Single- and multiple-dose pharmacokinetics and tolerability of telcagepant, an oral calcitonin gene-related peptide receptor antagonist, in adults.

Telcagepant is a novel, orally active, and selective calcitonin gene-related peptide receptor antagonist being developed for acute treatment of migraine with and without aura. Three separate clinical studies were conducted to evaluate the pharmacokinetics and tolerability of telcagepant following single oral doses in healthy young and elderly men and women and multiple oral doses in men. Telcagepant was rapidly absorbed with a time to maximum concentration of approximately 1.5 hours. The terminal half-life was approximately 6 hours. A greater than dose-proportional increase was observed in the area under the plasma concentration versus time curve from zero to infinity. Following twice-daily dosing, with each dose separated by 2 hours, steady state was achieved in approximately 3 to 4 days with an accumulation ratio of approximately 2. There were no clinically meaningful pharmacokinetic differences when compared across age and gender. Telcagepant was generally well tolerated up to single doses of 1200 mg and multiple doses of 400 mg twice daily.

Inhibition of capsaicin-induced increase in dermal blood flow by the oral CGRP receptor antagonist, telcagepant (MK-0974).

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Calcitonin gene-related peptide (CGRP) was first described as a potent vasodilator. * CGRP is also increasingly recognized as a key player in the pathophysiology of migraine, and CGRP receptor antagonists potentially offer a new approach for treating migraine. * A novel pharmacodynamic assay to measure CGRP receptor antagonist activity non-invasively in humans has been developed, which involves measuring the increase in dermal blood flow induced by topical application of capsaicin on the forearm. WHAT THIS STUDY ADDS: * This study shows that the novel oral CGRP receptor antagonist, telcagepant, inhibits the increases in dermal blood flow induced by the topical application of capsaicin on the human forearm. * This experimental medicine model may have utility to assist in dose selection for the development of CGRP receptor antagonists. AIMS: To evaluate inhibition of capsaicin-induced increase in dermal blood flow (DBF) following telcagepant (MK-0974), a potent and selective orally bioavailable calcitonin gene-related peptide (CGRP) receptor antagonist being developed for the acute treatment of migraine. METHODS: A three-period crossover study in 12 healthy adult men. Each subject received a single oral dose of telcagepant 300 mg, telcagepant 800 mg or placebo at 0 h, followed 0.5 and 3.5 h later by two topical doses of 300 and 1000 microg capsaicin per 20 microl water-ethanol mixture. Capsaicin was applied at two sites on the volar surface of the subjects' left and right forearms. DBF was assessed by laser Doppler perfusion imaging immediately before ('baseline'), and 0.5 h after each capsaicin application at 1 and 4 h. Plasma samples to determine telcagepant concentrations were collected immediately after laser Doppler perfusion imaging. A pharmacodynamic model was developed to explore the relationship between plasma concentration and inhibition of capsaicin-induced increase in DBF. RESULTS: Geometric mean plasma concentrations after dosing with 300 mg and 800 mg telcagepant were 720 and 1146 nm, respectively, at 1 h, vs. 582 and 2548 nm, respectively, at 4 h. The pharmacodynamic model suggested that the EC(90) for telcagepant inhibition of capsaicin-induced increases in DBF was 909 nm. CONCLUSIONS: Telcagepant inhibits the increases in DBF induced by the topical application of capsaicin on the human forearm. This experimental medicine model may have utility to assist in dose selection for the development of CGRP receptor antagonists.

Risks and outcomes of acute kidney injury requiring dialysis after cardiac transplantation.

BACKGROUND: Risk factors for postoperative acute kidney injury (AKI) are well described in nontransplantation settings. Data regarding risks and consequences of AKI after cardiac transplantation are unclear. METHODS: We analyzed 756 cardiac transplant recipients between 1993 and 2004. The primary outcome is postoperative AKI requiring dialysis therapy. Secondary outcomes are hospital mortality and postoperative morbidities, including cardiac, neurological, and serious infection. Wilcoxon rank-sum, chi-square, or Fisher exact tests were used for univariable comparison. A bootstrap-bagging procedure (1,000 repetitions) and multivariable logistic analysis with multiple imputation were used for the final model. RESULTS: AKI frequency was 5.8% (44 of 756 patients). By means of univariable analysis, preoperative risk factors for AKI were diabetes, prior cardiac surgery, intra-aortic balloon pump use, albumin level, creatinine level, clinical severity score, and cold ischemia time. Intraoperative risk factors were cardiopulmonary bypass time and transfusion requirement. By means of multivariate analysis, serum creatinine level (odds ratio [OR], 2.7; 95% confidence interval [CI], 1.6 to 4.6), serum albumin level (OR, 0.34; 95% CI, 0.21 to 0.54), insulin-requiring diabetes (OR, 3.5; 95% CI, 1.4 to 9.0), and cardiopulmonary bypass time (OR, 1.29; 95% CI, 1.02 to 1.64) were independent predictors of postoperative AKI. The overall postoperative mortality rate was 4.2%; it was 50% in patients with AKI compared with 1.4% in patients without AKI. AKI was associated with greater frequencies of cardiac, neurological, and serious infection morbidities (43.2%, 18.2%, and 54.6% versus 5.5%, 2.3%, and 7.2%, respectively; P < 0.001). CONCLUSION: AKI is associated with significant morbidity and mortality after cardiac transplantation. Predictors of AKI can be used to risk-stratify patients to ameliorate further kidney injury and offer a survival benefit.

Comparison of ability to identify left atrial thrombus by three-dimensional tomography versus transesophageal echocardiography in patients with atrial fibrillation.

We sought to determine the potential use of recently introduced cardiac 3-dimensional computed tomography as an alternative to transesophageal echocardiography for examination of the left atrial appendage. Our data suggest that computed tomography is a potential alternative for assessing the anatomy of the left atrial appendage and for detecting thrombi.