusted diabetes prevalence increased by 69%, from 5.2% in a population of 7,908,562 in 1995 to 8.8% of 9,276,945 in 2005. Prevalence increased by 27% from 6.9% in a population of 8,457,720 in 2000 to 8.8% of 9,276,945 in 2005. Although prevalence rates have remained higher in people aged 50 years or older (7.1% of 3,675,554) than in those aged 20–49 years (3.5% of 5,601,391), rates increased to a greater extent in the younger population (94% vs 63%, p < 0.0001). A 31% increase occurred in yearly incidence over 6 years, from 6.6 per 1,000 in 1997 to 8.2 per 1,000 in 2003. The adjusted mortality rate in people with diabetes fell by 25% from 1995 to 2005.” (L. L. Lipscombe, Inst. for Clin. Evaluative Sci., Toronto; Lorraine.Lipscombe@ices.on.ca)
Mild IVF Protocol: Similar pregnancy rates but significantly fewer instances of multiple live births can be achieved with a mild in vitro fertilization protocol, compared with standard IVF stimulation, according to a 404-patient study (pp. 743-9). Mild treatment consisted of mild ovarian stimulation with gonadotropin-releasing hormone antagonist co-treatment combined with single embryo transfer, while standard treatment comprised stimulation with a GnRH agonist long-protocol and transfer of two embryos. “The proportions of cumulative pregnancies that resulted in term livebirth after 1 year were 43.4% with mild treatment and 44.7% with standard treatment (absolute number of patients = 86 for both groups),” the authors report. “The lower limit of the one-sided 95% CI was −9.8%. The proportion of couples with multiple pregnancy outcomes was 0.5% with mild IVF treatment versus 13.1% (p < 0.0001) with standard treatment, and mean total costs were 8,333 euros and 10,745 euros, respectively (difference 2,412 euros, 95% CI 703–4,131). There were no significant differences between the groups in the anxiety, depression, physical discomfort, or sleep quality of the mother.” (B. C. J. M. Fauser, U. Med. Ctr., Utrecht, the Netherlands; b.c.fauser@umcutrecht.nl)

>>>BMJ Highlights
Source:
Mar. 3 issue of BMJ (www.bmj.org; 2007; 334).
Pharmacogenetics & Designer Drugs: The complexities of biology are delaying implementation of pharmacogenetic knowledge at patients’ bedside, but so-called “designer drugs” are likely to play a role in clinical medicine as time moves on (pp. 452-3). That conclusion is reached in a feature article that also notes: “[Klaus Lindpaintner, head of the Research Center for Medical Genetics with Roche] thinks that the genotype might be the wrong place to look for biomarkers of response to most drugs. ‘DNA sequences are not known aside from a few rare diseases. And DNA is the most remote level from where life happens, which is at the level of proteins and small molecules. Therefore, we are more likely to see diagnostic tools at the level of protein expression.’” (S. Mayor, susan@mayor.dircon.co.uk)

>>>PNN JournalWatch
* The Ketogenic Diet: One Decade Later, in Pediatrics, 2007; 119: 535–43. Reprints: J. M. Freeman.
* Internet-Based Home Monitoring and Education of Children with Asthma Is Comparable to Ideal Office-Based Care: Results of a 1-Year Asthma In-Home Monitoring Trial, in
Pediatrics, 2007; 119: 569–78. Reprints: D. S. Chan, Tripler Army Med. Ctr., Honolulu, Hawaii.
* Schizophrenia and Co-Occurring Substance Use Disorder, in
American Journal of Psychiatry, 2007; 164: 402–8. Reprints: A. I. Green.
* The Echinocandins, in
Pharmacotherapy, 2007; 27: 369–88. Reprints: D. Cappelletty, iane.cappelletty@utoledo.edu">Diane.cappelletty@utoledo.edu
* Darbepoetin alfa: An Effective Treatment with Flexible and Simplified Dosing for Anemia in Patients with Cancer, in
Pharmacotherapy, 2007; 27: 434–46. Reprints: J. G. Stevenson, jimsteve@med.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 © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 6, 2007 * Vol. 14, No. 44
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Mar. 6 issue of the Annals of Internal Medicine (www.annals.org; 2007; 146).
ASA/NSAIDs for Colorectal Cancer Prevention: The U.S. Preventive Services Task Force provides a summarizing statement (pp. 361-4; www.preventiveservices.ahrq.gov; 800-358-9295) and two supporting documents on the routine use of aspirin and NSAIDs for prevention of colorectal cancer. The task force’s bottom line is that drug risks outweigh benefits for those with average risk of colorectal cancer, but “these recommendations do not apply to patients with a personal history of colorectal cancer or other conditions that put them at high risk for the disease.”
“Regular use of aspirin reduced the incidence of colonic adenomas in [randomized controlled trials] (relative risk [RR], 0.82 [95% CI, 0.7 to 0.95]), case–control studies (RR, 0.87 [CI, 0.77 to 0.98]), and cohort studies (RR, 0.72 [CI, 0.61 to 0.85]),” write authors in an aspirin review (pp. 365-75). “In cohort studies, regular use of aspirin was associated with RR reductions of 22% for incidence of colorectal cancer. Two RCTs of low-dose aspirin failed to show a protective effect. Data for colorectal cancer mortality were limited. Benefits from chemoprevention were more evident when aspirin was used at a high dose and for periods longer than 10 years. Aspirin use was associated with a dose-related increase in incidence of gastrointestinal complications.”
The task force provides this analysis of nonaspirin NSAID trials (pp. 376-89): “A single cohort study showed no effect of non-ASA NSAIDs on death due to [colorectal cancer]. Colorectal cancer incidence was reduced with non-ASA NSAIDs in cohort studies (relative risk, 0.61 [95% CI, 0.48 to 0.77]) and case–control studies (relative risk, 0.70 [CI, 0.63 to 0.78]). Colorectal adenoma incidence was also reduced with non-ASA NSAID use in cohort studies (relative risk, 0.64 [CI, 0.48 to 0.85]) and case–control studies (relative risk, 0.54 [CI, 0.4 to 0.74]) and by COX-2 inhibitors in randomized, controlled trials (relative risk, 0.72 [CI, 0.68 to 0.77]). The ulcer complication rate associated with non-ASA NSAIDs is 1.5% per year. Compared with non-ASA NSAIDs, COX-2 inhibitors reduce this risk but, in multiyear use, have a higher ulcer complication rate than placebo. Cyclooxygenase-2 inhibitors and nonnaproxen NSAIDs increase the risk for serious cardiovascular events (relative risk, 1.86 [CI, 1.33 to 2.59] for COX-2 inhibitors vs. placebo).” (A. Rostom,
arostom@ucalgary.ca)
Parathyroid Hormone (1–84) in Osteoporosis: “Parathyroid hormone (1-84) reduced the overall risk for new or worsened vertebral fracture in postmenopausal women with osteoporosis,” conclude authors of a 2,532-patient study, but “hypercalciuria, hypercalcemia, and nausea were more common in women who took the drug” (pp. 326-39). The investigators write: “67.2% of patients who received at least 1 dose of the study drug completed the study. Parathyroid hormone reduced the risk for new or worsened vertebral fractures, but in sensitivity analyses, the magnitude of the reduction was changed with assumptions about fracture incidence in patients who did not complete the study (relative risk assuming no fractures, 0.42 [95% CI, 0.24 to 0.72] [P = 0.001]; relative risk assuming fracture incidence observed in all patients who completed the trial, 0.60 [CI, 0.36 to 1.00] [P = 0.05]; relative risk assuming fracture incidence observed in the placebo group, 0.62 [CI, 0.37 to 1.04] [P = 0.07]). Compared with placebo, mean bone mineral density increased at the spine by 6.9% (CI, 6.4% to 7.4%) and at the hip by 2.1% (CI, 1.7% to 2.5%) but decreased at the forearm in the PTH-treated group. Parathyroid hormone treatment increased the percentage of participants with hypercalciuria, hypercalcemia, and nausea by 24% (CI, 20% to 27%), 23% (CI, 21% to 26%), and 14% (CI, 11% to 16%), respectively, compared with placebo.” (S. L. Greenspan, U. Pittsburgh, Pittsburgh)
Anxiety Untreated: A two-item screening test could enhance detection of anxiety disorders in primary care practices, an article concludes (pp. 317-25). These “prevalent, disabling, and often untreated conditions” were detected using two core items from the Generalized Anxiety Disorder 7 scale. (K. Kroenke, Regenstrief Inst., Indianapolis; kkroenke@regenstrief.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 © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 7, 2007 * Vol. 14, No. 45
Providing news and information about medications and their proper use

>>>Aliskiren, Direct Renin Inhibitor, Approved for HTN
Aliskiren (Tekturna, Novartis) was approved yesterday by FDA for monotherapy or combination treatment of hypertension. The agent is the first in a new class of medications, the direct renin inhibitors, that lower blood pressure through direct antagonism of this kidney enzyme.
The U.S. is the first country to approve the drug, which will be available as 150- and 300-mg tablets that are dosed once daily. When approved in other parts of the world, aliskiren will be marketed under the trade name Rasilez.
The effectiveness of aliskiren in lowering blood pressure was demonstrated in six placebo-controlled, 8-week clinical trials, which included more than 2,000 patients with mild to moderate hypertension.
The effect was maintained for up to 1 year. Aliskiren was effective across all demographic subgroups, but African American patients tended to have smaller reductions in blood pressure than did whites and Asians, as is generally true for drugs that affect the renin–angiotensin system.
When aliskiren was used in combination with hydrochlorothiazide, further reductions in blood pressure were achieved.
Aliskiren was evaluated for safety in more than 6,460 patients, including 1,740 who were treated longer than 6 months, and more than 1,250 for more than 1 year. Adverse effects were usually mild and brief. The most common adverse effect experienced by patients taking aliskiren was diarrhea, reported by approximately 2% of patients on the higher of the two approved doses, compared with approximately 1% of those taking placebo. Rarely, patients taking aliskiren developed an allergic reaction with swelling of the face, lips, or tongue and difficulty breathing, as has been seen with other drugs for high blood pressure that act directly on the renin–angiotensin system.
Aliskiren and other drugs that act directly on the renin–angiotensin system should not be used during pregnancy because they can cause injury and death to the developing fetus.

>>>Pharmacotherapy Report
Source:
March issue of Pharmacotherapy (www.pharmacotherapy.org; 2007; 27).
Statins & Pneumonia Risk: Risks of pneumonia were reduced by current use of statins in a population-based, retrospective, nested case-control analysis (pp. 325-32). Among 134,262 patients aged 30 years or older, researchers found these trends in 55,118 patients who took statins and/or fibrates, 29,144 patients with hyperlipidemia not taking lipid-lowering agents, and 50,000 randomly selected patients without hyperlipidemia and without lipid-lowering treatment: “We identified 1,253 patients with pneumonia and matched them with 4,838 control subjects based on age, sex, general practice, and index date.... Current statin users had a significantly reduced risk of fatal pneumonia (adjusted odds ratio 0.47, 95% confidence interval 0.25–0.88) and slightly but not significantly reduced risks of uncomplicated pneumonia and pneumonia hospitalization with survival. Recent or past statin use and fibrate use at any time were not associated with a reduced risk of pneumonia.” (C. R. Meier, U. Hosp., Basel, Switzerland; meierch@uhbs.ch)
Amiodarone Prophylaxis for Atrial Fibrillation After Cardiac Surgery: Total amiodarone doses may need to be pushed to 3,000 mg or more to achieve full effects in preventing postoperative atrial fibrillation in patients who have undergone cardiac surgery, according to a meta-analysis of 14 trials of 2,864 patients (pp. 360-8). Categorizing amiodarone doses as low (<3,000 mg), medium (3,000–5,000 mg), or high (>5,000 mg), the authors report: “The incidence of postoperative atrial fibrillation was significantly reduced by amiodarone compared with placebo (p < 0.001). Although the odds of developing atrial fibrillation appeared to be somewhat higher in the low-dose group, no significant differences were noted in the odds ratios (ORs) of developing atrial fibrillation among the low-, medium-, and high-dose groups: OR 0.58, 95% confidence interval (CI) 0.44–0.77; OR 0.45, 95% CI 0.30–0.69; and OR 0.44, 95% CI 0.33–0.58; respectively (p = 0.238). In addition, the ORs for atrial fibrillation development associated with preoperative and postoperative initiation of amiodarone were not significantly different (OR 0.50, 95% CI 0.39–0.63; and OR 0.48, 95% CI 0.37–0.63; respectively, p = 0.862).” (M. S. Buckley, St. Joseph’s Hosp., Phoenix; mitch.buckley@chw.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 © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 8, 2007 * Vol. 14, No. 46
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Mar. 8 issue of the New England Journal of Medicine (http://content.nejm.org; 2007; 356).
Drug-Eluting Stents: Five articles, two perspectives, and an editorial explore the utility and risks of drug-eluting and bare-metal stents. The articles reach these conclusions:
* Sirolimus-eluting and bare-metal stents did not differ significantly in terms of rates of death, myocardial infarction, or stent thrombosis, according to a pooled analysis of four trials of 1,748 patients (pp. 989-97; P. W. Serruys, Erasmus U., Rotterdam, the Netherlands;
p.w.j.c.serruys@erasmusmc.nl).
* Two drug-eluting stents had higher rates of stent thrombosis after 1 year than did bare-metal stents, but target-lesion revascularization was significantly lower with the sirolimus- and paclitaxel-eluting stents. Pooling data from the above four trials and five other studies of 3,513 patients, the investigators found “no significant differences in the cumulative rates of death or myocardial infarction at 4 years” (pp. 998-1008; G. W. Stone,
gs2184@columbia.edu).
* In a study of 6,033 patients treated with drug-eluting stents and 13,738 patients implanted with bare-metal stents in 2003 and 2004, drug-eluting stents had an increased rate of death that appeared after 6 months (pp. 1009-19; B. Lagerqvist, Uppsala U. Hosp., Uppsala, Sweden;
bo.lagerqvist@ucr.uu.se).
* In a hierarchical classification of stent thrombosis across randomized trials of 878 patients treated with sirolimus-eluting stents, 1,400 treated with paclitaxel-eluting stents, and 2,267 treated with bare-metal stents, researchers found: “The incidence of stent thrombosis did not differ significantly between patients with drug-eluting stents and those with bare-metal stents in randomized clinical trials, although the power to detect small differences in rates was limited” (pp. 1020-9; D. E. Cutlip,
don.cutlip@hcri.harvard.edu).
* Sirolimus-eluting stents had no significant effect on overall long-term survival and survival free of myocardial infarction, compared with bare-metal stents, in an analysis of data from 14 trials of 4,958 patients. “There is a sustained reduction in the need for reintervention after the use of sirolimus-eluting stents,” the authors conclude. “The risk of stent thrombosis is at least as great as that seen with bare-metal stents” (pp. 1030-9; A. Kastrati, Deutsches Herzzentrum, Munich, Germany;
kastrati@dhm.mhn.de).
The situation with stents is not unlike that with drug approvals and drug safety, a between-the-lines reading of the first Perspectives article reveals (pp. 981-4): “The turmoil over drug-eluting stents and thrombosis represents both a success and a failure of the U.S. medical-device regulatory system. The FDA should be commended for recognizing the importance of the issue, organizing a panel meeting quickly, facilitating exchange of scientific information, and helping to educate physicians and patients. Unfortunately, despite the 5 years that have elapsed since the start of the clinical trials and the implantation of millions of drug-eluting stents, much remains uncertain about the long-term safety of the devices.
“Drug-eluting stents represent an important advance in the management of coronary artery disease and have benefited many patients. In the rush to bring ‘breakthrough’ technologies to market, unanticipated adverse events will inevitably occur. The solution is not to stop expediting the approval of novel products but to ensure a better, more timely exchange of information with the public and to require larger, longer-term post-marketing studies, particularly for permanent medical-device implants.” (W. H. Maisel, Harvard Med. Sch., Boston)
The second Perspectives article adds this caution (pp. 984-7): “Patients who cannot comply with extended clopidogrel use or have planned procedures requiring early discontinuation of antiplatelet therapy may not be candidates for a drug-eluting stent. Patients should be thoroughly educated about the need for strict adherence to the recommended course of antiplatelet therapy and should discuss any changes with their cardiologist.” (A. Farb, FDA, Rockville, Md.)

>>>PNN NewsWatch
* CPT codes for medication therapy management services are being moved from Category III (emerging) to Category I (permanent), APhA reports.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 9, 2007 * Vol. 14, No. 47
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
Mar. 13 issue of the Journal of the American College of Cardiology (http://content.onlinejacc.org; 2007; 49).
Vascular Endothelial Growth Factors: The biology and effects of vascular endothelial growth factors are reviewed in a state-of-the-art paper (pp. 1015-26). “Because of their profound effects on blood vessels, VEGFs have received much attention regarding their potential therapeutic use in cardiovascular medicine, especially for therapeutic vascular growth in myocardial and peripheral ischemia,” the authors write. “However, completed randomized controlled VEGF trials have not provided convincing evidence of clinical efficacy. On the other hand, recent preclinical proangiogenic VEGF studies have given insight, and anti-VEGF studies have shown that the disturbance of vascular homeostasis by blocking VEGF-A may lead to endothelial dysfunction and adverse vascular effects. Excess VEGF-A may contribute to neovascularization of atherosclerotic lesions but, currently, there is no evidence that transient overexpression by gene transfer could lead to plaque destabilization.” (S. Ylä-Herttuala, U. Kuopio, Kuopio, Finland; seppo.ylaherttuala@uku.fi)
Ranolazine in Severe Angina: Among 746 patients with severe chronic stable angina treated in the Ranolazine Open Label Experience (ROLE) program, long-term ranolazine was well tolerated (pp. 1027-34). Duke Treadmill Scores showed these results in these high-risk patients: “Mean follow-up was 2.82 years. Two years after initial dosing, 571 patients (76.7%) remained on therapy and 72 patients (9.7%) discontinued ranolazine due to adverse events. Among 6 factors evaluated, only age ≥64 years predicted for higher withdrawal rates. Patients with a history of CHF had lower withdrawal rates. Mean QTc interval was prolonged by 2.4 ms. No treatment discontinuations occurred due to QTc prolongation, and no Torsades de Pointes was reported. Sixty-four deaths occurred during a total of 2,102 patient-years (3.0% annually) during the ROLE program. When extending observations to all patients exposed to ranolazine during the double-blind trials (n = 972) preceding the ROLE program, annual mortality was 2.8% compared with >5% as predicted by DTS.” (M. J. Koren, Jacksonville Ctr. for Clinical Research, Jacksonville, Fla.; MichaelKoren@jaxresearch.com)
Statin Doses with Concomitant Ezetimibe: When using concomitant ezetimibe–statin therapy in patients with coronary artery disease, statin doses may need to remain high to achieve pleiotropic benefits that are independent of cholesterol lowering, such as improved platelet reactivity and reductions in a proinflammatory chemokine (pp. 1035-42). That conclusion comes from a study of 56 patients who received either atorvastatin 40 mg/day or ezetimibe 10 mg/day plus atorvastatin 10 mg/day for 4 weeks: “Platelet activation markers (P-selectin) after stimulation (adenosine diphosphate) were reduced by 40 mg/day of atorvastatin (–5.2 ± 1.6 arbitrary units) but not by ezetimibe plus low-dose atorvastatin (2.1 ± 1.8 arbitrary units; p < 0.005) despite a similar reduction of LDL-C (atorvastatin –1.01 ± 0.18 mmol/l vs. ezetimibe plus atorvastatin –1.36 ± 0.22 mmol/l, p = NS). Thrombin receptor-activating peptide-induced platelet aggregation as well as plasma [chemokine] levels were reduced by 40 mg/day of atorvastatin but not by ezetimibe plus low-dose atorvastatin.” (U. Rauch, Charité Universitätsmedizin, Berlin; ursula.rauch@charite.de)
Postpartum Prolongations in Long QT Syndrome: Beta-blocker therapy prevented cardiac events among women with long QT syndrome in the 9 months after pregnancy, a time when risks are elevated, according to a study of 391 patients who delivered firstborns in 1980–2003 (pp. 1092-8). “Compared with a time period before a woman’s first conception, the pregnancy time was associated with a reduced risk of cardiac events (hazard ratio [HR] 0.28, 95% confidence interval [CI] 0.10 to 0.76, p = 0.01), whereas the 9-month postpartum time had an increased risk (HR 2.7, 95% CI 1.8 to 4.3, p < 0.001),” report the authors. “After the 9-month postpartum period, the risk was similar to the period before the first conception (HR 0.91, 95% CI 0.55 to 1.5, p = 0.70).... The cardiac event risk during the high-risk postpartum period was reduced among women using beta-blocker therapy (HR 0.34, 95% CI 0.14 to 0.84, p = 0.02).” (A. J. Moss, heartajm@heart.rochester.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 © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 12, 2007 * Vol. 14, No. 48
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Early-release article from Lancet (www.thelancet.com; 2007; 369).
Neurostimulation for Intractable Cluster Headache: Occipital nerve stimulation provides an alternative cranially invasive and neurally destructive treatments of drug-resistant chronic cluster headache, according to a study of 8 patients (doi: 10.1016/S0140-6736(07)60328-6). Electrodes implanted in the suboccipital region (bilaterally in 7 patients and unilaterally in 1 individual) showed these results: “At a median follow-up of 20 months (range 6–27 months for bilateral stimulation), six of eight patients reported responses that were sufficiently meaningful for them to recommend the treatment to similarly affected patients with chronic cluster headache. Two patients noticed a substantial improvement (90% and 95%) in their attacks; three patients noticed a moderate improvement (40%, 60%, and 20–80%) and one reported mild improvement (25%). Improvements occurred in both frequency and severity of attacks. These changes took place over weeks or months, although attacks returned in days when the device malfunctioned (eg, with battery depletion). Adverse events of concern were lead migrations in one patient and battery depletion requiring replacement in four.” (P. J. Goadsby, Natl. Hosp. for Neurology and Neurosurgery, London; peterg@ion.ucl.ac.uk)

>>>BMJ Highlights
Source:
Mar. 10 issue of BMJ (www.bmj.org; 2007; 334).
Antithyroid Drugs & Radioiodine Treatment: Given in the week before or after radioiodine treatment, antithyroid drugs increase rates of failure and reduce rates of hypothyroidism, according to a meta-analysis of 14 trials of 1,306 participants (pp. 514 ff). The researchers report: “Adjunctive antithyroid medication was associated with an increased risk of treatment failure (relative risk 1.28, 95% confidence interval 1.07 to 1.52; P = 0.006) and a reduced risk for hypothyroidism (0.68, 0.53 to 0.87; P = 0.006) after radioiodine treatment. We found no difference in summary estimates for the different antithyroid drugs or for whether antithyroid drugs were given before or after radioiodine treatment.” (M. A. Walter, U. Hosp., Basel, Switzerland; m.a.walter@gmx.net)

>>>PNN NewsWatch
* FDA on Friday announced addition of a black-box warning to product labeling of erythropoiesis-stimulating agents (darbepoetin alfa [Aranesp, Amgen], epoetin alfa [Epogen, Amgen; Procrit, Ortho Biotech]) based on analyses of four new studies in patients with cancer showing a higher chance of serious and life-threatening adverse effects and/or death with the use of these agents.
*
FDA also announced early termination of the INSPIRE clinical study of interferon gamma-1b (Actimmune, Intermune) for idiopathic pulmonary fibrosis because of lack of benefit of the drug in an interim analysis. Overall, 14.5% of patients treated with interferon gamma-1b died, compared with 12.7% of patients treated with placebo. This product is not approved by FDA for treatment of IPF.
*
Takeda and FDA notified health care professionals of increased fractures in women taking pioglitazone-containing products. Most fractures were in the distal upper limb (forearm, hand, and wrist) or distal lower limb (foot, ankle, fibula, and tibia). Analyzed were data on more than 8,100 patients in the pioglitazone-treated groups and 7,400 patients in the comparator-treated groups. The duration of pioglitazone treatment was up to 3.5 years. Health professionals should consider the risk of fracture when girls or women with type 2 diabetes mellitus are being considered for or under treatment with pioglitazone-containing products, FDA and the company cautioned.

>>>PNN JournalWatch
* Long-Term Outcome After an Early Invasive Versus Selective Invasive Treatment Strategy in Patients with Non-ST-Elevation Acute Coronary Syndrome and Elevated Cardiac Troponin T (The Ictus Trial): A Follow-Up Study, in Lancet, 2007; 369: 827–35. Reprints: R. J. de Winter, Academic Med. Ctr., Amsterdam, the Netherlands; r.j.dewinter@amc.uva.nl
* Cervical Spondylosis and Neck Pain, in
BMJ, 2007; 334: 527–31. Reprints: A. I. Binder, Lister Hosp., Hertfordshire, U.K.; allan.binder@nhs.net

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 13, 2007 * Vol. 14, No. 49
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Mar. 12 issue of Archives of Internal Medicine (www.archinternmed.com; 2007; 167).
Dietary v. Supplemental Fiber: C-reactive protein levels were reduced by both high dietary intake of fiber and use of fiber supplements, indicating a possible role for fiber in modulating inflammation and its cardiovascular consequences (pp. 502-6). Comparing the high-fiber Dietary Approaches to Stop Hypertension (DASH) diet with a fiber-supplemented diet (each providing fiber at 30 grams/day) for 3 weeks using a crossover design, the investigators found that some benefits of increased fiber intake were difficult to identify among patients with obesity: “The study included 28 women and 7 men; 16 (46%) were black, the remainder white. The mean (SD) fiber intake on baseline diets was 11.9 (0.3) g/d; on the high-fiber DASH diet, 27.7 (0.6) g/d; and on the supplemented diet, 26.3 (0.4) g/d. Overall, the mean C-reactive protein (CRP) level changed from 4.4 to 3.8 mg/L (–13.7%; P = .046) in the high-fiber DASH diet group and to 3.6 mg/L (–18.1%) in the fiber-supplemented diet group (P = .03). However, CRP levels decreased in the 18 lean normotensive participants in either intervention diet group (2.0 mg/L [baseline] vs 1.4 mg/L [high-fiber DASH] vs 1.2 mg/L [supplemented]); P <.05) but did not change significantly (7.1 mg/L [baseline] vs 6.2 mg/L [high-fiber DASH] vs 6.5 mg/L [supplemented]; P >.05) in obese hypertensive participants. Neither age nor race influenced the response of CRP levels to the diets. No evidence of a crossover effect was detected.” (D. E. King, kingde@musc.edu)
Justice & Multitiered Health Care: Beginning with the acknowledgment that “the American health care system is a mess,” writers argue that ethical reform should be targeted to provide a multitiered system rather than single-tier health care like that available in Canada (pp. 433-7). “What sort of replacement should we want for our troubled health care system? Many argue that justice requires prohibiting private payment for medical services to enforce a Canadian-style single-tiered health care system. This egalitarian approach, while well intentioned, fails to recognize 3 fundamental claims of justice: Public resources are limited, society cannot provide everything, and individual liberties include the freedom to pay for benefits the state does not provide. A tiered system, like English or Israeli systems, can provide broad but necessarily finite universal public coverage without trampling freedom of choice. Many questions remain for American health care reformers, but on the question of tiering, the principles of justice call for a multitiered health care system.” (E. J. Emanuel, eemanuel@nih.gov)
An editorialist counters that two-tiered health care creates a “problematic double standard” (pp. 430-2): “If funding of the health care system remains roughly stable, and if we eliminate administrative waste and unnecessary medical interventions, people could receive comprehensive care within a single tier (preferably, in my view, in the context of a single-payer national health plan). Moreover, the kinds of interventions that would be appropriate for a second tier remain elusive: Effective evidence-based interventions should be included in the first tier, and ineffective or unproven interventions should not be provided in any tier, even if a patient is willing to pay for them. Of course, there always will be marginally beneficial—or promising but unproven—interventions about which reasonable people will disagree. Unbiased and publicly accountable procedures will be required to adjudicate such disagreements, even in tiered systems.” (A. S. Brett,
abrett@sc.edu)
Longevity & Cardiac Risk Factors: Advantageous cardiovascular risk profiles are evident in middle age among individuals with long-lived parents (mother and father surviving to 85 years or older), according to an analysis of Framingham Heart Study longitudinal data (pp. 438-44). Among 1,697 study participants whose parents were included in the original FHS cohort and either survived to 85 or died before Jan. 1, 2005, researchers observed: “The mean Framingham Risk Score was most favorable in offspring with both parents surviving to 85 years or older and was progressively worse in those with one or no long-lived parent (0.55, 1.08, and 1.71, respectively; P value for trend, <.001). Longitudinally, offspring of parents who lived longer had lower risk of blood pressure and Framingham Risk Score progression.” (D. F. Terry, Boston Med. Ctr., Boston; laterry@bu.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 © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 14, 2007 * Vol. 14, No. 50
Providing news and information about medications and their proper use

>>>Lapatinib Approved for Advanced Breast Cancer
FDA has approved lapatinib (Tykerb, GlaxoSmithKline) for use with capecitabine for patients with advanced, metastatic, HER2-positive breast cancer. The combination treatment is indicated for women who have received prior therapy with other cancer drugs, including an anthracycline, a taxane, and trastuzumab. The new drug will be available within 2 weeks.
Lapatinib works through multiple pathways to deprive tumor cells of signals needed to grow. Unlike, for example, the monoclonal antibody trastuzumab—which is a large protein molecule that targets the part of the HER2 protein on the outside of the cell—lapatinib is a small molecule that enters the cell and blocks the function of this and other proteins. Because of this difference in mechanism of action, lapatinib works in some HER2-positive breast cancers that have been treated with trastuzumab and are no longer benefiting.
The approval of lapatinib was based on a randomized clinical trial in about 400 women with advanced or metastatic breast cancer that was also HER2 positive. Compared with patients receiving capecitabine alone, those receiving lapatinib with capecitabine had a statistically significant improvement in the time to tumor progression. In addition, the tumor response rate was higher in the group of patients receiving lapatinib with capecitabine (24% versus 14%). The survival data are not yet mature.
In clinical trials, the most commonly reported lapatinib-related adverse effects included diarrhea, nausea, vomiting, rash, and hand-foot syndrome that may include numbness, tingling, redness, swelling, and discomfort of hands and feet. Generally reversible decreases in heart function have also been reported in a small percentage of patients.
Lapatinib is available in tablets of 250 mg. An undivided dose of 1,250 mg should be taken orally once daily for 21 days and in combination with capecitabine on days 1–14 of a 21-day cycle.
Through the Tykerb CARES program, consultants are available to answer product-related questions from patients and professionals and to assist them with obtaining the product. Additionally, Tykerb CARES reimbursement counselors will help patients understand their insurance coverage and, if appropriate, help with identifying alternative financial support. More information regarding Tykerb CARES can be obtained by calling 1-866-4-TYKERB.

>>>JAMA Highlights
Source:
Mar. 14 issue of JAMA (www.jama.com; 2007; 297), a theme issue on Access to Care.
Financial Barriers After MI: Patients with financial barriers to health services and medications had significantly worse recoveries following acute myocardial infarction, compared with those reporting no such problems (pp. 1063-72). In an observational, multicenter U.S. study of 2,498 individuals enrolled from Jan. 2003 through June 2004 in the Prospective Registry Evaluating Myocardial Infarction: Event and Recovery (PREMIER), researchers found more angina, poorer quality of life as measured on the Seattle Angina Questionnaire, and higher risk of rehospitalization in patients reporting barriers: “The prevalence of self-reported financial barriers to health care services or medication was 18.1% and 12.9%, respectively. Among individuals who reported financial barriers to health care services or medication, 68.9% and 68.5%, respectively, were insured. At 1-year follow-up, individuals with financial barriers to health care services were more likely to have lower SAQ quality-of-life score (77.9 vs 86.2; adjusted mean difference = –4.0; 95% confidence interval [CI], –6.3 to –1.8), and increased rates of all-cause rehospitalization (49.3% vs 38.1%; adjusted hazard ratio [HR], 1.3; 95% CI, 1.1–1.5) and cardiac rehospitalization (25.7% vs 17.7%; adjusted HR, 1.3; 95% CI, 1.0–1.6). At 1-year follow-up, individuals with financial barriers to medication were more likely to have angina (34.9% vs 17.9%; adjusted odds ratio, 1.55; 95% CI, 1.1–2.2), lower SAQ quality-of-life score (74.0 vs 86.1; adjusted mean difference = –7.6; 95% CI, –10.2 to –4.9), and increased rates of all-cause rehospitalization (57.0% vs 37.8%; risk-adjusted HR, 1.5; 95% CI, 1.2–1.8) and cardiac rehospitalization (33.7% vs 17.3%; adjusted HR, 1.7; 95% CI, 1.3–2.2).” (H. M. Krumholz, harlan.krumholz@yale.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 © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 15, 2007 * Vol. 14, No. 51
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Mar. 15 issue of the New England Journal of Medicine (http://content.nejm.org; 2007; 356).
Loss of Immunity After Varicella Vaccine: The now-recommended second dose of varicella vaccine for children between 4 and 6 years of age is needed to provide “protection from both primary vaccine failure and waning vaccine-induced immunity,” concludes a study of 10 years of surveillance data on a sentinel population of 350,000 people (pp. 1121-9). “A total of 11,356 subjects were reported to have varicella during the surveillance period, of whom 1,080 (9.5%) had breakthrough disease,” report the researchers. “Children between the ages of 8 and 12 years who had been vaccinated at least 5 years previously were significantly more likely to have moderate or severe disease than were those who had been vaccinated less than 5 years previously (risk ratio, 2.6; 95% confidence interval [CI], 1.2 to 5.8). The annual rate of breakthrough varicella significantly increased with the time since vaccination, from 1.6 cases per 1,000 person–years (95% CI, 1.2 to 2.0) within 1 year after vaccination to 9.0 per 1,000 person–years (95% CI, 6.9 to 11.7) at 5 years and 58.2 per 1,000 person–years (95% CI, 36.0 to 94.0) at 9 years.” (S. S. Chaves, bev8@cdc.gov)
Weekend v. Weekday MIs: Higher mortality rates and lower use of invasive procedures were evident among patients admitted for first myocardial infarctions on weekends, compared with weekdays, reports the Myocardial Infarction Data Acquisition System (MIDAS 10) study group (pp. 1099-109). Increased access to care on weekends has the potential to reverse this finding, the investigators added, based on these 1987–2002 data: “Patients admitted on weekends were less likely to undergo invasive cardiac procedures, especially on the first and second days of hospitalization (P < 0.001). In the interval from 1999 to 2002 (59,786 admissions), mortality at 30 days was significantly higher for patients admitted on weekends (12.9% vs. 12.0%, P = 0.006). The difference became significant the day after admission (3.3% vs. 2.7%, P < 0.001) and persisted at 1 year (1% absolute difference in mortality). The difference in mortality at 30 days remained significant after adjustment for demographic characteristics, coexisting conditions, and site of infarction (hazard ratio, 1.048; 95% confidence interval [CI], 1.022 to 1.076; P < 0.001), but it became nonsignificant after additional adjustment for invasive cardiac procedures (hazard ratio, 1.023; 95% CI, 0.997 to 1.049; P = 0.09).” (W. J. Kostis, U. Med. and Dentistry of N.J., New Brunswick; kostiswj@umdnj.edu)
Assigning Responsibility in P4P: In 2000–02, Medicare beneficiaries saw a median of 2 primary care and 5 specialist physicians, and this dispersion of care will “limit the effectiveness of pay-for-performance initiatives that rely on a single retrospective method of assigning responsibility for patient care,” authors write (pp. 1130-9). Based on analysis of claims for beneficiaries who were treated by 8,604 physicians in the Community Tracking Study Physician Study in 2000 and 2001, the researchers determined: “A median of 35% of beneficiaries’ visits each year were with their assigned physicians; for 33% of beneficiaries, the assigned physician changed from one year to another. On the basis of all visits to any physician, a primary care physician’s assigned patients accounted for a median of 39% of the physician’s Medicare patients and 62% of Medicare visits. For medical specialists, the respective percentages were 6% and 10%. On the basis of visits to primary care physicians only, 79% of beneficiaries could be assigned to a physician, and a median of 31% of beneficiaries’ visits were with that assigned primary care physician.” (H. H. Pham, Ctr. for Studying Health System Change, Washington; mpham@hschange.org)

>>>PNN NewsWatch
* FDA has requested that all manufacturers of sedative–hypnotic drug products strengthen their product labeling to include stronger language concerning potential risks, including anaphylaxis and complex sleep-related behaviors, which may include driving, making telephone calls, and preparing and eating food while asleep and with no memory of the event. Manufacturers must also develop Patient Medication Guides to give to patients, families, and caregivers when a sedative–hypnotics are dispensed. These will detail proper use and recommend avoidance of concomitant alcohol and/or other CNS depressants.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 16, 2007 * Vol. 14, No. 52
Providing news and information about medications and their proper use

>>>Psychiatry Highlights
Source:
Mar. issue of the American Journal of Psychiatry (http://ajp.psychiatryonline.org; 2007; 164).
Second-Generation Antipsychotics After Schizophrenia: Following discontinuation of the first-generation antipsychotic perphenazine in a group of 114 patients with schizophrenia, quetiapine and olanzapine had longer times to discontinuation than did risperidone, report Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study investigators (pp. 415-27). “The time to treatment discontinuation was longer for patients treated with quetiapine (median, 9.9 months) and olanzapine (7.1 months) than with risperidone (3.6 months),” the authors note. “There were no significant differences between treatments on discontinuation due to inefficacy, intolerability, or patient decision.” (T. S. Stroup)
Psychosocial Functioning with Antipsychotic Medications: In a second report from the CATIE trial, patients “made modest improvements in psychosocial functioning” during the 18-month trial, regardless of whether they were taking olanzapine, perphenazine, quetiapine, risperidone, or ziprasidone (pp. 428-36). Concluding that “more substantial improvements would likely require more intensive adjunctive psychosocial rehabilitation interventions,” the investigators report these results: “Psychosocial functioning modestly improved for the one-third of ... patients who reached the primary Quality of Life Scale analysis endpoint of 12 months (average effect size 0.19 SD units). Although for several of the drugs individually there were significant changes from baseline, overall there were no significant differences between the different agents. Results were similar at 6 and 18 months. There were no significant differences among the treatment groups in the amount of change in the Quality of Life Scale total score or subscale scores at 6, 12, or 18 months. Patients treated with clozapine in the efficacy pathway made comparable gains. Early treatment discontinuations, especially among patients most impaired at baseline, limited the ability to achieve more substantial functional gains.” (M. S. Swartz)

>>>Rheumatology Report
Source:
Mar. issue of the American Journal of Rheumatology (www3.interscience.wiley.com; 2007; 56).
Glucocorticoids in RF: Among 603 patients with incident rheumatoid arthritis between 1955 and 1995, those positive for rheumatoid factor had increased risks of cardiovascular events following exposure to glucocorticoids, while RF-negative patients were at not at increased risk (pp. 820-30). Based on reviews of patients’ medical records for a median of 13 years (9,066 person–years), researchers report: “RF-negative patients with exposure to glucocorticoids were not at increased risk of CV events, irrespective of the glucocorticoid dosage or timing of use, as compared with the reference group of RF-negative patients who had never been exposed to glucocorticoids. In contrast, RF-positive patients were at increased risk of CV events, particularly with higher cumulative exposure, higher average daily dosage, and recent use of glucocorticoids. RF-positive patients with high cumulative exposure to glucocorticoids had a 3-fold increased risk of CV events (hazard ratio 3.06 [95% confidence interval 1.81–5.18]), whereas RF-negative patients with high cumulative exposure were not at increased risk (hazard ratio 0.85 [95% confidence interval 0.39–1.87]).” (J. M. Davis III, davis.john4@mayo.edu)

>>>PNN NewsWatch
* APhA2007 opens today in Atlanta, and its House of Delegates will be considering policies on privacy of pharmacists’ personal information, therapeutic decision-making, biologic drug products, and redistribution of medications in sessions this and Monday afternoons. All-day workshops are scheduled for today on various medication therapy management topics, including a certificate training program on “Delivering Medication Therapy Management Services in Your Community” that is cosponsored by the American Society of Consultant Pharmacists, and others on diabetes, lipids management, self-care, and immunizations.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 19, 2007 * Vol. 14, No. 53
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Mar. 17 issue of Lancet (www.thelancet.com; 2007; 369).
Bivalirudin in ACS: Compared with unfractionated heparin or enoxaparin, bivalirudin produced equivalent efficacy with greater safety among 7,789 patients treated during percutaneous coronary interventions for moderate and high-risk acute coronary syndromes (pp. 907-19). In the Acute Catheterization and Urgent Intervention Triage strategy (ACUITY) trial, investigators looked at primary 30-day endpoints of composite ischemia (death, myocardial infarction, or unplanned revascularization for ischemia), major bleeding, and net clinical outcomes (composite ischemia or major bleeding): “There was no significant difference in the proportion of individuals with composite ischaemia, major bleeding, or net clinical outcomes at 30 days between those who received bivalirudin plus glycoprotein IIb/IIIa inhibitors and those who received heparin plus glycoprotein IIb/IIIa inhibitors (composite ischaemia: 243 [9%] patients vs 210 [8%] patients, p = 0.16; major bleeding: 196 [8%] patients vs 174 [7%] patients, p = 0.32; net clinical outcomes: 389 [15%] patients vs 341 [13%] patients, p = 0.1). Rates of composite ischaemia were much the same in those who received bivalirudin alone and those who received heparin plus glycoprotein IIb/IIIa inhibitors (230 [9%] patients vs 210 [8%] patients, p = 0.45); however, there were significantly fewer individuals who experienced major bleeding among those who received bivalirudin alone than among those who received heparin plus glycoprotein IIb/IIIa inhibitors (92 [4%] patients vs 174 [7%] patients, p <0.0001, relative risk 0.52, 95% CI 0.40–0.66), resulting in a trend towards better 30-day net clinical outcomes (303 [12%] patients vs 341 [13%] patients, p = 0.057; 0.87, 0.75–1.00).” (G. W. Stone, gs2184@columbia.edu)
Zinc & Childhood Mortality: Addressing inconsistencies in clinical research into zinc supplementation in Asia (where it has reduced mortality and morbidity) versus Africa (where it has made little impact in malarious populations), researchers found no significant difference in all-cause mortality among 42,546 children aged 1–36 months who received zinc 5–10 mg daily in a trial conducted in Zanzibar (pp. 927-34). Assignment to zinc or placebo was randomized by household, and these results were noted based on a mean of 484.7 days of treatment: “Overall, there was a non-significant 7% (95% CI −6% to 19%; p = 0.29) reduction in the relative risk of all-cause mortality associated with zinc supplementation.” Based on these findings, the authors recommend: “A meta-analysis of all studies of mortality and morbidity ... will help to make evidence-based recommendations for the role of zinc supplementation in public health policy to improve mortality, morbidity, growth, and development in young children.” (R. E. Black, Johns Hopkins Bloomberg School of Public Health, Baltimore; rblack@jhsph.edu)

>>>PNN JournalWatch
* Generalised Anxiety Disorder, in BMJ, 2007; 334: 579–81. Reprints: C. Gale, U. Otago, Dunedin, New Zealand; christopher.gale@stonebow.otago.ac.nz
* New Ideas in Epilepsy Genetics: Novel Epilepsy Genes, Copy Number Alterations, and Gene Regulation, in
Archives of Neurology, 2007; 64: 324–8. Reprints: C. A. Gurnett, Washington U., St. Louis; gurnettc@neuro.wustl.edu
* Advances in Pediatric Asthma 2006, in
Journal of Allergy and Clinical Immunology, 2007; 119: 558–62. Reprints: S. J. Szefler, Natl. Jewish Med. and Res. Ctr., Denver; szeflers@njc.org
* Advances in Adult Asthma 2006: Its Risk Factors, Course, and Management, in
Journal of Allergy and Clinical Immunology, 2007; 119: 563–6. Reprints: A. J. Apter, apter@mail.med.upenn.edu
* Update in Pediatric Lung Disease 2006, in
American Journal of Respiratory and Critical Care Medicine, 2007; 175: 532–40. Reprints: A. Bush, Royal Brompton Hosp., London; a.bush@rbh.nthames.nhs.uk
* Update in Tuberculosis 2006, in
American Journal of Respiratory and Critical Care Medicine, 2007; 175: 541–6. Reprints: W. W. Yew, Grantham Hosp., Hong Kong, China; yewww@ha.org.hk

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 20, 2007 * Vol. 14, No. 54
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Mar. 20 issue of the Annals of Internal Medicine (www.annals.org; 2007; 146).
Early RA Treatments: In a trial that included 508 patients with early active rheumatoid arthritis, investigators found that “initial combination therapies seem to provide earlier clinical improvement and less progression of joint damage, but all treatment strategies eventually showed similar clinical improvements” (pp. 406-15). In the BeSt study, patients were randomized to sequential monotherapy (group 1), step-up combination therapy (group 2), initial combination therapy with tapered high-dose prednisone (group 3), or initial combination therapy with infliximab (group 4), with these results: “Groups 3 and 4 had more rapid clinical improvement during the first year; all groups improved further to a mean functional ability score of 0.6 (overall, P = 0.257) and 42% were in remission (overall, P = 0.690) during the second year. Progression of joint damage remained better suppressed in groups 3 and 4 (median scores of 2.0, 2.0, 1.0, and 1.0 in groups 1, 2, 3, and 4, respectively [P = 0.004]). After 2 years, 33%, 31%, 36%, and 53% of patients in groups 1 through 4, respectively, were receiving single-drug therapy for initial treatment. There were no significant differences in toxicity.” (Y. P.M. Goekoop-Ruiterman, Leiden U. Med. Ctr., Leiden, the Netherlands; y.p.m.goekoop@lumc.nl)
An editorialist recommends this approach for treatment of newly diagnosed RA (pp. 459-60): “First, with the ever-increasing complexity, expense, and toxicity of modern therapy, a rheumatologist should be actively involved in the care of all patients with RA in conjunction with the primary care physician. Second, all patients should receive a DMARD (in most cases methotrexate) as soon as possible. Finally, rheumatologists should adjust therapy in a timely fashion (increasing doses or adding other DMARDs) until patients have achieved low levels of disease activity (or are in remission). Some patients do very well on single DMARD therapy whereas others need biologicals plus multiple conventional drugs. The critical challenge for the next decade will be to find ways to differentiate these groups at disease onset. Matching treatment to the patient’s clinical characteristics may save time and money and preserve quality of life.” (J. R. O’Dell, U. Nebraska Med. Ctr., Omaha)
Alendronate for Bone Loss in Men: Once-weekly oral alendronate 70 mg prevented and improved bone loss in a study of 112 men receiving androgen deprivation therapy for nonmetastatic prostate cancer (pp. 416-24). Assessing bone mineral density over the first year of partial crossover trial, researchers determined: “At baseline, 39% of men had osteoporosis and 52% had low bone mass. In men treated with alendronate, bone mineral density increased over 1 year by 3.7% (95% CI, 2.8% to 4.6%; P < 0.001) at the spine and 1.6% (CI, 0.4% to 2.8%; P = 0.008) at the femoral neck. Men in the placebo group had losses of 1.4% (CI, –2.7% to – 0.03%; P = 0.045) at the spine and 0.7% (CI, –1.5% to 0.01%; P = 0.081) at the femoral neck. At 12 months, the difference between the 2 groups was 5.1 percentage points (CI, 3.5 to 6.7 percentage points; P < 0.001) at the spine and was 2.3 percentage points (CI, 1.0 to 3.7 percentage points; P < 0.001) at the femoral neck. Bone turnover statistically significantly decreased with active therapy compared with placebo. The groups did not differ in adverse events.” (M. Miller, millerm@dom.pitt.edu)
DREAM & Diabetes Prevention: For patients with prediabetes who are not able to incorporate physical activity and a low-fat diet into their daily routines, metformin appears to be the best pharmacologic choice for prevention of diabetes, write editorialists (pp. 461-3). Reviewing data from the DREAM (Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication) trial, they write: “Although no drug is currently FDA-approved for prevention, metformin’s generally excellent efficacy and safety profile, its high level of acceptance, and its relatively low cost compared with other available agents suggest it has a role to play in preventing or delaying the onset of diabetes in people with documented impaired glucose tolerance and impaired fasting glucose who are younger (<60 years of age) and obese (body mass index >35 kg/m2).” (D. M. Nathan, dnathan@partners.org)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 21, 2007 * Vol. 14, No. 55
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Mar. 21 issue of JAMA (www.jama.com; 2007; 297).
RCTs & Eligibility Criteria: Inclusion and exclusion criteria, especially for multicenter, multi-intervention randomized controlled trials, often produce results that are not generalizable to many patients seen in general clinical practice, concludes an analysis of 283 RCTs published in 1994–2006 in general medical journals with high impact factor ratings (pp. 1233-40). The investigators also note that women, children, the elderly, and those with common medical conditions are frequently excluded from RCTs and suggest that journals need to emphasize “transparent reporting and justification of exclusion criteria in clinical trials.” (R. A. Fowler, Sunnybrook Hosp., Toronto; rob.fowler@sunnybrook.ca)
Industry Payments to Physicians: Publicly available records detailing pharmaceutical company payments to physicians in Vermont and Minnesota reveal “substantial numbers of payments of $100 or more,” explains a cross-sectional analysis of data from 2002 to 2004 (pp. 1216-23). Three other states (California, Maine, and West Virginia) and the District of Columbia require such disclosures, but only in Vermont and Minnesota are these disclosures publicly available. However, this study shows, access to the records is not easy, and quality of the information is limited: “Access to payment data required extensive negotiation with the Office of the Vermont Attorney General and manual photocopying of individual disclosure forms at Minnesota’s State Board of Pharmacy. In Vermont, 61% of payments were not released to the public because pharmaceutical companies designated them as trade secrets and 75% of publicly disclosed payments were missing information necessary to identify the recipient. In Minnesota, 25% of companies reported in each of the 3 years. In Vermont, among 12,227 payments totaling $2.18 million publicly disclosed, there were 2,416 payments of $100 or more to physicians; total, $1.01 million; median payment, $177 (range, $100–$20,000). In Minnesota, among 6,946 payments totaling $30.96 million publicly disclosed, there were 6,238 payments of $100 or more to physicians; total, $22.39 million; median payment, $1,000 (range, $100–$922,239). Physician-specific analyses were possible only in Minnesota, identifying 2,388 distinct physicians who received payment of $100 or more; median number of payments received, 1 (range, 1–88) and the median amount received, $1,000 (range, $100–$1,178,203).” (J. S. Ross, Mount Sinai Sch. of Med., New York; joseph.ross@mssm.edu)
Editorialists explore the conflicts between the need to innovate and assure shareholder value while addressing the growing mistrust of the pharmaceutical industry (pp. 1255-7): “Pharmaceutical companies have made profound contributions to medical therapy and public health. The achievements of their research programs speak volumes. However, their marketing techniques and their reluctance to disclose them invite further misgivings about the industry. Drug companies’ attempt to evade regulation may backfire, as public resentment over noncompliance with existing laws sparks demand for additional regulation.
“To be clear, for-profit industries do not share the same ethical norms to which physicians and other health care professionals must adhere. Their primary commitment is to create shareholder value, not maintain an altruistic commitment to patients. But at some point the leadership of the pharmaceutical industry and their boards of directors must begin to recognize that growing public and professional mistrust could substantially detract from that value.” (T. A. Brennan, Hartford;
brennant@aetna.com)

>>>PNN NewsWatch
* Experiences to date with the APhA Foundation’s Project ImPACT: Depression were shared during APhA2007 in Atlanta. Pharmacist–coaches meet with patients for 60–90 minutes initially, monthly for 3 months, and then every 1–3 months as required.
*
Prescription drug abuse in teens and the need for proper medication disposal to reduce drug contamination of streams were topics of news conferences during APhA2007. APhA is partnering with the White House Office of National Drug Control Policy and the U.S. Fish and Wildlife Service to address these problems.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 22, 2007 * Vol. 14, No. 56
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Mar. 22 issue of the New England Journal of Medicine (http://content.nejm.org; 2007; 356).
Coronary Risks of Firefighting: The risk of death from coronary heart disease is 10 to 100 times greater among firefighters while they are suppressing a fire than when they are performing nonemergency duties, according to an analysis of data from 1994 to 2004 (pp. 1207-15). Based on circumstances of 1,144 deaths of firefighters, the researchers observed: “Deaths from coronary heart disease were associated with suppressing a fire (32.1% of all such deaths), responding to an alarm (13.4%), returning from an alarm (17.4%), engaging in physical training (12.5%), responding to nonfire emergencies (9.4%), and performing nonemergency duties (15.4%). As compared with the odds of death from coronary heart disease during nonemergency duties, the odds were 12.1 to 136 times as high during fire suppression, 2.8 to 14.1 times as high during alarm response, 2.2 to 10.5 times as high during alarm return, and 2.9 to 6.6 times as high during physical training. These odds were based on three estimates of the time that firefighters spend on their duties.” (S. N. Kales, Cambridge Health Alliance, Cambridge, Mass.; skales@challiance.org)
Editorialists add that similar risks may be present among other workers who are exposed to chemicals, stress, and the demands of shift work (pp. 1261-3): “For firefighters as well as other workers who may face some of these risk factors for cardiac events, decreasing or eliminating occupational risk factors other than heavy exertion (e.g., chemicals, stress, and shift work) is likely to be of benefit. For all workers, whether or not they have physically demanding jobs, the evidence is clear, and this study provides further support for the idea that virtually all sudden deaths from cardiac causes are secondary to underlying coronary disease. Thus, although at least moderate exercise may mitigate the trigger effects of extreme exertion, minimizing the overall risk involves the usual menu of primary and secondary prevention measures. These measures include promoting healthy behaviors (such as a heart-healthy diet, no tobacco or excessive alcohol, and regular exercise) and modifying conditions (such as hypertension, diabetes, and obesity) that pose additional risks.” (L. Rosenstock, U. Calif., Los Angeles)
Intermittent Claudication: The case of a 58-year-old mail carrier with intermittent claudication is presented in a Clinical Practice article (pp. 1241-50): “Management in this case should include a supervised exercise program and a trial of cilostazol for claudication, an approach that is consistent with the AHA–ACC guidelines. Revascularization is warranted if the condition does not improve with conservative therapy and if the lesion has anatomical features that are associated with a good outcome of revascularization. [Percutaneous transluminal angioplasty] is preferred over surgery and may be considered up front if there is a high probability of success and a low procedural risk. An imaging study ... is indicated in patients who are candidates for revascularization in order to determine the location and morphologic characteristics of the obstructive lesion (or lesions). If a percutaneous intervention is considered to be likely, one can proceed directly to digital-subtraction angiography, with a plan to perform the percutaneous intervention immediately if the angiographic anatomy is suitable. Regardless of the initial therapy for this patient’s claudication, follow-up care should involve ongoing attention to control of atherosclerotic risk factors, antiplatelet therapy with aspirin, and encouragement of the patient to engage in regular exercise.” (C. White, cwhite@ochsner.org)

>>>PNN NewsWatch
* At the final session of the APhA House of Delegates meeting during APhA2007 in Atlanta, four policies were adopted: privacy of pharmacists’ personal information, pharmacists’ primary care role, biologic drug products, and medication redistribution. A policy on therapeutic decision-making by pharmacists was withdrawn by the policy committee. The new APhA Speaker of the House is Michael Ira Smith, and the new APhA president, Winnie A. Landis, took office during the meeting.
* At
APhA2007, FDA staffer Ilisa B. G. Bernstein, PharmD, JD, announced the agency is looking into establishing an intermediate class of drugs available through pharmacists. FDA’s goals are to expand drug access yet assure safety through pharmacist care.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 23, 2007 * Vol. 14, No. 57
Providing news and information about medications and their proper use

>>>Infectious Disease Report
Source:
Apr. 15 issue of Clinical Infectious Diseases (www.journals.uchicago.edu/CID; 2007; 44).
Varicella Prevention Among New Canadian Immigrants: Vaccination of newly arrived young adult immigrants “would be both cost-saving to society and beneficial to the individuals concerned,” concludes a paper reporting results of a cost-effectiveness analysis (pp. 1040-8). Four intervention strategies were compared with no varicella vaccination from a societal perspective: “At a seroprevalence of 84% (which is the seroprevalence found among South Asian immigrants <35 years old), all strategies were cost-saving relative to no intervention, although selective serological testing [followed by vaccination of susceptible individuals] remained the cheapest strategy. At a seroprevalence of 97%, corresponding to the overall seroprevalence among individuals aged 35 years, no intervention was the cheapest strategy. At a seroprevalence of 70%, the expected costs of the strategies changed, such that selective serological testing was no longer the cheapest. However, the probability of varicella immunity will exceed 70% among most adult immigrants. The threshold seroprevalences below which each of the strategies were cost-saving, compared with no intervention, were as follows: selective serological testing, 95%; serological testing of all individuals, 92%; selective vaccination, 90%; and vaccination of all individuals, 85%.” (K. Schwartzman, kevin.schwartzman@mcgill.ca)
Commenting on this study, an editorialist notes that the price of varicella vaccine included in the model, $26.75 in Canadian currency, is substantially lower than the U.S. prices of the product ($71 and $57 in the private and public sectors, respectively) and adds (pp. 1049-50): “This work highlights the growing need to strengthen the infrastructure of adult immunization programs, especially given the addition of tetanus, diphtheria, and acellular pertussis vaccine and herpes zoster vaccine to the list of recommended vaccines for adults in the United States. The current vaccine financing system relies on a patchwork of private and public funding, and many gaps exist, particularly for uninsured and underinsured adults. Additional resources are needed to implement and strengthen vaccination programs for all adults to overcome these barriers; otherwise, many individuals will be left unvaccinated, despite the rational development of vaccination policies.” (G. M. Lee, Harvard Med. Sch., Boston)
Lymphadenitis in Children: In 100 children with nontuberculous mycobacterial cervicofacial lymphadenitis, surgical excision proved more effective than antibiotic treatment with clarithromycin and rifabutin for at least 12 weeks (pp. 1057-64). Using a primary endpoint of regression of the lymph node enlargement by at least 75%, with cure of the fistula and total skin closure without local recurrence or de novo lesions after 6 months, the researchers found: “Intention-to-treat analysis revealed that surgical excision was more effective than antibiotic therapy (cure rates, 96% and 66%, respectively; 95% confidence interval for the difference, 16%–44%). Treatment failures were explained neither by noncompliance nor by baseline or acquired in vitro resistance to clarithromycin or rifabutin. Surgical complications were seen in 14 (28%) of 50 patients; staphylococcal wound infection occurred in 6 patients, and a permanent grade 2 facial marginal branch dysfunction occurred in 1 patient. The vast majority of patients who were allocated to antibiotic therapy reported adverse effects (39 [78%] of 50 patients), including 4 patients who had to discontinue treatment.” (J. A. Lindeboom, U. Amsterdam, Amsterdam; j.a.lindeboom@amc.uva.nl)
Swine Flu in Humans: A review article assesses the literature on swine influenza in humans (pp. 1084-8). “We found 50 cases of apparent zoonotic swine influenza virus infection, 37 of which involved civilians and 13 of which involved military personnel, with a case-fatality rate of 14% (7 of 50 persons). Most civilian subjects (61%) reported exposure to swine. Although sporadic clinical cases of swine influenza occur in humans, the true incidence of zoonotic swine influenza virus infection is unknown. Because prior studies have shown that persons who work with swine are at increased risk of zoonotic influenza virus infection, it is prudent to include them in pandemic planning efforts.” (K. P. Myers, kendall-myers@uiowa.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 © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 26, 2007 * Vol. 14, No. 58
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Early-release articles from and Mar. 24 issue of Lancet (www.thelancet.com; 2007; 369).
Assisted Reproduction: Thirty years of experiences with in vitro fertilization and other means of assisted reproduction are reviewed (doi:10.1016/S0140-6736(07)60456-5): “In developed countries at least 1% of births are from assisted reproductive therapies (ART). These children now represent a substantial proportion of the population but little is known about their health. Some of the morbidity associated with ART does not result from the techniques but from the underlying health risks of being subfertile. Much of the amplified risk associated with ART is related to high birth order. However, risk of intrauterine and subsequent perinatal complications is enhanced after ART, and urogenital malformations can be present in boys, even in singleton infants. No increase in discord or other difficulties within families has been recorded. Long-term follow-up of children born after ART to reproductive age and beyond is necessary.” (A. G. Sutcliffe, U. Coll., London; a.sutcliffe@medsch.ucl.ac.uk)
Assessing Abused Drugs’ Harm: “A systematic framework and process that could be used by national and international regulatory bodies to assess the harm of current and future drugs of abuse” is tested in study of drug misuse and abuse (pp. 1047-53). Applying a nine-category matrix of harm to both illicit and legal drugs of misuse, the authors found: “The process proved practicable, and yielded roughly similar scores and rankings of drug harm when used by two separate groups of experts. The ranking of drugs produced by our assessment of harm differed from those used by current regulatory systems.” (D. Nutt, U. Bristol, Bristol, U.K.; david.j.nutt@bristol.ac.uk)
Treatment of Partial Epilepsy: Lamotrigine was clinically superior to carbamazepine in a trial of 1,721 patients with partial-onset seizures and therefore is a “cost-effective alternative,” authors conclude (pp. 1000-15): “For time to treatment failure, lamotrigine was significantly better than carbamazepine (hazard ratio [HR] 0.78 [95% CI 0.63–0.97]), gabapentin (0.65 [0.52–0.80]), and topiramate (0.64 [0.52–0.79]), and had a non-significant advantage compared with oxcarbazepine (1.15 [0.86–1.54]). For time to 12-month remission carbamazepine was significantly better than gabapentin (0.75 [0.63–0.90]), and estimates suggest a non-significant advantage for carbamazepine against lamotrigine (0.91 [0.77–1.09]), topiramate (0.86 [0.72–1.03]), and oxcarbazepine (0.92 [0.73–1.18]). In a per-protocol analysis, at 2 and 4 years the difference (95% CI) in the proportion achieving a 12-month remission (lamotrigine-carbamazepine) is 0 (−8 to 7) and 5 (−3 to 12), suggesting non-inferiority of lamotrigine compared with carbamazepine.” (A. G. Marson, U. Liverpool, Liverpool, U.K.; a.g.marson@liv.ac.uk)
Valproate for Generalized Epilepsy: The first-line place of valproate in treatment of generalized-onset seizures is affirmed in a study of 716 patients (pp. 1016-26). Compared with topiramate, valproate was significantly better in time to treatment failure, and time to 12-month remission was improved for those with idiopathic conditions. (A. G. Marson, U. Liverpool, Liverpool, U.K.; a.g.marson@liv.ac.uk)

>>>PNN JournalWatch
* Management of Acute Organophosphorus Pesticide Poisoning, in BMJ, 2007; 334: 629–34. Reprints: C. K. Aaron, Children’s Hospital of Mich., Detroit; caaron@dmc.org
* Drug Therapy of High-Risk Lipid Abnormalities in Children and Adolescents. A Scientific Statement from the American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee, Council of Cardiovascular Disease in the Young, with the Council on Cardiovascular Nursing, in
Circulation, 2007; doi: 10.1161/CIRCULATIONAHA.107.181946. Reprints: B. W. McCrindle.
* ACCF/AHA/CDC Conference Report on Emerging Infectious Diseases and Biological Terrorism Threats. The Clinical and Public Health Implications for the Prevention and Control of Cardiovascular Diseases, in
Circulation, 2007; doi: 10.1161/CIRCULATIONAHA.107.182958. Reprints: G. A. Mensah.
* Lessons from Musculoskeletal Stem Cell Research: The Key to Successful Regenerative Medicine Development, in
Arthritis & Rheumatism, 2007; 56: 714–21. Reprints: D. McGonagle, U. Leeds, Leeds, U.K.; d.g.mcgonagle@leeds.ac.uk
* Syphilis and HIV Infection: An Update, in
Clinical Infectious Diseases, 2007; 44. Reprints: N. M. Zetola, U. California, San Francisco.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 27, 2007 * Vol. 14, No. 59
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Mar. 26 issue of the Archives of Internal Medicine (http://archinte.ama-assn.org; 2007; 167).
Improving Medication Adherence, Clinical Outcomes: Medication adherence can be improved through several types of interventions (including some by pharmacists), but making a significant difference in clinical outcomes is much more difficult, conclude authors of a systematic review (pp. 540-9). “Among 37 eligible trials (including 12 informational, 10 behavioral, and 15 combined informational, behavioral, and/or social investigations), 20 studies reported a significant improvement in at least 1 adherence measure,” write the researchers. “Adherence increased most consistently with behavioral interventions that reduced dosing demands (3 of 3 studies, large ES [0.89–1.20]) and those involving monitoring and feedback (3 of 4 studies, small to large ES [0.27–0.81]). Adherence also improved in 6 multisession informational trials (small to large ES [0.35–1.13]) and 8 combined interventions (small to large ES [absolute value, 0.43–1.20]). Eleven studies (4 informational, 3 behavioral, and 4 combined) demonstrated improvement in at least 1 clinical outcome, but effects were variable (very small to large ES [0.17–3.41]) and not consistently related to changes in adherence.” (S. Kripalani, skripal@emory.edu)
Chronic-Care Model for COPD: Lower rates of hospitalizations and emergency/unscheduled visits and shorter lengths of stay were demonstrated in patients with chronic obstructive pulmonary disease who received two or more components of chronic care models, report authors of a systematic review of 32 studies described in 37 articles (pp. 551-61). “Symptoms, quality of life, lung function, and functional status were not significantly different between the intervention and control groups,” the investigators explain. “However, pooled relative risks (95% confidence intervals) for emergency/unscheduled visits and hospitalizations for the group that received at least 2 CCM components were 0.58 (0.42–0.79) and 0.78 (0.66–0.94), respectively. The weighted mean difference (95% confidence interval) for hospital stay was –2.51 (–3.40 to –1.61) days shorter for the group that received 2 or more components. There were no significant differences for those receiving only 1 CCM component.” (S. G. Adams, adamssg@uthscsa.edu)
Aspirin & Mortality in Women: All-cause mortality was significantly lower among women in the Nurses’ Health Study who used low to moderate doses of aspirin, particularly when they had cardiac risk factors (pp. 562-72). Within 5 years, cardiac benefits of aspirin were evident, but reductions in cancer risks took longer (10 years) to develop, the authors note, adding: “During 24 years, we documented 9,477 deaths from all causes. In women who reported current aspirin use, the multivariate RR of death from all causes was 0.75 (95% confidence interval, 0.71–0.81) compared with women who never used aspirin regularly. The risk reduction was more apparent for death from cardiovascular disease (RR, 0.62; 95% confidence interval, 0.55–0.71) than for death from cancer (RR, 0.88; 95% confidence interval, 0.81–0.96). Use of aspirin for 1 to 5 years was associated with significant reductions in cardiovascular mortality (RR, 0.75; 95% confidence interval, 0.61–0.92). In contrast, a significant reduction in risk of cancer deaths was not observed until after 10 years of aspirin use (Plinear trend = .005). The benefit associated with aspirin was confined to low and moderate doses and was significantly greater in older participants (Pinteraction<.001) and those with more cardiac risk factors (Pinteraction = .02).” (A. T. Chan, Mass. Genl. Hosp., Boston)
“These new findings ... cannot overcome the accumulated evidence that aspirin is not particularly effective for the primary prevention of death from cardiovascular disease in women,” an editorialist writes (pp. 535-6): “Although the common finding of enhanced effects in older women leaves room for the hypothesis that aspirin reduces cardiovascular mortality in those patients, a large reduction in cardiovascular mortality in middle-aged women seems unlikely.” (J. A. Baron,
john.a.baron@dartmouth.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 © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 28, 2007 * Vol. 14, No. 60
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Mar. 28 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2007; 297).
Tolvaptan for Heart Failure: Two articles and an editorial present new information and ideas about use of tolvaptan in patients hospitalized for worsening heart failure.
The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial found no effect on long-term mortality or heart failure–related morbidity among 4,133 participants (pp. 1319-31). Oral tolvaptan 30 mg once daily or placebo was started within 48 hours of study admission and continued for at least 60 days, with these results: “During a median follow-up of 9.9 months, 537 patients (25.9%) in the tolvaptan group and 543 (26.3%) in the placebo group died (hazard ratio, 0.98; 95% confidence interval [CI], 0.87–1.11; P = .68). The upper confidence limit for the mortality difference was within the prespecified noninferiority margin of 1.25 (P < .001). The composite of cardiovascular death or hospitalization for heart failure occurred in 871 tolvaptan group patients (42.0%) and 829 placebo group patients (40.2%; hazard ratio, 1.04; 95% CI, 0.95–1.14; P = .55). Secondary end points of cardiovascular mortality, cardiovascular death or hospitalization, and worsening heart failure were also not different.” Tolvaptan improved some secondary outcomes and major adverse events were similar in the two groups, but active treatment produced increased thirst and dry mouth. (M. A. Konstam,
mkonstam@tufts-nemc.org)
The second article also reports results from the EVEREST study, showing that tolvaptan “improved many, though not all, heart failure signs and symptoms, without serious adverse events” (pp. 1332-43). Analysis of the primary outcome (combined changes in clinical status and body weight) showed significantly greater improvement in the tolvaptan groups than in the placebo groups. Average body weight reduction was greater with tolvaptan on day 1 and day 7 or discharge, whereas improvements in global clinical status were not different between groups. More patients in the tolvaptan groups reported an improvement in dyspnea when compared with the placebo groups. Edema at day 7 or discharge improved significantly with tolvaptan in one part of the study but did not reach significance in the other. Serious adverse event frequencies were similar between groups, without excess in kidney failure or hypotension. (M. Gheorghiade,
m-gheorghiade@northwestern.edu)
An editorialist is both cautious and optimistic (pp. 1374-6): “Given the characteristics of the patient cohort in EVEREST, the use of tolvaptan should not be extrapolated to patients who are dissimilar. More research is needed to better understand the role of [arginine vasopressin] antagonism in HF, particularly regarding the use of nonselective vasopressin antagonists. Additional study also is required in other [acute decompensated heart failure] cohorts, especially those with HF and preserved ejection fraction, acute-onset HF, and advanced HF—perhaps as characterized by hyponatremia. As additional reports from EVEREST and from new clinical trials with both medical and device therapies become available, the hope is that progress toward reaching additional evidence-based therapies on the mountain of ADHF will continue.” (C. W. Yancy,
clydey@baylorhealth.edu)
Rosuvastatin Effects on Atherosclerosis: In a group of middle-aged adults with mild to moderate subclinical atherosclerosis, rosuvastatin 40 mg once daily significantly reduced the rate of progression of maximum carotid intima-media thickness but did not induce disease regression (pp. 1344-53). Patients in the Measuring Effects on Intima-Media Thickness: an Evaluation of Rosuvastatin (METEOR) trial had Framingham risk scores of less than 10%, modest CIMT thickening, and elevated LDL cholesterol. The drug was well tolerated, with only 6 participants having 8 serious adverse cardiovascular events during the 2-year study. With the statin, LDL-C levels were reduced by 48.8% and HDL-C levels rose by 8.0%, and the change in maximum CIMT for 12 carotid sites was significantly smaller. However, CIMT measures did increase, even with treatment, and the authors conclude that further study of the clinical implication of this finding is needed. (J. R. Crouse III, Wake Forest U., Winston-Salem, N.C.; jrcrouse@wfubmc.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 © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 29, 2007 * Vol. 14, No. 61
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Mar. 29 issue of the New England Journal of Medicine (http://content.nejm.org; 2007; 356).
Torcetrapib & Atherosclerosis: While HDL cholesterol levels were raised and LDL cholesterol concentrations lowered by torcetrapib therapy, the cholesteryl ester transfer protein inhibitor failed to stop the progression of coronary atherosclerosis in the Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation (ILLUSTRATE) trial (pp. 1304-16). The study included 1,188 patients with coronary disease who underwent intravascular ultrasonography, 910 of whom also had a repeat imaging study 24 months later. Following treatment with atorvastatin to reduce levels of LDL cholesterol to less than 100 mg/dL, patients received either atorvastatin monotherapy or atorvastatin plus 60 mg of torcetrapib once daily, with these results: “Compared with atorvastatin monotherapy, the effect of torcetrapib–atorvastatin therapy was an approximate 61% relative increase in HDL cholesterol and a 20% relative decrease in LDL cholesterol, reaching a ratio of LDL cholesterol to HDL cholesterol of less than 1.0. Torcetrapib was also associated with an increase in systolic blood pressure of 4.6 mm Hg. The percent atheroma volume (the primary efficacy measure) increased by 0.19% in the atorvastatin-only group and by 0.12% in the torcetrapib–atorvastatin group (P = 0.72). A secondary measure, the change in normalized atheroma volume, showed a small favorable effect for torcetrapib (P = 0.02), but there was no significant difference in the change in atheroma volume for the most diseased vessel segment.” (S. E. Nissen, Cleveland Clinic, Cleveland; nissens@ccf.org)
Assessing whether these disappointing results represent a class effect or a problem with this particular CETP inhibitor, an editorialist writes (pp. 1364-6): “It is likely that at least part of the adverse effects were caused by nonmechanism-related toxicity of this particular drug. There was no evidence that CETP inhibition actually worsens atherosclerotic plaque burden, and there was even some improvement in a secondary measure of plaque volume. This finding suggests modest regression of plaque and provides a glimmer of hope for the future development of this class of drugs. Although the lowering of LDL cholesterol by CETP inhibition is likely to be antiatherogenic, it still needs to be shown that an increase in HDL levels by this mechanism is beneficial. A deeper understanding of the different functions of HDL and their associated biomarkers is badly needed. It would seem reasonable to proceed with caution in studies of other classes of CETP inhibitors that do not cause hypertension, while monitoring for potential adverse effects on vascular function. When used in conjunction with clinical trials, imaging studies such as intravascular or carotid ultrasonography to assess plaque burden will continue to be useful in the evaluation of promising atherosclerosis therapies. (A. R. Tall, Columbia U., New York)
Withdrawal of CFC Albuterol Inhalers: The reasons for market withdrawal of albuterol inhalers containing chlorofluorocarbon propellant are presented, along with guidance to health professionals on use of the new hydrofluoroalkane inhalers (pp. 1344-51): “The successful implementation of the Montreal Protocol worldwide has reduced CFC production, and stratospheric ozone levels have begun to recover. The reduced availability of CFCs has been a challenge to the pharmaceutical industry in its efforts to ensure the future supply of a range of inhaled medications for the millions of patients with asthma and COPD who depend on these treatments, including treatment with albuterol. Several reengineered albuterol inhalers that use HFAs in place of CFCs as propellants have been developed and are now widely available on the U.S. market and worldwide. Clinical trials in children and adults with asthma have demonstrated that when these HFA albuterol products are administered at the FDA-approved dose, their efficacy and safety profiles are similar to those of the CFC albuterol products they are intended to replace. However, there are differences between HFA and CFC albuterol products and among the various HFA albuterol products, all of which should be discussed with patients as they move from CFC to HFA albuterol. The transition is well under way in the United States, but this transition will increase expenditures for albuterol metered-dose inhalers.” (L. Hendeles, hendeles@cop.ufl.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 30, 2007 * Vol. 14, No. 62
Providing news and information about medications and their proper use

>>>Pergolide Being Withdrawn Gradually from US Market
FDA yesterday announced that manufacturers of pergolide drug products will voluntarily remove these antiparkinsonian drugs from the market because of the risk of serious damage to patients’ heart valves. Supplies of pergolide currently in pharmacies will not be immediately affected by this action, as FDA is allowing time for health care providers and patients to discuss appropriate treatment options and change treatments.
The products being withdrawn are Permax (
Valeant Pharmaceuticals) and two generic versions of pergolide (Par and Teva). In 2006, an estimated 12,000 patients received prescriptions for pergolide from community pharmacies in the United States. Patients taking pergolide should contact their physicians to discuss alternate treatments. Patients should not stop taking the medication abruptly.
Alternative therapies are available for Parkinson’s disease, including three other dopamine agonists that have not been associated with valvular heart disease. The removal of pergolide products is not expected to adversely affect patient care because of the alternative therapies available.
Two recent
New England Journal of Medicine studies (see PNN, Jan. 4) confirmed previous findings associating pergolide with increased chance of regurgitation of the mitral, tricuspid, and aortic valves of the heart. Symptoms of regurgitation include shortness of breath, fatigue, and heart palpitations.
In light of this additional postmarketing safety information, the companies that manufacture and sell pergolide will stop shipping pergolide for distribution and, in cooperation with FDA, will withdraw the products from the market.
Permax was approved in 1988 for Eli Lilly and Company as an adjunctive therapy with levodopa in Parkinson’s disease. Valvular heart disease was first described in association with pergolide in 2002. In 2003, FDA asked Lilly to add valvulopathy to the warnings section of Permax labeling, at which time a Dear Healthcare Practitioner letter was sent by Lilly. In 2006, the warning was upgraded to a black-box warning because of new data concerning risks of heart valve damage.
FDA is working with the manufacturers of pergolide to determine if it might be possible, once the drug is withdrawn from the market, to make the drug available under an Investigational New Drug Application for those few patients who are currently receiving pergolide and who cannot be successfully converted to other available treatments.

>>>Eculizumab OKd for Rare Hemoglobinuria
Eculizumab (Soliris, Alexion) earlier this month became the first product approved by FDA for treatment of paroxysmal nocturnal hemoglobinuria, a rare blood disorder that can lead to disability and premature death. PNH, which usually develops in adults, is characterized by red blood cells that develop abnormally. The abnormal cells are attacked in the bloodstream by the complement system, breaking these cells down and producing darkened urine and anemia. Depending upon the severity of the disorder, patients with PNH may have pain, fatigue, and debilitating weakness; the need for frequent blood transfusions; blood clots; and life-threatening or fatal strokes, heart attacks and intestinal disease.
Eculizumab does not cure PNH, but rather blocks complement system activity, including destruction of PNH erythrocytes.
A 26-week controlled study of 87 patients with PNH showed that eculizumab produced stabilization of blood hemoglobin concentrations, compared with placebo. Eculizumab-treated patients also required significantly fewer blood transfusions.
Eculizumab blockade of the body’s natural immune system increases the patient’s susceptibility to certain serious infections, particularly meningococcal infections. Serious meningococcal infection was the most important adverse reaction experienced by patients who received eculizumab in clinical studies. Because of the high risk for serious meningococcal infections, all 196 PNH patients in the clinical studies were vaccinated with a meningococcal vaccine; two of them developed meningococcal sepsis during treatment with eculizumab.
A special risk management plan for eculizumab includes a boxed warning, Med Guide, and physician education. It also requires that patients receive meningococcal vaccination before receiving eculizumab.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.

PNN Pharmacotherapy Line
Mar. 30, 2007 * Special Alert
Providing news and information about medications and their proper use

FDA has announced a voluntary discontinuation of marketing and sales of tegaserod maleate (Zelnorm) by Novartis Pharmaceuticals. The agency requested this action based on newly available information of an increased risk of serious cardiovascular adverse events, including myocardial infarction, unstable angina, and stroke associated with use of the drug. Based on this new information, FDA said that the overall risk versus benefit profile for the drug is unfavorable for continued marketing. More information will be in Monday’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 © 2007, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 800/211-4223 to request missing copies of PNN.