Citations

Background: This study evaluated the CGRP receptor antagonist MK-3207 for acute treatment of migraine. Methods: Multicenter, double-blind, randomized, placebo-controlled, parallel-group, two-stage adaptive study with two interim efficacy analyses to facilitate optimal dose selection. Migraine patients were initially randomized to MK-3207 2.5, 5, 10, 20, 50 and 100 mg or placebo to treat a moderate/severe migraine. One or more doses were to be discontinued based on the first interim analysis and a lower or higher dose could be added based on the second interim analysis. The primary endpoint was two-hour pain freedom. Results: A total of 547 patients took study medication. After the first interim analysis, the two lowest MK-3207 doses (2.5, 5 mg) were identified as showing insufficient efficacy. Per the pre-specified adaptive design decision rule, only the 2.5-mg group was discontinued and the five highest doses (5, 10, 20, 50, 100 mg) were continued into the second stage. After the second interim efficacy analysis, a 200 mg dose was added due to insufficient efficacy at the top three (20, 50, 100 mg) doses. A positive dose-response trend was demonstrated when data were combined across all MK-3207 doses for two-hour pain freedom ( p < .001). The pairwise difference versus placebo for two-hour pain freedom was significant for 200 mg ( p < .001) and nominally significant for 100 mg and 10 mg ( p < .05). The incidence of adverse events appeared comparable between active treatment groups and placebo, and did not appear to increase with increasing dose. Conclusions: MK-3207 was effective and generally well tolerated in the acute treatment of migraine.

Abstract Objective: To investigate the association of body mass index (BMI) and BMI change with change in prostate-specific antigen (PSA) level and to assess the possible roles of PSA hemodilution and prostate volume in explaining the obesity and PSA association. Methods: In 1990, a randomly selected cohort of Caucasian men, aged 40 to 79 years, from Olmsted County, Minnesota, completed questionnaires ascertaining demographic characteristics, current medical conditions, and medications biennially, with a subset undergoing blood draws and clinical examinations. Linear mixed models were used to predict annual changes and intercepts of individual changes in BMI, PSA, prostate volume, plasma volume, and PSA mass, adjusting for age in 545 men with at least 2 serial PSA, BMI, and prostate volume measurements. Results: Baseline BMI was inversely associated with the annual percent change in PSA, adjusting for age, baseline PSA, and prostate volume and for the rates of change in BMI and prostate volume (β = −0.003, 95% CI: −0.006 to −0.0003). Baseline obesity was positively associated with mean baseline levels and the rate of change in prostate volume (P = 0.002) and plasma volume (both P &lt; 0.001) but was not associated with either the mean baseline values or the rate of change in PSA mass. Conclusions: Baseline obesity was associated with baseline PSA and prostate volume and with the rate of change in PSA over 15 years of follow-up. Impact: The inverse association of obesity with prostate cancer diagnosis may be at least partly due to detection bias, which is due to larger prostate volumes and PSA hemodilution in obese men. Cancer Epidemiol Biomarkers Prev; 20(3); 501–8. ©2011 AACR.

Abstract Development of clinically relevant tumor model systems for glioblastoma multiforme (GBM) is important for advancement of basic and translational biology. One model that has gained wide acceptance in the neuro‐oncology community is the primary xenograft model. This model entails the engraftment of patient tumor specimens into the flank of nude mice and subsequent serial passage of these tumors in the flank of mice. These tumors are then used to establish short‐term explant cultures or intracranial xenografts. This unit describes detailed procedures for establishment, maintenance, and utilization of a primary GBM xenograft panel for the purpose of using them as tumor models for basic or translational studies. Curr. Protoc. Pharmacol . 52:14.16.1‐14.16.23. © 2011 by John Wiley & Sons, Inc.

Background: Neurohospitalists may improve the efficiency and quality of care delivered to hospitalized patients with neurological disease. However, there is limited systematic data to support this hypothesis. The primary purpose of this study was to compare length of stay (LOS) for patients with ischemic stroke cared for by either neurohospitalists or community-based neurologists at a single institution. Methods: A retrospective chart review was performed for all patients with ischemic stroke discharged from St. Luke’s Hospital in Jacksonville, Florida, between January 2006 and December 2007. The LOS for patients cared for by neurohospitalists was compared to the LOS for patients cared for by community neurologists. Compliance with Joint Commission inpatient stroke quality metrics was also compared. Results: A total of 533 patients were discharged with a principal diagnosis of ischemic stroke over the 24-month study period. Neurohospitalists cared for 313 patients with mean (± SD) LOS of 4.9 (5.2) days (95% CI: 4.3-5.5 days), and community-based neurologists cared for 220 patients with a mean LOS of 6.5 (8.2) days (95% CI: 5.4-7.6 days). The mean LOS was significantly less for the neurohospitalists compared to the community-based neurologists ( P = .005). Neurohospitalists achieved a higher compliance rate in 10 of 11 inpatient stroke quality metrics and achieved significantly higher compliance rate of smoking cessation education ( P = .019). Conclusions: Neurohospitalists achieved significantly shorter LOS for patients with ischemic stroke compared to community-based neurologists. These data suggest that neurohospitalists can also improve compliance with quality metrics necessary for Joint Commission Primary Stroke Center designation.

Abstract SR13668, an orally active Akt pathway inhibitor, has demonstrated cancer chemopreventive potential in preclinical studies. To accelerate the clinical development of this promising agent, we designed and conducted the first-ever phase 0 chemoprevention trial to evaluate and compare the effects of food and formulation on SR13668 bioavailability. Healthy adult volunteers were randomly assigned to receive a single, 38-mg oral dose of SR13668 in one of five different formulations, with or without food. On the basis of existing animal data, SR13668 in a PEG400/Labrasol oral solution was defined as the reference formulation. Blood samples were obtained pre- and post-agent administration for pharmacokinetic analyses. Area under the plasma concentration–time curve (AUC0–∞) was defined as the primary endpoint. Data were analyzed and compared using established statistical methods for phase 0 trials with a limited sample size. Participants (n = 20) were rapidly accrued over a 5-month period. Complete pharmacokinetic data were available for 18 randomized participants. AUC0–∞ values were highest in the fed state (range = 122–439 ng/mL × hours) and were statistically significantly different across formulations (P = 0.007), with Solutol HS15 providing the highest bioavailability. SR13668 time to peak plasma concentration (3 hours; range, 2–6 hours) and half-life were (11.2 ± 3.1 hours) were not formulation-dependent. Using a novel, highly efficient study design, we rapidly identified a lead formulation of SR13668 for further clinical testing. Our findings support application of the phase 0 trial paradigm to accelerate chemoprevention agent development. Cancer Prev Res; 4(3); 347–53. ©2011 AACR.