Jun 2008

PNN Quarterly File—Second Quarter 2008

PNN Pharmacotherapy Line
Apr. 1, 2008 * Vol. 15, No. 63
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Apr. 1 issue of the Annals of Internal Medicine (www.annals.org/current.shtml; 2008; 148).
Preventive Lamivudine During Chemotherapy: The risk of hepatitis B virus reactivation and associated morbidity and mortality was reduced when seropositive patients received lamivudine during cancer chemotherapy, according to a systematic review of 14 studies (pp. 519-28): ìThere were 275 patients in the preventive lamivudine group and 475 control participants for the primary end point of HBV reactivation. With preventive lamivudine, the relative risk for both HBV reactivation and HBV-related hepatitis ranged from 0.00 to 0.21. None of the patients in the preventive lamivudine group developed HBV-related hepatic failure (0 of 108 patients vs. 21 of 162 patients), and only 4 deaths were attributable to HBV (4 of 208 patients vs. 27 of 394 patients) in the preventive lamivudine group. Lamivudine was well tolerated, and no adverse effects were noted.î (R. Loomba, roloomba@ucsd.edu)
Treating Tobacco Dependence as Chronic Disease: Diabetes and tobacco dependence have many similarities, yet the former is well covered by insurance but payment for treatment of the latter is often denied, authors note (pp. 554-6). Arguing in a commentary that ìtobacco dependence should share the status of other chronic illnesses, with effective treatments given as long as is necessary to achieve successful clinical outcomes,î the writers explain: ìSmoking remains the leading cause of preventable death in the United States, yet it is still regarded by many as merely a bad habit. Most smokers want to quit but find it difficult. Behavioral counseling and pharmacotherapies are available, safe, and effective in the treatment of tobacco dependence. Nicotine replacement therapy effectively delivers nicotine in safer doses without exposure to the toxins and chemicals in cigarette smoke. The optimal duration of tobacco dependence treatment is unknown, and some smokers may require extended courses. For smokers using long-term cessation medications, health care providers should encourage treatment and insurance carriers should cover it. Both tobacco dependence and such conditions as diabetes are similar in their potential to exacerbate other diseases, their behavioral components of treatment, and their effectiveness of medications.î (M. B. Steinberg, U. Medicine and Dentistry of New Jersey, New Brunswick; michael.steinberg@umdnj.edu)

>>>Pharmacotherapy Report
Source:
Apr. issue of Pharmacotherapy (www.pharmacotherapy.org; 2008; 28).
Pharmacist Interventions in Diabetes: In comparative trials of pharmacist versus other interventions in patients with type 1 or 2 diabetes, clinically important improvements in A1C levels were produced by pharmacist–case managers, authors of a systematic review report (pp. 421-36). Data are limited by flaws in study design, especially a high potential for selection bias, the pair writes, adding these details: ìTwenty-one articles met the inclusion criteria: nine randomized controlled trials, one controlled clinical trial, and 11 cohort studies. All interventions involved additional visits by pharmacists with expanded roles to care for adult patients with diabetes. The A1C was the primary outcome of interest for all but two studies. Results of this review revealed overall improvement in A1C for patients in a diverse group of settings and across multiple study designs. Studies with smaller numbers of participants and those performed in the United States generally showed greater improvements in intervention group measures of A1C. A greater effect was also noted when pharmacists were afforded prescriptive authority. Only a few studies examined health care resource use; their results suggested that pharmacist interventions can reduce long-term costs by improving glycemic control and thus diminishing future diabetes complications.î (D. P. Wubben, dpw@medicine.wisc.edu)
Adherence Across Diseases: Patients take 80% or more of their prescribed medications at similar rates for most chronic diseases, a longitudinal analysis of health claims data concludes (pp. 437-43). Proportions of adherent patients were 72.3%, 68.4%, 65.4%, 60.8%, 54.6%, 51.2%, and 36.8% among those with hypertension, hypothyroidism, type 2 diabetes, seizure disorders, hypercholesterolemia, osteoporosis, and gout, respectively. (B. A. Briesacher, Becky.Briesacher@umassmed.edu)

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


PNN Pharmacotherapy Line
Apr. 2, 2008 * Vol. 15, No. 64
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Early-release articles from and Apr. 2 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2008; 299).
MC-1 in CABG: The naturally occurring pyridoxine metabolite and purinergic receptor antagonist pyridoxal 5’-phosphate (MC-1), administered to patients immediately before and for 30 days after coronary artery bypass graft surgery, had no significant effect on cardiovascular mortality or nonfatal myocardial infarction (doi: 10.1001/jama.299.15.joc80027). In the MC-1 to Eliminate Necrosis and Damage in Coronary Artery Bypass Graft Surgery II Trial (MEND-CABG II), researchers found these outcomes in 3,023 intermediate- to high-risk patients who underwent CABG with cardiopulmonary bypass in 2006–07: ìThe primary efficacy outcome occurred in 140 of 1,510 patients (9.3%) in the MC-1 group and 133 of 1,486 patients (9.0%) in the placebo group (risk ratio, 1.04; 95% confidence interval, 0.83–1.30; P = .76). All-cause mortality was higher among patients assigned to MC-1 than placebo at 4 days (1.0% vs 0.3%; P = .03) but was similar at 30 days (1.9% vs 1.5%; P = .44). There was no difference in the 8- to 24-hour CK-MB area under the curve between the MC-1 and placebo groups (median, 270 [interquartile range, 175–492] vs 268 [interquartile range, 170–456] hours x ng/mL; P = .11).î (J. H. Alexander, john.h.alexander@duke.edu)
Antiplatelet Therapy During PCI for STEMI: Among 745 patients with ST-segment elevation myocardial infarction who had percutaneous coronary intervention with stent placement, tirofiban was noninferior to abciximab at 90 minutes after PCI with respect to resolution of ST-segment elevation, and sirolimus-eluting stents provided significantly better outcomes at 8 months than uncoated stents (doi: 10.1001/jama.299.15.joc80026). The open-label trial, MULTISTRATEGY (Multicentre Evaluation of Single High-Dose Bolus Tirofiban vs Abciximab With Sirolimus-Eluting Stent or Bare Metal Stent in Acute Myocardial Infarction Study), had these results during its 2004–07 timeframe: ìST-segment resolution occurred in 302 of 361 patients (83.6%) who had received abciximab infusion and 308 of 361 (85.3%) who had received tirofiban infusion (relative risk, 1.020; 97.5% confidence interval, 0.958–1.086; P < .001 for noninferiority). Ischemic and hemorrhagic outcomes were similar in the tirofiban and abciximab groups. At 8 months, major adverse cardiac events occurred in 54 patients (14.5%) with uncoated stents and 29 (7.8%) with sirolimus stents (P = .004), predominantly reflecting a reduction of revascularization rates (10.2% vs 3.2%). The incidence of stent thrombosis was similar in the 2 stent groups.î (M. Valgimigli, Azienda Opedaliera Universitaria di Ferrara, Ferrara, Italy; vlgmrc@unife.it)
Rimonabant & Progression of Atherosclerosis: Rimonabant, a cannabinoid type 1 antagonist marketed in other countries but not approved in the U.S., significantly reduced a secondary parameter measuring atherosclerosis progression among 839 patients with abdominal obesity and metabolic syndrome (pp. 1547-60). Comparing 20-mg doses of rimonabant and placebo, researchers in the Strategy to Reduce Atherosclerosis Development Involving Administration of Rimonabant—The Intravascular Ultrasound Study (STRADIVARIUS) found no significant effect of the drug on percent atheroma volume, their primary efficacy parameter, but the 18-month normalized total atheroma volume was reduced by 1.95 cu mm (95% CI, –3.8 to –0.10) with the drug, compared with an increase of 1.19 cu mm (–0.73 to 3.12) with placebo. (S. E. Nissen, Cleveland Clinic Foundation, Cleveland; nissens@ccf.org)
Pioglitazone & Progression of Atherosclerosis: Compared with glimepiride, pioglitazone significantly lowered the rate of progression of coronary atherosclerosis among 543 patients with coronary artery disease and type 2 diabetes (pp. 1561-73). During 18 months of treatment with glimepiride 1–4 mg, or pioglitazone 15–45 mg in the PERISCOPE (Pioglitazone Effect on Regression of Intravascular Sonographic Coronary Obstruction Prospective Evaluation) trial, the researchers report. ìLeast squares mean [percent atheroma volume] increased 0.73% (95% CI, 0.33% to 1.12%) with glimepiride and decreased 0.16% (95% CI, –0.57% to 0.25%) with pioglitazone(P = .002).î (S. E. Nissen, Cleveland Clinic Foundation, Cleveland; nissens@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 © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 3, 2008 * Vol. 15, No. 65
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Apr. 3 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2008; 358).
FDA Regulation of Off-Label Drug Use: An FDA proposal about distribution of journal articles to physicians portends a more permissive attitude at the agency regarding off-label use of medications, a Perspective article suggests (pp. 1427-9). The author calls on clinicians to comment on the proposal by focusing on ways FDA might step up and regulate off-label drug use, including ìsystematically collecting postmarketing data to quantify the harms and benefits of common off-label uses; synthesizing evidence regarding off-label uses and disseminating its reports; scrutinizing marketing efforts to restrict materials on off-label uses that don’t have strong support; increasing the use of active drugs as comparators in postmarketing clinical trials; and requiring information about anticipated off-label uses to be presented at the time of a drug’s review for initial approval.î (R. S. Stafford, Stanford U., Stanford, Calif.)
Imiquimod for Vulvar Intraepithelial Neoplasia: Among 52 patients with grade 2 or 3 vulvar intraepithelial neoplasia, imiquimod proved to be an effective treatment (pp. 1465-73). Active or placebo formulations were applied twice weekly for 16 weeks, with these results: ìLesion size was reduced by more than 25% at 20 weeks in 21 of the 26 patients (81%) treated with imiquimod and in none of those treated with placebo (P <0.001). Histologic regression was significantly greater in the imiquimod group than in the placebo group (P <0.001). At baseline, 50 patients (96%) tested positive for HPV DNA. HPV cleared from the lesion in 15 patients in the imiquimod group (58%), as compared with 2 in the placebo group (8%) (P <0.001). The number of immune epidermal cells increased significantly and the number of immune dermal cells decreased significantly with imiquimod as compared with placebo. Imiquimod reduced pruritus and pain at 20 weeks (P = 0.008 and P = 0.004, respectively) and at 12 months (P = 0.04 and P = 0.02, respectively). The lesion progressed to invasion (to a depth of <1 mm) in 3 of 49 patients (6%) followed for 12 months (2 in the placebo group and 1 in the imiquimod group). Nine patients, all treated with imiquimod, had a complete response at 20 weeks and remained free from disease at 12 months.î (T. J. M. Helmerhorst, Erasmus Med. Ctr., Rotterdam, the Netherlands; t.helmerhorst@erasmusmc.nl)

>>>Circulation Highlights
Source:
Apr. 1 issue of Circulation (http://circ.ahajournals.org/current.dtl; 2008; 117).
Abdominal Obesity & Mortality: Abdominal obesity—or even increased waist circumference without obesity—is strongly associated with all-cause, cardiovascular, and cancer-related mortality, data from the Nurses’ Health Study show (pp. 1658-67). These risks were found among 44,636 women studied prospectively: ìDuring 16 years of follow-up, 3,507 deaths were identified, including 751 cardiovascular deaths and 1,748 cancer deaths. After adjustment for body mass index and potential confounders, the relative risks across the lowest to the highest waist circumference quintiles were 1.00, 1.11, 1.17, 1.31, and 1.79 (95% confidence interval [CI], 1.47 to 1.98) for all-cause mortality; 1.00, 1.04, 1.04, 1.28, and 1.99 (95% CI, 1.44 to 2.73) for CVD mortality; and 1.00, 1.18, 1.20, 1.34, and 1.63 (95% CI, 1.32 to 2.01) for cancer mortality (all P <0.001 for trend). Among normal-weight women (body mass index, 18.5 to <25 kg/m2), abdominal obesity was significantly associated with elevated CVD mortality: Relative risk associated with waist circumference 88 cm was 3.02 (95% CI, 1.31 to 6.99) and for waist-to-hip ratio >0.88 was 3.45 (95% CI, 2.02 to 6.92). After adjustment for waist circumference, hip circumference was significantly and inversely associated with CVD mortality.î (C. Zhang, zhangcu@mail.nih.gov)

>>>PNN NewsWatch
* Delirium and abnormal behavior of abrupt onset and leading to injury in patients with influenza who are receiving neuraminidase inhibitors, first reported several years ago in Japan among pediatric patients, has been added to the product labeling for zanamivir (Relenza), GlaxoSmithKline announced yesterday. Patients with influenza should be closely monitored for signs of abnormal behavior, the warning states.

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

PNN Pharmacotherapy Line
Apr. 4, 2008 * Vol. 15, No. 66
Providing news and information about medications and their proper use

>>>Psychiatry Highlights
Source:
Apr. issue of the American Journal of Psychiatry (http://ajp.psychiatryonline.org/current.dtl; 2008; 165).
Fluoxetine & Relapse of Adolescent Depression: Continuation of fluoxetine therapy was significantly more effective than placebo in preventing relapse of major depressive disorder among children and adolescents (pp. 459-67). Patients, aged 7 to 18 years, had responded to 12 weeks of open-label fluoxetine before randomization to continued therapy or placebo for an additional 6 months. Results showed: ìOf 168 participants enrolled in acute fluoxetine treatment, 102 were randomly assigned to continuation treatment with fluoxetine (N = 50) or placebo (N = 52). Of these, 21 participants (42.0%) in the fluoxetine group relapsed, compared with 36 (69.2%) in the placebo group, a significant difference. Similarly, under [a] stricter definition of relapse, fewer participants in the fluoxetine group relapsed (N = 11; 22.0%) than in the placebo group (N = 25; 48.1%). Time to relapse was significantly shorter in the placebo group.î (G. J. Emslie)
Cannabis & Schizophrenia: Decreases in brain volume may explain some of the detrimental effects of cannabis use among patients with first-episode schizophrenia, researchers conclude (pp. 490-6). Magnetic resonance imaging of 51 patients with recent-onset schizophrenia and 31 health controls was performed on study admission and 5 years later. Based on cannabis (but no other illicit drug) use by 19 of the patients with schizophrenia, the investigators found these patterns: ìSchizophrenia patients showed a larger gray matter volume decrease over time than healthy subjects. They also showed larger increases in lateral and third ventricle volumes than healthy subjects and patients who did not use cannabis during follow-up. This decrement was significantly more pronounced in the patients who continued to use cannabis. These differences could not be attributed to outcome or baseline characteristics.î (M. Rais)
Depression & Ischemic Heart Disease Mortality: Major depression is an independent and significant risk factor for mortality in patients with ischemic heart disease, a study shows (pp. 515-23). In a prospective cohort study of 8,261 men and 11,388 women 41–80 years of age who were free of clinical manifestations of heart disease at study entry in 1996–2000, these trends were observed: ìAs of July 31, 2006, 274 deaths from ischemic heart disease were recorded over a total follow-up of 162,974 person–years (the median follow-up period was 8.5 years). Participants who had major depression during the year preceding baseline assessment were 2.7 times more likely to die from ischemic heart disease over the follow-up period than those who did not, independently of age, sex, smoking, systolic blood pressure, cholesterol, physical activity, body mass index, diabetes, social class, heavy alcohol use, and antidepressant medication use. This association remained after exclusion of the first 6 years of follow-up data. Consideration of measures of major depression history (including recency of onset, recurrence, chronicity, and age at first onset) revealed recency of onset to be associated most strongly with ischemic heart disease mortality.î (P. G. Surtees)

>>>PNN NewsWatch
* FDA has licensed Rotarix [Rotavirus Vaccine, live, oral; GlaxoSmithKline] for prevention of rotavirus gastroenteritis in infants. Clinical trials of nearly 75,000 infants have shown that the vaccine produces immunity against the G1 and non-G1 types (G3, G4, and G9) when administered as a two-dose series—which can be started earlier and completed 2 months earlier than the currently available three-dose product—in infants and children, with protection sustained through the first 2 years of life. In those receiving the vaccine, hospitalizations were reduced by 96% and episodes of severe rotavirus gastroenteritis by 90%. The CDC Advisory Committee on Immunization Practices, the American Academy of Pediatrics, and the American Academy of Family Physicians recommend that infants receive routine rotavirus vaccination. Rotarix will be available in the U.S. during the second half of 2008.

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

PNN Pharmacotherapy Line
Apr. 7, 2008 * Vol. 15, No. 67
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Apr. 5 issue of Lancet (www.thelancet.com; 2008; 371).
Efficacy, Safety of Rotavirus Vaccine: Among 15,183 healthy infants aged 6–13 weeks, two doses of the rotavirus vaccine (RIX4414, Rotarix; GlaxoSmithKline) licensed last week by FDA were effective against severe rotavirus gastroenteritis during the first 2 years of life (pp. 1181-9). Administered at 2 and 4 months by investigators in 10 Latin American countries, the vaccine produced these results: ì897 infants were excluded from the according-to-protocol analysis. Fewer cases (p <0.0001) of severe rotavirus gastroenteritis were recorded for the combined 2-year period in the RIX4414 group (32 [0.4%] of 7,205; 95% CI 0.3–0.6) than in the placebo group (161 [2.3%] of 7,081; 1.9–2.6), resulting in a vaccine efficacy of 80.5% (71.3–87.1) to 82.1% (64.6–91.9) against wild-type G1, 77.5% (64.7–86.2) against pooled non-G1 strains, and 80.5% (67.9–88.8) against pooled non-G1 P[8] strains. Vaccine efficacy for hospital admission for rotavirus gastroenteritis was 83.0% (73.1–89.7) and for admission for diarrhoea of any cause was 39.3% (29.1–48.1). No cases of intussusception were reported during the second year of follow-up.î (M. O’Ryan, U. Chile, Chile; moryan@med.uchile.cl)

>>>BMJ Highlights
Source:
Apr. 5 issue of BMJ (www.bmj.org; 2008; 336).
Parental Decisions Regarding MMR Vaccine: In a study of 14,578 children born in the U.K. in 2000–02, substantial numbers of children remain unimmunized against measles, mumps, and rubella, largely because of parental decisions not to immunize, researchers report (pp. 754-7): ì88.6% (13,013) were immunised with MMR and 5.2% (634) had received at least one single antigen vaccine. Children were more likely to be unimmunised if they lived in a household with other children (risk ratio 1.74, 95% confidence interval 1.35 to 2.25, for those living with three or more) or a lone parent (1.31, 1.07 to 1.60) or if their mother was under 20 (1.41, 1.08 to 1.85) or over 34 at cohort child’s birth (reaching 2.34, 1.20 to 3.23, for 40), more highly educated (1.41, 1.05 to 1.89, for a degree), not employed (1.43, 1.12 to 1.82), or self employed (1.71, 1.18 to 2.47). Use of single vaccines increased with household income (reaching 2.98, 2.05 to 4.32, for incomes of £52,000 (69,750 euros, $102,190)), maternal age (reaching 3.04, 2.05 to 4.50, for 40), and education (reaching 3.15, 1.78 to 5.58, for a degree). Children were less likely to have received single vaccines if they lived with other children (reaching 0.14, 0.07 to 0.29, for three or more), had mothers who were Indian (0.50, 0.25 to 0.99), Pakistani or Bangladeshi (0.13, 0.04 to 0.39), or black (0.31, 0.14 to 0.64), or aged under 25 (reaching 0.14, 0.05 to 0.36, for 14–19). Nearly three quarters (74.4%, 1110) of parents who did not immunise with MMR made a ‘conscious decision’ not to immunise.î (H. Bedford, UCL Institute of Child Health,, London; h.bedford@ich.ucl.ac.uk)

>>>PNN JournalWatch
* Options for Slowing the Growth of Health Care Costs, in New England Journal of Medicine, 2008; 358: 1509–14. Reprints: J. J. Mongan.
* Intimate Partner Violence and Women’s Physical and Mental Health in the WHO Multi-Country Study on Women’s Health and Domestic Violence: An Observational Study, in
Lancet, 2008; 371: 1165–72. Reprints: C. Garcia-Moreno, garciamorenoc@who.int
* Neurobiology of Aggression and Violence, in
American Journal of Psychiatry, 2008; 165: 429–42. Reprints: L. J. Siever.
* Effectiveness of Single Dose Rifampicin in Preventing Leprosy in Close Contacts of Patients with Newly Diagnosed Leprosy: Cluster Randomised Controlled Trial, in
BMJ, 2008; 336: 761–4. Reprints: J. H. Richardus, U. Med. Ctr., Rotterdam, the Netherlands; j.richardus@erasmusmc.nl
* Use of Aromatase Inhibitors in Children and Adolescents with Disorders of Growth and Adolescent Development, in
Pediatrics, 2008; 121: e975–83. Reprints: Dorothy I. Shulman, U. South Fla., Tampa.
* Global Initiatives for Improving Hospital Care for Children: State of the Art and Future Prospects, in
Pediatrics, 2008; 121: e984–92. Reprints: H. Campbell, U. Edinburgh, Edinburgh, U.K.
* Telavancin: An Antimicrobial with a Multifunctional Mechanism of Action for the Treatment of Serious Gram-Positive Infections, in
Pharmacotherapy, 2008; 28: 458–68. Reprints: M. J. Rybak, m.rybak@wayne.edu
* Effectiveness of Probiotics in the Treatment of Irritable Bowel Syndrome, in
Pharmacotherapy, 2008; 28: 496–505. Reprints: P. Kale-Pradhan, Pkale@wayne.edu

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

PNN Pharmacotherapy Line
Apr. 8, 2008 * Vol. 15, No. 68
Providing news and information about medications and their proper use

>>>Infectious Disease Report
Source:
May 1 issue of Clinical Infectious Diseases (www.journals.uchicago.edu/toc/cid/current; 2008; 46).
Causes of Failure with Antifungal Therapy: Antifungal therapy failure remains a substantial clinical problem, authors of a review article write, adding that clinicians often misinterpret the reasons for failure (pp. 1426-33): ìThe clinician is tempted to attribute therapeutic failure to specific drug resistance and then to change therapy or add another antifungal drug to the regimen. However, other factors may play an even greater role in antifungal therapy failure, such as host factors, low concentration of the drug at the site of infection, drug toxicities, wrong diagnosis, and misdiagnosis of failure because of the occurrence of immune reconstitution inflammatory syndrome. In this review, we discuss the differential diagnosis and management of antifungal therapy failure in invasive mycoses, to help clinicians appreciate the meaning of primary antifungal therapy failure.î (M. Nucci, Hospital Universit·rio Clementino Fraga Filho, Rio de Janeiro; mnucci@hucff.ufrj.br)
Extranasal MRSA Colonization in Nursing Home Residents: Indwelling devices were a common site of colonization of methicillin-resistant Staphylococcus aureus in a study of 213 residents in 14 nursing homes (pp. 1368-73). ìOne hundred thirty-one residents (62%) were colonized with S. aureus (MRSA colonization in 86),î the researchers report. ìS. aureus colonization occurred in 80 (76%) of 105 residents with indwelling devices and in 51 (47%) of 108 residents without indwelling devices (P < .001). Of the 86 residents who were colonized with MRSA, nares culture results were positive for only 56 (65%). Residents with devices in place were more likely to be colonized at multiple sites. Eleven different strains of MRSA were identified by pulsed-field gel electrophoresis. Seventy-three residents (85%) were colonized with hospital-associated SCCmec II strains, and 8 (9%) were colonized with community-associated SCCmec IV strains, 2 of which carried Panton-Valentine leukocidin.î (L. Mody, lonamody@umich.edu)
Prevention of Aspergillosis During Neutropenia: In a study of patients at high risk for invasive pulmonary aspergillosis (IPA) during 10 days or more of chemotherapy-induced prolonged neutropenia, incidence of the condition was significantly lower when prophylactic inhalations of aerosolized liposomal amphotericin B were used (pp. 1401-8). The investigators write: ìA total of 271 patients were studied during 407 neutropenic episodes. According to the intent-to-treat analysis, 18 of 132 patients in the placebo group developed IPA versus 6 of 139 patients in the liposomal amphotericin B group (odds ratio, 0.26; 95% confidence interval, 0.09–0.72; P = .005). According to the on-treatment analysis, 13 of 97 patients receiving placebo versus 2 of 91 receiving liposomal amphotericin B developed IPA (odds ratio, 0.14; 95% confidence interval, 0.02–0.66; P= .007). Some adverse effects, but none serious, in the liposomal amphotericin B group were reported, most frequently coughing (16 patients vs. 1 patient; P = .002).î (B. J. Rijnders, Erasmus Med. Ctr., Rotterdam, the Netherlands; b.rijnders@erasmusmc.nl)

>>>PNN NewsWatch
* U.S. Marshals last week seized dietary supplements worth more than $1.3 million from LG Sciences, LLC, of Brighton, Mich., because the products contained unapproved food additives and/or new dietary ingredients that cause the products to violate the law, FDA said. Labeled as dietary supplements and marketed for use by body builders, the products were marketed and distributed online and in retail stores under the names Methyl 1-D, Methyl 1-D XL, and Formadrol Extreme XL.
* Some 5.6 million federal workers with federal health insurance will now be covered for
substance abuse prevention and treatment procedure using Screening and Brief Intervention, the White House Office of National Drug Control Policy announced yesterday. The coverage will reimburse physicians under new CPT codes for screening patients for substance use behaviors and providing appropriate intervention.

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

PNN Pharmacotherapy Line
Apr. 9, 2008 * Vol. 15, No. 69
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Apr. 9 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2008; 299).
Lower BP, LDL Targets in Diabetes: Aggressive treatment of elevated systolic blood pressure and LDL cholesterol in patients with type 2 diabetes yielded improvements in carotid artery intimal medial thickness (IMT) and left ventricular mass, but a lower-than-expected number of clinical events precluded detection of a significance difference in the Stop Atherosclerosis in Native Diabetics Study (SANDS) (pp. 1678-89). The open-label trial included 499 Native Americans who were randomized to aggressive or standard treatment of hypertension and dyslipidemia for 3 years, with these results: ìMean target LDL-C and SBP levels for both groups were reached and maintained. Mean (95% confidence interval) levels for LDL-C in the last 12 months were 72 (69–75) and 104 (101–106) mg/dL and SBP levels were 117 (115–118) and 129 (128–130) mm Hg in the aggressive vs standard groups, respectively. Compared with baseline, IMT regressed in the aggressive group and progressed in the standard group (–0.012 mm vs 0.038 mm; P < .001); carotid arterial cross-sectional area also regressed (–0.02 mm2 vs 1.05 mm2; P < .001); and there was greater decrease in left ventricular mass index (–2.4 g/m2.7 vs –1.2 g/m2.7; P = .03) in the aggressive group. Rates of adverse events (38.5% and 26.7%; P = .005) and serious adverse events (n = 4 vs 1; P = .18) related to blood pressure medications were higher in the aggressive group. Clinical CVD events (1.6/100 and 1.5/100 person–years; P = .87) did not differ significantly between groups.î (B. V. Howard, MedStar Res. Inst., Hyattsville, Md.; barbara.v.howard@medstar.net)
Questioning ìhow low to go in preventive cardiology,î editorialists propose an intermediate approach (pp. 1718-20): ìA practical middle-of-the-road approach might be to support intensive lipid lowering with statin therapy in patients with diabetes, because this is supported by prior large, randomized, clinical, end point–driven trials, and has relatively few adverse effects or patient risks. For intensive blood pressure management, however, more data are needed because the benefits are not assured and there are modest, but measurement-negative effects on patients’ finances and well-being. The blood pressure lowering group of the ACCORD trial, comparing a goal of lower than 120 mm Hg vs lower than 140 mm Hg, as well as the recently announced National Heart, Lung, and Blood Institute’s Systolic Blood Pressure Intervention Trial (SPRINT), comparing aggressive vs standard blood pressure management in a large end point–driven trial, should provide these much needed data.î (E. D. Peterson,
peter016@mc.duke.edu)
Omega-3 Free Fatty Acids in Crohn Disease: Data from the Epanova Program in Crohn’s Study, parts 1 and 2, show that omega-3 free fatty acids were not effective for prevention of relapse in patients with Crohn disease (pp. 1690-7). Data from 363 and 375 patients with quiescent Crohn disease show the following: ìFor EPIC-1, 188 patients were assigned to receive omega-3 free fatty acids and 186 patients to receive placebo. Corresponding numbers for EPIC-2 were 189 and 190 patients, respectively. The rate of relapse at 1 year in EPIC-1 was 31.6% in patients who received omega-3 free fatty acids and 35.7% in those who received placebo (hazard ratio, 0.82; 95% confidence interval, 0.51–1.19; P = .30). Corresponding values for EPIC-2 were 47.8% and 48.8% (hazard ratio, 0.90; 95% confidence interval, 0.67–1.21; P = .48). Serious adverse events were uncommon and mostly related to Crohn disease.î (B. G. Feagan, Robarts Res. Inst., London, Ont., Canada; bfeagan@robarts.ca)
Specialized Palliative Care: Among 22 studies of specialized palliative care for the terminally ill, these trends were evident (pp. 1698-709): ìThere was most consistent evidence for effectiveness of specialized palliative care in improvement of family satisfaction with care (7 of 10 studies favored the intervention). Only 4 of 13 studies assessing quality of life and 1 of 14 assessing symptoms showed a significant benefit of the intervention; however, most studies lacked statistical power to report conclusive results, and quality-of-life measures were not specific for terminally ill patients. There was evidence of significant cost savings of specialized palliative care in only 1 of the 7 studies that assessed this outcome.î (C. Zimmermann, Princess Margaret Hosp., Toronto; camilla.zimmermann@uhn.on.ca)

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

PNN Pharmacotherapy Line
Apr. 10, 2008 * Vol. 15, No. 70
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Apr. 10 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2008; 358).
ARB v. ACE in High-Risk Patients: Among more than 25,000 patients with vascular disease or high-risk diabetes, the angiotensin receptor blocker telmisartan provided effectiveness equivalent to that of the ACE inhibitor ramipril and was associated with less angioedema (pp. 1547-59). The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) randomized patients to ramipril 10 mg, telmisartan 80 mg, or both on a daily basis. These results were found for a primary endpoint of death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure: ìMean blood pressure was lower in both the telmisartan group (a 0.9/0.6 mm Hg greater reduction) and the combination-therapy group (a 2.4/1.4 mm Hg greater reduction) than in the ramipril group. At a median follow-up of 56 months, the primary outcome had occurred in 1,412 patients in the ramipril group (16.5%), as compared with 1,423 patients in the telmisartan group (16.7%; relative risk, 1.01; 95% confidence interval [CI], 0.94 to 1.09). As compared with the ramipril group, the telmisartan group had lower rates of cough (1.1% vs. 4.2%, P <0.001) and angioedema (0.1% vs. 0.3%, P = 0.01) and a higher rate of hypotensive symptoms (2.6% vs. 1.7%, P <0.001); the rate of syncope was the same in the two groups (0.2%). In the combination-therapy group, the primary outcome occurred in 1,386 patients (16.3%; relative risk, 0.99; 95% CI, 0.92 to 1.07); as compared with the ramipril group, there was an increased risk of hypotensive symptoms (4.8% vs. 1.7%, P <0.001), syncope (0.3% vs. 0.2%, P = 0.03), and renal dysfunction (13.5% vs. 10.2%, P <0.001).î (S. Yusuf, yusufs@mcmaster.ca)
Comparing these results with those in the almost-identical Valsartan in Acute Myocardial Infarction Trial (VALIANT), an editorialist concludes (pp. 1615-6): ìBoth the ONTARGET and the VALIANT studies show that telmisartan and valsartan provide a benefit similar to that of a proven ACE inhibitor. However, because ARBs are more costly than ACE inhibitors and have more side effects, their primary value is as an alternative for patients who cannot tolerate ACE inhibitors because of cough. The addition of an ARB to an ACE inhibitor has no benefit and causes an increased number of adverse events in patients with arterial disease but seems to be beneficial in patients with heart failure, although the trials in heart failure did not test the addition of an ARB to a full dose of a proven ACE inhibitor.î (J. J. V. McMurray, U. Glasgow, Glasgow, Scotland)

>>>PNN NewsWatch
* Six patients who received Pfizer’s inhaled insulin (Exubera; withdrawn from general distribution) in clinical trials have been newly diagnosed with primary lung malignancies, the company announced yesterday, compared with just one patient in a comparator arm of the study. A single postmarketing report of a primary lung malignancy in an Exubera-treated patient has also been received. All patients were smokers, making a definitive link to causality difficult, especially with such small numbers. Because of the limited availability of Exubera, Pfizer recommends that health professionals seek alternative treatment options to maintain patients’ glycemic control.
*
FDA has found extremely high levels of selenium—up to 200 times the labeled amount—in samples of certain flavors of the dietary supplement products ìTotal Body Formulaî and ìTotal Body Mega Formula.î The agency has received 43 reports of persons from nine states who experienced serious adverse reactions using these products. These products were the focus of a Mar. 27 warning in which FDA cautioned consumers against their purchase or use. Adverse reactions associated with the products generally occurred after 5–10 days of daily ingestion of the product, and included significant hair loss, muscle cramps, diarrhea, joint pain, deformed fingernails, and fatigue.
* Health professionals should not use
ReadyMED elastomeric infusion pumps (Cardinal) with daptomycin (Cubicin; Cubist) because a potentially significant impurity, 2-mercaptobenzothiazole, has been found in reconstituted admixtures after storage in the pumps, FDA warns.

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

PNN Pharmacotherapy Line
Apr. 11, 2008 * Vol. 15, No. 71
Providing news and information about medications and their proper use

>>>Chest Highlights
Source:
Apr. issue of Chest (www.chestjournal.org/current.shtml; 2008; 133).
Outcomes with Combined Antiplatelet/Anticoagulant Therapy: The risks of bleeding in patients on combined antiplatelet/anticoagulant therapy ìappears to outweigh the benefits,î conclude investigators who conducted a retrospective, longitudinal, pharmacoepidemiologic analysis (pp. 948-54). Comparing 1,623 patients managed by the anticoagulation service who were also on the antiplatelet agents aspirin, clopidogrel, and/or dipyridamole (the combination-therapy cohort) with 2,560 patients on anticoagulants only (the monotherapy cohort), the authors determined: ìPatients in the combination-therapy cohort were more likely to have had anticoagulation-related hemorrhages (4.2% vs 2.0%, respectively; unadjusted p < 0.001) and coronary events (0.9% vs 0.3%, respectively; p = 0.009), but not death (0.1% vs 0.2%, respectively; unadjusted p = 0.186) or thrombotic events (0.3% vs 0.4%, respectively; unadjusted p = 0.812). With adjustment, combined warfarin and antiplatelet use was independently associated with hemorrhagic events (odds ratio [OR], 2.75; 95% confidence interval [CI], 1.44 to 5.28), but not with coronary events (OR, 0.99; 95% CI, 0.37 to 2.62).î (S. G. Johnson, Kaiser Permanente, Aurora, Colo.; samuel.g.johnson@kp.org)
Treating Airway Inflammation in Asthma: A variety of therapeutic options are reviewed for managing the airway inflammation of asthma (pp. 989-98): ìIt may be possible to target antiinflammatory therapy to various aspects of the disease and consequently to improve the treatment of patients with inadequate responses to standard ICS-based therapy. Several novel antiinflammatory therapies are in different stages of clinical development. The most clinically advanced of these is omalizumab, a recombinant humanized monoclonal antibody that specifically targets IgE and is indicated for patients with moderate-to-severe asthma caused by allergies. Omalizumab has demonstrated efficacy in patients with moderate-to-severe asthma and documented evidence of allergen sensitivity. Other key therapy options in clinical development either target proinflammatory cytokines (eg, interleukin-4 and tumor necrosis factor-) or inflammatory cells (eg, T-helper type 2 cells and eosinophils).î (N. A. Hanania, Baylor College of Med., Houston; Hanania@bcm.tmc.edu)
Aerosolized Salbutamol After Lung Resection: In a pilot study of 24 high-risk patients undergoing lung resection, aerosolized salbutamol accelerated the resolution of lung edema, improved blood oxygenation, and stimulated cardiovascular function, researchers report (pp. 845-52). Various indices of pulmonary and cardiac function were significantly better among patients treated with salbutamol on postoperative days 0 and 1, while those who received ipratropium bromide had no significant changes in these indicators. (M. Licker, Hopital Universitaire, GenËve, Switzerland; licker-marc-joseph@diogenes.hcuge.ch)
Aerosolized Salbutamol After Lung Resection: Patients who were young, pregnant or postpartum, and/or uninsured, and those having adverse drug effects were more likely to fail to complete isoniazid treatment for latent tuberculosis infection in a Rhode Island retrospective analysis of 845 patients (pp. 862-8). Just over 60% of patients completed the 9-month regimens, while 35.6% of patients were lost to follow-up. (A. Kwara, Miriam Hosp., Providence, R.I.; akwara@lifespan.org)

>>>PNN NewsWatch
* FDA announced yesterday that it is investigating a potential association between the use of the immunosuppressant agents mycophenolate mofetil (CellCept, Roche) or mycophenolic acid (Myfortic, Novartis) and the development of progressive multifocal leukoencephalopathy (PML). Roche is aware of cases of PML in transplant recipients and in patients treated off label for systemic lupus erythematosus. FDA is reviewing data submitted by Roche and has asked Novartis for any data it has on PML cases. FDA’s review is expected to take 2 months.

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

PNN Pharmacotherapy Line
Apr. 14, 2008 * Vol. 15, No. 72
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Early-release articles from Lancet (www.thelancet.com; 2008; 371).
Human-to-Human Avian Flu Transmission: Limited and nonsustained person-to-person transmission of a highly pathogenic strain of avian influenza A (H5N1) was found among close contacts of a father and son who were infected with the virus in China (doi: 10.1016/S0140-6736(08)60493-6). Based on clinical symptoms and serologic analysis of 91 individuals, the investigators found: ìThe 24-year-old index case died, and the second case, his 52-year-old father, survived after receiving early antiviral treatment and post-vaccination plasma from a participant in an H5N1 vaccine trial. The index case’s only plausible exposure to H5N1 virus was a poultry market visit 6 days before the onset of illness. The second case had substantial unprotected close exposure to his ill son. 91 contacts with close exposure to one or both cases without adequate protective equipment provided consent for serological investigation. Of these individuals, 78 (86%) received oseltamivir chemoprophylaxis and two had mild illness. Both ill contacts tested negative for H5N1 by [reverse transcriptase polymerase chain reaction]. All 91 close contacts tested negative for H5N1 antibodies. H5N1 viruses isolated from the two cases were genetically identical except for one non-synonymous nucleotide substitution.î (Y. Wang, Chinese Ctr. for Disease Control and Prevention, Beijing; wangyu@chinacdc.cn)

>>>BMJ Highlights
Source:
Early-release articles from and Apr. 12 issue of BMJ (www.bmj.org; 2008; 336).
Bisphosphonates & Atrial Fibrillation/Flutter: Use of bisphosphonates was not associated with any identifiable increases the risk of atrial fibrillation and flutter in a study conducted in northern Denmark (pp. 813-6). Among 13,586 patients with atrial fibrillation and flutter and 68,054 population controls with complete hospital and prescription histories, these trends were noted: ì435 cases (3.2%) and 1,958 population controls (2.9%) were current users of bisphosphonates for osteoporosis. Etidronate and alendronate were used with almost the same frequency among cases and controls. The adjusted relative risk of current use of bisphosphonates compared with non-use was 0.95 (95% confidence interval 0.84 to 1.07). New users had a relative risk of 0.75 (95% confidence interval 0.49 to 1.16), broadly similar to the estimate for continuing users (relative risk 0.96, 95% confidence interval 0.85 to 1.09). The relative risk estimates were independent of number of prescriptions and the position of the atrial fibrillation and flutter diagnosis in the discharge record, and were similar for inpatients and outpatients.î (H. T. S¯rensen, Aarhus U. Hosp., Aarhus, Denmark; hts@dce.au.dk)
U.K. Immigrant Maternal Health Behaviors: In a study of 6,478 British/Irish white mothers and 2,110 mothers from ethnic minority groups in England, the likelihood of immigrant mothers smoking during pregnancy rose by 31% for every 5 additional years they had lived in the U.K., and they were 5% less likely to breast feed for at least 4 months (doi: 10.1136/bmj.39532.688877.25). The authors conclude, ìHealth professionals should not underestimate women’s likelihood of engaging in risky health behaviours because of their ethnicity.î (S. S. Hawkins, UCL Institute of Child Health, London; s.hawkins@ich.ucl.ac.uk)

>>>PNN JournalWatch
* Countdown to 2015 for Maternal, Newborn, and Child Survival: The 2008 Report on Tracking Coverage of Interventions, in Lancet, 2008; 371: 1247–58. Reprints: J. Bryce, Johns Hopkins Sch. of Public Health, Ithaca, N.Y.; jbrycedanby@aol.com
* Toward a Policy-Relevant Analysis of Geographic and Racial/Ethnic Disparities in Child Health, in
Health Affairs, 2008; 27: 321–33. Reprints: D. Acevedo-Garcia, Harvard U., Boston.
* Advances in the Care of Adults with Asthma and Allergy in 2007, in
Journal of Allergy and Clinical Immunology, 2008; 121: 839–44. Reprints: A. J. Apter, apter@mail.med.upenn.edu
* Therapeutic Approaches for Control of Transcription Factors in Allergic Disease, in
Journal of Allergy and Clinical Immunology, 2008; 121: 803–9. Reprints: D. J. Cousins, King’s College, London; david.cousins@kcl.ac.uk
* Parental Obesity and Offspring Serum Alanine and Aspartate Aminotransferase Levels: The Framingham Heart Study, in
Gastroenterology, 2008; 134: 953–9.e1. Reprints: C. S. Fox, foxca@nhlbi.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 © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 15, 2008 * Vol. 15, No. 73
Providing news and information about medications and their proper use

>>>Internal Medicine Report I
Source:
Apr. 14 issue of the Archives of Internal Medicine (http://archinte.ama-assn.org/current.dtl; 2008; 168).
Pharmacists’ Impact on HF Care: Incorporation of pharmacists into heart failure care teams should be strongly considered because patients have lower risk of all-cause and disease-related hospitalizations when they receive pharmacist care, according to a systematic review of randomized trials (pp. 687-94). ìA total of 12 randomized controlled trials (2,060 patients) were identified,î the author write. ìExtent of pharmacist involvement varied among studies, and each study intervention was categorized as pharmacist-directed care or pharmacist collaborative care using a priori definitions and feedback from primary study authors. Pharmacist care was associated with significant reductions in the rate of all-cause hospitalizations (11 studies [2,026 patients]) (OR, 0.71; 95% CI, 0.54–0.94) and HF hospitalizations (11 studies [1,977 patients]) (OR, 0.69; 95% CI, 0.51–0.94),and a nonsignificant reduction in mortality (12 studies [2,060 patients])(OR, 0.84; 95% CI, 0.61–1.15). Pharmacist collaborative care led to greater reductions in the rate of HF hospitalizations (OR, 0.42; 95%CI, 0.24–0.74) than pharmacist-directed care (OR, 0.89; 95% CI, 0.68–1.17).î (R. T. Tsuyuki, ross.tsuyuki@ualberta.ca)
Statins & BP: Systolic and diastolic blood pressures were lowered with both hydrophilic and lipophilic statins in both hypertensive and normotensive patients, report investigators from the UCSD Statin Study (pp. 721-7). Comparing randomized daily doses of simvastatin 20 mg, pravastatin 40 mg, and placebo, the researchers noted: ìStatins modestly but significantly reduced BP relative to placebo, by 2.2 mm Hg for SBP (P = .02) and 2.4 mm Hg for DBP (P < .001) in [an intention-to-treat] analysis. Blood pressure reductions ranged from 2.4 to 2.8 mm Hg for both SBP and DBP with both simvastatin and pravastatin, in those subjects with full follow-up, and without potential for influence by BP medications (ie, neither receiving nor meriting BP medications).î (B. A. Golomb, bgolomb@ucsd.edu)

>>>Internal Medicine Report II
Source:
Apr. 15 issue of the Annals of Internal Medicine (www.annals.org/current.shtml; 2008; 148).
Testosterone Transdermal Spray in Women: Among 261 premenopausal women with reduced libido and low serum-free testosterone levels, daily doses of a transdermal testosterone spray significantly improved self-reported sexual satisfaction (pp. 569-77). In a 16-week, dose-ranging trial, these effects on self-reported satisfactory sexual events (SSEs) were noted with three doses of the spray: ìThe number of SSEs increased during the treatment period in the active treatment groups and the placebo group. The mean number of SSEs over 28 days at week 16 was statistically significantly greater for women treated with the intermediate dose of testosterone therapy (one 90-µL spray) than for women treated with placebo. The least-squares mean was 2.48 versus 1.70 SSEs, respectively (event rate ratio, 1.49 [95% CI, 1.01 to 2.18]; P = 0.04). The frequency of SSEs in women treated with low and high doses of testosterone did not differ from that in women who took placebo. The rate ratios based on the least-squares mean rates of SSEs during weeks 4 to 16 for each treatment group showed statistically significant or borderline significant increases in all testosterone groups compared with the placebo group. The rate ratios for the one 56-µL spray, one 90-µL spray, and two 90-µL sprays treatment groups were 1.34 (CI, 0.97 to 1.85; P = 0.081), 1.48 (CI, 1.07 to 2.06; P = 0.018), and 1.38 (CI, 1.00 to 1.92; P = 0.052), respectively. At week 16, 95% of women treated with the one 90-µL dose had a free testosterone level less than the upper limit of the reference range for women. The most frequently reported adverse event was hypertrichosis, which was dose-related and mostly confined to the application site. No clinically relevant changes in blood test values, serum biochemical variables, or vital signs occurred.î (S. Davis, Monash U., Prahran, Victoria, Australia; susan.davis@med.monash.edu.au)

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

PNN Pharmacotherapy Line
Apr. 16, 2008 * Vol. 15, No. 74
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Apr. 16 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2008; 299).
Guest Authorship, Ghostwriting in Rofecoxib Studies: Company employees and contracted ghostwriters often prepared research and review articles about the Merck drug rofecoxib, a case study reports, and those to whom first authorship was attributed in such papers often failed to disclose industry financial support (pp. 1800-12). Analyzing about 250 court documents obtained during litigation of rofecoxib-related suits against Merck, the investigators determined: ìFor the publication of clinical trials, documents were found describing Merck employees working either independently or in collaboration with medical publishing companies to prepare manuscripts and subsequently recruiting external, academically affiliated investigators to be authors. Recruited authors were frequently placed in the first and second positions of the authorship list. For the publication of scientific review papers, documents were found describing Merck marketing employees developing plans for manuscripts, contracting with medical publishing companies to ghostwrite manuscripts, and recruiting external, academically affiliated investigators to be authors. Recruited authors were commonly the sole author on the manuscript and offered honoraria for their participation. Among 96 relevant published articles, we found that 92% (22 of 24) of clinical trial articles published a disclosure of Merck’s financial support, but only 50% (36 of 72) of review articles published either a disclosure of Merck sponsorship or a disclosure of whether the author had received any financial compensation from the company.î (J. S. Ross, Mount Sinai Sch. of Med., New York; joseph.ross@mssm.edu)
A second case study reaches similar conclusions based on trials of rofecoxib for prevention of Alzheimer disease and cognitive impairment (pp. 1813-7): ìIn one article (reporting results of protocol 091) published in 2004, 11 ‘non-drug related deaths’ were reported (9 deaths among 346 rofecoxib patients and 2 deaths among 346 placebo patients). In another article (reporting results of protocol 078) published in 2005, 39 deaths were reported among patients taking study treatment or within 14 days of the last dose (24 among 725 rofecoxib patients and 15 among 732 placebo patients) and an additional 22 deaths in the off-drug period (17 in rofecoxib patients and 5 in placebo patients). However, these articles did not include analyses or statistical tests of the mortality data, and the 2 articles concluded that regarding safety, rofecoxib is ‘well tolerated.’
ìIn contrast, in April 2001, the company’s internal intention-to-treat analyses of pooled data from these 2 trials identified a significant increase in total mortality (hazard ratio [HR], 4.43; 95% CI, 1.26–15.53 for protocol 091, and HR, 2.55; 95% CI, 1.17–5.56 for protocol 078), with overall mortality of 34 deaths among 1,069 rofecoxib patients and 12 deaths among 1,078 placebo patients (HR, 2.99; 95% CI, 1.55–5.77). These mortality analyses were neither provided to the FDA nor made public in a timely fashion.î (B. M. Psaty,
psaty@u.washington.edu)

>>PNN NewsWatch
* FDA has approved olopatadine hydrochloride nasal spray (Patanase, Alcon) for the relief of the symptoms of seasonal allergic rhinitis in patients 12 years of age and older. Slated to be available in May, the antihistamine provides an additional intranasal option for the 40–50 million American with allergies. FDA approval of Patanase nasal spray—which contains the same active ingredient as Patanol and Pataday, ophthalmic products previously marketed by Alcon—was based primarily on 2-week, randomized, double-blind clinical trials in patients with seasonal allergic rhinitis. Trials were conducted to determine the ability of olopatadine to relieve allergy symptoms based on total nasal symptom scores (TNSS, a composite of stuffy, runny, itchy nose, and sneezing). Patients treated with olopatadine, two sprays per nostril twice daily, had significantly greater decreases in TNSS compared with a placebo nasal spray. The most common adverse effects with olopatadine have been bitter taste, headache, epistaxis, pharyngolaryngeal pain, postnasal drip, cough, and urinary tract infection.

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

PNN Pharmacotherapy Line
Apr. 17, 2008 * Vol. 15, No. 75
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Apr. 17 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2008; 358).
Weekly Paclitaxel for Breast Cancer: In a study of 4,950 women with axillary lymph node–positive or high-risk lymph node–negative breast cancer, weekly doses of paclitaxel after standard adjuvant chemotherapy with doxorubicin and cyclophosphamide improved disease-free and overall survival, compared with standard adjuvant therapy (pp. 1663-71). The researchers report: ìAs compared with patients receiving standard therapy (paclitaxel every 3 weeks), the odds ratio for disease-free survival was 1.27 among those receiving weekly paclitaxel (P = 0.006), 1.23 among those receiving docetaxel every 3 weeks (P = 0.02), and 1.09 among those receiving weekly docetaxel (P = 0.29) (with an odds ratio >1 favoring the groups receiving experimental therapy). As compared with standard therapy, weekly paclitaxel was also associated with improved survival (odds ratio, 1.32; P = 0.01). An exploratory analysis of a subgroup of patients whose tumors expressed no human epidermal growth factor receptor type 2 protein found similar improvements in disease-free and overall survival with weekly paclitaxel treatment, regardless of hormone-receptor expression. Grade 2, 3, or 4 neuropathy was more frequent with weekly paclitaxel than with paclitaxel every 3 weeks (27% vs. 20%).î (J. A. Sparano, jsparano@montefiore.org)
Considering Factors Other Than Gestational Age in Extreme Prematurity: For infants born at 22–25 weeks’ gestation, additional factors should be considered when deciding whether to administer intensive care, a study concludes, including whether the child has been exposed to corticosteroids (pp. 1672-81). These results were noted in a cohort of 4,446 such infants when followed to a corrected age of 18–22 months of age: ìAmong study infants, 3,702 (83%) received intensive care in the form of mechanical ventilation. Among the 4,192 study infants (94%) for whom outcomes were determined at 18 to 22 months, 49% died, 61% died or had profound impairment, and 73% died or had impairment. In multivariable analyses of infants who received intensive care, exposure to antenatal corticosteroids, female sex, singleton birth, and higher birth weight (per each 100-g increment) were each associated with reductions in the risk of death and the risk of death or profound or any neurodevelopmental impairment; these reductions were similar to those associated with a 1-week increase in gestational age. At the same estimated likelihood of a favorable outcome, girls were less likely than boys to receive intensive care. The outcomes for infants who underwent ventilation were better predicted with the use of the above factors than with use of gestational age alone.î (J. E. Tyson, U. Texas Med. Sch., Houston; jon.e.tyson@uth.tmc.edu)

PNN NewsWatch
n As the first of the nation’s 78 million baby boomers begin reaching age 65 in 2011, they will face a health care work force that is too small and woefully unprepared to meet their specific health needs, warns a new report from the Institute of Medicine. ìRetooling for an Aging America: Building the Health Care Workforceî calls for bold initiatives starting immediately to train all health care providers in the basics of geriatric care and to prepare family members and other informal caregivers, who the report says currently receive little or no training in how to tend to their aging loved ones. Only 7,100 physicians are certified in geriatrics in the U.S. at this time. Older adults as a group are living healthier and longer than previous generations, but they live with an average of three chronic diseases that require four or more prescription medications. Medicare, Medicaid, and other health plans should pay higher rates to boost recruitment and retention of geriatric specialists and care aides, said the committee that wrote the report. The committee set a target date of 2030—the year by which all baby boomers will have turned 65 or older—for the necessary reforms to take place. Pharmacy was represented on the committee by Miriam A. Mobley Smith of the Chicago State University College of Pharmacy.

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

PNN Pharmacotherapy Line
Apr. 18, 2008 * Vol. 15, No. 76
Providing news and information about medications and their proper use

>>>Neurology Highlights
Source:
Apr. 15 issue of Neurology (www.neurology.org/current.shtml; 2008; 70).
Statins & Parkinson Disease: In recruiting 312 patients with incident idiopathic Parkinson disease and 342 controls, researchers observed significantly higher use of statins among controls than cases (pp. 1418-22). Concluding that ìascribing causality to these associations is premature and further studies are needed to confirm a potential neuroprotective role for statins in PD,î the investigators provide these details about their data: ìWe observed a higher frequency of statin use among controls vs cases (OR 0.45; 95% CI 0.29 to 0.71) and a strong dose-response relation. The strongest protective association between statin use and PD was observed in long-term (5 years) users (OR 0.37; 95% CI 0.18 to 0.78). There was no difference by gender or age. We noted 60 to 70% risk reductions for each individual statin except pravastatin.î (A. D. Wahner, UCLA, Los Angeles)
Antihypertensives & Parkinson Disease: Current use of calcium-channel blockers was associated with a reduced risk of Parkinson disease, but use of other antihypertensives showed no reduction in such risks, according to data from the U.K.-based General Practice Research Database (pp. 1438-44). ìWe identified 3,637 cases with a first-time diagnosis of idiopathic PD and an equal number of matched controls,î write the researchers. ìAs compared to nonuse of antihypertensive drugs, the adjusted OR for current use of 30 prescriptions was 1.08 (95% CI 0.85 to 1.37) for ACE inhibitors, 0.91 (95% CI 0.41 to 2.00) for [angiotensin] II antagonists, 1.16 (95% CI 0.95 to 1.41) for beta-blockers, and 0.77 (95% CI 0.63 to 0.95) for calcium channel blockers.î (C. R. Meier, U. Hosp., Basel, Switzerland)
Genetics of Dopa-Responsive Dystonia: A study of a multigenerational Swiss family with dopa-responsive dystonia rules out the previously reported DYT14 locus as a cause of the disease and identifies ìa novel multiexonic deletion ... in [GTP cyclohydrolase I (GCH1)]î (pp. 1377-83): ìWe evaluated 32 individuals, of whom 6 were clinically diagnosed with DRD, with childhood-onset progressive foot dystonia, later generalizing, followed by parkinsonism in the two older patients. The response to levodopa was very good. Two additional patients had late onset dopa-responsive parkinsonism. Three other subjects had DRD symptoms on historical grounds. We found suggestive linkage to the previously reported DYT14 locus, which excluded GCH1. However, further study with more stringent criteria for disease status attribution showed linkage to a larger region, which included GCH1. No mutation was found in GCH1 by gene sequencing but dosage methods identified a novel heterozygous deletion of exons 3 to 6 of GCH1. The mutation was found in seven subjects. One of the patients with dystonia represented a phenocopy.î (Christian Wider, Mayo Clinic, Jacksonville, Fla.)

>>>Gastroenterology Report
Source:
Apr. issue of Gastroenterology (www.gastrojournal.org; 2008; 134).
HRT as Risk Factor for GERD in Female Twins: Postmenopausal use of hormone-replacement therapy—but perhaps not progestin therapy or oral contraceptives—was an independent risk factor for gastroesophageal reflux symptoms in a study of female twins (pp. 921-8). ìThe cross-sectional study design comprised 4,365 twins with reflux and 17,321 without,î the investigators report of their telephone interviews conducted in 1998–2002 of women in the Swedish Twin Registry. ìIn ever users of estrogen HT, the risk of reflux symptoms was increased by 32% (odds ratio, 1.32; 95% confidence interval, 1.18–1.47). This association remained in the nested case-control analyses and increased slightly with higher body mass index. A similar pattern was observed for the use of progestin in the cross-sectional design, but no association remained in the nested case-control analysis. Use of oral contraceptives was not associated with an increased risk of reflux symptoms. Generally, the risk estimates remained virtually unchanged after adjustments for potential confounding factors, including genetic factors.î (H. Nordenstedt, Karolinska Institutet, Stockholm; helena.nordenstedt@ki.se)

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

PNN Pharmacotherapy Line
Apr. 21, 2008 * Vol. 15, No. 77
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Apr. 19 issue of Lancet (www.thelancet.com; 2008; 371).
Management of Chronic Cough: More research is needed into the basic mechanisms and pharmacologic control of abnormally heightened cough reflexes, authors of a review article conclude (pp. 1375-84): ìCough that remains unexplained after basic clinical assessment is a common reason for referral to secondary care. Much of the evidence about management of isolated chronic cough is derived from case series; this evidence suggests that isolated chronic cough is usually due to asthma, gastro-oesophageal reflux disease, and upper airway conditions, and that it can be cured in most people by treatment of these conditions. However, there is increasing recognition that satisfactory control of chronic cough is not achieved in a substantial number of patients seen in secondary care. Moreover, there is a concern that perpetuation of the belief that chronic cough is solely due to the effects of comorbid conditions is inhibiting research into the pathophysiology of an abnormally heightened cough reflex, and jeopardising development of improved treatments. We advocate a change in emphasis, which makes a clear distinction between cough due to corticosteroid-responsive eosinophilic airway diseases and corticosteroid-resistant non-eosinophilic cough. We recommend that some factors with weak evidence of an association with cough are best viewed as potential aggravating factors of an intrinsic abnormality of the cough reflex, rather than the cause.î (I. D. Pavord, U. H. Leicester NHS Trust, Leicester, U.K.; ian.pavord@uhl-tr.nhs.uk)

>>>BMJ Highlights
Source:
Early-release article from BMJ (www.bmj.org; 2008; 336).
Preventing ADRs Among the Elderly: Adverse drug reactions occur commonly in elderly patients for a variety of reasons, but many of them are preventable, opine authors of a Making a Difference article (doi: 10.1136/bmj.39520.671053.94). After noting that much of primary care has appropriately shifted from its traditional acute-care focus to one on the chronic diseases common in older patients, the writers list these causes of the high prevalence of adverse drug events in this patient population: ìOne is the altered pharmacokinetic status of elderly people; they are less able to metabolise and excrete many common drugs, even in the absence of liver or kidney diseases. They may also have altered pharmacodynamic responses, with some receptor systems (such as those for opiates and benzodiazepines) having greater sensitivity with advancing age, and others (such as those for insulin) showing reduced sensitivity. Unfortunately, the under-representation of older patients (especially frail ones) in clinical trials makes it even harder for the prescribing doctor to anticipate and prevent untoward drug reactions in older patients.î (J. Avorn, javorn@medsoc.harvard.edu)

>>>PNN JournalWatch
* Biologic Drugs for Rheumatoid Arthritis in the Medicare Program: A Cost-Effectiveness Analysis, in Arthritis & Rheumatism, 2008; 58: 939–46. Reprints: A. J. Wailoo, U. Sheffield, Sheffield, U.K.; a.j.wailoo@sheffield.ac.uk
* Diabetes Patients Requiring Glucose-Lowering Therapy and Nondiabetics with a Prior Myocardial Infarction Carry the Same Cardiovascular Risk: A Population Study of 3.3 Million People, in
Circulation, 2008; 117: 1945–54. Reprints: T. K. Schramm, Gentofte U. Hosp., Hellerup, Denmark; tks@heart.dk
* The Case for Vancomycin as the Preferred Drug for Treatment of
Clostridium difficile Infection, in Clinical Infectious Diseases, 2008; 46: 1489–92. Reprints: J. G. Bartlett, Johns Hopkins U., Baltimore; jb@jhmi.edu
* Moxifloxacin Monotherapy Is Effective in Hospitalized Patients with Community-Acquired Pneumonia: The MOTIV Study—A Randomized Clinical Trial, in
Clinical Infectious Diseases, 2008; 46: 1499–509. Reprints: R. C. Read, Sheffield U., Sheffield, U.K.; r.c.read@sheffield.ac.uk
* Development of a Tool for Eliciting Patient Priority from Among Competing Cardiovascular Disease, Medication-Symptoms, and Fall Injury Outcomes, in
Journal of the American Geriatrics Society, 2008; 56: 730–6. Reprints: M. E. Tinetti, mary.tinetti@yale.edu
* Can Methylphenidate Reduce Fall Risk in Community-Living Older Adults? A Double-Blind, Single-Dose Cross-Over Study, in
Journal of the American Geriatrics Society, 2008; 56: 695–700. Reprints: J. M. Hausdorff, Tel Aviv Sourasky Med. Ctr., Tel Aviv, Israel; jhausdor@tasmc.health.gov.il

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

PNN Pharmacotherapy Line
Apr. 22, 2008 * Vol. 15, No. 78
Providing news and information about medications and their proper use

>>>Neurology Highlights
Source:
Apr. 22 issue of Neurology (www.neurology.org/current.shtml; 2008; 70).
Menstrually Related Migraine Headache: Perimenstrual use of transcutaneous estrogen 1.5 mg, frovatriptan 2.5 mg twice daily, and naratriptan 1 mg twice daily for prevention of menstrually related migraine (MRM) headache is supported by grade B recommendations, conclude authors of a review article (pp. 1555-63). Noting that ìMRM attacks are more severe, longer in duration, and have a poorer response to analgesics treatment of MRM headaches,î the group was not able to identify specific agents for treatment of such headaches, concluding only that treatment of MRM headaches ìmust be based on clinical considerations.î (T. Pringsheim, tamara.pringsheim@utoronto.ca)
Lessening Disruptive Physician Behavior: The reasons for and possible solutions to the problem of disruptive physician behavior in health care situations are reviewed (pp. 1564-70). Noting that such behaviors ìcan adversely affect patient safety and quality outcomes of care,î the authors provide these descriptors and ideas: ìDisruptive behavior causes stress, anxiety, frustration, and anger, which can impede communication and collaboration, which can result in avoidable medical errors, adverse events, and other compromises in quality care. Health care organizations need to be aware of the significance of disruptive behaviors and develop appropriate policies, standards, and procedures to effectively deal with this serious issue and reinforce appropriate standards of behavior. Having a better understanding of what contributes to, incites, or provokes disruptive behaviors will help organizations provide appropriate educational and training programs that can lessen the likelihood of occurrence and improve the overall effectiveness of communication among the health care team.î (A. H. Rosenstein, VHA West Coast, Pleasanton, Calif.; arosenst@vha.com)

>>>Cardiology Highlights
Source:
Apr. 29 issue of the Journal of the American College of Cardiology (http://content.onlinejacc.org/current.dtl; 2008; 51).
Bivalirudin Monotherapy in Diabetes and ACS: Patients with diabetes and acute coronary syndromes, who have higher rates of ischemia and major bleeding than nondiabetic patients, can be managed with bivalirudin monotherapy, a study shows (pp. 1645-52). Comparing outcomes with bivalirudin only, heparin (unfractionated or enoxaparin) plus glycoprotein IIb/IIIa inhibition (GPI), and bivalirudin plus GPI, the authors report these results from the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial: ìDiabetes was present in 3,852 randomized patients (27.9%). Compared with nondiabetic patients, diabetic patients had higher 30-day rates of net adverse clinical outcomes (12.9% vs. 10.6%; p < 0.001), composite ischemia (8.7% vs. 7.2%; p = 0.003), and major bleeding (5.7% vs. 4.2%; p < 0.001). Among diabetic patients, compared with heparin plus GPI, bivalirudin plus GPI resulted in similar rates of net adverse clinical outcomes (14.0% vs. 13.8%; p = 0.89), while bivalirudin monotherapy resulted in a similar rate of composite ischemia (7.9% vs. 8.9%; p = 0.39) and less major bleeding (3.7% vs. 7.1%; p < 0.001), yielding fewer net adverse clinical outcomes (10.9% vs. 13.8%; p = 0.02).î (F. Feit, frederick.feit@med.nyu.edu)

>>>PNN NewsWatch
* FDA yesterday reported oversulfated chondroitin sulfate has been found in samples of unprocessed heparin dating back to 2006 and from at least 10 Chinese firms. FDA also said that it has initial animal data showing that this contaminant could cause adverse events similar to those observed in humans. The agency additionally warned that the contaminant has been found in some lots of low molecular weight heparin products, which if problematic, could greatly expand the scope of this situation. FDA has posted a map of countries that have found the heparin contaminant within their borders, showing Europe, Japan and China in Asia, Australia and New Zealand, the U.S., and Canada, have been affected.

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

PNN Pharmacotherapy Line
Apr. 23, 2008 * Vol. 15, No. 79
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Apr. 23/30 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2008; 299).
Cost-Related Nonadherence with Medicare Part D: While some Medicare beneficiaries experienced less cost-related medication nonadherence (CRN) following implementation of Part D, the sickest beneficiaries continued to experience similar rates of CRN, rates that were higher than among other patients, researchers report (pp. 1922-8). Using logistic regression to analyze the community-dwelling sample of the nationally representative Medicare Current Beneficiary Survey (unweighted unique sample of 24,234 patients), the investigators did find that Medicare beneficiaries were having to choose less between basic needs and medications after Part D implementation: ìThe unadjusted, weighted prevalence of CRN was 15.2% in 2004, 14.1% in 2005, and 11.5% after Part D implementation in 2006. The prevalence of spending less on basic needs was 10.6% in 2004, 11.1% in 2005, and 7.6% in 2006. Adjusted analyses comparing 2006 with 2005 and controlling for historical changes (2005 vs 2004) demonstrated significant decreases in the odds of CRN (ratio of odds ratios [ORs], 0.85; 95% confidence interval [CI], 0.74–0.98; P = .03) and spending less on basic needs (ratio of ORs, 0.59; 95% CI, 0.48–0.72; P < .001). No significant changes in CRN were observed among beneficiaries with fair to poor health (ratio of ORs, 1.00; 95% CI, 0.82–1.21; P = .97), despite high baseline CRN prevalence for this group (22.2% in 2005) and significant decreases among beneficiaries with good to excellent health (ratio of ORs, 0.77; 95% CI, 0.63–0.95; P = .02). However, significant reductions in spending less on basic needs were observed in both groups (fair to poor health: ratio of ORs, 0.60; 95% CI, 0.47–0.75; P < .001; and good to excellent health: ratio of ORs, 0.57; 95% CI, 0.44–0.75; P < .001).î (J. M. Madden, jeanne_madden@hms.harvard.edu)
Knowledge of Medicare Part D Costs: Lack of understanding of the cost-sharing aspects of Medicare Part D was common among Medicare Advantage patients in northern California, a telephone survey shows, and poorly informed patients more often had to borrow money or go without necessities to cover copayments (pp. 1929-36). ìAn estimated 40% (95% confidence interval [CI], 35%–45%) of beneficiaries were aware that their drug plan in 2006 included a coverage gap; knowledge of the gap was greater among individuals who reached the gap during the year. Approximately 36% (95% CI, 32%–41%) of beneficiaries reported at least 1 of the following responses to drug costs: cost-coping behavior (26%), reduced adherence (15%), or experiencing financial burden (7%). In multivariate analyses, beneficiaries with lower household income more frequently reported cost responses (difference of 14.5 percentage points for < $40 000/y vs $40 000/y [95% CI, 3.6–25.4 percentage points]). Compared with beneficiaries who were unaware of having a coverage gap, those who were aware more frequently reported any cost response (difference of 11.3 percentage points [95% CI, 0.8–21.9 percentage points]), but had fewer reports of borrowing money or going without necessities (difference of 5.5 percentage points [95% CI, 1.1–10.0 percentage points]).î (J. Hsu, jth@dor.kaiser.org)

>>>PNN NewsWatch
* FDA has approved certolizumab pegol (Cimzia, UCB), a pegylated antibody indicated for reducing signs and symptoms of Crohn’s disease and maintaining clinical response in adult patients with moderate to severe active disease who have an inadequate response to conventional therapy. Approval of the anti–tumor necrosis factor-alpha agent was based on clinical trials of 1,500 patients with Crohn’s disease showing a statistically significant greater proportion clinical response with certolizumab pegol for up to 6 months, compared with placebo. Most patients in remission after initial dosing maintained remission without dose escalation. Certolizumab pegol is administered subcutaneously every 4 weeks after three initial doses administered every 2 weeks. Injection site reactions and pain were infrequent. The most common reported adverse events in pivotal studies were upper respiratory tract infection (cold, influenza), urinary tract infection (bladder infection), and joint pain. As seen with other anti-TNF-alpha agents, serious but infrequent infections and malignancies have been reported.

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

PNN Pharmacotherapy Line
Apr. 24, 2008 * Vol. 15, No. 80
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Early-release article from and the Apr. 24 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2008; 358).
Contaminated Heparin & the Coagulation Contact System: In vitro assays and in vivo tests in swine link presence of oversulfated chondroitin sulfate (OSCS) in heparin products with activation of the contact system of coagulation, researchers report (doi: 10.1056/NEJMoa0803200). Blinded tests of control and suspect heparin samples provided by FDA showed these results when tested for effects on the contact system and the complement cascade: ìThe OSCS found in contaminated lots of unfractionated heparin, as well as a synthetically generated OSCS reference standard, directly activated the kinin–kallikrein pathway in human plasma, which can lead to the generation of bradykinin, a potent vasoactive mediator. In addition, OSCS induced generation of C3a and C5a, potent anaphylatoxins derived from complement proteins. Activation of these two pathways was unexpectedly linked and dependent on fluid-phase activation of factor XII. Screening of plasma samples from various species indicated that swine and humans are sensitive to the effects of OSCS in a similar manner. OSCS-containing heparin and synthetically derived OSCS induced hypotension associated with kallikrein activation when administered by intravenous infusion in swine.î
The authors conclude: ìThese findings also suggest that a simple in vitro bioassay could complement the previously described analytic tests to help protect the global supply chain of heparin, by allowing the screening of heparin lots for the presence not only of OSCS but also of other polysulfated contaminants that may have unintended pharmacologic consequences.î (R. Sasisekharan,
rams@mit.edu)
ìTrying Timesî at FDA: The proportion of active pharmaceutical ingredients (APIs) supplied by U.S. or European Union manufacturers has declined from 90% two decades ago to 20% today, notes the author of a Perspective article (pp. 1773-7). FDA has responded by developing a method for prioritizing Good Manufacturing Practice (GMP) inspections that focuses on those establishments the agency believes most likely to have problems, the writer notes, adding: ìAlthough this represents a rational strategy for maximizing the effectiveness of screening within tight resource constraints, the evidence suggests that inspection needs have overwhelmed the agency’s capacity. A 2004 FDA report on the risk-based method indicated that the number of ‘registered human drug establishments’ had more than quadrupled during the previous 25 years, whereas the number of GMP inspections conducted dropped by more than 60%. As a result, the agency could not possibly achieve ‘uniformly intensive . . . inspectional coverageî for all facilities.’î (S. O. Schweitzer, UCLA, Los Angeles)
Playing ìKick the FDAî: Using incidents such as those related to use of contaminated heparin to attack FDA could have unintended adverse consequences, concludes the author of a second Perspectives piece (pp. 1774-5). Writing that placing the onus on FDA rather than manufacturers who choose to outsource production leads to an inappropriate financial burden for U.S. taxpayers, the author adds: ìIt is easier to attack the FDA than to assume one’s own share of responsibility. The press, for its part, frequently reports legislators’ criticisms of the agency without providing any analysis of their voting records on FDA appropriations. But the bigger scandal is Congress’s grossly inadequate funding of the agency, which demands swift and decisive action. No longer should our legislators be able to publicly excoriate FDA employees while ignoring their own complicity. No longer should any of us berate the FDA while failing to acknowledge that we are asking it to do more and more work with fewer and fewer resources. No longer should manufacturers be able to imply that inadequate FDA inspection is an excuse for adulteration of their product during manufacture. We must stop allowing the game of ‘kick the FDA’ to be risk-free to participants. The public’s health is at stake, and the time for adequate federal funding of the FDA is now.î (A. J. J. Wood, Cornell U., New York)

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

PNN Pharmacotherapy Line
Apr. 25, 2008 * Vol. 15, No. 81
Providing news and information about medications and their proper use

>>>Rheumatology Report
Source:
Apr. issue of Arthritis & Rheumatism (www3.interscience.wiley.com/journal/76509746/home; 2008; 58).
Abatacept for Rheumatoid Arthritis: During a 1-year extension of a previously published 1-year study of patients with rheumatoid arthritis, improvements seen with abatacept therapy were maintained, and radiographic films revealed an increasing inhibition of the agent on structural damage (pp. 953-63). ìOf 539 patients enrolled in the initial 1-year study, 488 completed 1 year of the long-term extension (2% discontinued for lack of efficacy),î write the researchers. ìAt 2 years, patients taking abatacept had maintained their responses on the American College of Rheumatology (ACR) improvement criteria and the Disease Activity Score in 28 joints (DAS28; using the C-reactive protein [CRP] level), as well as their physical function (according to the Health Assessment Questionnaire [HAQ] disability index [DI]) and health-related quality of life (HRQOL; assessed with the Short Form 36 [SF-36] health survey), that were observed at the end of the double-blind period (year 1 versus year 2 values were 81.9% versus 80.3% for ACR 20% improvement, 25.4% versus 30.9% for a DAS28 [CRP] of <2.6, 71.8% versus 66.8% for the HAQ DI, and 9.7 versus 10.6 and 7.3 versus 7.2, respectively, for the mean change in the physical and mental components summary scores of the SF-36). In the abatacept group, post hoc analysis demonstrated further inhibition of radiographic progression during year 2 (57% reduction in mean change of total score in year 2 versus year 1; P < 0.0001), and minimal radiographic progression was observed (mean change in total score from baseline was 1.1 and 1.6 at year 1 and 2, respectively). Rates of adverse events (AEs) and severe AEs were consistent throughout the cumulative period.î (J. M. Kremer, Albany Med. Coll., Albany, N.Y.; jkremer@joint-docs.com)
Golimumab for Active Rheumatoid Arthritis: In patients with active rheumatoid arthritis despite treatment with methotrexate, subcutaneous golimumab significantly reduced signs and symptoms of the disease and was generally well tolerated (pp. 964-75). Given with methotrexate, golimumab administered every 2 or 4 weeks through 48 weeks of the trial produced a 20% improvement in the American College of Rheumatology criteria at week 16 in 61% of patients, compared with 37% of those receiving methotrexate plus placebo. Patients on a higher dose of golimumab every 2 weeks had an even higher response rate, 79%. Serious adverse events occurred in 9% of those on golimumab and 6% of patients receiving placebo. (J. Kay, Mass. Genl. Hosp., Boston; jkay@partners.org)

>>>PNN NewsWatch
* FDA has approved methylnaltrexone bromide (Relistor, Wyeth) subcutaneous injection for treatment of opioid-induced constipation (OIC) in patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient. The safety and effectiveness of the drug was demonstrated in two randomized, double-blind, placebo-controlled, 4-month studies involving 287 participants. The median age of the study participants was 68 years, and 51% of the participants were women. In both studies, all patients had advanced late-stage illnesses with a life expectancy of less than 6 months. Before treatment with methylnaltrexone, participants had either fewer than three bowel movements in the week before treatment or no bowel movement for more than 2 days. Patients treated with methylnaltrexone had a significantly higher rate of elimination than those receiving placebo, and the drug did not interfere with pain relief. The safety and effectiveness of methylnaltrexone have not been studied in pediatric populations, and use of the drug beyond 4 months has not been studied. The recommended starting schedule is one dose every other day as needed for patients with late-stage advanced illness. Methylnaltrexone is not recommended for patients with known or suspected intestinal obstructions. Common adverse effects include abdominal pain, gas, nausea, dizziness and diarrhea. If severe diarrhea, vomiting, nausea, or abdominal pain occurs while taking methylnaltrexone, patients should discontinue use of the medication in consultation with their health professional. Wyeth expects to make the product available in the United States in early June.

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

PNN Pharmacotherapy Line
Apr. 28, 2008 * Vol. 15, No. 82
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Apr. 26 issue of Lancet (www.thelancet.com; 2008; 371).
NRTIs & MIs: Use of the nucleoside reverse transcriptase inhibitors abacavir and didanosine within the preceding 6 months was associated with an increased risk of myocardial infarction in 33,347 patients enrolled in the Data Collection on Adverse Events of Anti-HIV Drugs (D:ALaugh) study (pp. 1417-26). Poisson regression models revealed these relationships between medication use and events: ìOver 157,912 person–years, 517 patients had a myocardial infarction. We found no associations between the rate of myocardial infarction and cumulative or recent use of zidovudine, stavudine, or lamivudine. By contrast, recent—but not cumulative—use of abacavir or didanosine was associated with an increased rate of myocardial infarction (compared with those with no recent use of the drugs, relative rate 1.90, 95% CI 1.47–2.45 [p = 0.0001] with abacavir and 1.49, 1.14–1.95 [p = 0.003] with didanosine); rates were not significantly increased in those who stopped these drugs more than 6 months previously compared with those who had never received these drugs. After adjustment for predicted 10-year risk of coronary heart disease, recent use of both didanosine and abacavir remained associated with increased rates of myocardial infarction (1.49, 1.14–1.95 [p = 0.004] with didanosine; 1.89, 1.47–2.45 [p = 0.0001] with abacavir).î (J. D. Lundgren, U. Copenhagen, Copenhagen; jdl@cphiv.dk)

>>>BMJ Highlights
Source:
Apr. 26 issue of BMJ (www.bmj.org; 2008; 336).
Rapid Screening Tests for MRSA: Increased costs associated with use of rapid screening tests for methicillin-resistant Staphylococcus aureus are not likely justified, compared with alternative control measures, concludes a research study conducted in medical, surgical, elderly care, and oncology wards (pp. 927-30). Screening all patients for MRSA using rapid polymerase chain reaction screening tests, the investigators determined: ìOf 9,608 patients admitted to study wards, 8374 met entry criteria and 6,888 had full data (82.3%); 3,335 in the control arm and 3,553 in the rapid test arm. The overall MRSA carriage rate on admission was 6.7%. Rapid tests led to a reduction in median reporting time from admission, from 46 to 22 hours (P < 0.001). Rapid testing also reduced the number of inappropriate pre-emptive isolation days between the control and intervention arms (399 v 277, P < 0.001). This was not seen in other measurements of resource use. MRSA was acquired by 108 (3.2%) patients in the control arm and 99 (2.8%) in the intervention arm. When predefined confounding factors were taken into account the adjusted odds ratio was 0.91 (95% confidence interval 0.61 to 1.234). Rates of MRSA transmission, wound infection, and bacteraemia were not statistically different between the two arms.î (D. Jeyaratnam, King’s College Hosp. NHS Foundation Trust, London; dakshika.jeyaratnam@kcl.ac.uk)

>>>PNN JournalWatch
* Characteristics of Patients Receiving Pharmaceutical Samples and Association Between Sample Receipt and Out-of-Pocket Prescription Costs, in Medical Care, 2008; 46: 394–402. Reprints: G. C. Alexander, galexand@uchicago.edu
* What Does the Value of Modern Medicine Say About the $50,000 per Quality-Adjusted Life-Year Decision Rule?, in
Medical Care, 2008; 46: 349–56. Reprints: R. S. Braithwaite.
* Disparities In Human Resources: Addressing the Lack Of Diversity in the Health Professions, in
Health Affairs, 2008; 27: 413–22. Reprints: K. Grumbach.
* Late Extended Adjuvant Treatment with Letrozole Improves Outcome in Women with Early-Stage Breast Cancer Who Complete 5 Years of Tamoxifen, in
Journal of Clinical Oncology, 2008; 26: 1948–55. Reprints: P. Goss, pgoss@partners.org
* Asparaginase May Influence Dexamethasone Pharmacokinetics in Acute Lymphoblastic Leukemia, in
Journal of Clinical Oncology, 2008; 26: 1932–9. Reprints: M. V. Relling, mary.relling@stjude.org
* Efficacy and Safety of Fondaparinux and Enoxaparin for Acute Coronary Syndromes in CKD, in
American Journal of Kidney Diseases, 2008; 51: 719–23. Reprints: D. F. Brophy, dbrophy@vcu.edu
* Diabetes Insipidus With Deficient Thirst: Report of a Patient and Review of the Literature, in
American Journal of Kidney Diseases, 2008; 51: 851–9. Reprints: A. N. Mavrakis.

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

PNN Pharmacotherapy Line
Apr. 29, 2008 * Vol. 15, No. 83
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Apr. 28 issue of the Archives of Internal Medicine (http://archinte.ama-assn.org/current.dtl; 2008; 168).
Adjunctive Rifampin for Staph. aureus: Promising results with use of adjunctive rifampin in treatment of Staphylococcus aureus infections should be explored further in adequately powered clinical trials, authors of a review article conclude (pp. 805-19). Adding that in vitro tests are not reliable for determining whether the drug might be useful, the writers offered these details about their systematic review: ìThe methods of in vitro studies varied substantially among investigations. The effect of rifampin therapy was often inconsistent, it did not necessarily correlate with in vivo investigations, and findings seemed heavily dependent on the method used. In addition, the quality of data reporting in these investigations was often suboptimal. Animal studies tended to show a microbiologic benefit of adjunctive rifampin use, particularly in osteomyelitis and infected foreign body infection models; however, many studies failed to show a benefit of adjunctive therapy. Few human studies have addressed the role of adjunctive rifampin therapy. Adjunctive therapy seems most promising for the treatment of osteomyelitis and prosthetic device–related infections, although studies were typically underpowered and benefits were not always seen.î (L. G. Miller, lgmiller@ucla.edu)
Thiazolidinediones & Fracture Risk: Long-term use of thiazolidinediones are associated with increased risk of fractures, particularly of the hip and wrist, according to a case–control analysis of data on the U.K. General Practice Research Database (pp. 820-5). The investigators calculated odds ratios for fractures associated with use of rosiglitazone pioglitazone, other oral antidiabetic agents, or insulin, with these results: ìThere were 1020 case patients with an incident low-trauma fracture and 3728 matched controls. After adjustment for age, body mass index, other antidiabetic drugs, comedication, and comorbidities, the ORs for users of 8 or more thiazolidinedione prescriptions (corresponding to approximately 12–18 months of therapy) compared with nonuse was 2.43 (95% confidence interval [CI], 1.49–3.95). Rosiglitazone (OR, 2.38; 95% CI, 1.39–4.09) and pioglitazone (OR, 2.59; 95% CI, 0.96–7.01) were used more frequently by case patients with fracture (predominantly hip and wrist fractures) than by controls. The association was independent of patient age and sex and tended to increase with thiazolidinedione dose. No materially altered relative fracture risk was found in association with the use of other oral antidiabetic drugs.î (C. R. Meier, U. Hosp., Basel, Switzerland; meierch@uhbs.ch)
Alendronate & Atrial Fibrillation: The risk of new-onset atrial fibrillation is increased among women who have used alendronate, concludes a study of 719 patients and 966 controls at Group Health in Seattle (pp. 826-31). Data from 2001–04 show these trends: ìMore AF case patients than controls had ever used alendronate (6.5% [n = 47] vs 4.1% [n = 40]; P = .03). Compared with never use of any bisphosphonate, ever use of alendronate was associated with a higher risk of incident AF (odds ratio, 1.86; 95% confidence interval, 1.09–3.15) after adjustment for the matching variables, a diagnosis of osteoporosis, and a history of cardiovascular disease. Based on the population-attributable fraction, we estimated that 3% of incident AF in this population might be explained by alendronate use.î (S. R. Heckbert, heckbert@u.washington.edu)

>>>PNN NewsWatch
* Actavis Totowa LLC has issued a Class I nationwide recall of all strengths of Digitek, which is distributed by Mylan Pharmaceuticals Inc., under a ìBertekî label and by UDL Laboratories, Inc. under a ìUDLî label. The digoxin product is being recalled due to the possibility that tablets with double the appropriate thickness may contain twice the approved level of active ingredient.
* FDA has issued a nonapprovable letter for Merck’s new antidyslipidemic product,
niacin/laropiprant (Cordaptive), the Wall Street Journal reports.

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

PNN Pharmacotherapy Line
Apr. 30, 2008 * Vol. 15, No. 84
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
May issue of Diabetes Care (http://care.diabetesjournals.org/current.shtml; 2008; 31).
Including the Patient in Diabetes Performance Measures: Patient-centered, self-management measures should be added to major diabetes performance measures for a variety of reasons, authors of a commentary write (pp. 1046-50). Concluding that ìwhat gets measured, gets done,î the writers provide this summary of their advice: ìWe review the case for and propose a set of patient-centered, self-management indicators to be included as a standard part of diabetes quality indicators. The proposed indicators include: patient self-management goal(s), measures of health behaviors (e.g., healthy eating, medication taking, physical activity, and smoking status), quality of life, and patient-centered collaborative care. We discuss the evidence and the concerns about patient-report measures and summarize successful incorporation of such patient-centered measures in other countries and by the American Association of Diabetes Educators.î (R. E. Glasgow, Kaiser Permanente Colorado, Penrose; russg@re-aim.net)
Race, Medication Adherence, & Glycemic Control: Racial differences in A1C levels persist that are not explained by differences in medication adherence, a study shows (pp. 916-21). Among 467 black and 1,339 white patients with type 2 diabetes, newly initiated oral hypoglycemic medications showed these results over the first 12 months of therapy: ìAt initiation of therapy, black patients had higher average A1C values compared with whites (9.8 vs. 8.9, a difference of 0.88; P < 0.0001). Blacks had lower average medication adherence during the first year of therapy (72 vs. 78%; P < 0.0001). Although more frequent medication refills were associated with lower average A1C values, adjustment for adherence did not eliminate the black–white gap.î The authors suggest further research ìto explore possible genetic and environmental determinants of higher A1C among blacks at diagnosis, which may represent a critical period for more intensive intervention.î (A. S. Adams, aadams@hms.harvard.edu)
Acetylcysteine, Arginine Use in Diabetes with Hypertension: Long-term administration of N-acetylcysteine (NAC) and l-arginine (ARG) was well-tolerated and effective for improving endothelial function in 24 men with type 2 diabetes and hypertension (pp. 940-4). The beneficial mechanism appeared to be improved nitric oxide (NO) bioavailability through reduction of oxidative stress and increase of NO production, the researchers conclude, adding these details: ìThe NAC + ARG treatment caused a reduction of both systolic (P < 0.05) and diastolic (P < 0.05) mean arterial blood pressure, total cholesterol (P < 0.01), LDL cholesterol (P < 0.005), oxidized LDL (P < 0.05), high-sensitive C-reactive protein (P < 0.05), intracellular adhesion molecule (P < 0.05), vascular cell adhesion molecule (P < 0.01), nitrotyrosine (P < 0.01), fibrinogen (P < 0.01), and plasminogen activator inhibitor-1 (P < 0.05), and an improvement of the intima-media thickness during endothelial postischemic vasodilation (P < 0.02). HDL cholesterol increased (P < 0.05). No changes in other parameters studied were observed.î (V. Martina, U. Torino, Torino, Italy; valentino.martina@unito.it)

>>>PNN NewsWatch
* Lubiprostone (Amitiza; Sucampo, Takeda) has received FDA approval for an additional indication, treatment of irritable bowel syndrome with constipation in adult women. In two major studies involving 1,154 mostly women patients diagnosed with IBS-C, more patients treated with lubiprostone reported that their IBS symptoms were moderately or significantly relieved over a 12-week treatment period than patients who received placebo. The safety of long-term treatment was assessed in a study in which all patients were treated with lubiprostone for a duration that ranged from 9 to 13 months.
*
Hemoglobin-based blood substitutes are associated with increased risk of mortality and myocardial infarction, according to a meta-analysis released in advance of print by JAMA. In 16 trials of five different products tested in 3,711 patients, those receiving the products had a significant 30% increase in mortality (relative risk 95% CI, 1.05–1.61) and a 171% increase in risk of MIs (RR 95% CI, 1.67–4.40).

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

PNN Pharmacotherapy Line
May 1, 2008 * Vol. 15, No. 85
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
May 1 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2008; 358).
Treating Hypertension in the Very Old: Sustained-released indapamide administered with or without an ACE inhibitor proved beneficial in a group of 3,845 international patients over age 80 and with sustained systolic blood pressure of 160 mm Hg or more (pp. 1887-98). The Hypertension in the Very Elderly Trial (HYVET) patients from Europe, China, Australasia, and Tunisia took the diuretic agents in daily doses of 1.5 mg or matching placebo. Perindopril was later added for those not achieving a target blood pressure of 150/80 mm Hg, and these results were noted: ìThe active-treatment group (1,933 patients) and the placebo group (1,912 patients) were well matched (mean age, 83.6 years; mean blood pressure while sitting, 173.0/90.8 mm Hg); 11.8% had a history of cardiovascular disease. Median follow-up was 1.8 years. At 2 years, the mean blood pressure while sitting was 15.0/6.1 mm Hg lower in the active-treatment group than in the placebo group. In an intention-to-treat analysis, active treatment was associated with a 30% reduction in the rate of fatal or nonfatal stroke (95% confidence interval [CI], –1 to 51; P = 0.06), a 39% reduction in the rate of death from stroke (95% CI, 1 to 62; P = 0.05), a 21% reduction in the rate of death from any cause (95% CI, 4 to 35; P = 0.02), a 23% reduction in the rate of death from cardiovascular causes (95% CI, –1 to 40; P = 0.06), and a 64% reduction in the rate of heart failure (95% CI, 42 to 78; P < 0.001). Fewer serious adverse events were reported in the active-treatment group (358, vs. 448 in the placebo group; P = 0.001).î (N. S. Beckett, Imperial College, London)
This study begins to answer several important questions about hypertension in the very old, an editorialist writes (pp. 1958-60): ìThe results of HYVET prove that it is not too late to start antihypertensive therapy in older people and expands the upper limit of the age spectrum for which there is evidence from clinical trials of a treatment benefit. The question of the benefit, risk, and expense associated with therapy for young, low-risk patients who may need treatment for decades deserves attention. Current practice is based on incomplete evidence as well as speculation. The HYVET investigators deserve to be congratulated for persevering and ultimately succeeding in proving the benefit of treating hypertension in the very old.î (J. B. Kostis, U. Med. and Dentistry of New Jersey, New Brunswick)
Nonsurgical Treatment of Obesity: Appropriate interventions for patients with obesity who do not qualify for bariatric surgery are detailed in a Clinical Practice article (pp. 1941-50). Using the case of a 44-year-old woman with a body mass index of 32.7 kg/sq m as a springboard, the authors note, ìCurrent therapies for obesity remain inadequate. Although it is recognized that caloric restriction is key to short-term weight loss and that maintenance of weight loss depends on increases in physical activity, it remains uncertain how to facilitate adherence to the lifestyle changes required for sustained success. Translational studies are needed to determine whether the successful weight losses in studies of such interventions as the Diabetes Prevention Program can be achieved in the primary care setting, in commercial programs, or through Internet programs. Large studies involving long-term follow-up of patients after bariatric surgery have suggested significant reductions in the risk of cardiovascular events and death. Although it is logical to assume that weight loss and maintenance achieved through nonsurgical approaches should also reduce these risks, confirmatory data are currently lacking.î (Robert H. Eckel, U. Colorado, Aurora; robert.eckel@uchsc.edu)

>>>PNN NewsWatch
* Pharmacists are among the types of professionals being sought by FDA to fill some 1,300 new and vacant positions at agency offices in the Maryland cities of Rockville, Silver Spring, and College Park, as well as at district offices around the country and at newly opened offices overseas.

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

PNN Pharmacotherapy Line
May 2, 2008 * Vol. 15, No. 86
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
May issue of Pharmacotherapy (www.pharmacotherapy.org; 2008; 28).
Pharmacist Management of Statin Conversion: Patients switched from atorvastatin to alternative formulary regimens had better lipids control when the conversion was managed by clinical pharmacists rather than through usual care, researchers report (pp. 553-61). In a family medical center, 30 patients were switched by pharmacists from atorvastatin to simvastatin, rosuvastatin, or ezetimibe–simvastatin using an algorithm designed to achieve patient-specific goals for LDL cholesterol, and their outcomes were compared with these results among 87 patients whose transitions were managed through usual care: ìPrimary end points were LDL concentration and LDL goal attainment before and after conversion. Before and after conversion, respectively, mean LDL concentrations were 86.7 and 82.3 mg/dl in the therapeutic conversion group (p = 0.44) versus 78.3 and 85.2 mg/dl in the usual care group (p = 0.01). Percentages of patients attaining LDL goal were 80% before and 97% after conversion in the therapeutic conversion group (p = 0.04) compared with 90% before and 75% after conversion in the usual care group (p = 0.01).î (J. J. Saseen, U. Colorado, Aurora; joseph.saseen@uchsc.edu)
Body Mass & Arginine Vasopressin Response: Weight-based dosing of arginine vasopressin is not supported by a study of 66 mechanically ventilated patients receiving the agent for hemodynamic support during septic shock, as investigators determined that a fixed dose of 0.04 U/minute was adequate (pp. 591-9). Assessing the proportion of patients achieving a mean arterial pressure of 65 mm Hg or higher, magnitude of the change in MAP at 1 hour, and the need for additional rescue vasopressors. the researchers found these patterns among patients with body mass indexes in normal and three overweight/obese groups: ìThe four groups similarly achieved hemodynamic stability at 1 hour after the administration of arginine vasopressin (p = 0.41). We observed no significant differences among groups in the magnitude of MAP change (p = 0.62), need for rescue catecholamine vasopressors (p = 0.17), 28-day mortality rates (p = 0.31), or length of stay in the intensive care unit (p = 0.43).î (S. Lam, Columbia U. Med. Ctr., New York, sil9006@nyp.org)

>>>PNN NewsWatch
* FDA’s final analysis of certain flavors of ìTotal Body Formulaî and ìTotal Body Mega Formula,î previously reported to contain high levels of selenium (see PNN, Apr. 10), shows the products also have hazardous amounts of chromium, the agency reported yesterday. Excessive consumption of chromium can cause fatigue, muscle cramps, hyperactivity, hypoglycemia, renal failure, and liver toxicity. Excessive chromium intake also can interfere with certain medications. CDC reports that the number of confirmed cases of adverse reactions in consumers using these products has climbed to at least 195 individuals in Alabama, Florida, Georgia, Kentucky, Michigan, New Jersey, North Carolina, Tennessee, and Texas.
* A new boxed warning in the product labeling of
etanercept (Enbrel) warns of use-related infections, some of them serious enough to require hospitalizations, Amgen and Wyeth are reporting. The adverse reactions section of the labeling is also changed, with information added on global clinical studies and the rate of occurrence of tuberculosis in patients treated with etanercept. Patients should be screened for latent tuberculosis infection before beginning therapy with the drug and should be educated about the symptoms of infection and closely monitored for signs and symptoms of infection during and after treatment with the drug. Patients who develop an infection should be evaluated for appropriate antimicrobial treatment and, in patients who develop a serious infection, etanercept should be discontinued.
*
PNN is 14 today! The newsletter began as 1-page fax service—in a format it still uses—on May 2, 1994, and has since sent out nearly 3,400 morning issues by fax or e-mail.

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

PNN Pharmacotherapy Line
May 5, 2008 * Vol. 15, No. 87
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
May 3 issue of Lancet (www.thelancet.com; 2008; 371).
Genetic Basis of Osteoporosis: Identification of two genes that are associated with osteoporosis could open the way for screening for the disease, researchers conclude (pp. 1505-12). Noting that the genes are present in about 20% of whites, the investigators report these findings regarding single nucleotide polymorphisms (SNPs) among 2,094 women in a U.K. study and 6,463 individuals from three other European cohorts: ìWe identified genome-wide evidence for an association between bone mineral density and two SNPs (p < 510−8). The SNPs were rs4355801, on chromosome 8, near to the TNFRSF11B (osteoprotegerin) gene, and rs3736228, on chromosome 11 in the LRP5 (lipoprotein-receptor-related protein) gene. A non-synonymous SNP in the LRP5 gene was associated with decreased bone mineral density (rs3736228, p = 6.310−12 for lumbar spine and p = 1.910−4 for femoral neck) and an increased risk of both osteoporotic fractures (odds ratio [OR] 1.3, 95% CI 1.09–1.52, p = 0.002) and osteoporosis (OR 1.3, 1.08–1.63, p = 0.008). Three SNPs near the TNFRSF11B gene were associated with decreased bone mineral density (top SNP, rs4355801: p = 7.610−10 for lumbar spine and p = 3.310−8 for femoral neck) and increased risk of osteoporosis (OR 1.2, 95% CI 1.01–1.42, p = 0.038).î (T. D. Spector, St Thomas’ Hospital, London; tim.spector@kcl.ac.uk)
Pain in America: Pain is present among as many as one-fourth of Americans at any given point in time, according to a study based on telephone interviews (pp. 1519-25). Diary information was collected for a 24-hour period, and ratings of pain at three randomly selected 15-minute intervals during that period showed the following: ì3,982 individuals were interviewed (response rate 37%). After adjustment for weighting, 28.8% of men and 26.6% of women reported feeling some pain at sampled times. Those with lower income or less education spent a higher proportion of time in pain and reported higher average pain than did those with higher income or more education. The average pain rating increased with age, although it reached a plateau between the ages of about 45 years and 75 years, with little difference between men and women. Satisfaction with life or health and the pain indicators tended to move in opposite directions.î (A. B. Krueger, akrueger@princeton.edu)

>>>BMJ Highlights
Source:
Early-release article from and May 3 issue of BMJ (www.bmj.org; 2008; 336).
Antitubercular Resistance: In London, isoniazid resistance is increasing, especially among patients from sub-Saharan Africa and the Indian subcontinent, according to data from England, Wales, and Northern Ireland from 1998 to 2005 (doi:10.1136/bmj.39546.573067.25; M. E. Kruijshaar, Health Protection Agency, London; michelle.kruijshaar@hpa.org.uk).
Corticosteroid in ARDS: A meta-analysis of nine randomized trials of patients with acute respiratory distress syndrome concludes that corticosteroids lack support for a definitive role in treatment (pp. 1006-9). While morbidity may be reduced through use of the agents and the number of ventilator-free days is possibly increased, the authors also found that use of preventive steroids may increase the incidence of ARDS in critically ill adults. (J. L. Moran, Queen Elizabeth Hosp., Woodville, Australia; john.moran@adelaide.edu.au)

>>>PNN JournalWatch
* Beyond Cat Scratch Disease: Widening Spectrum of Bartonella henselae Infection, in Pediatrics, 2008; 121: e1413–25. Reprints: T. A. Florin, Children’s Hosp., Philadelphia.
* Amino Acid Requirements in Critically Ill Patients with Acute Kidney Injury Treated with Continuous Renal Replacement Therapy, in
Pharmacotherapy, 2008; 28: 600–13. Reprints: I. F. Btaiche, imadb@umich.edu
* Osteonecrosis of the Jaw in Patients Receiving Intravenous or Oral Bisphosphonates, in
Pharmacotherapy, 2008; 28: 667–77. Reprints: A. E. King, Thomas Jefferson U. Hosp., Philadelphia.
* Continued Challenges with the Use of Erythropoiesis-Stimulating Agents in Patients with Cancer: Perspectives and Issues on Policy-Guided Health Care, supplement to
Pharmacotherapy, 2008; 28 (5 suppl). Reprints: R. B. Arbuckle, U. Tex. M. D. Anderson Cancer Ctr., Houston.
* Cure, Care, and Commitment: What Can We Look Forward To?, in
Diabetes Care, 2008; 31: 1051–9. Reprints: R. A. Rizza, rizza.robert@mayo.edu

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

PNN Pharmacotherapy Line
May 6, 2008 * Vol. 15, No. 88
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release articles from and May 6 issue of the Annals of Internal Medicine (www.annals.org/current.shtml; 2008; 148).
Hydroxyurea in Sickle Cell Disease: In articles slated for June 17 publication, an NIH consensus conference examines use of hydroxyurea in treating adult patients with sickle cell disease and the evidence basis for this use (early release).
In an evidence-based review, authors provide these details about clinical trials of hydroxyurea: ìIn the single randomized trial, the hemoglobin level was higher in hydroxyurea recipients than placebo recipients after 2 years (difference, 6 g/L), as was fetal hemoglobin (absolute difference, 3.2%). The median number of painful crises was 44% lower than in the placebo arm. The 12 observational studies that enrolled adults reported a relative increase in fetal hemoglobin of 4% to 20% and a relative reduction in crisis rates by 68% to 84%. Hospital admissions declined by 18% to 32%. The evidence suggests that hydroxyurea may impair spermatogenesis. Limited evidence indicates that hydroxyurea treatment in adults with sickle cell disease is not associated with leukemia. Likewise, limited evidence suggests that hydroxyurea and leg ulcers are not associated in patients with sickle cell disease, and evidence is insufficient to estimate the risk for skin neoplasms, although these outcomes can be attributed to hydroxyurea in other conditions.î (S. Lanzkron, Johns Hopkins U., Baltimore)
NIH consensus conference panelists provide this bottom-line recommendation to clinicians: ìHydroxyurea is an important major advance in the treatment of sickle cell disease. Strong evidence supports the efficacy of hydroxyurea in adults to decrease severe painful episodes, hospitalizations, number of blood transfusions, and acute chest syndrome. Although the evidence for efficacy of hydroxyurea treatment for children is not as strong, the emerging data are encouraging. The current data on the risks of both short- and long-term harms of hydroxyurea therapy are reassuring, and the risks of hydroxyurea use in adults are acceptable compared with the risks of untreated sickle cell disease.î (
www.consensus.nih.gov; 888/644-2667)
Effectiveness of Osteoporosis Drugs: Risks of nonvertebral fractures were similar among 43,135 patients taking risedronate, raloxifene, or alendronate, but those on nasal calcitonin ìmay have a higher risk for nonvertebral fractures compared with alendronate recipients,î researchers conclude (pp. 637-46). The cohort study relied on data from two statewide pharmaceutical benefits programs for patients older than 65; mean age of patients in the analysis was 79 ± 6.9 years, and 96% of participants were women. ìA total of 1,051 nonvertebral fractures were observed within 12 months (2.62 fractures per 100 person–years),î the investigators write. ìNo large differences in fracture risk were found between risedronate (hazard ratio [HR], 1.01 [95% CI, 0.85 to 1.21]) or raloxifene (HR, 1.18 [CI, 0.96 to 1.46]) and alendronate. However, among those with a fracture history, raloxifene recipients experienced more nonvertebral fractures within 12 months (HR, 1.78 [CI, 1.20 to 2.63]) compared with alendronate recipients. Patients who received calcitonin experienced more nonvertebral fractures than those who received alendronate (HR, 1.40, [CI, 1.20 to 1.63]). Results were similar in sensitivity analyses that examined different lengths of follow-up (6 months and 24 months), were restricted to hip fracture as the outcome, and were completed in various subgroups.î (S. M. Cadarette, Brigham and Women’s Hosp., Boston)
The lack of head-to-head comparisons of medications continues to be problematic, an editorialist comments (pp. 702-3): ìThese results underscore, once more, the lack of good comparative data for choosing drug therapy. Cadarette and colleagues conclude, in accord with many previous articles and reviews, that more randomized, controlled studies are needed, implicitly acknowledging that their approach has important shortcomings. However, the dearth of head-to-head trials suggests that our system for evaluating health technology has not created the incentives to do these trials. Without incentives, the needed studies may never materialize, and we will continue to cope with uncertainty when choosing a drug.î (S. Malozowski,
sm87j@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 © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 7, 2008 * Vol. 15, No. 89
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
May 7 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2008; 299).
Folate/B Vitamins & Cardiovascular Disease: Daily ingestion of a combination tablet containing folic acid, vitamin B6, and vitamin B12 for a mean of 7.3 years failed to reduce cardiovascular events among 5,442 women health professionals at high risk for such diseases, compared with placebo, report researchers in the Women’s Antioxidant and Folic Acid Cardiovascular Study (WAFACS), despite a significant reduction in homocysteine level (pp. 2027-36). Based on a composite outcome of myocardial infarction, stroke, coronary revascularization, or CVD mortality, the investigators determined: ìCompared with placebo, a total of 796 women experienced a confirmed CVD event (406 in the active group and 390 in the placebo group). Patients receiving active vitamin treatment had similar risk for the composite CVD primary end point (226.9/10,000 person–years vs 219.2/10,000 person–years for the active vs placebo group; relative risk [RR], 1.03; 95% confidence interval [CI], 0.90–1.19; P = .65), as well as for the secondary outcomes including myocardial infarction (34.5/10,000 person–years vs 39.5/10,000 person–years; RR, 0.87; 95% CI, 0.63–1.22; P = .42), stroke (41.9/10,000 person–years vs 36.8/10,000 person–years; RR, 1.14; 95% CI, 0.82–1.57; P = .44), and CVD mortality (50.3/10,000 person–years vs 49.6/10,000 person–years; RR, 1.01; 95% CI, 0.76–1.35; P = .93). In a blood substudy, geometric mean plasma homocysteine level was decreased by 18.5% (95% CI, 12.5%–24.1%; P < .001) in the active group (n = 150) over that observed in the placebo group (n = 150), for a difference of 2.27 µmol/L (95% CI, 1.54–2.96 µmol/L).î (C. M. Albert, calbert@partners.org)
Questioning whether medicine has been ìwrong againî about the use of B vitamins for lowering homocysteine as a means of preventing CVD events, an editorialist writes (pp. 2086-7): ìB vitamin supplements cannot currently be recommended for the prevention of CVD events (with the exception of rare genetic disorders) and there is no role for routine screening for elevated homocysteine levels. However, ongoing clinical research should provide further evidence on whether there may be any role for homocysteine-lowering B vitamin supplements in CVD prevention and for the overall importance of homocysteine as a CVD risk factor.î (E. Lonn, Hamilton General Hosp., Hamilton, Ont., Canada;
lonnem@mcmaster.ca)
Smoking & Mortality in Women: Smoking-related deaths from vascular causes subside quickly when women stop smoking, while reductions in risk of lung diseases takes about 20 years to return to baseline, a study shows (pp. 2037-47). Data from the Nurses’ Health Study show these trends among 104,519 participants between 1980 and 2004: ìA total of 12,483 deaths occurred in this cohort, 4,485 (35.9%) among never smokers, 3,602 (28.9%) among current smokers, and 4,396 (35.2%) among past smokers. Compared with never smokers, current smokers had an increased risk of total mortality (HR, 2.81; 95% confidence interval [CI], 2.68–2.95) and all major cause-specific mortality. The HR for cancers classified by the 2004 surgeon general’s report to be smoking-related was 7.25 (95% CI, 6.43–8.18) and 1.58 (95% CI, 1.45–1.73) for other cancers. Compared with never smokers, the HR for colorectal cancer was 1.63 (95% CI, 1.29–2.05) for current smokers and 1.23 (95% CI, 1.02–1.49) for former smokers. A significant association was not observed for ovarian cancer. Significant trends were observed for earlier age at initiation of smoking for total mortality (P = .003), respiratory disease mortality (P = .001), and all smoking-related cancer mortality (P = .001). The excess risk for all-cause mortality decreases to the level of a never smoker 20 years after quitting, with different time frames for risk reduction observed across outcomes. Approximately 64% of deaths among current smokers and 28% of deaths among former smokers were attributable to cigarette smoking.î (S. A. Kenfield, skenfiel@hsph.harvard.edu)

>>>PNN NewsWatch
* Hydrox Labs has recalled lot number 26228 of Cardinal Health–labeled alcohol-free mouthwash because the product was found to contain Burkholderia cepacia.

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

PNN Pharmacotherapy Line
May 8, 2008 * Vol. 15, No. 90
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
May 8 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2008; 358).
Treatment of Gestational Diabetes: Oral metformin, administered as monotherapy or supplemented with insulin for treatment of gestational diabetes, was not associated with adverse perinatal outcomes but was preferred by patients, according to results of the Metformin in Gestational Diabetes Trial (pp. 2003-15). Providing results that are contrary to those of a previously published study, the authors share these details about a primary composite outcome of neonatal hypoglycemia, respiratory distress, need for phototherapy, birth trauma, 5-minute Apgar score less than 7, or prematurity among 751 women and their babies: ìOf the 363 women assigned to metformin, 92.6% continued to receive metformin until delivery and 46.3% received supplemental insulin. The rate of the primary composite outcome was 32.0% in the group assigned to metformin and 32.2% in the insulin group (relative risk, 1.00; 95% confidence interval, 0.90 to 1.10). More women in the metformin group than in the insulin group stated that they would choose to receive their assigned treatment again (76.6% vs. 27.2%, P < 0.001). The rates of other secondary outcomes did not differ significantly between the groups. There were no serious adverse events associated with the use of metformin.î (J. A. Rowan, Auckland City Hosp., Auckland, New Zealand; jrowan@internet.co.nz)
Commenting on this and an additional study that describes increased birth weight and cord-blood serum C-peptide levels among infants born to mothers with glucose levels below those that are diagnostic of gestational diabetes (pp. 1991-2002; B. E. Metzger, bem@northwestern.edu), editorialists comment on ìsetting limits, exploring treatments (pp. 2061-3): ìNot surprisingly, patients preferred pills to shots. The main question now is whether metformin is better or worse than glyburide, an acceptable alternative pill. On the basis of a previous trial in which 404 women with gestational diabetes achieved equivalent metabolic control using either glyburide supplemented as necessary with insulin or insulin alone, glyburide has replaced insulin as the first-line pharmacologic treatment of gestational diabetes in many practices. Although the two oral agents have not been directly compared in trials, it is notable that in the Metformin in Gestational Diabetes Trial, 46% of subjects in the metformin group required supplemental insulin, whereas in the previous trial, only 4% of women treated with glyburide needed insulin. These differences could be the result of varying populations and protocols but deserve further evaluation.î (J. L. Ecker, Massachusetts Genl. Hosp., Boston)
Early Repolarization Following Sudden Cardiac Arrest: An editorialist (pp. 2063-5) provides this advice to clinicians concerning a study showing increased prevalence of early repolarization among 206 patients resuscitated after life-threatening ventricular arrhythmia (pp. 2016-23; M. HaÔssaguerre, HÙpital Cardiologique du Haut-LÈvÍque, Bordeaux-Pessac, France; michel.haissaguerre@chu-bordeaux.fr): ìPlacement of implantable cardiac defibrillators is the standard of care for patients who have been resuscitated after life-threatening ventricular arrhythmia. Pharmacologically, only quinidine has been found to prevent arrhythmic recurrences, but few patients have undergone evaluation. In the study by HaÔssaguerre et al., a few patients who underwent catheter ablation at the area of ventricular ectopic activity had short-term elimination of arrhythmias. Long-term follow-up of such an intervention is needed, especially in relation to the size of the area showing changes in repolarization, along with analysis of the electrocardiographic characteristics of the ectopic beat.î (H. J. Wellens, Cardiovascular Research Institute Maastricht, Maastricht, the Netherlands)
Etiquette-Based Medicine: Imploring physicians to pay more attention to etiquette when interacting with patients, an author offers these tips—ones that are also appropriate for pharmacists and other health professionals—for a first meeting with a hospitalized patient (pp. 1988-9): Ask permission to enter room and wait for answer; introduce yourself, showing ID badge; shake hands (wear glove if needed); sit down, smiling if appropriate; briefly explain your role on the team; and ask the patient how he or she is feeling about being in the hospital. (M. W. Kahn, Harvard Med. Sch., Boston)

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

PNN Pharmacotherapy Line
May 9, 2008 * Vol. 15, No. 91
Providing news and information about medications and their proper use

>>>Infectious Diseases Report
Source:
June 1 issue of Clinical Infectious Diseases (www.journals.uchicago.edu/toc/cid/current; 2008; 46).
Telavancin for Skin Infections: Among 1,867 patients with complicated skin and skin-structure infections, including some infected with methicillin-resistant Staphylococcus aureus, once-daily intravenous telavancin was at least as effective as vancomycin, according to results of two Phase III trials of this investigational lipoglycopeptide (pp. 1683-93). ìIn the clinically evaluable population, at 7–14 days after receipt of the last antibiotic dose, success was achieved in 88% and 87% of patients who received telavancin and vancomycin, respectively (95% confidence interval for the difference, −2.1 to 4.6),î authors write. ìMethicillin-resistant Staphylococcus aureus was isolated at baseline from samples from 579 clinically evaluable patients. Among these patients with methicillin-resistant S. aureus infection, cure rates were 91% among patients who received telavancin and 86% among patients who received vancomycin (95% confidence interval for the difference, −1.1 to 9.3). Microbiologic eradication among patients infected with methicillin-resistant S. aureus was 90% in the telavancin treatment group and 85% in the vancomycin treatment group (95% confidence interval for the difference, −0.9 to 9.8). Therapy was discontinued because of adverse events in 8% and 6% of patients who received telavancin and vancomycin, respectively. Except for mild taste disturbance, nausea, vomiting, and serum creatinine concentration elevation in the telavancin treatment group and pruritus in the vancomycin treatment group, adverse events were similar between groups with regard to type and severity.î (M. E. Stryjewski, stryj001@mc.duke.edu)
Paratyphoid Fever in U.S. Travelers: A vaccine against paratyphoid fever is ìurgently needed,î investigators conclude, because of increasing incidence of this Salmonella infection in the U.S., especially among those who have traveled internationally (pp. 1656-63). Over a 12-month period in 2005–06, the authors found: ìOf 149 patients infected with Salmonella Paratyphi A, we obtained epidemiologic information for 89 (60%); 55 (62%) of 86 were hospitalized. Eighty-five patients (96%) reported having [traveled] internationally, and 80 (90%) had traveled to South Asia. Of the 146 isolates received at the CDC, 127 (87%) were nalidixic acid resistant; nalidixic acid resistance was associated with travel to South Asia (odds ratio, 17.0; 95% confidence interval, 3.8–75.9). All nalidixic acid–resistant isolates showed decreased susceptibility to ciprofloxacin (minimum inhibitory concentration, 0.12 µg/mL). Of 49 patients infected with Salmonella Paratyphi B, only 12 (24%) were confirmed to have Paratyphi B when tested at the CDC. Four (67%) of 6 patients were hospitalized, and 5 (83%) reported travel (4 to the Andean region of South America). One case of Salmonella Paratyphi C infection was reported in a traveler to West Africa with a urinary tract infection.î (S. K. Gupta, scg7@ug.cdc.gov)
Bactericidal Effects of Medical-Grade Honey: Bacteria, including some strains resistant to antibiotics, were killed by a medical-grade honey product, Revamil, in both in vitro experiments and topical challenges involving forearm colonization in healthy volunteers (pp. 1677-82). Researchers report these results: ìWith Bacillus subtilis as a test strain, we demonstrated that the variation in bactericidal activity of 11 batches of medical-grade honey was <2-fold. Antibiotic-susceptible and -resistant isolates of Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecium, Escherichia coli, Pseudomonas aeruginosa, Enterobacter cloacae, and Klebsiella oxytoca were killed within 24 h by 10%–40% (vol/vol) honey. After 2 days of application of honey, the extent of forearm skin colonization in healthy volunteers was reduced 100-fold (P < 0.001), and the numbers of positive skin cultures were reduced by 76% (P < 0.001).î (S. A. J. Zaat, Academic Med. Ctr., Amsterdam, The Netherlands; s.a.zaat@amc.uva.nl)

>>>PNN NewsWatch
* At an FDA hearing, an advisory panel recommended approval of fospropofol (Aquavan), a light-sedation agent that Eisai has proposed be used in patients undergoing procedures such as colonoscopies. Panelists voted against expanded use of Cephalon’s buccal fentanyl (Fentora) product.

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

PNN Pharmacotherapy Line
May 12, 2008 * Vol. 15, No. 92
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
May 10 issue of Lancet (www.thelancet.com; 2008; 371).
Stem Cells for Steroid-Resistant GVHD: Among 55 patients with steroid-resistant graft-versus-host disease, infusions of mesenchymal stem cells produced complete and partial responses in 30 and 9 patients, respectively (pp. 1579-86). ì27 patients received one dose, 22 received two doses, and six three to five doses of cells obtained from HLA-identical sibling donors (n = 5), haploidentical donors (n = 18), and third-party HLA-mismatched donors (n = 69),î the researchers report. ì30 patients had a complete response and nine showed improvement. No patients had side-effects during or immediately after infusions of mesenchymal stem cells. Response rate was not related to donor HLA-match. Three patients had recurrent malignant disease and one developed de-novo acute myeloid leukaemia of recipient origin. Complete responders had lower transplantation-related mortality 1 year after infusion than did patients with partial or no response (11 [37%] of 30 vs 18 [72%] of 25; p = 0.002) and higher overall survival 2 years after haemopoietic-stem-cell transplantation (16 [53%] of 30 vs four [16%] of 25; p = 0.018).î (K. Le Blanc, Karolinska Institutet, Stockholm, Sweden; katarina.leblanc@ki.se)
Enlisting Peers for Adolescent Smoking Cessation: Training influential students to act as peer supporters during informal interactions with classmates can reduce the incidence of smoking among adolescents, according to 1- and 2-year data from the ASSIST [A Stop Smoking In Schools Trial] program (pp. 1595-602). Using a block-randomization scheme, the investigators compared results with trained students versus usual smoking education in 59 English and Welsh schools with 10,730 students ages 12 and 13 years: ìThe odds ratio of being a smoker in intervention compared with control schools was 0.75 (95% CI 0.55–1.01) immediately after the intervention (n = 9,349 students), 0.77 (0.59–0.99) at 1-year follow-up (n = 9,147), and 0.85 (0.72–1.01) at 2-year follow-up (n = 8,756). The corresponding odds ratios for the high-risk group were 0.79 (0.55–1.13 [n = 3,561]), 0.75 (0.56–0.99 [n = 3,483]), and 0.85 (0.70–1.02 [n = 3,294]), respectively. In a three-tier multilevel model with data from all three follow-ups, the odds of being a smoker in intervention compared with control schools was 0.78 (0.64–0.96).î (R. Campbell, U. Bristol, Bristol, U.K.; Rona.Campbell@bristol.ac.uk)
Investigational Vaptans: Several investigational nonpeptide arginine-vasopressin antagonists should soon join conivaptan in clinical use, write authors of a review article (pp. 1624-32): ìRelcovaptan is a selective V1a-receptor antagonist, which has shown initial positive results in the treatment of Raynaud’s disease, dysmenorrhoea, and tocolysis. SSR-149415 is a selective V1b-receptor antagonist, which could have beneficial effects in the treatment of psychiatric disorders. V2-receptor antagonists—mozavaptan, lixivaptan, satavaptan, and tolvaptan—induce a highly hypotonic diuresis without substantially affecting the excretion of electrolytes (by contrast with the effects of diuretics). These drugs are all effective in the treatment of euvolaemic and hypervolaemic hyponatraemia. Conivaptan is a V1a/V2 non-selective vasopressin-receptor antagonist that has been approved by the US Food and Drug Administration as an intravenous infusion for the in-hospital treatment of euvolaemic or hypervolaemic hyponatraemia.î (G. Decaux, Erasmus U. Hosp., Brussels, Belgium; guy.decaux@skynet.be)

>>>PNN JournalWatch
* Premorbid IQ in Schizophrenia: A Meta-analytic Review, in American Journal of Psychiatry, 2008; 165: 579–87. Reprints: K. A. Woodberry.
* Three Phase II Cytokine Working Group Trials of gp100 (210M) Peptide Plus High-Dose Interleukin-2 in Patients with HLA-A2–Positive Advanced Melanoma, in
Journal of Clinical Oncology, 2008; 26: 2292–8. Reprints: J. A. Sosman, jeff.sosman@vanderbilt.edu
* High-Dose Melphalan and the Development of Hematopoietic Stem-Cell Transplantation: 25 Years Later, in
Journal of Clinical Oncology, 2008; 26: 2240–3. Reprints: H. M. Lazarus.
* Acute Febrile Respiratory Illness in the ICU: Reducing Disease Transmission, in
Chest, 2008; 133: 1221–31. Reprints: C. Sandrock, cesandrock@ucdavis.edu
* Forty-six Million Americans Have Arthritis: True or False?, in
Arthritis & Rheumatism, 2008; 58: 1220–5. Reprints: A. J. Silman, Arthritis Research Campaign, Chesterfield, U.K.; a.silman@arc.org.uk

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

PNN Pharmacotherapy Line
May 13, 2008 * Vol. 15, No. 93
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
May 12 issue of the Archives of Internal Medicine (http://archinte.ama-assn.org/current.dtl; 2008; 168).
Obesity & Cardiovascular Risk: While very common among most racial/ethnic groups in the U.S., obesity is not inevitable, according to data from the Multi-Ethnic Study of Atherosclerosis (pp. 928-35). Investigators found these relationships among demographics, body mass index, and cardiovascular disease in 6,814 middle-aged and elderly patients in 2000–02: ìA large proportion of white, African American, and Hispanic participants were overweight (60% to 85%) and obese (30% to 50%), while fewer Chinese American participants were overweight (33%) or obese (5%). Hypertension and diabetes were more prevalent in obese participants despite a much higher use of antihypertensive and/or antidiabetic medications. Obesity was associated with a greater risk of coronary artery calcium (17%), internal carotid artery intimal medial thickness greater than 80th percentile (32%), common carotid artery intimal medial thickness greater than 80th percentile (45%), and left ventricular mass greater than 80th percentile (2.7-fold greater) compared with normal body size. These associations persisted after adjustment for traditional CVD risk factors.î (G. L. Burke, Wake Forest U., Winston-Salem, N.C.; gburke@wfubmc.edu)
Metabolic Syndrome & Mortality in Older Adults: Compared with assessment of fasting glucose and blood pressure alone, presence of metabolic syndrome is of ìlimited utilityî in predicting total or cardiovascular mortality in older adults, researchers conclude (pp. 969-78). Among 4,258 U.S. adults who were 65 years or older and free of prevalent cardiovascular disease when they were admitted to the Cardiovascular Health Study in 1989–2004, these trends were observed based on MetS definitions provided by the Adult Treatment Panel III, the International Diabetes Foundation, and the World Health Organization: ìAt baseline (mean age, 73 years), 31% of men and 38% of women had MetS (ATPIII). During 15 years of follow-up, 2,116 deaths occurred. After multivariable adjustment, compared with persons without MetS, those with MetS had a 22% higher mortality (RR, 1.22; 95% confidence interval [CI], 1.11–1.34). Higher risk with MetS was confined to persons having elevated fasting glucose level (EFG) (defined as 110 mg/dL [6.1 mmol/L] or treated diabetes mellitus) (RR, 1.41; 95% CI, 1.27–1.57) or hypertension (RR, 1.26; 95% CI, 1.15–1.39) as one of the criteria; persons having MetS without EFG (RR, 0.97; 95% CI, 0.85–1.11) or MetS without hypertension (RR, 0.92; 95% CI, 0.71–1.19) did not have higher risk. Evaluating MetS criteria individually, we found that only hypertension and EFG predicted higher mortality; persons having both hypertension and EFG had 82% higher mortality (RR, 1.82; 95% CI, 1.58–109). Substantially higher proportions of deaths were attributable to EFG and hypertension (population attributable risk fraction [PAR%], 22.2%) than to MetS (PAR%, 6.3%). Results were similar when we used WHO or IDF criteria, when we evaluated different cut points of each individual criterion, and when we evaluated CVD mortality.î (D. Mozaffarian, dmozaffa@hsph.harvard.edu)
Counseling Patients for Home Exercise: In 224 aging male veterans, a relatively brief counseling session significantly increased time spent in and intensity level of home-based walking and strength exercise programs (pp. 979-86). During primary care visits, patients were randomized to either counseling for exercise or a discussion of a health topic of their choice. Results of the interventions at 0, 1, and 5 months showed significantly greater time spent in exercise and more frequent moderate- and higher-intensity physical activity. (P. M. Dubbert, patricia.dubbert@med.va.gov)

>>>PNN NewsWatch
* FDA has approved a formulation of the genetically engineered version of Factor VIIa (NovoSeven RT, Novo Nordisk) that can be stored at room temperature for up to 2 years and several generic forms of ropinirole.

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

PNN Pharmacotherapy Line
May 14, 2008 * Vol. 15, No. 94
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
May 14 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2008; 299).
Clopidogrel & Fistula Thrombosis in Hemodialysis: Early thrombosis of new arteriovenous fistulas created for hemodialysis was reduced by clopidogrel therapy, but the drug had no effect on the proportion of fistulas that became suitable for dialysis, researchers report (pp. 2164-71). At nine U.S. centers in 2003–07, 877 patients were followed for 150–180 days after fistula creation or 30 days after dialysis initiation, whichever came first, with these results: ìFistula thrombosis occurred in 53 (12.2%) participants assigned to clopidogrel compared with 84 (19.5%) participants assigned to placebo (relative risk, 0.63; 95% confidence interval, 0.46–0.97; P = .018). Failure to attain suitability for dialysis did not differ between the clopidogrel and placebo groups (61.8% vs 59.5%, respectively; relative risk, 1.05; 95% confidence interval, 0.94–1.17; P = .40).î (L. M. Dember, Boston U., Boston; ldember@bu.edu)
Calling for researchers to ìstep up to the plateî and conduct more and better investigations in patients on dialysis, an editorialist describes these areas of possible focus (pp. 2205-7): ìAlthough important, vascular access is just one of many aspects of hemodialysis care in which there is little evidence to defend contemporary practices. Other recent trials conducted in dialysis patients have also failed to show a benefit of the experimental therapy despite strong a priori rationale, which has been discouraging for clinicians and may have contributed to a sense of therapeutic nihilism. However, this skepticism must not affect the resolve of the nephrology community to conduct and recruit to future trials (or the willingness of funding agencies to pay for them). ‘Negative’ trials move the field forward by preventing needless use of unhelpful or possibly harmful treatments and by informing future research. Therefore, the real barrier to improving the care of dialysis patients is not the failure of past trials to find a statistically significant result, but rather the striking paucity of randomized studies.î (M. Tonelli, U. Alberta, Edmonton)
Complementary Medicine After Brain Death: Ethical considerations are discussed and other aspects presented of an unusual case in which administration of an intravenous Chinese medical substance was requested in a 19-year-old woman who was brain dead following postoperative intracranial hemorrhage (pp. 2188-93). ìThe treating team wanted to respect the family’s cultural values and recognized that administration of the traditional medication posed no risks to the (dead) patient,î write the authors. ìIn addition, the clinical team thought that a limited administration would help the family come to terms with the patient’s death. The ethics consultation team concluded that ‘given the psychological benefits to the family Ö and the absence of risk to the patient’ (since she was dead), it was permissible for the team to accommodate the family’s request so long as clear time limits were in place (2–3 days maximum).î (D. Wendler, dwendler@cc.nih.gov)
Bar-Coded Medication Administration: Calling bar-coded medication administration (BCMA) systems ìa last line of defense against medication errors [that] warrant greater advocacy and implementation,î authors of a Commentary article call for action by hospitals (pp. 2200-2): ìAlthough care must be taken to avoid hindering progress, the health care system can no longer afford to defer the solution at hand. Moreover, funding agencies should prioritize research into BCMA implementation strategies to optimize its benefits and minimize potential downsides, as well as support efforts to develop new and more effective electronic medication administration technologies.
ìNurses have long served as the last line of defense against medication errors. The health care system must wait no longer to provide them, and all patients, with the systematic safety net that they deserve.î (E. Etchells,
edward.etchells@sunnybrook.ca)

>>>PNN NewsWatch
* In recognition of May being Asthma and Allergy Awareness Month, FDA published a safety update on its Web site covering incorrect use of formoterol fumarate inhalation powder (Foradil Aerolizer), suicidality and behavior/mood changes with montelukast (Singulair), safety of long-acting beta agonists, and anaphylaxis and omalizumab (Xolair).

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

PNN Pharmacotherapy Line
May 15, 2008 * Vol. 15, No. 95
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Early-release articles from and May 15 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2008; 358).
Aprotinin Study Results & Complete Market Withdrawal: Final results of the Blood Conservation Using Antifibrinolytics in a Randomized Trial (BART) were released yesterday in advance of print publication, and they confirm the increase in 30-day mortality with aprotinin found in a preliminary analysis (see PNN, Oct. 26, 2007; doi: 10.1056/NEJMoa0802395). As a result, Bayer announced that it is pulling remaining Trasylol stock from the U.S. market, extending a marketing suspension instituted last fall (see PNN, Nov. 5, 2007).
BART, a comparison of aprotinin, tranexamic acid, and aminocaproic acid in 2,331 high-risk cardiac surgery patients, showed these results in the final analysis: ìThe trial was terminated early because of a higher rate of death in patients receiving aprotinin. A total of 74 patients (9.5%) in the aprotinin group had massive bleeding, as compared with 93 (12.1%) in the tranexamic acid group and 94 (12.1%) in the aminocaproic acid group (relative risk in the aprotinin group for both comparisons, 0.79; 95% confidence interval [CI], 0.59 to 1.05). At 30 days, the rate of death from any cause was 6.0% in the aprotinin group, as compared with 3.9% in the tranexamic acid group (relative risk, 1.55; 95% CI, 0.99 to 2.42) and 4.0% in the aminocaproic acid group (relative risk, 1.52; 95% CI, 0.98 to 2.36). The relative risk of death in the aprotinin group, as compared with that in both groups receiving lysine analogues, was 1.53 (95% CI, 1.06 to 2.22).î (P. C. HÈber, Ottawa Health Res. Ins., Ottawa, Ont., Canada;
paul.hebert@cma.ca)
Editorialists provide this denouement in what they predict will be ìthe final chapterî for this drug (10.1056/NEJMe0803514): ìIn all likelihood, this is the end of the aprotinin story. What are the lessons we can learn with regard to future testing of hemostatic agents? First, there must be less emphasis on comparisons of new agents with placebo and more emphasis on adequately powered, head-to-head comparisons with other available drugs. Second, although blood loss in the setting of cardiac surgery is of undisputed clinical importance, it has some of the characteristics of a surrogate end point. Just as is the case for antidiabetic agents, nonsteroidal antiinflammatory drugs, weight-loss drugs, and therapies to prevent reocclusion of coronary arteries, antifibrinolytic drugs cannot be judged solely by their effects on the primary physiological target. Evaluation of future agents for preventing blood loss in cardiac surgery must include effects on mortality and other clinical end points.î (W. A. Ray, Vanderbilt U., Nashville)
Class-Sparing HIV Therapy: An initial antiretroviral regimen that spares nucleoside reverse-transcriptase inhibitors was effective but induced more drug resistance, report researchers who studied 797 patients with HIV type 1 infection (pp. 2095-106). Concluding that their findings ìhighlight the complexity of choosing initial therapy,î the authors provide these details about those receiving efavirenz plus two NRTIs (efavirenz group), lopinavir–ritonavir plus two NRTIs (lopinavir–ritonavir group), and lopinavir–ritonavir plus efavirenz (NRTI-sparing group): ìAt a median follow-up of 112 weeks, the time to virologic failure was longer in the efavirenz group than in the lopinavir–ritonavir group (P = 0.006) but was not significantly different in the NRTI-sparing group from the time in either of the other two groups. At week 96, the proportion of patients with fewer than 50 copies of plasma HIV-1 RNA per milliliter was 89% in the efavirenz group, 77% in the lopinavir–ritonavir group, and 83% in the NRTI-sparing group (P = 0.003 for the comparison between the efavirenz group and the lopinavir–ritonavir group). The groups did not differ significantly in the time to discontinuation because of toxic effects. At virologic failure, antiretroviral resistance mutations were more frequent in the NRTI-sparing group than in the other two groups.î (S. A. Riddler, riddler@dom.pitt.edu)
Vaccines & Autism: The mixed messages generated by the compensation provided to a child with autism under the Vaccine Injury Compensation Program and the subsequent clarifying statements of the CDC are analyzed in a Perspective article (pp. 2089-91; P. A. Offit, Children’s Hosp., 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 © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 16, 2008 * Vol. 15, No. 96
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
May 20 issue of the Journal of the American College of Cardiology (http://content.onlinejacc.org/current.dtl; 2008; 51).
Genetic Effects on Clopidogrel Efficacy: Patients with at least one CYP2C19*2 allele are at greater risk for high (>14%) residual platelet aggregation while receiving clopidogrel, and this high-on RPA is associated with adverse clinical outcomes at 1 year after stent placement, according to findings from the EXCELSIOR (Effect of Clopidogrel Loading and Risk of PCI) trial (pp. 1925-34). Among 797 consecutive patients undergoing percutaneous coronary intervention who received clopidogrel 600 mg loading dose followed by 75 mg maintenance dose, these 1-year trends were noted: ìOf the patients included, 552 (69.3%) were CYP2C19 wild-type homozygotes (*1/*1) and 245 (30.7%) carried at least one *2 allele. Residual platelet aggregation at baseline did not differ significantly between genotypes. On clopidogrel, RPA was significantly (p < 0.001) higher in *2 carriers than in wild-type homozygotes (23.0% [interquartile range (IQR) 8.0% to 38.0%] vs. 11.0% [IQR 3.0% to 28.0%] after loading; 11.0% [IQR 5.0% to 22.0%] vs. 7.0% [IQR 3.0% to 14.0%] at pre-discharge). Between *2 carriers and wild-type homozygotes, we found significant (p < 0.001) differences in the proportion of patients with RPA >14%, both after loading (62.4% vs. 43.4%) and at pre-discharge (41.3% vs. 22.5%). Residual platelet aggregation >14% at pre-discharge incurred a 3.0-fold increase (95% confidence interval 1.4 to 6.8; p = 0.004) in the 1-year incidence of death and myocardial infarction.î (D. Trenk, Herz-Zentrum Bad Krozingen, Bad Krozingen, Germany; dietmar.trenk@herzzentrum.de)
Intensive LDL Cholesterol Reduction: Major cardiovascular events were lowered by 27% and the need for repeat revascularization by 30% in patients on intensive LDL-cholesterol lowering with atorvastatin 80 mg/day, according to a post-hoc analysis from the TNT (Treating to New Targets) study (pp. 1938-43). Based on data from 10,001 patients with documented coronary diseases (including 4,654 patients who had previous coronary artery bypass grafting surgery) for a median of 4.9 years, the investigators determined: ìA first major cardiovascular event occurred in 11.4% of the patients with prior CABG and 8.5% of those without prior CABG (p < 0.001). In CABG patients, mean LDL-cholesterol levels at study end were 79 mg/dl in the 80-mg arm and 101 mg/dl in the 10-mg arm, and the primary event rate was 9.7% in the 80-mg arm and 13.0% in the 10-mg arm (hazard ratio 0.73, 95% confidence interval 0.62 to 0.87, p = 0.0004). Repeat revascularization during follow-up, either CABG or percutaneous coronary intervention, was performed in 11.3% of the CABG patients in the 80-mg arm and 15.9% in the 10-mg arm (hazard ratio 0.70, 95% confidence interval 0.60 to 0.82, p < 0.0001).î (D. D. Waters, dwaters@medsfgh.ucsf.edu)

>>>Allergy/Immunology Report
Source:
May Journal of Allergy and Clinical Immunology (www.jacionline.org/current; 2008; 121).
Obesity & Asthma: In a review article, an author explores potential connections between asthma and obesity (pp. 1087-93): ìEpidemiologic data indicate that obesity increases the prevalence and incidence of asthma and reduces asthma control. Obese mice exhibit innate airway hyperresponsiveness and augmented responses to certain asthma triggers, further supporting a relationship between obesity and asthma.... In obesity, lung volume and tidal volume are reduced, events that promote airway narrowing. Obesity also leads to a state of low-grade systemic inflammation that may act on the lung to exacerbate asthma. Obesity-related changes in adipose-derived hormones, including leptin and adiponectin, may participate in these events. Comorbidities of obesity, such as dyslipidemia, gastroesophageal reflux, sleep-disordered breathing, type 2 diabetes, or hypertension may provoke or worsen asthma. Finally, obesity and asthma may share a common etiology, such as common genetics, common in utero conditions, or common predisposing dietary factors. Novel therapeutic strategies for treatment of the obese patient with asthma may result from an increased understanding of the mechanisms underlying this relationship.î (S. A. Shore, sshore@hsph.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 © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 19, 2008 * Vol. 15, No. 97
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Early-release articles from Lancet (www.thelancet.com; 2008; 371).
Risks of Perioperative Beta-Blockers: Use of perioperative beta-blocker prophylaxis in patients undergoing noncardiac surgery cannot be assumed to be without risks and large randomized trials of the intervention are needed, according to investigators from the PeriOperative ISchemic Evaluation (POISE) trial (doi: 10.1016/S0140-6736(08)60601-7). Researchers randomized 8,351 surgical patients with or at risk of atherosclerotic disease to extended-release metoprolol succinate or placebo, with therapy beginning 2–4 hours before noncardiac surgery and continuing for 30 days. Data were analyzed for a primary endpoint of a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal cardiac arrest: ìFewer patients in the metoprolol group than in the placebo group reached the primary endpoint (244 [5.8%] patients in the metoprolol group vs 290 [6.9%] in the placebo group; hazard ratio 0.84, 95% CI 0.70–0.99; p = 0.0399). Fewer patients in the metoprolol group than in the placebo group had a myocardial infarction (176 [4.2%] vs 239 [5.7%] patients; 0.73, 0.60–0.89; p = 0.0017). However, there were more deaths in the metoprolol group than in the placebo group (129 [3.1%] vs 97 [2.3%] patients; 1.33, 1.03–1.74; p = 0.0317). More patients in the metoprolol group than in the placebo group had a stroke (41 [1.0%] vs 19 [0.5%] patients; 2.17, 1.26–3.74; p = 0.0053).î (P. J. Devereaux, philipj@mcmaster.ca)
Editorialists ascribe these implication of this study (doi: 10.1016/S0140-6736(08)60662-5): ìThe over-riding theme is that tachycardia caused by perioperative events, such as bleeding, hypovolaemia, inadequate control of pain, or infection, should not be initially treated with additional beta-blocker therapy. The underlying cause of these conditions should be treated first. If tachycardia persists, then we recommend that a beta-blocker can be used cautiously in high-risk patients with proven or suspected coronary artery disease, preferably supervised in the perioperative setting by physicians who have experience with perioperative haemodynamics, such that hypotension and other haemodynamic aberrations which might have led to the increased incidence of stroke or septic death are avoided.î (L. A. Fleisher,
Lee.fleisher@uphs.upenn.edu)

>>>BMJ Highlights
Source:
May 17 issue of BMJ (www.bmj.org; 2008; 336).
Nonadherence with Antihypertensive Therapy: Poor results with antihypertensive therapy may be caused by patients both discontinuing therapy and failing to take once-daily medications as prescribed, according to a longitudinal analysis of clinical-study databases from 1989 to 2006 (pp. 1114-7): ìThe database contained dosing histories of 4,783 patients with hypertension. The data came from 21 phase IV clinical studies, with lengths ranging from 30 to 330 days and involving 43 different antihypertensive drugs, including angiotensin II receptor blockers (n = 2,088), calcium channel blockers (n = 937), angiotensin converting enzyme inhibitors (n = 665), beta-blockers (n = 195), and diuretics (n = 155). About half of the patients who were prescribed an antihypertensive drug had stopped taking it within one year. On any day, patients who were still engaged with the drug dosing regimen omitted about 10% of the scheduled doses: 42% of these omissions were of a single day’s dose, whereas 43% were part of a sequence of several days (three or more days—that is, drug ìholidaysîWinking. Almost half of the patients had at least one drug holiday a year. The likelihood that a patient would discontinue treatment early was inversely related to the quality of his or her daily execution of the dosing regimen.î (B. Vrijens, Pharmionic Res. Ctr., VisÈ, Belgium; bernard.vrijens@pharmionic.com)

>>>PNN JournalWatch
* Autonomic Ganglia: Target and Novel Therapeutic Tool, in Neurology, 2008; 70: 1926–32. Reprints: P. A. Low, low@mayo.edu
* Glucose-Insulin-Potassium for Acute Myocardial Infarction: Continuing Controversy Over Cardioprotection, in
Circulation, 2008; 117: 2523–33. Reprints: R. A. Kloner.
* Magnetic Resonance Imaging Characterization of Brain Structure and Function in Mild Cognitive Impairment: A Review, in
Journal of the American Geriatrics Society, 2008; 56: 920–34. Reprints: M. L. Ries, mlr@medicine.wisc.edu

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

PNN Pharmacotherapy Line
May 20, 2008 * Vol. 15, No. 98
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release articles from and May 20 issue of the Annals of Internal Medicine (www.annals.org/current.shtml; 2008; 148).
Sequential H. pylori Therapy: Sequential regimens eradicate Helicobacter pylori at higher rates than do standard regimens, according to a meta-analysis of 10 trials (early release). The trials, conducted mostly in Italy, compared sequential regimens—those using 5 days of treatment with a proton-pump inhibitor and 1 antibiotic (usually amoxicillin) followed by 5-day treatment with the proton-pump inhibitor and 2 other antibiotics (usually clarithromycin and a 5-nitroimidazole)—with standard triple-therapy regimens for 7 or 10 days. Results showed: ìThe crude rates of H. pylori eradication in 10 RCTs involving 2,747 patients were 93.4% (95% CI, 91.3% to 95.5%) for sequential therapy (n = 1,363) and 76.9% (CI, 71.0% to 82.8%) for standard triple therapy (n = 1,384) (relative risk reduction, 71% [CI, 64% to 77%]; absolute risk reduction, 16 percentage points [CI, 14 to 19 percentage points]). The median rates of adherence were 97.4% (range, 90.0% to 98.9%) for sequential therapy and 96.8% (range, 93.0% to 100%) for standard therapy. Sequential therapy appeared superior in prespecified sensitivity (subgroup) analyses stratified by trial quality; smoking status; diagnosis (ulcer disease or nonulcer dyspepsia); resistance to clarithromycin, imidazoles, or both; duration of triple therapy; and method of diagnosis. Both treatments had similar side effect profiles.î (C. W. Howden, c-howden@northwestern.edu)
An editorialist suggests special packaging to increase patient adherence with sequential regimens (early release): ìHow should one implement this regimen when all these drugs are generic? Because the sequential therapy seems so cost-effective, prescribers could make up special individual patient packs to enhance adherence. Sequential treatment may take up some extra physician time initially, but the time will be well-invested because fewer patients need second and third attempts.î (B. Marshall, U. Western Australia, Nedlands, Australia;
admin@hpylori.com.au)
Uncertainty About Uncontrolled Blood Pressure: Clinical uncertainty about blood pressure measurements frequently led prescribers to not intensify treatment in one-half of patients with diabetes presenting with substantially elevated blood pressures, researchers report (pp. 717-27). At nine VA facilities, 1,169 patients with diabetes were seen by 92 primary care providers, with these results: ìOverall, 573 (49%) patients had a blood pressure treatment change at the visit. The following factors made treatment change less likely: repeated blood pressure by provider recorded as less than 140/90 mm Hg versus 140/90 mm Hg or greater or no recorded repeated blood pressure (13% vs. 61%; P < 0.001); home blood pressure reported by patients as less than 140/90 mm Hg versus 140/90 mm Hg or greater or no recorded home blood pressure (18% vs. 52%; P < 0.001); provider systolic blood pressure goal greater than 130 mm Hg versus 130 mm Hg or less (33% vs. 52%; P = 0.002); discussion of conditions unrelated to hypertension and diabetes versus no discussion (44% vs. 55%; P = 0.008); and discussion of medication issues versus no discussion (23% vs. 52%; P < 0.001).î (E. A. Kerr, kerr@umich.edu)
Editorialists call for an end to the ìclinical inertiaî that is preventing prescribers from treating elevated blood pressure more aggressively, adding that a ìnew paradigmî will be needed (pp. 783; L. S. Phillips).

>>>PNN NewsWatch
* Used in some pregnant women despite a Category D rating, mycophenolate mofetil (MMF) can produce serious congenital anomalies, including microtia and cleft lip and palate, following exposure to during pregnancy, FDA warned yesterday. MMF, the active drug substance in CellCept (Roche), is an ester of the active metabolite mycophenolic acid, the active drug substance in Myfortic (Novartis). In most reports, mothers were taking MMF following an organ transplant to prevent organ rejection. However, some mothers taking MMF were being treated for immune-mediated conditions such as systemic lupus erythematosus and erythema multiforme, FDA added. Treatment began before their pregnancies and continued into the first trimester or until the pregnancy was detected.

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

PNN Pharmacotherapy Line
May 21, 2008 * Vol. 15, No. 99
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
May 21 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2008; 299).
Improving Sepsis Care: At 59 medical–surgical intensive care units across Spain, improved guideline compliance and lower hospital mortality initially followed a national educational effort (pp. 2294-303). Compliance rate was low, however, and improvement produced by the ìbundles of careî program (consisting of a resuscitation bundle of six tasks to begin immediately and be accomplished within 6 hours and a management bundle of four tasks to be completed within 24 hours) lapsed within 1 year, the authors noted, adding these results: ìPatients included before and after the intervention were similar in terms of age, sex, and Acute Physiology and Chronic Health Evaluation II score. At baseline, only 3 process-of-care measurements (blood cultures before antibiotics, early administration of broad-spectrum antibiotics, and mechanical ventilation with adequate inspiratory plateau pressure) ... had compliance rates higher than 50%. Patients in the postintervention cohort had a lower risk of hospital mortality (44.0% vs 39.7%; P = .04). The compliance with process-of-care variables also improved after the intervention in the sepsis resuscitation bundle (5.3% [95% confidence interval [CI], 4%–7%] vs 10.0% [95% CI, 8%–12%]; P < .001) and in the sepsis management bundle (10.9% [95% CI, 9%–13%] vs 15.7% [95% CI, 14%–18%]; P = .001). Hospital length of stay and ICU length of stay did not change after the intervention. During long-term follow-up, compliance with the sepsis resuscitation bundle returned to baseline but compliance with the sepsis management bundle and mortality remained stable with respect to the postintervention period.î (R. Ferrer, Hospital de Sabadell, Sabadell, Barcelona, Spain; rferrer@tauli.cat)

>>>Gastroenterology Report
Source:
May issue of Gastroenterology (www.gastrojournal.org; 2008; 134).
Efficacy of Terlipressin: Two research articles report clinical results with the vasopressin analogue terlipressin.
Among 46 patients with cirrhosis and hepatorenal syndrome, terlipressin plus albumin was significantly more effective than albumin alone for improving renal function (pp. 1352-9). Concluding that larger trials of the agent are warranted in an effort to explore a survival advantage provided by the agent, the researchers report these results for up to 15 days of treatment: ìImprovement of renal function occurred in 10 patients (43.5%) treated with terlipressin and albumin compared with 2 patients (8.7%) treated with albumin alone (P = .017). Independent predictive factors of improvement of renal function were baseline urine volume, serum creatinine and leukocyte count, and treatment with terlipressin and albumin. Survival at 3 months was not significantly different between the 2 groups (terlipressin and albumin: 27% vs albumin 19%, P = .7). Independent predictive factors of 3-month survival were baseline model for end-stage liver disease score and improvement of renal function. Cardiovascular complications occurred in 4 patients treated with albumin alone and in 10 patients treated with terlipressin and albumin, yet permanent terlipressin withdrawal was required in only 3 cases.î (P. GinËs, U. Barcelona, Barcelona, Spain;
pgines@clinic.ub.es)
Terlipressin plus albumin was effective among 56 patients with hepatorenal syndrome type 1, concludes a second comparison with placebo plus albumin (pp. 1352-9). ìTreatment success with terlipressin was double that with placebo (25% vs 12.5%, P = .093),î the investigators noted of their 14-day trial. ìSCr level improved from baseline to day 14 on terlipressin (−0.7 mg/dL) as compared with placebo (0 mg/dL), P < .009. Terlipressin was superior to placebo for HRS reversal (34% vs 13%, P = .008), defined by decrease in SCr level
1.5 mg/dL. Overall and transplantation-free survival was similar between study groups; HRS reversal significantly improved survival at day 180. One nonfatal myocardial infarction occurred with terlipressin, but the total adverse event rate was similar to placebo.î (A. J. Sanyal, ajsanyal@hsc.vcu.edu)

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

PNN Pharmacotherapy Line
May 22, 2008 * Vol. 15, No. 100
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
May 22 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2008; 358).
Bivalirudin During PCI for MI: Among 3,602 patients with ST-segment elevation myocardial infarction who presented within 12 hours symptom onset and were undergoing primary percutaneous coronary intervention, anticoagulation with bivalirudin significantly reduced 30-day rates of major bleeding and adverse clinical events, compared with heparin plus glycoprotein IIb/IIIa inhibitors (pp. 2218-30). In the open-label HORIZONS-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) trial, major bleeding and net adverse clinical events (major bleeding or major adverse cardiovascular events, including death, reinfarction, target-vessel revascularization for ischemia, and stroke within 30 days) showed these trends: ìAnticoagulation with bivalirudin alone, as compared with heparin plus glycoprotein IIb/IIIa inhibitors, resulted in a reduced 30-day rate of net adverse clinical events (9.2% vs. 12.1%; relative risk, 0.76; 95% confidence interval [CI] 0.63 to 0.92; P = 0.005), owing to a lower rate of major bleeding (4.9% vs. 8.3%; relative risk, 0.60; 95% CI, 0.46 to 0.77; P < 0.001). There was an increased risk of acute stent thrombosis within 24 hours in the bivalirudin group, but no significant increase was present by 30 days. Treatment with bivalirudin alone, as compared with heparin plus glycoprotein IIb/IIIa inhibitors, resulted in significantly lower 30-day rates of death from cardiac causes (1.8% vs. 2.9%; relative risk, 0.62; 95% CI, 0.40 to 0.95; P = 0.03) and death from all causes (2.1% vs. 3.1%; relative risk, 0.66; 95% CI, 0.44 to 1.00; P = 0.047).î (G. W. Stone, gs2184@columbia.edu)
Social Networks & Smoking Cessation: Clinicians and public health professionals should consider the implications of social networks in patients’ smoking behaviors, note investigators who analyzed connections among 12, 067 people in the Framingham Heart Study (pp. 2249-58): ìDiscernible clusters of smokers and nonsmokers were present in the network, and the clusters extended to three degrees of separation. Despite the decrease in smoking in the overall population, the size of the clusters of smokers remained the same across time, suggesting that whole groups of people were quitting in concert. Smokers were also progressively found in the periphery of the social network. Smoking cessation by a spouse decreased a person’s chances of smoking by 67% (95% confidence interval [CI], 59 to 73). Smoking cessation by a sibling decreased the chances by 25% (95% CI, 14 to 35). Smoking cessation by a friend decreased the chances by 36% (95% CI, 12 to 55 ). Among persons working in small firms, smoking cessation by a coworker decreased the chances by 34% (95% CI, 5 to 56). Friends with more education influenced one another more than those with less education.î (N. A. Christakis, christakis@hcp.med.harvard.edu)

>>>PNN NewsWatch
* Alvimopan (Entereg, Adolor Corp. and GlaxoSmithKline) has been approved for short-term use (15 doses) in hospitalized adult patients to accelerate upper and lower gastrointestinal recovery following partial large or small bowel resection surgery with primary anastomosis. Alvimopan, a mu-opioid receptor antagonist, targets the postoperative ileus that can be produced by opioid analgesics, which can temporarily impair gastrointestinal motility. The recommended dose for alvimopan 12 mg orally just before surgery and then twice daily for up to 7 days. Safety and efficacy of alvimopan in postoperative patients were demonstrated in five studies that included 2,177 patients. Bowel recovery times were 10–26 hours shorter for alvimopan-treated patients compared with placebo-treated patients. The most common adverse effects reported were hypocalcemia, anemia, and gastrointestinal problems, including constipation, dyspepsia, and flatulence. In one 12-month study of alvimopan in patients treated with opioid medications for chronic pain, myocardial infarctions occurred more frequently in patients treated with alvimopan 0.5 mg twice daily than among receiving placebo. This problem has not been observed in other clinical trials. As part of an FDA-mandated Risk Evaluation and Mitigation Strategy (REMS), Adolor has developed the Entereg Access Support and Education (E.A.S.E.) program, which limits distribution of the drug to hospitals that complete a registration process.

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

PNN Pharmacotherapy Line
May 23, 2008 * Vol. 15, No. 101
Providing news and information about medications and their proper use

>>>Geriatrics Highlights
Source:
May issue of the Journal of the American Geriatrics Society (www.blackwell-synergy.com/toc/jgs/56/5; 2008; 56).
ADR Signals in Nursing Homes: A list of signals that can be used to detect potential adverse drug reactions among residents of nursing homes was developed by an expert panel (pp. 808-15). Relying on data that can be accessed electronically or manually from laboratory and pharmacy databases and from Minimum Data Sets, the expert panel ìreached consensus agreement on 40 signals: 15 laboratory and medication combinations, 12 medication concentrations, 10 antidotes, and three Resident Assessment Protocols (RAPs). Highest consensus scores (4.6, 95% CI = 4.4–4.9 or 4.4–4.8) were for naloxone when taking opioid analgesics; phytonadione when taking warfarin; dextrose, glucagon, or liquid glucose when taking hypoglycemic agents; medication-induced hypoglycemia; supratherapeutic international normalized ratio when taking warfarin; and triggering the Falls RAP when taking certain medications.î (S. M. Handler, handler@pitt.edu)
Dual Use of Bladder Anticholinergics and Cholinesterase Inhibitors: Concomitant use of cholinesterase inhibitors (ChIs) and the bladder anticholinergic agents oxybutynin or tolterodine may have detrimental effects on cognition among higher-functioning residents of nursing homes, an analysis of Indiana Medicaid data indicates (pp. 847-53). Merging claims data with information from Minimum Data Sets, the researchers found these patterns in activities of daily living (ADLs) and other parameters among 3,536 Medicaid-eligible residents aged 65 years or older who were taking a ChI in 2003–04: ìThree hundred seventy-six (10.6%) residents were prescribed oxybutynin or tolterodine concomitantly with a ChI. In residents in the top quartile of ADL function, ADL function declined an average of 1.08 points per quarter when not taking bladder anticholinergics (ChI alone), compared with 1.62 points per quarter when taking dual therapy, a 50% greater rate in quarterly decline in ADL function (P=.01). There was no excess decline attributable to dual therapy in [Minimum Data Set Cognition Scale] scores or in ADL function for residents who started out with lower functioning.î (K. M. Sink, Wake Forest U., Winston-Salem, N.C.; kmsink@wfubmc.edu)
Oxybutynin Use in Women with Dementia: Short-term doses of oxybutynin 5 mg once daily had no significant effects on delirium among 50 women aged 65 years or older with concomitant urge incontinence and dementia (pp. 862-70). Concluding that such use is safe and effective, the researchers provided these data from their 4-week controlled trial: ìParticipants’ mean age ± standard deviation was 88.6 ± 6.2, and [Mini-Mental State Examination] baseline score was 14.5 ± 4.3. Ninety-six percent of subjects receiving oxybutynin (n = 26) and 92% receiving placebo (n = 24) completed treatment (P = .50). The differences in mean change in [Confusion Assessment Method] score from baseline to all time points were equivalent between the oxybutynin and placebo groups. Delirium did not occur in either group. One participant receiving oxybutynin was withdrawn because of urinary retention, which resolved without treatment. Mild adverse events occurred in 38.5% of participants receiving oxybutynin and 37.5% receiving placebo (P = .94).î (T. E. Lackner, lackn001@umn.edu)

>>>PNN NewsWatch
* Multiple safety problems with the smoking cessation agent varenicline (Chantix) have been identified by the Institute of Safe Medication Practices, and these led this week to the Federal Aviation Administration banning use of the product in airline pilots and air traffic controllers. Some 988 serious injuries have been reported to FDA, ISMP notes, more than any other drug. Among 3,063 cases of serious injury were 227 reports of suicidal thoughts, behaviors, and acts (28 of which resulted in death); 397 cases of possible psychosis; and 525 reports of hostility or aggression. Accidental injuries included 28 road traffic accidents and 77 falls, some leading to fractures. Severe sensory disturbances (hallucinations, transient blindness) and affect motor control (seizures, movement abnormalities) problems have also been reported.
*
PNN will not be published on Mon., May 26, Memorial Day.

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

PNN Pharmacotherapy Line
May 27, 2008 * Vol. 15, No. 102
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
May 24 issue of Lancet (www.thelancet.com; 2008; 371).
Early Intensive Insulin Therapy: In this theme issue on diabetes, researchers report that early intensive insulin therapy optimized recovery and maintenance of beta-cell function among 382 patients aged 25–70 years (pp. 1753-60). Followed at nine Chinese centers from 2004 to 2006, the patients showed these effects on homeostasis model assessment (HOMA) of continuous subcutaneous insulin infusion, multiple daily insulin injections, or oral hypoglycemic agents used for rapid initial correction of hyperglycemia: ìMore patients achieved target glycaemic control in the insulin groups (97.1% [133 of 137] in CSII and 95.2% [118 of 124] in MDI) in less time (4.0 days [SD 2.5] in CSII and 5.6 days [SD 3.8] in MDI) than those treated with oral hypoglycaemic agents (83.5% [101 of 121] and 9.3 days [SD 5.3]). Remission rates after 1 year were significantly higher in the insulin groups (51.1% in CSII and 44.9% in MDI) than in the oral hypoglycaemic agents group (26.7%; p = 0.0012). Beta-cell function represented by HOMA B and acute insulin response improved significantly after intensive interventions.î (J. Weng, Sun Yat-Sen U., Guangzhou, China; wjianp@mail.sysu.edu.cn)
Lifestyle Interventions in Prediabetes: Intensive lifestyle education, delivered to groups of 577 patients with impaired glucose tolerance over a 6-year period, delayed onset of diabetes by up to 14 years, according to a study conducted at 33 clinics in China (pp. 1783-9). Comparing interventions in three groups (diet, exercise, or diet plus exercise), the investigators found: ìCompared with control participants, those in the combined lifestyle intervention groups had a 51% lower incidence of diabetes (hazard rate ratio [HRR] 0.49; 95% CI 0.33–0.73) during the active intervention period and a 43% lower incidence (0.57; 0.41–0.81) over the 20 year period, controlled for age and clustering by clinic. The average annual incidence of diabetes was 7% for intervention participants versus 11% in control participants, with 20-year cumulative incidence of 80% in the intervention groups and 93% in the control group. Participants in the intervention group spent an average of 3.6 fewer years with diabetes than those in the control group. There was no significant difference between the intervention and control groups in the rate of first [cardiovascular disease] events (HRR 0.98; 95% CI 0.71–1.37), CVD mortality (0.83; 0.48–1.40), and all-cause mortality (0.96; 0.65–1.41).î (G. Li , China–Japan Friendship Hosp., Beijing; guangwei_li@medmail.com.cn)

>>>BMJ Highlights
Source:
Early-release article from BMJ (www.bmj.org; 2008; 336).
HRT & VT Risk: Transdermal estrogens are associated with lower risk of venous thromboembolism, compared with oral drug, in women on hormonal-replacement therapy, according to a systematic review and meta-analysis of 8 observational and 9 randomized controlled studies (doi:10.1136/bmj.39555.441944.BE): ìCompared with non-users of oestrogen, the odds ratio of first time venous thromboembolism in current users of oral oestrogen was 2.5 (95% confidence interval 1.9 to 3.4) and in current users of transdermal oestrogen was 1.2 (0.9 to 1.7).... The risk of venous thromboembolism in women using oral oestrogen was higher in the first year of treatment (4.0, 2.9 to 5.7) compared with treatment for more than one year (2.1, 1.3 to 3.8; P < 0.05).î (M. Canonico, UniversitÈ Paris-Sud Villejuif, France; canonico@vjf.inserm.fr)

>>>PNN NewsWatch
* Chlorphenesin and phenoxyethanol in Mommy’s Bliss Nipple Cream (MOM Enterprises) can cause vomiting and diarrhea in infants, and chlorphenesin can produce dermatitis in mothers, FDA has warned. The agency advised consumers to avoid the cream.

>>>PNN JournalWatch
* N-of-1 Trials of Expensive Biological Therapies: A Third Way?, in Archives of Internal Medicine, 2008; 168: 1030–3. Reprints: R. L. Kravitz, rlkravitz@ucdavis.edu
* Colonoscopic Screening in Average-Risk Individuals Ages 40 to 49 vs 50 to 59 Years, in
Gastroenterology, 2008; 134: 1311–5. Reprints: A. I. Neugut, ain1@columbia.edu
* Sublingual Immunotherapy, in
New England Journal of Medicine, 2008; 358: 2259–64. Reprints: A. J. Frew, Brighton Genl. Hosp., Brighton, U.K.; anthony.frew@bsuh.nhs.uk

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

PNN Pharmacotherapy Line
May 28, 2008 * Vol. 15, No. 103
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
May 28 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2008; 299).
Prophylactic Escitalopram After Stroke: Among 176 nondepressed patients with recent stroke, escitalopram was significantly more effective than placebo for preventing poststroke depression over the ensuing 12 months, while a problem-solving intervention in one analysis was not significantly superior to placebo (pp. 2391-400). In a comparison of double-blind active drug/placebo and nonblinded problem-solving therapy, these results were noted: ìPatients who received placebo were significantly more likely to develop depression than individuals who received escitalopram (11 major and 2 minor cases of depression [22.4%] vs 3 major and 2 minor cases of depression [8.5%], adjusted hazard ratio [HR], 4.5; 95% confidence interval [CI], 2.4–8.2; P < .001) and also more likely than individuals who received problem-solving therapy (5 major and 2 minor cases of depression [11.9%], adjusted HR, 2.2; 95% CI, 1.4–3.5; P < .001). These results were adjusted for history of mood disorders and remained significant after considering possible confounders such as age, sex, treatment site, and severity of impairment in the model. Using an intention-to-treat conservative method of analyzing the data, which assumed that all 27 patients who did not start randomized treatment would have developed depression, and controlling for prior history of mood disorders, escitalopram was superior to placebo (23.1% vs 34.5%; adjusted HR, 2.2; 95% CI, 1.2–3.9; P = .007), while problem-solving therapy was not significantly better than placebo (30.5% vs 34.5%; adjusted HR, 1.1; 95% CI, 0.8–1.5; P = .51). Adverse events, including all-cause hospitalizations, nausea, and adverse effects associated with escitalopram were not significantly different between the 3 groups.î (R. G. Robinson, robert-robinson@uiowa.edu)
Trends in Pediatric Body Mass: The increases in overweight and obesity in American children between 1980 and 2004 may have peaked, CDC researchers report (pp. 2401-5). Height and weight measurements in 8,165 children and adolescents, taken in the 2003–2004 and 2005–2006 National Health and Nutrition Examination Surveys (NHANES), showed these differences: ìBecause no statistically significant differences in the prevalence of high BMI for age were found between estimates for 2003–2004 and 2005–2006, data for the 4 years were combined to provide more stable estimates for the most recent time period. Overall, in 2003–2006, 11.3% (95% confidence interval [CI], 9.7%–12.9%) of children and adolescents aged 2 through 19 years were at or above the 97th percentile of the 2000 BMI-for-age growth charts, 16.3% (95% CI, 14.5%–18.1%) were at or above the 95th percentile, and 31.9% (95% CI, 29.4%–34.4%) were at or above the 85th percentile. Prevalence estimates varied by age and by racial/ethnic group. Analyses of the trends in high BMI for age showed no statistically significant trend over the 4 time periods (1999–2000, 2001–2002, 2003–2004, and 2005–2006) for either boys or girls (P values between .07 and .41).î (C. L. Ogden, cogden@cdc.gov)
Editorialists provided this perspective about ìan index of uncertaintyî (pp. 2442-3): ìAfter years of unremittingly bad news about increasing rates of pediatric obesity, Ogden et al. report no increase in prevalence between 1999–2000 and 2005–2006. Perhaps recent public health campaigns aimed at raising awareness of childhood obesity and improving the quality of school food have begun to pay off. However, it is too early to know whether these data reflect a true plateau or a statistical aberration in an inexorable epidemic, and pre-existing racial/ethnic disparities show no sign of abating. On one point there is no uncertainty: without substantial declines in prevalence, the public health toll of childhood obesity will continue to mount, because it can take many years for an obese child to develop life-threatening complications.î (D. S. Ludwig,
david.ludwig@childrens.harvard.edu)

>>>PNN NewsWatch
* FDA yesterday requested that SEI Pharmaceuticals recall Xiadafil VIP Tabs, a dietary supplement promoted for sexual enhancement and treatment of erectile dysfunction, that allegedly contains the sildenafil analogue hydroxyhomosildenafil. If enacted, the recall would include 8-tablet bottles (lot no. 6K029) and blister cards of 2 tablets (lot no. 6K029-SEI) of the product.

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

PNN Pharmacotherapy Line
May 29, 2008 * Vol. 15, No. 104
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
May 29 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2008; 358).
Methylnaltrexone for Opioid-Induced Constipation: Among 133 patients with opioid-induced constipation during advanced illness, subcutaneous methylnaltrexone rapidly induced laxation (defecation) without affecting central analgesia or precipitating opioid withdrawal (pp. 2332-43). Compared with placebo, methylnaltrexone 0.15 mg/kg every other day for 2 weeks produced these results: ìIn the methylnaltrexone group, 48% of patients had laxation within 4 hours after the first study dose, as compared with 15% in the placebo group, and 52% had laxation without the use of a rescue laxative within 4 hours after two or more of the first four doses, as compared with 8% in the placebo group (P < 0.001 for both comparisons). The response rate remained consistent throughout the extension trial. The median time to laxation was significantly shorter in the methylnaltrexone group than in the placebo group. Evidence of withdrawal mediated by central nervous system opioid receptors or changes in pain scores was not observed. Abdominal pain and flatulence were the most common adverse events.î (J. Thomas, San Diego Hospice and Palliative Care, San Diego; jthomas@sdhospice.org)
Prucalopride for Severe Chronic Constipation: The selective, high-affinity 5-hydroxytryptamine–4 receptor agonist prucalopride significantly improved bowel function and reduced the severity of symptoms among 620 patients with severe chronic constipation in a 12-week trial (pp. 2344-54). Comparing 2- and 4-mg doses of the prokinetic agent with placebo, the investigators found: ìThe proportion of patients with three or more spontaneous, complete bowel movements per week was 30.9% of those receiving 2 mg of prucalopride and 28.4% of those receiving 4 mg of prucalopride, as compared with 12.0% in the placebo group (P < 0.001 for both comparisons). Over 12 weeks, 47.3% of patients receiving 2 mg of prucalopride and 46.6% of those receiving 4 mg of prucalopride had an increase in the number of spontaneous, complete bowel movements of one or more per week, on average, as compared with 25.8% in the placebo group (P < 0.001 for both comparisons). All other secondary efficacy end points, including patients’ satisfaction with their bowel function and treatment and their perception of the severity of their constipation symptoms, were significantly improved with the use of 2 or 4 mg of prucalopride as compared with placebo, at week 12. The most frequent treatment-related adverse events were headache and abdominal pain. There were no significant cardiovascular effects of treatment.î (M. Camilleri, camilleri.michael@mayo.edu)

>>>JAPhA Highlights
Source:
May/June issue of the Journal of the American Pharmacists Assoc. (www.japha.org; 2008; 48).
Safety of Energy Drinks: Consumption of caffeine and processed sugar in commercially available energy drinks can have an impact on health, writes the author of a review article (e55-67): ìMost energy drinks contain natural products such as guarana, ginseng, and taurine. As much as 80 to 300 mg of caffeine and 35 grams of processed sugar per 8-ounce serving are commonly present in energy drinks such as Cocaine, Pimp Juice, Red Bull, and Spike Shooter. No reports were identified of negative effects associated with taurine, ginseng, and guarana used in the amounts found in most energy drinks. Commonly reported adverse effects seen with caffeine in the quantities present in most energy drinks are insomnia, nervousness, headache, and tachycardia. Four documented case reports of caffeine-associated deaths were found, as well as four separate cases of seizures associated with the consumption of energy drinks.î (K. A. Clauson, clauson@nova.edu)

>>>PNN NewsWatch
* FDA on Thursday proposed phasing out the current rating system for use of drugs during pregnancy and breastfeeding. Instead of risk categories denoted by the letters A, B, C, D, or X, product labeling would contain pregnancy and lactation sections, each with three subsections: fetal risk summary (what is known about effects of the drug on the fetus/neonate), clinical considerations (use of drug before mother knows she is pregnant), and data.

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

PNN Pharmacotherapy Line
May 30, 2008 * Vol. 15, No. 105
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
June issue of Diabetes Care (http://care.diabetesjournals.org/current.shtml; 2008; 31).
Moving Beyond IFG, IGT: Creation of a nomogram to show patients their risk of developing diabetes is proposed by commentary authors who argue that trying to refine fasting plasma glucose cut points for impaired glucose tolerance, impaired fasting glucose, and prediabetes is futile (pp. 1093-6). Recognizing a gradient of risk rather than a point at which ìriskî and ìno riskî can be separated, the authors propose: ìTo aid physicians, we could create nomograms with odds ratios for the risk of developing diabetes for every 10 mg/dl increment in FPG above 80 mg/dl as the referent of 1.0. A similar nomogram with an appropriate baseline and increments can now be constructed for A1C, as standardization of the assay has proceeded well and we are deriving accurate and precise estimates of equivalence between A1C and average glucose levels. Moreover, it now seems likely that an A1C level can be established for the diagnosis of diabetes. Even more appropriate and relevant are global risk assessment algorithms that address both the risk of diabetes and the risk of developing [cardiovascular disease] by integrating all the major risk factors for both conditions.î (S. Genuth, Case Western Reserve U., Cleveland, Ohio; smg15@cwru.edu)
Adverse Effects of HIV Drugs: Direct mitochondrial toxicity may be the mechanism through which the thymidine analogues stavudine and zidovudine produce diabetes during combination antiretroviral therapy (cART), researchers report (pp. 1224-9). Among 33,389 patients with HIV infection, Poisson regression models determined these relationships between drug use and diabetes onset: ìOver 130,151 person–years of follow-up (PYFU), diabetes was diagnosed in 744 patients (incidence rate of 5.72 per 1,000 PYFU [95% CI 5.31–6.13]). The incidence of diabetes increased with cumulative exposure to cART, an association that remained significant after adjustment for potential risk factors for diabetes. The strongest relationship with diabetes was exposure to stavudine; exposures to zidovudine and didanosine were also associated with an increased risk of diabetes. Time-updated measurements of total cholesterol, HDL cholesterol, and triglycerides were all associated with diabetes. Adjusting for each of these variables separately reduced the relationship between cART and diabetes slightly. Although lipodystrophy was significantly associated with diabetes, adjustment for this did not modify the relationship between cART and diabetes.î (S. De Wit, St. Pierre U. Hosp., Brussels, Belgium; stephane_dewit@stpierre-bru.be)
After noting flaws and limitations in the above study, an editorialist sheds this light on the relationship between antiretroviral therapy and adverse metabolic effects (pp. 1267-8): ìIt is reassuring that the estimate for incident diabetes observed by De Wit et al. (5.72 cases per 1,000 person–years) is much lower than previous estimates from smaller studies (17–47 per 1,000 person–years). Clearly, physicians who treat patients with HIV-AIDS need to be alert to the adverse metabolic effects of the expanding antiretroviral armamentarium. Furthermore, as a result of the efficacy of cART and improved nutritional status, many HIV-infected patients in remission experience significant weight gain, which is an additional risk factor for insulin resistance, diabetes, and dyslipidemia.î (S. Dagogo-Jack,
sdj@utmem.edu)
Accuracy of Continuous Glucose Monitors: Four continuous glucose monitors performed comparably in euglycemia but varied during periods of low blood glucose values, according to a study of 34 adults with type 1 diabetes (pp. 1160-4). At clinical research centers in the U.S. and Germany, hyperinsulinemic-clamp studies during which euglycemia for 1.5–2 hours was followed by descent into hypoglycemia for 30 minutes showed the following: ìDuring euglycemia, the mean absolute relative differences (MARDs) of Guardian, DexCom, Navigator, and Glucoday were 15.2, 21.2, 15.3, and 15.6%, respectively. During hypoglycemia, the MARDs were 16.1, 21.5, 10.3, and 17.5%, respectively.... Because of frequent loss of sensitivity, there were insufficient hypoglycemic DexCom data to [determine its clinical accuracy].î (B. Kovatchev, boris@virginia.edu)

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

PNN Pharmacotherapy Line
June 2, 2008 * Vol. 15, No. 106
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Early-release article from and May 31 issue of Lancet (www.thelancet.com; 2008; 371).
Oral Prednisolone for Gout Arthritis: Among 120 primary care patients with gout arthritis, oral prednisolone was as effect as naproxen when used as initial therapy (pp. 1854-60). Seeking an alternative without the gastrointestinal, renal, and cardiovascular adverse effects of NSAIDs, the investigators compared 5 days of prednisolone 35 once daily with naproxen 500 mg twice daily, with these results: ìData were incomplete for one patient in each treatment group, so per-protocol analyses included 59 patients in each group. After 90 h the reduction in the pain score was 44.7 mm and 46.0 mm for prednisolone and naproxen, respectively (difference 1.3 mm; 95% CI −9.8 to 7.1), suggesting equivalence. The difference in the size of change in pain was 1.57 mm (95% CI −8.65 to 11.78). Adverse effects were similar between groups, minor, and resolved by 3 week follow-up.î (H. J. E. M. Janssens, Radboud U. Nijmegen Med. Ctr., Nijmegen, the Netherlands; h.janssens@hag.umcn.nl)
Treating Advanced Pancreatic Cancer: An open-label, Phase II comparison showed similar safety for gemcitabine plus axitinib compared with gemcitabine alone in a group of 103 patients with unresectable, locally advanced, or metastatic pancreatic cancer (doi: 10.1016/S0140-6736(08)60661-3). Combination treatment yielded a small nonsignificant gain in overall survival that the authors concluded should be explored in a randomized Phase III trial: ìMedian overall survival was longer with gemcitabine plus axitinib than with gemcitabine alone (6.9 [95% CI 5.3–10.1] months vs 5.6 [3.9–8.8] months). The hazard ratio for survival with gemcitabine plus axitinib versus with gemcitabine alone, adjusted for stratification factors, was 0.71 (95% CI 0.44–1.13). The most common grade 3 or worse adverse events were fatigue (15 [22%] patients in the gemcitabine plus axitinib group vs one [3%] in the gemcitabine alone group), abdominal pain (eight [12%] vs five [16%]), and asthenia (eight [12%] vs one [3%]).î (J-P Spano, Groupe Hospitalier PitiÈ-SalpÍtriËre, Paris; jean-philippe.spano@psl.ap-hop-paris.fr)

>>>BMJ Highlights
Source:
May 31 issue of BMJ (www.bmj.org; 2008; 336).
Nortriptyline in Smoking Cessation: The combination of nortriptyline plus nicotine-replacement therapy is less effective than either agent alone when used for smoking cessation, researchers report (pp. 1223-7). At U.K. National Health Service clinics, these results were noted: ì72 of 445 (16%) people using nortriptyline and 55 of 456 (12%) using placebo achieved prolonged abstinence at six months (relative risk 1.34, 95% confidence interval 0.97 to 1.86). At 12 months the corresponding values were 49 (11%) for nortriptyline and 40 (9%) for placebo (1.26, 0.84 to 1.87). 337 (79%) people in the nortriptyline arm and 325 (75%) in the placebo arm were taking combination treatment on quit day, median 75 mg per day in both groups.... The nortriptyline arm had noticeably higher severity ratings for dry mouth and constipation than the placebo arm, with slightly higher ratings for sweating and feeling shaky. Both groups had similar urges to smoke, but nortriptyline reduced depression and anxiety. Overall, withdrawal symptom scores did not differ.î (P. Aveyard, U. Birmingham, Birmingham, U.K.; p.n.aveyard@bham.ac.uk)

>>>PNN NewsWatch
* FDA has issued a public health advisory to alert patients, caregivers, and health professionals of the need to switch to hydrofluoroalkane-propelled albuterol inhalers because chlorofluorocarbon-propelled inhalers will not be available in the U.S. after Dec. 31, 2008. CFC-propelled albuterol inhalers, being phased out because CFC depletes the ozone layer, should be replaced with one of three FDA-approved HFA-propelled albuterol inhalers: Proair HFA Inhalation Aerosol, Proventil HFA Inhalation Aerosol, or Ventolin HFA Inhalation Aerosol, or with the HFA-propelled levalbuterol inhaler, Xopenex HFA Inhalation Aerosol.

>>>PNN JournalWatch
* Efficacy of Rotigotine for Treatment of Moderate-to-Severe Restless Legs Syndrome: A Randomised, Double-Blind, Placebo-Controlled Trial, in Lancet Neurology, 2008; doi: 10.1016/S1474-4422(08)70112-1. Reprints: C. Trenkwalder, Paracelsus-Elena Hosp., Kassel, Germany; ctrenkwalder@gmx.de

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

PNN Pharmacotherapy Line
June 3, 2008 * Vol. 15, No. 107
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
June 3 issue of the Annals of Internal Medicine (www.annals.org/current.shtml; 2008; 148).
Intensivists & Mortality: Patients in intensive-care units who were managed by critical care physicians had higher mortality rates than those cared for by other doctors, but confounders such as generally sicker patients in the former group might explain the unexpected finding (pp. 801-9). Researchers retrospectively analyzed data on 101,832 critically ill adults in 123 ICUs at 100 U.S. hospitals and found: ìPatients who received critical care management (CCM) were generally sicker, received more procedures, and had higher hospital mortality rates than those who did not receive CCM. After adjustment for severity of illness and propensity score, hospital mortality rates were higher for patients who received CCM than for those who did not. The difference in adjusted hospital mortality rates was less for patients who were sicker and who were predicted by propensity score to receive CCM.î (M. M. Levy, Mitchell_Levy@brown.edu)
Thyroid Function & Heart Disease: Patients with subclinical hypothyroidism and hyperthyroidism had modestly increased risks for coronary heart disease and mortality in a meta-analysis of 10 studies that included 14,449 patients (pp. 832-45). Subgroup analyses showed lower, but significantly elevated, risks when higher-quality studies were analyzed separately. Data for subclinical hyperthyroidism had larger confidence intervals for risks of CHD and mortality, indicating more variability among those study participants. (N. Rodondi, U. Lausanne, Lausanne, Switzerland; nicolas.rodondi@hospvd.ch)

>>>Pharmacotherapy Report
Source:
June issue of Pharmacotherapy (www.atypon-link.com/PPI/toc/phco/28/6; 2008; 28).
Economics of Surgical Vancomycin Dosing: The duration of hospitalization and total hospital costs were minimized when vancomycin was administered to surgical patients 16–20 minutes before incision, researchers report (pp. 699-706). Comparing data on 928 patients with appropriate timing of antibiotic administration and 738 patients with inappropriate timing, the investigators found: ìMedian numbers of hospitalization and intensive care unit days were significantly fewer in patients given appropriate prophylaxis at an appropriate time (9 and 2 days, respectively) compared with inappropriate time (10 and 3 days, respectively, p < 0.001 for both analyses). Hospital costs were significantly lower in patients who had appropriate timing of antibiotic prophylaxis (median $25,321, interquartile range [IQR] $19,429–35,471) compared with inappropriate timing (median $29,475, IQR $21,507–46,488, p < 0.001). Multivariate linear regression and a Heckman two-stage model confirmed that appropriate antibiotic prophylaxis timing was associated with decreased hospitalization duration and hospital costs.î (K. W. Garey, Texas Med. Ctr., Houston; kgarey@uh.edu)
Uniform v. Nonuniform Warfarin Dosages: Both uniform and nonuniform warfarin dosages can be used to reach target INRs, according to small study of healthy volunteers (pp. 707-11). Study participants were 20 healthy adults who were extensive metabolizers of the drug and who received either warfarin 5.75 mg/day or warfarin 7.5 mg/day on Mondays and Fridays and 5 mg/day on each of the remaining days of the week for 17 days in crossover fashion, with these results: ìThe Scheffe post hoc test revealed no significant differences in mean INR values obtained during receipt of the two dosage regimens. In both dosage groups, variation in the INR became more pronounced as INR values increased. No adverse events (i.e., major or minor bleeding) or changes in drug therapy were reported during the study.î (J. S. Bertino, Jr., Bertino Consulting, Schenectady, N.Y.; sbertino@ix.netcom.com)
Clinical Pharmacist Definition & Competencies: Two white papers authored by ACCP seek to define clinical pharmacy (pp. 816-7) and spell out those competencies needed by clinical pharmacists (pp. 806-15). Clinical pharmacy is defined as ìthat area of pharmacy concerned with the science and practice of rational medication use.î The competency document emphasizes postgraduate training needed to acquire knowledge and skills, along with lifelong learning to maintain those requisites. (www.accp.com)

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

PNN Pharmacotherapy Line
June 4, 2008 * Vol. 15, No. 108
Providing news and information about medications and their proper use

>>>Oncology Highlights
Source:
Early-release articles from and June 1 issue of the Journal of Clinical Oncology, and studies released at the American Society of Clinical Oncology annual meeting (http://jco.ascopubs.org and www.asco.org; 2008; 26).
Combining Lapatinib, Trastuzumab in Metastatic Breast Cancer : Among 54 women with heavily pretreated ErbB2-positive advanced breast cancer, a combination of lapatinib 1,000 mg/day plus standard weekly trastuzumab was the optimally tolerated regimen (OTR) in a Phase I trial (doi: 10.1200/JCO.2007.13.5202). Testing escalating doses of lapatinib in an effort to assess safety, clinical activity, and pharmacokinetics (PK) of the drug combination, the investigators made these observations: ìOverall, adverse events were mild to moderate in severity, with no drug-related grade 4 events. The most frequent drug-related grade 3 events included diarrhea (17%), fatigue (11%), and rash (6%). The OTR was 1,000 mg lapatinib with standard weekly trastuzumab. One patient had a complete response and seven patients had partial responses. The PK parameters (maximum concentration in plasma and area under the curve) of lapatinib and trastuzumab in combination were not significantly different than when either was administered alone.î (A. M. Storniolo, Indiana U., Indianapolis; astornio@iupui.edu)
Editorialists laud the possibility of ìkilling one bird with two stonesî in an accompanying editorial (doi: 10.1200/JCO.2008.16.3972): ìTo better determine the utility of this approach in the treatment of metastatic breast cancer, this would have to be studied in patients who have not previously been treated with an agent blocking the ErbB2 pathway, and would require obtaining serial tumor biopsies before and during therapy to determine optimal doses of each of the agents inhibiting the ErbB2 receptor and the downstream pathways mediating its effects when used in combination. Characterization of a ‘receptor-sensitive signature’ would be of use in identifying tumors sensitive to such approaches in the clinic. The next step would be to study the dual-targeting approach in an ErbB2-positive population of patients who are ErbB2 inhibitor naive, with pharmacodynamic monitoring of effects on ErbB2 and downstream signaling pathways and correlating this with tumor response. To determine the contribution of lapatinib and trastuzumab in the clinical effect, it would be most appropriate to do this in a randomized setting in this population.î (H. W. Hirte, McMaster U., Hamilton, Ont., Canada)
Tumor Lysis Syndrome Guidelines: Guidelines developed by a panel of experts in pediatric and adult tumor lysis syndrome are presented in a review article (pp. 2767-78): ìThe best management of TLS is prevention. Prevention strategies include hydration and prophylactic rasburicase in high-risk patients, hydration plus allopurinol or rasburicase for intermediate-risk patients, and close monitoring for low-risk patients. Primary management of established TLS involves similar recommendations, with the addition of aggressive hydration and diuresis, plus allopurinol or rasburicase for hyperuricemia. Alkalinization is not recommended. Although guidelines for rasburicase use in adults are provided, this agent is currently only approved for use in pediatric patients in the United States.î (M. S. Cairo, mc1310@columbia.edu)
Personalized Medicine: Advances in pharmacogenomics that contribute to emergence of ìpersonalized medicineî were detailed at a news conference held on Sunday during the ASCO Annual Meeting. These studies were highlighted:
* Patients with newly diagnosed metastatic colorectal cancer were most likely to benefit from the monoclonal antibody cetuximab when their tumors contained the normal rather than mutated forms of the gene
KRAS.
* Elderly patients were more likely to experience hematologic adverse effects from chemotherapy if they were also taking drugs that inhibited cytochrome P450 (e.g., ketoconazole, amiodarone) or interfered with protein binding (e.g., amlodipine, omeprazole, celecoxib).
* Patients whose head and neck tumors contained high levels of erythropoietin receptor messenger RNA levels had more rapid tumor progression after receiving erythropoietin, researchers reported. Similar results were found in those with high mRNA levels of Jak2, the primary transmitter of EpoR signals in erythrocytes.

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

PNN Pharmacotherapy Line
June 5, 2008 * Vol. 15, No. 109
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
June 5 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2008; 358).
Aliskiren plus Losartan in Diabetes/Nephropathy: In 599 patients with hypertension and type 2 diabetes with nephropathy, addition of aliskiren to optimal losartan-based antihypertensive therapy provided renoprotective effects beyond those associated with lowering of blood pressure, according to AVOID (Aliskiren in the Evaluation of Proteinuria in Diabetes) study investigators (pp. 2433-46). Following an open-label, 3-month, run-in-period during which patients were stabilized on losartan 100 mg daily, placebo or aliskiren 150 mg daily was added for 3 months, and aliskiren was then increased to 600 mg daily for 3 additional months, with these results: ìTreatment with 300 mg of aliskiren daily, as compared with placebo, reduced the mean urinary albumin-to-creatinine ratio by 20% (95% confidence interval, 9 to 30; P < 0.001), with a reduction of 50% or more in 24.7% of the patients who received aliskiren as compared with 12.5% of those who received placebo (P < 0.001). A small difference in blood pressure was seen between the treatment groups by the end of the study period (systolic, 2 mm Hg lower [P = 0.07] and diastolic, 1 mm Hg lower [P = 0.08] in the aliskiren group). The total numbers of adverse and serious adverse events were similar in the groups.î (H-H Parving, U. Hosp., Copenhagen; hhparving@dadlnet.dk)
An editorialist wonders about combining these renin and angiotensin blockers (pp. 2503-5): ìConcerns about dual-agent blockade of the renin–angiotensin–aldosterone system have been raised, with particular concern expressed about the potential increase in the incidence of hyperkalemia and decrease in the glomerular filtration rate. The dual therapy in the AVOID trial achieved the goal of reducing albuminuria; however, it is not known how the patients would have fared if they had taken the medications for a longer period of time. Although adverse events were not marked, participating patients were chosen carefully — patients with glomerular filtration rates of less than 30 ml per minute or potassium levels greater than 5.1 mmol per liter were excluded. Whether dual therapy to block the renin–angiotensin–aldosterone system with aliskiren and another agent or agents would provide sustained renoprotection remains to be demonstrated.î (J. R. Ingelfinger)
Contaminated Heparin: Commenting on an early-release research study into the causes of adverse reactions to contaminated heparin products (pp. 2457-67; see PNN, Apr. 24), an editorialist writes of the need for heparin to ìcome cleanî (pp. 2505-9): ìAlthough the heparin glycosaminoglycan used clinically is derived from the heparin proteoglycan stored in the mast cells of porcine intestines, the source of the [oversulfated chondroitin sulfate] contaminant implicated in the clinical reactions of concern is unclear. The tetra-sulfated chondroitin sulfate disaccharides of the contaminant glycosaminoglycan are not known to occur naturally in mammals. If there is in fact no natural mammalian source, a careful investigation of the procedures used to prepare the contaminated lots of heparin will be needed to unravel this mystery.î (L. B. Schwartz, Virginia Commonwealth U., Richmond)
A Perspectives author discusses the challenges facing FDA in dealing with a global pharmaceutical supply market (pp. 2429-31): ìIt would be wrong to view the heparin debacle as primarily an FDA failure. An agency can do only what it is staffed to do, and the FDA’s budget for surveillance of foreign drug manufacturers is an order of magnitude or two too small. It has been estimated that at current funding levels, it would take the FDA more than 13 years to inspect all foreign plants exporting prescription drugs to the United States and 27 years to inspect all foreign plants exporting medical devices. Criticizing the FDA for failing to stay on top of such inspections when it doesn’t have the requisite funds is victim blaming, not policy analysis.
ìTeddy Roosevelt, a Republican, knew that commerce without enlightened regulation can have potentially devastating consequences for individuals and societies. The burgeoning federal deficit will make it difficult to implement the surveillance responsibilities that a globalized pharmaceutical industry requires, but if we fail to do so, more disasters surely await.î (J. Avorn, Harvard Med. Sch., Boston)

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

PNN Pharmacotherapy Line
June 6, 2008 * Vol. 15, No. 110
Providing news and information about medications and their proper use

>>>Psychiatry Highlights
Source:
June issue of the American Journal of Psychiatry (http://ajp.psychiatryonline.org/current.dtl; 2008; 165).
Atomoxetine v. Osmotically Released Methylphenidate in ADHD: Patients with attention-deficit/hyperactivity disorder may respond preferentially to atomoxetine or osmotically released methylphenidate, although more improve with the latter agent, a research study concludes (pp. 721-30). In a placebo-controlled crossover study of 516 children and adolescents with ADHD, these results were noted using a threshold of 40% improvement on the ADHD Rating Scale: ìThe response rates for both atomoxetine (45%) and methylphenidate (56%) were markedly superior to that for placebo (24%), but the response to osmotically released methylphenidate was superior to that for atomoxetine. Each medication was well tolerated, with completion rates and discontinuations for adverse events not significantly different from those for placebo. Of the 70 subjects who did not respond to methylphenidate, 30 (43%) subsequently responded to atomoxetine. Likewise, 29 (42%) of the 69 patients who did not respond to atomoxetine had previously responded to osmotically released methylphenidate.î (J. H. Newcorn)
Genetics may explain these differences, an editorialist surmises (pp. 666-7): ìThe data provide support for the presence of preferential treatment response: nearly half of the patients who had not responded to methylphenidate responded to atomoxetine, while, of the methylphenidate responders switched to atomoxetine, 18% showed an even greater response and 36% showed a worse response. Preferential response has also been observed among children with ADHD treated with different stimulant medications. A review of within-subject comparisons of methylphenidate and amphetamine found that while 41% of patients improved equally well with either medication, 44% responded better to one of them.
ìThis preferential treatment response is likely to be genetically determined. As in other areas of medicine, in the treatment of ADHD there is a need for investigating individual variation in treatment response and elucidating the underlying mechanisms as a step toward personalization of care.î (B. Vitiello,
bvitiell@mail.nih.gov)

>>>Pediatrics Report
Source:
June issue of Pediatrics (http://pediatrics.aappublications.org/current.shtml; 2008; 121).
Intussusception After RotaTeq Vaccination: The rotavirus vaccine introduced in 2006, RotaTeq, does not appear to be associated with intussusception (pp.1206-12 ). However, a lower-level association cannot yet be ruled out, and continued monitoring is needed, the group adds, reporting these details: ìBetween February 1, 2006, and September 25, 2007, the Vaccine Adverse Event Reporting System received 160 intussusception reports after RotaTeq vaccination. With the assumptions that reporting completeness was 75% and that 75% of the distributed doses of RotaTeq were administered, the observed versus expected rate ratios were 0.53 and 0.91 for the 1–21 and 1–7 day interval after vaccination, respectively. In the Vaccine Safety Datalink, 3 intussusception cases occurred within 30 days after 111,521 RotaTeq vaccinations, compared with 6 cases after 186,722 non–RotaTeq vaccinations during the same period. If, like RotaShield, RotaTeq had a 37-fold increased risk of intussusception within 3 to 7 days after vaccination, then 8 intussusception cases would be expected within 3 to 7 days among the 84,000 infants vaccinated with the first dose of RotaTeq in the Vaccine Safety Datalink (N = 49,902) and the prelicensure trial (N = 34,035) combined, whereas no cases have been observed.î (P. Haber, CDC, Atlanta)
Gluten & Hepatitis B Vaccine Response: Patients not responding to hepatitis B vaccine may have undiagnosed celiac disease, according to a 241-patient analysis (pp. e1570-6). Failure to adhere to a strict gluten-free diet can also interfere with responses in those with the disease. (E. Nemes, U. Debrecen, Debrecen, Hungary)

>>>PNN NewsWatch
* Thirty pediatric patients and young adults have developed cancers, especially lymphomas, associated with use of tumor necrosis factor blockers, prompting an FDA investigation, the agency announced this week.

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

PNN Pharmacotherapy Line
June 9, 2008 * Vol. 15, No. 111
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
June 7 issue of Lancet (www.thelancet.com; 2008; 371).
Thrombus Aspiration After Myocardial Infarction: Patients with ST-elevation myocardial infarction whose thrombi were aspirated before percutaneous coronary intervention had improved outcomes at 1 year, according to findings from TAPAS, the Thrombus Aspiration during Percutaneous coronary intervention in Acute myocardial infarction Study (pp. 1915-20). ìCardiac death at 1 year was 3.6% (19 of 535 patients) in the thrombus aspiration group and 6.7% (36 of 536) in the conventional PCI group (hazard ratio [HR] 1.93; 95% CI 1.11–3.37; p = 0.020),î the investigators report. ì1-year cardiac death or non-fatal reinfarction occurred in 5.6% (30 of 535) of patients in the thrombus aspiration group and 9.9% (53 of 536) of patients in the conventional PCI group (HR 1.81; 95% CI 1.16–2.84; p = 0.009).î (P. J. Vlaar, U. Med. Ctr. Groningen, the Netherlands; p.j.j.vlaar@thorax.umcg.nl)

>>>Circulation Highlights
Source:
June 3 issue of Circulation (http://circ.ahajournals.org/current.dtl; 2008; 117).
Aspirin Costs in Primary Prevention: A differentiated approach to use of aspirin for primary prevention of cardiovascular events is warranted based on the results of a cost-effectiveness analysis (pp. 2875-83). Using a Markov model to assess costs and outcomes over a 10-year period, researchers found aspirin to be cost-effective for men with a risk above 10% but for women only when risks exceeded 15%: ìIn 55-year-old persons, aspirin prevented myocardial infarctions in men (127 events per 100,000 person–years) and ischemic strokes in women (17 events per 100,000 person–years). Aspirin implies a net investment and a quality-adjusted life-year gain in men 55 years of age; the incremental cost-effectiveness ratio was 111,949 euros per quality-adjusted life-year (1 euro=$1.27 as of June 2007). Aspirin was cost-effective for 55- and 65-year-old men with moderate cardiovascular risk and men 75 years of age (10-year cardiovascular disease risk >10%). Conversely, aspirin was beneficial for women 65 years of age with high cardiovascular risk and women 75 years of age with moderate cardiovascular risk (10-year cardiovascular disease risk >15%). Results were sensitive to drug treatment costs, effectiveness of aspirin treatment, and utility of taking aspirin.î (J. P. Greving, U. Med. Ctr., Utrecht, the Netherlands; J.P.Greving@umcutrecht.nl)
Medication Adherence in Hypertension: Physicians paid insufficient attention to elevated blood pressures and poor medication adherence during primary care visits of 38,327 patients with elevated systolic or diastolic pressures (pp. 2884-92). In midwestern VA facilities, investigators found that prescribers took these actions in visits where systolic BPs were 141–199 mm Hg and diastolic readings were above 90 mm Hg: ìProviders intensified medications in 30% of the 68,610 elevated BP events, with almost no variation in intensification regardless of whether patients had good or poor BP medication adherence. After adjustment, intensification rates were 31% among patients who had ‘gaps’ of <20% (days on which patients should have had medication but no medication was available because medications had not been refilled), 34% among patients with refill gaps of 20% to 59%, and 32% among patients with gaps of 60% or more.î (M. Heisler, mheisler@umich.edu)

>>>PNN JournalWatch
* Management of Type 2 Diabetes: Summary of Updated NICE Guidance, in BMJ, 2008; 336: 1306–8. Reprints: P. Home, Newcastle U., Newcastle upon Tyne, U.K.; philip.home@ncl.ac.uk
* Diagnosis and Management of Hypocalcaemia, in
BMJ, 2008; 336: 1298–302. Reprints: N. J. L. Gittoes, Queen Elizabeth Hosp., Birmingham, U.K.; n.j.gittoes@bham.ac.uk
* Prevalence and Clinical Implications of Sarcopenic Obesity in Patients with Solid Tumours of the Respiratory and Gastrointestinal Tracts: A Population-Based Study, in
Lancet Oncology, 2008; doi: 10.1016/S1470-2045(08)70153-0. Reprints: V. E. Baracos, vickieb@cancerboard.ab.ca
* Febrile Seizures: Clinical Practice Guideline for the Long-term Management of the Child with Simple Febrile Seizures, in
Pediatrics, 2008; 121: 1281–6. Reprints: American Academy of Pediatrics Steering Committee on Quality Improvement and Management, Subcommittee on Febrile Seizures.
* Management of Chronic Hepatitis C Virus Infection in HIV-Infected Patients, in
Clinical Infectious Diseases, 2008; 47: 97–101. Reprints: S. Pol, HÙpital Cochin, Paris; stanislas.pol@cch.aphp.fr

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

PNN Pharmacotherapy Line
June 10, 2008 * Vol. 15, No. 112
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
June 9 issue of the Archives of Internal Medicine (http://archinte.ama-assn.org/current.dtl; 2008; 168).
Treating Herpes Simplex Infections: The available antiviral agents for treatment of oral and genital herpes simplex infections are reviewed, with emphasis on deciding whether to use intermittent episodic therapy, intermittent suppressive therapy, or chronic suppressive therapy (CST) (pp. 1137-44). Intermittent suppressive therapy can be used when stressors and recurrences can be anticipated, the authors note. These observations are made regarding CST: ìAlthough most patients with HSV infections do not require CST, those with frequent recurrences who experience severe pain or disfigurement, have difficulty swallowing, or experience a protracted disease course are appropriately treated with CST.8 Of all patients with labial herpes, 5% to 10% experience frequent recurrences (6 per year). Of patients infected with genital herpes, 20% to 50% have symptomatic, recurrent flares. Patients have a median of 4 recurrences the year after a first symptomatic episode and usually enjoy a decline in frequency of outbreaks over time. Recurrences of any frequency can negatively affect a patient’s quality of life. Thus, CST is appropriate for patients who are psychologically distressed by their disease. Long-term prophylactic therapy for genital herpes may also be used in an effort to decrease the risk of transmission to uninfected partners.î (R. T. Brodell, Brodell Medical Inc., Warren, Ohio; rtb@neoucom.edu)
Vitamin D Levels & MI Risk in Men: In a nested case–control analysis of the Health Professionals Follow-up Study, 18,225 men with low levels of 25-hydroxyvitamin D had higher risk of myocardial infarction (pp. 1174-80). The relationship held after controlling for known risk factors, researchers report, adding these details: ìMen deficient in 25(OH)D (15 ng/mL [to convert to nanomoles per liter, multiply by 2.496]) were at increased risk for MI compared with those considered to be sufficient in 25(OH)D (30 ng/mL) (relative risk [RR], 2.42; 95% confidence interval [CI], 1.53–3.84; P < .001 for trend). After additional adjustment for family history of myocardial infarction, body mass index, alcohol consumption, physical activity, history of diabetes mellitus and hypertension, ethnicity, region, marine omega-3 intake, low- and high-density lipoprotein cholesterol levels, and triglyceride levels, this relationship remained significant (RR, 2.09; 95% CI, 1.24–3.54; P = .02 for trend). Even men with intermediate 25(OH)D levels were at elevated risk relative to those with sufficient 25(OH)D levels (22.6–29.9 ng/mL: RR, 1.60 [95% CI, 1.10–2.32]; and 15.0-22.5 ng/mL: RR, 1.43 [95% CI, 0.96–2.13], respectively).î (E. Giovannucci, egiovann@hsph.harvard.edu)
Risk of Stroke with NSAIDs, COX-2 Inhibitors: Patients on either nonselective NSAIDs or COX-2–selective agents—but not COX-1–selective NSAIDs—had increased risk of stroke in an analysis of data on 7,636 individuals who had first strokes before Sept. 2004 (pp. 1219-24). ìAt baseline, the mean age of the study sample was 70.2 years, and 61.3% were female,î write the researchers. ìDuring 70,063 person–years of follow-up (mean, 9.2 years), 807 persons developed a stroke (460 ischemic, 74 hemorrhagic, and 273 unspecified). Current users of nonselective (HR, 1.72; 95% confidence interval [CI], 1.22–2.44) and COX-2–selective (HR, 2.75; 95% CI, 1.28–5.95) NSAIDs had a greater risk of stroke, but not users of COX-1–selective NSAIDs (HR, 1.10; 95% CI, 0.41–2.97). Hazard ratios (95% CIs) for ischemic stroke were 1.68 (1.05–2.69) for nonselective and 4.54 (2.06–9.98) for COX-2–selective NSAIDs. For individual NSAIDs, current use of the nonselective naproxen (HR, 2.63; 95% CI, 1.47–4.72) and the COX-2–selective rofecoxib (HR, 3.38; 95% CI, 1.48–7.74) was associated with a greater risk of stroke. Hazard ratios (95% CIs) for diclofenac (1.60 [1.00–2.57]), ibuprofen (1.47 [0.73–3.00]), and celecoxib (3.79 [0.52–27.6]) were greater than 1.00 but were not statistically significant.î (B. H. C. Stricker, Erasmus Med. Ctr., Rotterdam, the Netherlands; b.stricker@erasmusmc.nl)

>>>PNN NewsWatch
* Patients using three or more tubes of becaplermin (Regranex, Ortho-McNeil) have a 5-fold greater risk of cancer-related death than nonusers, FDA warns, even though the risk of developing new cancers is not increased by use of the drug.

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

PNN Pharmacotherapy Line
June 11, 2008 * Vol. 15, No. 113
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
June 11 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2008; 299).
St. John’s Wort for ADHD: Hypericum perforatum, the active agent in St. John’s wort products that some parents try in children with attention-deficit/hyperactivity disorder, produced no significant benefits in a group of 54 children and adolescents in an 8-week randomized controlled trial (pp. 2633-41). Comparing St. John’s wort that was standardized to 0.3% hypericin against a matched placebo, the investigators found: ìOne patient in the placebo group withdrew because of an adverse event. No significant difference was found in the change in ADHD Rating Scale–IV scores from baseline to week 8 between the treatment and placebo groups: inattentiveness improved 2.6 points (95% confidence interval [CI], –4.6 to –0.6 points) with H perforatum vs 3.2 points (95% CI, –5.7 to –0.8 points) with placebo (P = .68) and hyperactivity improved 1.8 points (95% CI, –3.7 to 0.1 points) with H perforatum vs 2.0 points (95% CI, –4.1 to 0.1 points) with placebo (P = .89). There was also no significant difference between the 2 groups in the percentage of participants who met criteria for improvement (score 2) on the Clinical Global Impression Improvement Scale (H perforatum, 44.4%; 95% CI, 25.5%–64.7% vs placebo, 51.9%; 95% CI, 31.9%–71.3%; P = .59). No difference between groups was found in the number of participants who experienced adverse effects during the study period (H perforatum, 40.7%; 95% CI, 22.4%–61.2% vs placebo, 44.4%; 95% CI, 25.5%–64.7%; P = .78).î (W. Weber, Bastyr U., Kenmore, Wash.; wendyw@bastyr.edu)
An editorialist, writing about this study and investigations into complementary and alternative medicine in general, notes (pp. 2685-6): ìMost studies of CAM efficacy, both in adults and children, are generally of poor quality; this is true for many conventional medical practices as well. In mainstream medicine, the concepts of outcomes research, evidence-based medicine, and the need for rigorous methods and quality standards for reporting clinical trials have emerged just in the past few decades. Only very recently have these standards been extended to RCTs of nonpharmacologic treatments....
ìUltimately, increased attention to and emphasis on deepening a rigorous evidence base for all health care practices will benefit patients and families. The time for bad science, whether in conventional or unconventional medicine, is past.î (E. Chan,
eugenia.chan@childrens.harvard.edu)
Light/Melatonin Effects on Cognition in Elderly Residents: Because of adverse effects of melatonin on mood, the agent should only be used with light therapy, concludes a study of 189 elderly residents of 12 group care facilities in the Netherlands (pp. 2642-55). Participants were randomly assigned to whole-day bright or dim light and evening melatonin or placebo. Researchers found that light had a ìmodestî beneficial effect on cognitive and noncognitive symptoms of dementia: ìLight attenuated cognitive deterioration by a mean of 0.9 points (95% confidence interval [CI], 0.04–1.71) on the Mini-Mental State Examination or a relative 5%. Light also ameliorated depressive symptoms by 1.5 points (95% CI, 0.24–2.70) on the Cornell Scale for Depression in Dementia or a relative 19%, and attenuated the increase in functional limitations over time by 1.8 points per year (95% CI, 0.61–2.92) on the nurse-informant activities of daily living scale or a relative 53% difference. Melatonin shortened sleep onset latency by 8.2 minutes (95% CI, 1.08–15.38) or 19% and increased sleep duration by 27 minutes (95% CI, 9–46) or 6%. However, melatonin adversely affected scores on the Philadelphia Geriatric Centre Affect Rating Scale, both for positive affect (–0.5 points; 95% CI, –0.10 to –1.00) and negative affect (0.8 points; 95% CI, 0.20–1.44). Melatonin also increased withdrawn behavior by 1.02 points (95% CI, 0.18–1.86) on the Multi Observational Scale for Elderly Subjects scale, although this effect was not seen if given in combination with light. Combined treatment also attenuated aggressive behavior by 3.9 points (95% CI, 0.88–6.92) on the Cohen–Mansfield Agitation Index or 9%, increased sleep efficiency by 3.5% (95% CI, 0.8%–6.1%), and improved nocturnal restlessness by 1.00 minute per hour each year (95% CI, 0.26–1.78) or 9% (treatment X time effect).î (E. J. W. Van Someren, Netherlands Inst. for Neuroscience, Amsterdam; e.van.someren@nin.knaw.nl)

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

PNN Pharmacotherapy Line
June 12, 2008 * Vol. 15, No. 114
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
June 12 New England Journal of Medicine (http://content.nejm.org/current.shtml; 2008; 358).
Intensive Glucose Lowering in Type 2 Diabetes—ACCORD: Among 10,251 high-risk patients, intensive glucose-lowering therapy significantly increased mortality and failed to reduce major cardiovascular events, compared with standard therapy, reports the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study group (pp. 2545-59). Patients began with a median glycated hemoglobin level of 8.1% and were assigned to intensive (target, 6.0%) or standard (target, 7.0–7.9%) therapy, with these results: ìAt 1 year, stable median glycated hemoglobin levels of 6.4% and 7.5% were achieved in the intensive-therapy group and the standard-therapy group, respectively. During follow-up, the primary outcome occurred in 352 patients in the intensive-therapy group, as compared with 371 in the standard-therapy group (hazard ratio, 0.90; 95% confidence interval [CI], 0.78 to 1.04; P = 0.16). At the same time, 257 patients in the intensive-therapy group died, as compared with 203 patients in the standard-therapy group (hazard ratio, 1.22; 95% CI, 1.01 to 1.46; P = 0.04). Hypoglycemia requiring assistance and weight gain of more than 10 kg were more frequent in the intensive-therapy group (P < 0.001).î (R. P. Byington, Wake Forest U., Winston–Salem, N.C.; bbyingto@wfubmc.edu)
Intensive Glucose Lowering in Type 2 Diabetes—ADVANCE: A 10% relative reduction in major macrovascular and microvascular events was observed among 11,140 patients with type 2 diabetes in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, and most of that was the result of a 21% drop in relative risk of nephropathy (pp. 2560-72). Assessing rates of major macrovascular events (cardiovascular deaths, nonfatal myocardial infarction, or nonfatal stroke) and major microvascular events (new or worsening nephropathy or retinopathy) in patients who were randomly assigned to standard or intensive (use of modified-release gliclazide plus other drugs as required to achieve a glycated hemoglobin value of 6.5% or less) glucose control, the investigators determined: ìAfter a median of 5 years of follow-up, the mean glycated hemoglobin level was lower in the intensive-control group (6.5%) than in the standard-control group (7.3%). Intensive control reduced the incidence of combined major macrovascular and microvascular events (18.1%, vs. 20.0% with standard control; hazard ratio, 0.90; 95% confidence interval [CI], 0.82 to 0.98; P = 0.01), as well as that of major microvascular events (9.4% vs. 10.9%; hazard ratio, 0.86; 95% CI, 0.77 to 0.97; P = 0.01), primarily because of a reduction in the incidence of nephropathy (4.1% vs. 5.2%; hazard ratio, 0.79; 95% CI, 0.66 to 0.93; P = 0.006), with no significant effect on retinopathy (P = 0.50). There were no significant effects of the type of glucose control on major macrovascular events (hazard ratio with intensive control, 0.94; 95% CI, 0.84 to 1.06; P = 0.32), death from cardiovascular causes (hazard ratio with intensive control, 0.88; 95% CI, 0.74 to 1.04; P = 0.12), or death from any cause (hazard ratio with intensive control, 0.93; 95% CI, 0.83 to 1.06; P = 0.28). Severe hypoglycemia, although uncommon, was more common in the intensive-control group (2.7%, vs. 1.5% in the standard-control group; hazard ratio, 1.86; 95% CI, 1.42 to 2.40; P < 0.001).î (A. Patel, U. Sydney, Sydney, Australia; apatel@george.org.au)
In one of two accompanying editorials,
NEJM editors note (pp. 2630-3): ìNeither the ADVANCE trial nor the ACCORD trial undermines the importance of meeting the current guidelines for care, and they should not be interpreted as diminishing the importance of glycemic control. The lower-than-anticipated rate of cardiovascular events seen in the intensive-treatment group and the standard-treatment group in these studies is an affirmation of the success of modern therapeutics, even when incompletely implemented.... Clinicians caring for patients with diabetes should continue to focus on smoking cessation, dietary and exercise counseling, blood-pressure control, and providing aspirin and a statin to a greater extent than achieved even in the ADVANCE and ACCORD studies. For now, rather than changing our current glycemic target, we may best serve our patients with type 2 diabetes by implementing programs to help more of them reach the currently recommended goals.î (R. G. Dluhy)

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

PNN Pharmacotherapy Line
June 13, 2008 * Vol. 15, No. 115
Providing news and information about medications and their proper use

>>>Gastroenterology Report
Source:
June issue of Gastroenterology (www.gastrojournal.org/current; 2008; 134).
Immunosuppression Withdrawal in Crohn’s Disease: Patients with Crohn’s disease can be transitioned from immunosuppressive therapy to scheduled infliximab (IFX) maintenance therapy at 6 months after initiation of the latter agent, a research study shows (pp. 1861-8). Patients in the open-label study had controlled disease and had been on IFX for 6 or more months, and all continued the drug throughout 104 weeks of the study. Randomization to continued (Con) or discontinued (Dis) immunosuppression showed few differences between the two groups: ìA similar proportion (24/40, 60% Con) and (22/40, 55% Dis) of patients needed a change in IFX dosing interval or stopped IFX therapy (11/40 Con, 9/40 Dis). C-reactive protein (CRP) was higher and IFX trough levels were lower in the Dis group (Dis: CRP, 2.8 mg/L; interquartile range [IQR], 1.0–8.0; Con: CRP, 1.6 mg/L; IQR, 1.0–5.6, P < .005; trough IFX: Dis: 1.65 µg/mL; IQR, 0.54–3.68; Con: 2.87 µg/mL; IQR, 1.35–4.72, P < .0001). Low IFX trough levels correlated with increased CRP and clinical score. Mucosal ulcers were absent at week 104 in 64% (Con) and 61% (Dis) of evaluated patients with ongoing response to IFX.î (G. Van Assche, U. Leuven Hosp., Leuven, Belgium; gert.vanassche@uz.kuleuven.be)
Oral v. Intravenous PPIs for Bleeding Ulcers: Frequent oral dosing of proton-pump inhibitors is statistically similar in its benefits to intravenous administration of the drugs in patients with bleeding ulcers, investigators report (pp. 1836-41). Relatively wide confidence intervals in the data prevented the researchers from definitively concluding that two routes of administration are equivalent, as noted in these results: ìIntragastric pH was >6 for 67.8% of the study period with intravenous PPI (n = 32) and 64.8% with oral PPI (n = 34): difference, 3.0%; 95% confidence interval (CI): −9.2% to 15.2%. Intragastric pH was >6 for >60% of the study period in 22 (68.8%) patients receiving intravenous and 22 (64.7%) patients receiving oral PPI: difference, 4.0%; 95% CI: −18.7% to 26.8%. At 1 hour, mean pHs for intravenous vs oral were 5.3 ± 0.4 vs 3.3 ± 0.4, respectively (difference, 2.0; 95% CI: 0.8–3.1; P = .001). At 1.5 hours, 95% CIs of the differences for all hourly mean pHs included zero. Mean pH rose above 6 after 2–3 hours of intravenous PPI and 3–4 hours of oral PPI.î (L. Laine, llaine@usc.edu)

>>>Nephrology Highlights
Source:
June issue of the American Journal of Kidney Diseases (www.ajkd.org/current; 2008; 51).
Effects of Short-Term Fenofibrate on GFR: While fenofibrate therapy has been associated with increases in serum creatinine concentrations, short-term administration of the agent in 24 healthy, middle-aged patients had no effect on glomerular filtration rates (pp. 904-13). Looking at a primary outcome of changes in GFR as measured by inulin clearance, the researchers found these results with fenofibrate 160 mg/day or placebo administered in crossover 6-week periods: ìInulin clearance was unchanged after fenofibrate (change [] between treatments on 6-week values, 0.8 mL/min; 95% CI, −10.5 to 12.2; P = 0.9), but [para-aminohippurate (PAH)] clearance decreased (, −33; 95% CI, −66 to −1; P = 0.05). Changes in inulin and PAH clearances were not greater than 20%. Plasma creatinine level increased (, 0.11 mg/dL; 95% CI, 0.05 to 0.18; P < 0.05), and creatinine clearance decreased (, −9.5 mL/min; 95% CI, −14.4 to −4.7; P < 0.001). Creatinine secretion and urinary creatinine excretion were unchanged (, −0.05; 95% CI, −0.11 to 0.02; P = 0.2; , 0.37 g/24 h; 95% CI, −0.13 to 0.88; P = 0.1, respectively). Plasma cystatin C level increased (, 0.18 mg/L; 95% CI, 0.03 to 0.34; P = 0.02) and serum uric acid level decreased (, −0.7 mg/dL; 95% CI, −1.2 to −0.3; P = 0.1). Urinary albumin and retinol-binding protein levels were unchanged, but urinary N-acetyl-fl-d-glucosaminidase activity increased (, 20.0 µmol/h/mmol creatinine; 95% CI, 9.3 to 30.7; P = 0.001).î (C. Foucher, Laboratoires Fournier, Dijon, France; christelle.foucher@solvay.com)
Education in Kidney Disease: Multicomponent structured educational interventions can help delay or prevent progression of kidney disease, a systematic review concludes (pp. 933-51; J. Mason, Leicester Genl. Hosp., Leicester, U.K.; jo.l.mason@uhl-tr.nhs.uk).

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

PNN Pharmacotherapy Line
June 16, 2008 * Vol. 15, No. 116
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
June 14 issue of Lancet (www.thelancet.com; 2008; 371).
Carbocisteine for COPD: Among 709 patients treated for chronic obstructive pulmonary disease at 22 Chinese centers, the mucolytic carbocisteine was ìa worthwhile treatment for prevention of exacerbations,î researchers report (pp. 2013-8). Compared with placebo, carbocisteine 1,500 mg daily for 1 year produced these results: ìNumbers of exacerbations per patient per year declined significantly in the carbocisteine group compared with the placebo group (1.01 [SE 0.06] vs 1.35 [SE 0.06]), risk ratio 0.75 (95% CI 0.62–0.92, p = 0.004). Non-significant interactions were found between the preventive effects and COPD severity, smoking, as well as concomitant use of inhaled corticosteroids. Carbocisteine was well tolerated.î (N-S Zhong, First Affiliated Hosp. of Guangzhou Med. Coll., Guangzhou, China; nanshan@vip.163.com)
Transdermal Vaccine for Travelers’ Diarrhea: A skin patch delivering heat-labile enterotoxin (LT) from enterotoxigenic Escherichia coli (ETEC) significantly reduced the frequency and severity of travelers’ diarrhea among those visiting Mexico or Guatemala (pp. 2019-25). Before traveling to the areas, study participants applied two patches containing LT 37.5 mcg or placebo about 2–3 weeks apart. Diary cards and stool analysis revealed these trends among 170 travellers: ì24 (22%) of 111 placebo recipients had diarrhoea, of whom 11 (10%) had ETEC diarrhoea. The vaccine was safe and immunogenic. The 59 LT-patch recipients were protected against moderate-to-severe diarrhoea (protective efficacy [PE] 75%, p = 0.0070) and severe diarrhoea (PE 84%, p = 0.0332). LT-patch recipients who became ill had shorter episodes of diarrhoea (0.5 days vs 2.1 days, p = 0.0006) with fewer loose stools (3.7 vs 10.5, p < 0.0001) than placebo.î (G. M. Glenn, IOMAI Corp., Gaithersburg, Md.; gglenn@iomai.com)

>>>BMJ Highlights
Source:
June 14 issue of BMJ (www.bmj.org; 2008; 336).
Injectable Dexamethasone for Migraine Prevention: Single doses of injectable dexamethasone reduce by one-quarter the risk of severe migraine headaches over the ensuing 72 hours, authors of a meta-analysis report (pp. 1359-61): ìFrom 666 potentially relevant abstracts, seven studies met the inclusion criteria. All included trials used standard abortive therapy and subsequently compared single dose parenteral dexamethasone with placebo, examining pain relief and recurrence of headache within 72 hours. Dexamethasone and placebo provided similar acute pain reduction (weighted mean difference 0.37, 95% confidence interval –0.20 to 0.94). Dexamethasone was, however, more effective than placebo in reducing recurrence rates (relative risk 0.74, 95% confidence interval 0.60 to 0.90). Side effect profiles between dexamethasone and placebo groups were similar.î (B. H. Rowe, brian.rowe@ualberta.ca)

>>>PNN JournalWatch
* Tobacco Addiction, in Lancet, 2008; 371: 2027–38. Reprints: D. K. Hatsukami, hatsu001@umn.edu
* Preventing Malaria in Travellers, in
BMJ, 2008; 336: 1362–6. Reprints: D. G. Lalloo, Liverpool Sch. of Tropical Med., Liverpool, U.K.; dlalloo@liverpool.ac.uk
* Control of Gastric Acid Secretion in Health and Disease, in
Gastroenterology, 2008; 134: 1842–60. Reprints: M. L. Schubert, Mitchell.Schubert@va.gov
* Multigene Analysis Can Discriminate Between Ulcerative Colitis, Crohn’s Disease, and Irritable Bowel Syndrome, in
Gastroenterology, 2008; 134: 1869–81. Reprints: P. von Stein, Karolinska Inst., Stockholm; petra.stein@indexdiag.com
* Impact of a Medicaid Copayment Policy on Prescription Drug and Health Services Utilization in a Fee-for-Service Medicaid Population, in
Medical Care, 2008; 46: 565–72. Reprints: D. M. Hartung.
* Medicaid Prior Authorization and Controlled-Release Oxycodone, in
Medical Care, 2008; 46: 573–80. Reprints: N. E. Morden.
* Hemorrhagic Stroke in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels Study, in
Neurology, 2008; 70: 2364–70. Reprints: L. B. Goldstein, golds004@mc.duke.edu
* CKD Following Kidney Transplantation in Children and Adolescents, in
American Journal of Kidney Diseases, 2008; 51:996–1004. Reprints: C. T. White, British Columbia Children’s Hospital, Vancouver; cwhite@cw.bc.ca

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

PNN Pharmacotherapy Line
June 17, 2008 * Vol. 15, No. 117
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
June 17 issue of the Annals of Internal Medicine (http://www.annals.org/current.shtml; 2008; 148).
Hydroxyurea in Sickle Cell Disease: In articles released previously (see PNN, May 6), an NIH consensus conference examines use of hydroxyurea for treating adult patients with sickle cell disease.
In an evidence-based review, authors provide these details about clinical trials of hydroxyurea (pp. 939-55): ìIn the single randomized trial, the hemoglobin level was higher in hydroxyurea recipients than placebo recipients after 2 years (difference, 6 g/L), as was fetal hemoglobin (absolute difference, 3.2%). The median number of painful crises was 44% lower than in the placebo arm. The 12 observational studies that enrolled adults reported a relative increase in fetal hemoglobin of 4% to 20% and a relative reduction in crisis rates by 68% to 84%. Hospital admissions declined by 18% to 32%. The evidence suggests that hydroxyurea may impair spermatogenesis. Limited evidence indicates that hydroxyurea treatment in adults with sickle cell disease is not associated with leukemia. Likewise, limited evidence suggests that hydroxyurea and leg ulcers are not associated in patients with sickle cell disease, and evidence is insufficient to estimate the risk for skin neoplasms, although these outcomes can be attributed to hydroxyurea in other conditions.î (S. Lanzkron, Johns Hopkins U., Baltimore)
NIH consensus conference panelists provide this bottom-line recommendation to clinicians (pp. 932-8): ìHydroxyurea is an important major advance in the treatment of sickle cell disease. Strong evidence supports the efficacy of hydroxyurea in adults to decrease severe painful episodes, hospitalizations, number of blood transfusions, and acute chest syndrome. Although the evidence for efficacy of hydroxyurea treatment for children is not as strong, the emerging data are encouraging. The current data on the risks of both short- and long-term harms of hydroxyurea therapy are reassuring, and the risks of hydroxyurea use in adults are acceptable compared with the risks of untreated sickle cell disease.î (
www.consensus.nih.gov; 888/644-2667)
Coffee & Mortality: Regular coffee consumption was not associated with increased mortality among participants in either the Health Professionals Follow-up Study or the Nurses’ Health Study, researchers report (pp. 904-14). In fact, a modest benefit on all-cause and cardiovascular disease mortality was evident with consumption of either caffeinated or decaffeinated brews. This should be explored further, the group writes, adding these details on the 41,736 men and 86,214 women in the studies: ìAfter adjustment for age, smoking, and other CVD and cancer risk factors, the relative risks for all-cause mortality in men across categories of coffee consumption (<1 cup per month, 1 cup per month to 4 cups per week, 5 to 7 cups per week, 2 to 3 cups per day, 4 to 5 cups per day, and 6 cups per day) were 1.0, 1.07 (95% CI, 0.99 to 1.16), 1.02 (CI, 0.95 to 1.11), 0.97 (CI, 0.89 to 1.05), 0.93 (CI, 0.81 to 1.07), and 0.80 (CI, 0.62 to 1.04), respectively (P for trend = 0.008). For women, the relative risks were 1.0, 0.98 (CI, 0.91 to 1.05), 0.93 (CI, 0.87 to 0.98), 0.82 (CI, 0.77 to 0.87), 0.74 (CI, 0.68 to 0.81), and 0.83 (CI, 0.73 to 0.95), respectively (P for trend < 0.001). This inverse association was mainly due to a moderately reduced risk for CVD mortality and was independent of caffeine intake. By contrast, coffee consumption was not statistically significantly associated with risk for cancer death after adjustment for potential confounders. Decaffeinated coffee consumption was associated with a small reduction in all-cause and CVD mortality.î (E. Lopez-Garcia, Universidad AutÛnoma de Madrid, Madrid; esther.lopez@uam.es)

>>>PNN NewsWatch
* Using new authority granted under a 2007 law, FDA yesterday moved to require manufacturers of first-generation (typical) antipsychotic drugs to warn of an increased risk of death associated with the off-label use of these drugs for treating behavioral problems in older people with dementia. The warnings are similar to those added to second-generation (atypical) agents in 2005 and are based on findings in two epidemiological studies. People taking antipsychotic drugs should not abruptly stop taking them. Caregivers and patients should talk to the patient’s health professionals about any concerns.

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

PNN Pharmacotherapy Line
June 18, 2008 * Vol. 15, No. 118
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
June 18 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2008; 299).
Bidirectional Diabetes & Depression: Depressive symptoms may predispose patients to type 2 diabetes through unhealthy behaviors such as physical inactivity and through metabolic changes in biochemical pathways, investigators report, and treatment for diabetes can lead to additional depressive symptoms (pp. 2751-9). This bidirectional relationship between the two diseases is evident among nearly 10,000 patients without type 2 diabetes (analysis 1) or depression (analysis 2) at baseline: ìIn analysis 1, the incidence rate of type 2 diabetes was 22.0 and 16.6 per 1,000 person–years for those with and without elevated depressive symptoms, respectively.... In analysis 2, the incidence rates of elevated depressive symptoms per 1,000 person–years were 36.8 for participants with normal fasting glucose; 27.9 for impaired fasting glucose; 31.2 for untreated type 2 diabetes, and 61.9 for treated type 2 diabetes.î (S. H. Golden, Johns Hopkins U., Baltimore; sahill@jhmi.edu)
CETP Genotypes & Coronary Risks:
In a Clinician’s Corner contribution, authors show that three cholesteryl ester transfer protein (CETP) genotypes produce moderate CETP inhibition and thereby modestly raise HDL cholesterol levels (pp. 2777-88). Using data from 92 studies of 113,833 healthy participants and 46 studies of 27,196 patients with coronary disease and 55,338 control patients, the authors determined: ìIndividuals with (presumably lifelong) increased HDL-C levels as a result of genetically mediated reductions in CETP may be at slightly reduced coronary risk. This apparent discrepancy may relate to ‘off-target’ effects potentially specific to torcetrapib (notably interference with the renin-angiotensin system and blood pressure elevation). On the other hand, it has been suggested that HDL particles produced under conditions of CETP inhibition may be dysfunctional, with any apparent increase in HDL-C levels offset by compensatory HDL-C clearance through direct hepatic pathways and reduced apolipoprotein A-I–mediated removal of intracellular-free cholesterol from macrophages. Further trials of other CETP inhibitors and investigations of CETP genotypes in relation to blood pressure and other traits may help to address such mechanistic concerns.î (J. Danesh, U. Cambridge, Cambridge, England; john.danesh@phpc.cam.ac.uk)
Growth Hormone for Antiaging and Bodybuilding: ìIllegal distributionî of human growth hormone through antiaging clinics, compounding pharmacies, and pharmaceutical companies is the subject of a commentary article, which reaches this conclusion (pp. 2792-4): ìUntil and unless efficacy and safety of hGH is demonstrated by unbiased scientifically rigorous clinical trials for purposes advocated by the antiaging industry, hGH should not be distributed or prescribed for any purpose other than its narrowly defined clinical and legal indications. Legislative, regulatory, and professional actions are needed to effectively curtail the extensive promotion and illegal distribution and use of hGH for antiaging and bodybuilding.î (S. J. Olshansky, sjayo@uic.edu)
Overutilization & U.S. Health Care’s ‘Perfect Storm’: A number of factors are contributing to the crisis now evident in the U.S. health care system, write authors of a commentary article (pp. 2789-91). Exploring ways to stem the tide of rising costs and excessive demand, the pair concludes: ìThe United States has created the perfect storm for overutilization of health care. Costs cannot be controlled unless overutilization is substantially reduced. Many physician and patient factors—ingrained values, physician culture, advertising, payment—drive and synergistically intensify overutilization. The best hope for reining in costs is to devise financial incentives for physicians and patients that result in greater health care value.î (E. J. Emanuel, eemanuel@nih.gov)

>>>PNN NewsWatch
* FDA has warned 23 U.S. companies and two foreign individuals to stop marketing a wide range of products fraudulently claiming to prevent and cure cancer. The agency also warned North American consumers against using or purchasing the products, which contain ingredients such as bloodroot, shark cartilage, coral calcium, cesium, ellagic acid, Cat’s Claw, an herbal tea called Essiac, and mushroom varieties such as Agaricus Blazeii, Shitake, Maitake, and Reishi.

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

PNN Pharmacotherapy Line
June 19, 2008 * Vol. 15, No. 119
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
June 19 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2008; 358).
Rhythm v. Rate Control in AF/HF: In the Atrial Fibrillation and Congestive Heart Failure trial, a strategy of rhythm control was no more effective for reducing cardiovascular mortality than a rate-control strategy, researchers report (pp. 2667-77). Rhythm control was aggressively directed toward preventing atrial fibrillation using electrical cardioversion (including repeat interventions as needed), amiodarone, and as-needed sotalol or dofetilide. Pacemakers were implanted when drugs could not be used. Medications used in the rate-control arm were beta-blockers and digitalis; atrioventricular nodal ablation and pacemaker therapy were also used as needed. Results showed: ìA total of 1,376 patients were enrolled (682 in the rhythm-control group and 694 in the rate-control group) and were followed for a mean of 37 months. Of these patients, 182 (27%) in the rhythm-control group died from cardiovascular causes, as compared with 175 (25%) in the rate-control group (hazard ratio in the rhythm-control group, 1.06; 95% confidence interval, 0.86 to 1.30; P = 0.59 by the log-rank test). Secondary outcomes were similar in the two groups, including death from any cause (32% in the rhythm-control group and 33% in the rate-control group), stroke (3% and 4%, respectively), worsening heart failure (28% and 31%), and the composite of death from cardiovascular causes, stroke, or worsening heart failure (43% and 46%). There were also no significant differences favoring either strategy in any predefined subgroup.î (D. Roy, Montreal Heart Inst., Montreal; d_roy@icm-mhi.com)
Editorialists, assessing the current status of rhythm control in atrial fibrillation, note that research has provided ìone setback after anotherî (pp. 2725-7): ìUntil [numerous] questions are answered, it is difficult to support a primary approach of rhythm control that relies on antiarrhythmic drugs in any patient with atrial fibrillation, including those with heart failure. Even for symptomatic patients, it seems prudent first to attempt to eliminate symptoms with drugs that control the ventricular rate and then to consider therapy with antiarrhythmic drugs only if symptoms persist. Anticoagulation should be prescribed to all appropriate patients on the basis of the [Cardiac Failure, Hypertension, Age, Diabetes, Stroke (Doubled)] score. Champions of sinus rhythm must await the results of comparative ablation trials to learn whether the field suffers another setback or moves forward.î (M. E. Cain, U. Buffalo, Buffalo, N.Y.)
Mortality with Dronedarone for Severe HF: Increased early mortality was observed when patients hospitalized with symptomatic heart failure and severe left ventricular systolic dysfunction were treated with the multichannel blocker dronedarone, according to results of the Antiarrhythmic Trial with Dronedarone in Moderate to Severe CHF Evaluating Morbidity Decrease (ANDROMEDA) study (pp. 2678-87). Compared with placebo, twice-daily 400-mg doses of the drug produced these outcomes: ìAfter inclusion of 627 patients (310 in the dronedarone group and 317 in the placebo group), the trial was prematurely terminated for safety reasons, at the recommendation of the data and safety monitoring board, in accordance with the board’s predefined rules for termination of the study. During a median follow-up of 2 months, 25 patients in the dronedarone group (8.1%) and 12 patients in the placebo group (3.8%) died (hazard ratio in the dronedarone group, 2.13; 95% confidence interval [CI], 1.07 to 4.25; P = 0.03). The excess mortality was predominantly related to worsening of heart failure—10 deaths in the dronedarone group and 2 in the placebo group. The primary end point did not differ significantly between the two groups; there were 53 events in the dronedarone group (17.1%) and 40 events in the placebo group (12.6%) (hazard ratio, 1.38; 95% CI, 0.92 to 2.09; P = 0.12). More increases in the creatinine concentration were reported as serious adverse events in the dronedarone group than in the placebo group.î (L. K¯ber, Rigshospitalet, Copenhagen; lk@heart.dk)
OTC Statins: The chair of FDA’s Nonprescription Drugs Advisory Committee reviews the possibility of over-the-counter or behind-the-counter availability of statins and other agents for asymptomatic conditions (pp. 2728-32; M. E. Tinetti).

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

PNN Pharmacotherapy Line
June 20, 2008 * Vol. 15, No. 120
Providing news and information about medications and their proper use

>>>Rheumatology Highlights
Source:
June issue of Arthritis & Rheumatism (www3.interscience.wiley.com/journal/76509746/home; 2008; 58).
Rituximab in RA: Repeated treatments with the anti-CD20 agent rituximab in patients with rheumatoid arthritis support the concept that it works through effects on memory B cells, a research study concludes (pp. 1566-75). In an open-label study, patients with refractory RA had these outcomes during rituximab therapy: ìTwelve of 17 patients showed a good European League Against Rheumatism response after receiving 1 cycle of rituximab therapy. At the time of B cell recovery, the IgD+,CD27+ memory B cell subset was significantly larger (P = 0.019) in the nonresponder group. Within the group of 12 responders, 6 patients, whose disease was characterized by a significantly higher proportion of overall CD27+ memory B cells before therapy, experienced an early relapse (weeks 24–40 posttreatment). Eleven patients were re-treated, again resulting in a good clinical response. B cell reconstitution followed a similar pattern after each cycle. The early reconstitution phase was characterized by immature CD38++,IgD+,CD10+ B cells, whereas the number of naive B cells increased continuously thereafter. The number of memory B cells was still reduced at the time of the second depletion but recovered to levels similar to those following the first cycle of therapy.î (H-P Tony, U. Wuerzburg, Wurzburg, Germany; Tony_H@medizin.uni-wuerzburg.de)
Strontium Ranelate in Osteoporosis: In 5,091 postmenopausal women with osteoporosis, strontium ranelate was significantly more effective than placebo for preventing fractures during 5 years of treatment (pp. 1687-95). Doses of the agent at 2 grams/day showed these effects: ì2,714 (53%) completed the study up to 5 years. The risk of nonvertebral fracture was reduced by 15% in the strontium ranelate group compared with the placebo group (relative risk 0.85 [95% confidence interval 0.73–0.99]). The risk of hip fracture was decreased by 43% (relative risk 0.57 [95% confidence interval 0.33–0.97]), and the risk of vertebral fracture was decreased by 24% (relative risk 0.76 [95% CI 0.65–0.88]) in the strontium ranelate group. After 5 years, the safety profile of strontium ranelate remained unchanged compared with the 3-year findings.î (J-Y Reginster, U. Liege-CHU Centreville, Liege, Belgium; jyreginster@ulg.ac.be)

>>>Allergy/Immunology Report
Source:
June issue of the Journal of Allergy and Clinical Immunology (www.jacionline.org/current; 2008; 121).
Asthma Exacerbations During Pregnancy: Congenital malformations were common among women who had asthma exacerbations during the first trimester of pregnancy in an analysis of three Canadian administrative databases (pp. 1379-84). In a cohort of 4,344 pregnancies of women with asthma who filled a prescription for oral corticosteroids, had an emergency department visit, or were hospitalized for asthma during the first trimester, these outcomes were recorded: ìIn the cohort we identified 398 (9.2%) babies with at least 1 malformation and 261 (6.0%) with a major malformation. The crude prevalences of malformations were 12.8% and 8.9%, respectively, for women who had and those who did not have an exacerbation. The adjusted odds ratio for all malformations was 1.48 (95% CI, 1.04–2.09) when comparing women who had and those who did not have an exacerbation. The corresponding figures were 1.32 (95% CI, 0.86–2.04) for major malformations.î (L. Blais, lucie.blais@umontreal.ca)
Probiotics & Cow’s Milk Tolerance: Added to extensively hydrolyzed formula, probiotics were no more effective than placebo for inducing tolerance to cow’s milk in infants over a 1-year period (pp. 1448-54). A combination of probiotics (Lactobacillus casei CRL431 and Bifidobacterium lactis Bb-12) or placebo was added to formula for 12 months in 119 infants with cow’s milk allergy. The cumulative percentages of tolerance to cow’s milk at 6 and 12 months was statistically similar in the two groups: 77% and 81% in the probiotic and placebo groups, respectively. (E. E. S. Nieuwenhuis, Erasmus Med. Ctr.–Sophia Children’s Hosp., Rotterdam, the Netherlands; e.nieuwenhuis@erasmusmc.nl)

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

PNN Pharmacotherapy Line
June 23, 2008 * Vol. 15, No. 121
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
June 21 issue of Lancet (www.thelancet.com; 2008; 371).
Laquinimod in MS: Measures of disease activity were significantly reduced by the orally active immunomodulator laquinimod, according to results of a study of 720 patients with relapsing-remitting multiple sclerosis (pp. 2085-92). All patients in the 51-center, 9-country study had at least one gadolinium-enhancing (GdE) lesion on screening magnetic resonance imaging study, and results showed the following for placebo and two doses of laquinimod: ìCompared with placebo, treatment with laquinimod 0.6 mg per day showed a 40.4% reduction of the baseline adjusted mean cumulative number of GdE lesions per scan on the last four scans (simple means 4.2 [SD 9.2] vs 2.6 [5.3], p = 0.0048); treatment with 0.3 mg per day showed no significant effects (3.9 [5.5] vs placebo, p = 0.6740). Both doses of laquinimod were well tolerated, with some transient and dose-dependent increases in liver enzymes. A case of Budd–Chiari syndrome—ie, a thrombotic venous outflow obstruction of the liver—occurred after 1 month of exposure in a patient with underlying hypercoagulability who received 0.6 mg laquinimod. Anticoagulant treatment resulted in a decline of liver enzymes to normal without any clinical signs of hepatic decompensation.î (G. Comi, University Vita-Salute, Milan, Italy; g.comi@hsr.it)

>>>BMJ Highlights
Source:
June 21 issue of BMJ (www.bmj.org; 2008; 336).
Industry Cultivation of Key Opinion Leaders: Commenting on a three-part point–counterpoint on whether the pharmaceutical industry should use key opinion leaders in seeking to garner increased market share for its products, the BMJ editor writes (doi:10.1136/bmj.a413): ìPerhaps most troubling is the way industry grooms potential opinion leaders. Quoting from the magazine Pharmaceutical Marketing, Moynihan says that industry staff are told to find doctors who will endorse their products ‘who may be further down the influence ladder’ and then help ‘raise their profile, and so develop them into opinion leaders....’
ìTransparency is crucial if we are to understand the full extent of the influences we are under. But can we look ahead to something even better, to an era of truly independent medical leadership? Giovanni Fava thinks we can and should. He envisages ‘a reservoir of truly independent experts’ and calls for an end to ‘business disguised as science.’ Medicine sorely needs leaders, but not if they’ve been bought.î (F. Godlee)
Vitamin A with BCG Vaccine: High-dose vitamin A supplementation given at birth with BCG vaccine had no significant effect on infant mortality, according to a study conducted in a high-risk area of Africa (pp. 1416-20). Among 4,345 infants, these effects were noted within the first 12 months of life for those receiving vitamin A 50,000 IU or placebo at birth: ì174 children died during follow-up (mortality = 47/1,000 person–years). Vitamin A supplementation was not significantly associated with mortality; the mortality rate ratio was 1.07 (95% confidence interval 0.79 to 1.44). The effect was 1.00 (0.65 to 1.56) during the first four months and 1.13 (0.75 to 1.68) from 4 to 12 months of age. The mortality rate ratio in boys was 0.84 (0.55 to 1.27) compared with 1.39 (0.90 to 2.14) in girls (P for interaction = 0.10). An explorative analysis revealed a strong interaction between vitamin A and season of administration.î (C. S. Benn, Statens Serum Institut, Copenhagen; cb@ssi.dk)

>>>PNN JournalWatch
* Effectiveness of Nonpharmacological Interventions in Delaying the Institutionalization of Patients with Dementia: A Meta-Analysis, in Journal of the American Geriatrics Society, 2008; 56: 1116–28. Reprints: A. Spijker, Radboud U. Nijmegen Med. Ctr., Nijmegen, the Netherlands; A.Spijker@kwazo.umcn.nl
* Obesity, Behavioral Lifestyle Factors, and Risk of Acute Coronary Events, in
Circulation, 2008; 117: 3062–9. Reprints: M. K. Jensen, Aarhus U. Hosp., Aalborg, Denmark; mkj@dce.au.dk
* Managing Dyslipidemia in Chronic Kidney Disease, in
Journal of the American College of Cardiology, 2008; 51: 2375–84. Reprints: T. A. Jacobson, tjaco02@emory.edu
* Clinical Efficacy of Drug-Eluting Stents in Diabetic Patients: A Meta-Analysis , in
Journal of the American College of Cardiology, 2008; 51: 2385–95. Reprints: E. Mahmud, emahmud@ucsd.edu

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

PNN Pharmacotherapy Line
June 24, 2008 * Vol. 15, No. 122
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
June 23 issue of the Archives of Internal Medicine (http://archinte.ama-assn.org/current.dtl; 2008; 168).
Choice of Perioperative Heparins in Cancer: No survival advantage was evident for low molecular weight versus unfractionated heparins in a systematic review and meta-analysis of studies using the drugs in patients with cancer undergoing surgery (pp. 1261-9). Looking at various outcomes, the researchers found: ìOf 3,986 identified citations, we included 14 randomized clinical trials in the meta-analysis (all using preoperative prophylactic anticoagulation). The overall methodological quality was moderate. The meta-analysis showed no differences in mortality in patients receiving LMWH compared with UFH (relative risk [RR], 0.89; 95% confidence interval [CI], 0.61–1.28) or in clinically suspected deep venous thrombosis (RR, 0.73; 95% CI, 0.23–2.28). In a post hoc analysis including all studies assessing deep venous thrombosis, irrespective of the diagnostic strategy used, LMWH was superior to UFH (RR, 0.72; 95% CI, 0.55–0.94). There were no differences in rates of pulmonary embolism (RR, 0.60; 95% CI, 0.22–1.64), minor bleeding (RR, 0.88; 95% CI, 0.47–1.66), or major bleeding (RR, 0.95; 95% CI, 0.51–1.77).î (E. A. Akl, elieakl@buffalo.edu)
Importance of Subtle Neurologic Abnormalities: In older, community-dwelling people without overt neurologic conditions, the presence of subtle but clinically detectable neurologic abnormalities (SNAs) proved a significant predictor of cognitive and functional decline, mortality, and cerebrovascular vents (CVEs), researchers report (pp. 1270-6). Baseline analysis and reassessment 4 years later showed that the number of SNAs detected during neurologic examination ìincreased with age and with declining cognitive and physical performance, depressive symptoms, and disability, after adjusting for several covariates, but did not increase with falls and urinary incontinence.î For patients with 0, 1, 2, 3, and 4 or more SNAs, the mortality rates were 22.6, 23.3, 23.9, 58.6, and 91.9 per 1,000 person–years, respectively. (M. Inzitari, U. Florence, Florence, Italy; marcoinzitari@gmail.com)
Editorialists provide this perspective on how these results might apply in practice (pp. 1252-3): ìInzitari et al suggest accumulated injuries in the subcortical white matter of older adults might be the underlying biological process that explains the relationship between SNAs and the various outcomes measures of cognitive decline, functional decline, cerebrovascular events, and mortality. However, another interpretation of these relationships might be that an SNA is a biomarker or indicator for the presence of marked subcortical vascular damage that leads to impaired functional cognition, which may subsequently lead to increased mortality. The term
functional cognition might be the most appropriate term to describe the aspects of cognitive processing that are necessary to perform activities of daily living, both basic and instrumental.î (J. Boustani, mboustani@regenstrief.org)
Hospitalist—Good or Not?: In two articles and two rebuttals, authors debate the impact of hospitalists during their first 10 years in the nation’s acute care facilities. ìNo valid reason exists to continue debating whether hospitalists focused on improving the system of hospital care will be the future of care delivery in hospitals,î writes the proponent (pp. 1254-6, 1259; M. V. Williams, mark-williams@northwestern.edu). ìWith more than 20,000 hospitalists in the United States and growth projections as high as 50,000 in the next decade, we should focus our efforts on determining how hospitalists can best collaborate with their colleagues. Hospitalists need to establish teamwork-based models involving nurses, pharmacists, and others inside hospitals. Hospitalists also should reach out to their partners in the outpatient setting to optimize communication of essential information.î Countering this view, R. M. Centor (pp. 1257-8, 1260; rcentor@uab.edu) writes: ìGiven the reality of hospital medicine, we should not assume that patient care has improved. Because the growth of hospital medicine has become a reality, we should rather focus future research on optimizing both inpatient and outpatient care. Future efforts should address the patient rather than the admission as a unit of analysis. Our duty is to develop a system that best integrates patient care over time, including—but not limited to—hospitalizations.î

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

PNN Pharmacotherapy Line
June 25, 2008 * Vol. 15, No. 123
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
June 25 issue of JAMA (http://jama.ama-assn.org/current.dtl; 2008; 299).
Pharmacist Care, Home Monitoring in Hypertension: In the Electronic Communications and Home Blood Pressure Monitoring study, pharmacist care delivered to patients with essential hypertension over secure Web connections significantly improved blood pressure control (pp. 2857-67). In this three-group randomized trial modeled on the Chronic Care Model, patients received either usual care, home BP monitoring and secure patient Web site training only, or home BP monitoring and secure patient Web site training plus pharmacist care management delivered through Web communications, with these results: ìOf 778 patients, 730 (94%) completed the 1-year follow-up visit. Patients assigned to the home BP monitoring and Web training only group had a nonsignificant increase in the percentage of patients with controlled BP (<140/90 mm Hg) compared with usual care (36% [95% confidence interval {CI}, 30%–42%] vs 31% [95% CI, 25%–37%]; P = .21). Adding Web-based pharmacist care to home BP monitoring and Web training significantly increased the percentage of patients with controlled BP (56%; 95% CI, 49%–62%) compared with usual care (P < .001) and home BP monitoring and Web training only (P < .001). Systolic BP was decreased stepwise from usual care to home BP monitoring and Web training only to home BP monitoring and Web training plus pharmacist care. Diastolic BP was decreased only in the pharmacist care group compared with both the usual care and home BP monitoring and Web training only groups. Compared with usual care, the patients who had baseline systolic BP of 160 mm Hg or higher and received home BP monitoring and Web training plus pharmacist care had a greater net reduction in systolic BP (–13.2 mm Hg [95% CI, –19.2 to –7.1]; P < .001) and diastolic BP (–4.6 mm Hg [95% CI, –8.0 to –1.2]; P < .001), and improved BP control (relative risk, 3.32 [95% CI, 1.86 to 5.94]; P <.001).î (B. B. Green, Group Health Ctr. for Health Studies, Seattle; green.b@ghc.org)
Editorialists explore technology, people, and systems as means of improving hypertension control (pp. 2896-8): ìWhy did the addition of a pharmacist markedly improve BP control? One reason may be the pharmacist’s expertise in formulating and implementing evidence-based hypertension care plans. Yet an alternative explanation is that frequent patient contacts with a pharmacist stimulated patient engagement. As proof, the patients receiving the Web service and BP monitoring plus pharmacist care had significantly more Web interchanges with their clinicians (an average of 22 e-mail threads annually) relative to the other 2 groups. It remains to be seen whether a human content expert is required for the system’s success or whether less costly, programmed reminder e-mail or electronic exception management prompts could have achieved similar degrees of BP control.î (E. D. Peterson,
peter016@mc.duke.edu)
Electromagnetic Interference by RFID: Radiofrequency identification tags (RFID) such as those on medical equipment can produce electromagnetic interference (EMI) in critical-care medical devices, according to a controlled research study (pp. 2884-90). RFID systems emitting active 125 kHz and passive 868 MHz signals were placed in the proximity of 41 medical devices, and these potential problems were identified: ìIn 123 EMI tests (3 per medical device), RFID induced 34 EMI incidents: 22 were classified as hazardous, 2 as significant, and 10 as light. The passive 868-MHz RFID signal induced a higher number of incidents (26 incidents in 41 EMI tests; 63%) compared with the active 125-kHz RFID signal (8 incidents in 41 EMI tests; 20%); difference 44% (95% confidence interval, 27%–53%; P < .001). The passive 868-MHz RFID signal induced EMI in 26 medical devices, including 8 that were also affected by the active 125-kHz RFID signal (26 in 41 devices; 63%). The median distance between the RFID reader and the medical device in all EMI incidents was 30 cm (range, 0.1–600 cm).î (E. J. van Lieshout, U. Amsterdam, Amsterdam; e.j.vanlieshout@amc.nl)

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

PNN Pharmacotherapy Line
June 26, 2008 * Vol. 15, No. 124
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
June 26 issue of the New England Journal of Medicine (http://content.nejm.org/current.shtml; 2008; 358).
Rivaroxaban After Hip, Knee Arthroplasty: Two research studies and an editorial assess the effectiveness of rivaroxaban, an orally active direct factor Xa inhibitor, for thromboprophylaxis after orthopedic surgeries.
Compared with enoxaparin 40 mg subcutaneously once daily, oral rivaroxaban 10 mg once daily was significantly more effective for extended thromboprophylaxis in patients undergoing elective total hip arthroplasty, according to investigators in the Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism 1 (RECORD1) study (pp. 2765-75). Safety profiles of the two agents were similar, the group concluded, adding these details about a primary efficacy outcome of composite of deep-vein thrombosis, nonfatal pulmonary embolism, or death from any cause at 36 days: ìA total of 3,153 patients were included in the superiority analysis (after 1,388 exclusions), and 4,433 were included in the safety analysis (after 108 exclusions). The primary efficacy outcome occurred in 18 of 1,595 patients (1.1%) in the rivaroxaban group and in 58 of 1,558 patients (3.7%) in the enoxaparin group (absolute risk reduction, 2.6%; 95% confidence interval [CI], 1.5 to 3.7; P < 0.001). Major venous thromboembolism occurred in 4 of 1686 patients (0.2%) in the rivaroxaban group and in 33 of 1,678 patients (2.0%) in the enoxaparin group (absolute risk reduction, 1.7%; 95% CI, 1.0 to 2.5; P < 0.001). Major bleeding occurred in 6 of 2,209 patients (0.3%) in the rivaroxaban group and in 2 of 2,224 patients (0.1%) in the enoxaparin group (P = 0.18).î (B. I. Eriksson, Sahlgrenska U. Hosp.–÷stra, Gothenburg, Sweden;
b.eriksson@orthop.gu.se)
Similar findings come from the RECORD3 trial, which compared the same agents in patients undergoing total knee arthroplasty (pp. 2776-86). The study used the same primary efficacy outcome as RECORD1 but over a timeframe of 13–17 days after surgery: ìThe primary efficacy outcome occurred in 79 of 824 patients (9.6%) who received rivaroxaban and in 166 of 878 (18.9%) who received enoxaparin (absolute risk reduction, 9.2%; 95% confidence interval [CI], 5.9 to 12.4; P < 0.001). Major venous thromboembolism occurred in 9 of 908 patients (1.0%) given rivaroxaban and 24 of 925 (2.6%) given enoxaparin (absolute risk reduction, 1.6%; 95% CI, 0.4 to 2.8; P = 0.01). Symptomatic events occurred less frequently with rivaroxaban than with enoxaparin (P = 0.005). Major bleeding occurred in 0.6% of patients in the rivaroxaban group and 0.5% of patients in the enoxaparin group. The incidence of drug-related adverse events, mainly gastrointestinal, was 12.0% in the rivaroxaban group and 13.0% in the enoxaparin group.î (M. R. Lassen, NordsjÊllands Hosp., H¯rsholm, Denmark;
mirula@noh.regionh.dk)
Editorialists provide this perspective on emerging anticoagulants (pp. 2827-9): ìOnly through continued investigation and understanding of thrombosis and hemostasis can progress in anticoagulant therapy be realized. Myths, such as ‘an effective anticoagulant will, by definition, carry with it a risk of bleeding’ or ‘it is easier to give a transfusion than to treat a blood clot’ or ‘monitoring of an anticoagulant will prevent its uptake in clinical practice,’ are obstacles that must be pushed aside to make way for change. The path to safer and more effective anticoagulants is paved by scientific knowledge, discovery, due diligence on the part of sponsors working collaboratively with experienced clinicians, and evidence-based translation to patient care and widespread clinical practice.î (J. Lohrmnn, U. Freiburg, Freiburg, Germany)
ARBs in Marfan’s Syndrome: A small study of 18 pediatric patients with Marfan’s syndrome shows that angiotensin II receptor blockers should be studied further for slowing the rate of progressive aortic-root dilation (pp. 2787-95). During 12–47 months of treatment in patients who had not responded to other medical therapy, the sinotubular junction also showed a reduced rate of change in diameter, the authors noted, adding: ìThe distal ascending aorta, which does not normally become dilated in Marfan’s syndrome, was not affected by ARB therapy.î (H. C. Dietz III, Johns Hopkins U., Baltimore; hdietz@jhmi.edu)

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

PNN Pharmacotherapy Line
June 27, 2008 * Vol. 15, No. 125
Providing news and information about medications and their proper use

>>>Chest Highlights
Source:
June issue of Chest (www.chestjournal.org/current.shtml; 2008; 133).
Defining Glucose Control: Pediatric clinicians are less concerned about blood glucose levels in the 110–150 mg/dL range than are those caring for adult patients, according to a national survey of 163 physicians at 50 institutions (pp. 1328-35). ìAdult ICU clinicians defined hyperglycemia (120 mg/dL [6.2 mmol/L]) at a lower threshold than pediatric ICU clinicians (150 mg/dL [8.3 mmol/L]),î the researchers write. ìHypoglycemia was defined similarly by both groups (median, 60 mg/dL [3.3 mmol/L]; range, 40 to 80 mg/dL [2.2 to 4.4 mmol/L]). More pediatric ICU clinicians (84.5%) than adult ICU clinicians (59.1%) considered hypoglycemia to be more dangerous than hyperglycemia. A larger percentage of adult ICU clinicians (82.5%) than pediatric ICU clinicians (49.3%) preferred a target blood glucose level between 80 and 110 mg/dL (4.4 to 6.1 mmol/L).î (E. Hirshberg, ellie.hirshberg@hsc.utah.edu)
Inhaled Mannitol in Cystic Fibrosis: Among 39 patients with mild to moderate cystic fibrosis lung disease, inhalation of mannitol 420 mg twice daily for 2 weeks was significantly better than placebo for improving lung function (pp. 1388-96). These results were identified in the crossover trial: ìMannitol treatment increased FEV1 from baseline by a mean of 7.0% (95% confidence interval [CI], 3.3 to 10.7) compared to placebo 0.3% (95% CI, – 3.4 to 4.0; p < 0.001). The absolute improvement with mannitol therapy was 121 mL (95% CI, 56.3 to 185.7), which was significantly more than that with placebo (0 mL; 95% CI, – 64.7 to 64.7). The forced expiratory flow in the middle half of the FVC increased by 15.5% (95% CI, – 6.5 to 24.6) compared to that with placebo (increase, 0.7%; 95% CI, – 8.3 to 9.7; p < 0.02). The safety profile of mannitol was adequate, and no serious adverse events related to treatment were observed.î (A. Jaques, Pharmaxis Ltd., Frenchs Forest, NSW, Australia; anna.jaques@pharmaxis.com.au)

>>>Pharmacotherapy Report
Source:
July issue of Pharmacotherapy (www.pharmacotherapy.org; 2008; 28).
Misoprostol, Diclofenac, & Cardiorenal Effects in Salt-Sensitive Elders: Coadministration of misoprostol can attenuate hypertensive and renal vasoconstrictive effects of diclofenac among salt-sensitive seniors, report authors of a 19-patient study (pp. 838-42). In crossover fashion among patients aged 55–73 years, the results were observed when diclofenac 75 mg was administered with or without misoprostol 200 mcg twice daily for 14 days: ìDiclofenac alone increased [mean arterial pressure] by a mean ± SEM of 5.0 ± 1.0 mm Hg and [rate-pressure product] by 337 ± 181 units compared with baseline. The [effective renal plasma flow] rate and [glomerular filtration rate] decreased by 40.5 ± 26.9 ml/minute and 14.1 ± 6.5 ml/minute, respectively. Diclofenac plus misoprostol decreased the diclofenac-induced increase in [mean arterial pressure] by 3.3 ± 1.0 mm Hg (95% confidence interval [CI] 1.1–5.3 mm Hg, p = 0.004) and decreased the RPP by 724 ± 238 units (95% CI 225–1223 units, p = 0.007). The ERPF rate increased by 56.1 ± 35.0 ml/minute (95% CI -24.7–137.0 ml/min, p = 0.15) and GFR by 18.1 ± 7.1 ml/minute (95% CI 1.9–34.5 ml/min, p = 0.03). Diclofenac alone was relatively well tolerated; no adverse effects were reported with diclofenac plus misoprostol.î (M. A. Munger, mmunger@deans.pharm.utah.edu)
Hypertension Guideline Adherence by Physicians: Physicians adherence to blood pressure guidelines and control of blood pressures were better for 105 nonseniors than 74 seniors in a study of uncontrolled hypertension (pp. 843-51): ìGuideline adherence scores were significantly higher for nonsenior patients than for senior patients (59.3% vs 56.1%, p = 0.024). Blood pressure control rate was also higher, although not significantly, in nonseniors versus seniors (68.6% vs 56.8%, p = 0.063). No factors in the senior group were significantly associated with blood pressure control, but one was significantly correlated in the nonsenior group (p <0.0001). It included diuretic therapy, adjusting a drug when a patient’s blood pressure was uncontrolled, documentation of uncontrolled blood pressure in the medical record at the visit, documentation of the correct blood pressure goal, documentation of cardiovascular risk factors, and measurement of urine albumin level.î (B. L. Carter, barry-carter@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 © 2008, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 30, 2008 * Vol. 15, No. 126
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
June 28 issue of Lancet (www.thelancet.com; 2008; 371).
Buprenorphine for Heroin Dependence: A research study from Malaysia supports use of buprenorphine maintenance in patients who have been dependent on heroin (pp. 2192-200). Concluding that the drug offers ìan effective public-health approach to reduce problems associated with heroin dependence,î the authors note these outcomes in 126 detoxified patients who received buprenorphine, naltrexone, or placebo during maintenance: ìWe observed consistent, linear contrasts in days to first heroin use (p = 0.0009), days to heroin relapse (p = 0.009), and maximum consecutive days abstinent (p = 0.0007), with all results best for buprenorphine and worst for placebo. Buprenorphine was associated with greater time to first heroin use than were naltrexone (hazard ratio 1.87 [95% CI 1.21–2.88]) or placebo (2.02 [1.29–3.16]). With buprenorphine, we also recorded significantly greater time to heroin relapse (2.17 [1.38–3.42]), and maximum consecutive days abstinent than with placebo (mean days 59 [95% CI 43–76] vs 24 [13–35]; p = 0.003); however, for these outcomes, differences between buprenorphine and naltrexone were not significant. Differences between naltrexone and placebo were not significant for any outcomes. HIV risk behaviours were significantly reduced from baseline across all three treatments (p = 0.003), but the reductions did not differ significantly between the three groups.î (R. S. Schottenfeld, Richard.schottenfeld@yale.edu)
Prevalence of Diagnosed, Unknown Chronic Kidney Disease: Taiwan has a high incidence of chronic kidney disease, according to an epidemiologic report, and many of the patients are unaware they have the condition (pp. 2173-82). The authors suggest that promotion of recognition of chronic kidney disease should be a public-health priority, especially among those of lower socioeconomic status, based on their analysis of 14,436 deaths among 462,293 individuals aged 20 years or more: ìThe national prevalence of chronic kidney disease was 11.93% (95% CI 11.66–12.28), but only 3.54% (3.37–3.68) of participants in the cohort were aware of their disorder. Prevalence was substantially higher in the group with low socioeconomic status than in the high status group (19.87% [19.84–19.91] vs 7.33% [7.31–7.35]). 56,977 (12%) of cohort participants had chronic kidney disease; those with disease had 83% higher mortality for all cause (HR 1.83 [1.73–1.93]) and 100% higher for cardiovascular diseases (2.00 [1.78–2.25]), in a cohort that was observed for 13 years with median follow-up of 7.5 years (IQR 4.0–10.1). 10.3% (95% CI 9.57–11.03) of deaths in the entire population were attributable to chronic kidney disease, but 17.5% (16.27–18.67) of deaths in the low socioeconomic status population. 2,350 (39%) deaths occurred before 65 years of age in those with chronic kidney disease. Regular users of Chinese herbal medicines had a 20% (odds ratio 1.20 [1.16–1.24]) increased risk of developing chronic kidney disease.î (C-P Wen, National Health Res. Inst., Zhunan, Miaoli County, Taiwan; cwengood@nhri.org.tw)

>>>PNN JournalWatch
* Refeeding Syndrome: What It Is, and How To Prevent and Treat It, in BMJ, 2008; 336: 1495–8. Reprints: H. M. Mehanna, U. Hosp., Coventry, U.K.; Hisham.Mehanna@uhcw.nhs.uk
* Seroprotection Against Serogroup C Meningococcal Disease in Adolescents in the United Kingdom: Observational Study, in
BMJ, 2008; 336: 1487–91. Reprints: M. Snape, Churchill Hosp., Oxford, U.K.; matthew.snape@paediatrics.ox.ac.uk
* Nonadherence to Antiepileptic Drugs and Increased Mortality: Findings from the RANSOM Study, in
Neurology, 2008; doi: 10.1212/01.wnl.0000319693.10338.b9. Reprints: E. Faught, faught@uab.edu
* The Role of Protein Digestibility and Antacids on Food Allergy Outcomes, in
Journal of Allergy and Clinical Immunology, 2008; 121: 1301–8. Reprints: E. Untersmayr, Med. U., Vienna; eva.untersmayr@meduniwien.ac.at
* Central Sleep Apnea: Implications for Congestive Heart Failure, in
Chest, 2008; 133: 1495–504. Reprints: S. M. Caples, caples.sean@mayo.edu
* Pharmacotherapy for Heart Failure with Left Ventricular Dysfunction: Beyond Angiotensin-Converting Enzyme Inhibitors and Beta-Blockers, in
Pharmacotherapy, 2008; 28: 920–31. Reprints: N. B. Norgard, nick-norgard@ouhsc.edu
* The Politics Of Health Reform: A Collection Of Perspectives, in
Health Affairs, 2008; 688 ff. Reprints: Various authors.

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