This was a double-blind, randomised, placebo-controlled study to investigate the pharmacokinetics and safety of trans-resveratrol. In four groups of ten healthy adult subjects (five males and five females), two subjects were randomized to receive placebo and eight subjects to receive trans-resveratrol 25, 50, 100 or 150 mg, six times/day, for thirteen doses. Peak plasma concentrations of trans-resveratrol were reached at 0.8-1.5 h postdose. Following the 13th dose of trans-resveratrol 25, 50, 100 and 150 mg, mean peak plasma concentration (C(max)) was 3.89, 7.39, 23.1 and 63.8 ng/mL and mean area under the plasma concentration-time curve (AUC(0-tau)) was 3.1, 11.2, 33.0 and 78.9 ng.h/mL. Interindividual variability was high, with coefficients of variation >40%. Trans-resveratrol half-life was 1-3 h following single-doses and 2-5 h following repeated dosing. Trough (C(min)) concentrations were < or = 1 ng/mL following 25 and 50 mg, 3 ng/mL following 100 mg and < 10 ng/mL following 150 mg. Trans-resveratrol pharmacokinetics showed circadian variation. Adverse events were mild in severity and similar between all groups. In conclusion, repeated administration was well-tolerated but produced relatively low plasma concentrations of trans-resveratrol, despite the high doses and short dosing interval used. Bioavailability was higher after morning administration.

No abstract

Background: Etamicastat is a novel, potent, and reversible peripheral dopamineb-hydroxylase inhibitor that has been administered orally at doses up to 600 mg once daily for 10 days to male healthy volunteers and appears to be well tolerated. Objective: The aim of this study was to investigate the effect of food on the pharmacokinetics of etamicastat. Material and Methods: A single-center, open-label, randomized, two-way crossover study in 12 healthy male subjects was performed. Subjects were administered a single dose of etamicastat 200 mg following either a standard high-fat and high-calorie content meal (test) or 10 hours of fasting (reference). The statistical method for testing the effect of food on the pharmacokinetic parameters of interest was based upon the 90% confidence interval (CI) for the test/reference geometric mean ratio (GMR). The parameters of interest were maximum plasma concentration (C max), area under the plasma concentration-time curve (AUC) from time zero to the last measurable concentration (AUC last), and AUC from time zero to infinity (AUC ¥). Bioequivalence was assumed when the 90% CI fell within the recommended acceptance interval (80, 125). Results: Etamicastat C max , AUC last , and AUC ¥ were 229 ng/mL, 1856 ng Á h/mL, and 2238 ng Á h/mL, respectively, following etamicastat in the fasting, and 166 ng/mL, 1737 ng Á h/mL, and 2119 ng Á h/mL, respectively, following etamicastat in the fed condition. Etamicastat test/reference GMR was 72.27% (90% CI 64.98, 80.38) for C max , 93.59% (90% CI 89.28, 98.11) for AUC last , and 96.47% (90% CI 91.67, 101.53) for AUC ¥. Time to C max was prolonged by the presence of food (p < 0.001). The C max , AUC last , and AUC ¥ values of the inactive metabolite BIA 5-961 were 275 ng/mL, 1827 ng Á h/mL, and 2009 ng Á h/mL, respectively, in the fasting, and 172 ng/mL, 1450 ng Á h/mL, and 1677 ng Á h/mL, respectively, in the fed condition. BIA 5-961 test/reference GMR was 62.42%

In this short-term study in healthy subjects, coadministration of warfarin and ESL 1200 mg once daily was associated with a small, but statistically significant, reduction in systemic exposure to S-warfarin. There was no statistically significant effect on R-warfarin pharmacokinetics or on coagulation as measured by the INR. Protocol identifier: UFH/BIA-2093-108.

Eslicarbazepine acetate (ESL) is a new-generation voltage-gated sodium channel blocker, which has been demonstrated to be effective and well tolerated in the treatment of epilepsy. The primary objective of this study was to investigate the effect of ESL on the pharmacokinetics of digoxin. This study was a randomized, double-blind, placebo-controlled, two-way crossover study of 12 healthy subjects (six men and six women). The study included two 8-day treatment periods with a washout of >or=10 days. In each period, subjects received either ESL 1200 mg once-daily or placebo, concomitantly with a loading oral dose of digoxin 0.5 mg on days 1 and 2, followed by a once-daily maintenance dose of 0.25 mg on days 3-8. Maximum serum digoxin plasma concentrations (C(max)) were reached (t(max)) at 0.5-2.0 h post-dose (median = 1.0 h) and at 0.5-4.0 h post-dose (median = 1.0 h) with Reference (digoxin plus placebo) and Test (digoxin plus ESL) treatments, respectively. The Test/Reference digoxin geometric mean ratios and 90% confidence intervals (90% CI) were 0.96 and 0.90-1.03 for the area under the plasma concentration-time curve over the dosing interval (AUC(0-24)) and 0.85 and 0.68-1.07 for C(max). The 90% CI was within the bioequivalence range (0.80-1.25) for AUC(0-24), thus demonstrating bioequivalence. The 90% CI was outside the 0.80-1.25 range for digoxin C(max), but it appeared to be caused by a higher variability in digoxin C(max) following co-administration of digoxin with placebo than with ESL. Co-administration of ESL and digoxin was well tolerated. Concomitant administration of ESL has no clinically relevant effect in the systemic exposure to digoxin.