Sexual dysfunction (SD) is a common and underestimated effect of antidepressants. Healthy volunteers are the most adequate group to study this adverse event avoiding influence of depression itself. Sexual acceptability of agomelatine (a melatonergic agonist and 5HT(2C) antagonist) paroxetine and placebo by using the Psychotropic-Related Sexual Dysfunction Salamanca Sex Questionnaire (PRSEXDQ-SALSEX) was explored. A total of 92 healthy male volunteers were randomised to agomelatine (25 or 50 mg), paroxetine 20 mg or placebo for 8 weeks. SD, defined as at least one sexual impairment in one of the following PRSEXDQ-SALSEX items (decreased libido, delayed orgasm/ejaculation, anorgasmia/no ejaculation and erectile dysfunction), was evaluated at baseline and after 2, 4 and 8 weeks. At the last post-baseline assessment, SD was significantly lower in each agomelatine group (22.7% on 25 mg and 4.8% on 50 mg) than in the paroxetine group (85.7%; p < 0.0001). In the placebo group, 8.7% of volunteers reported a SD. The percentages of volunteers with moderate or severe SD were 4.5% for agomelatine 25 mg, 4.8% for agomelatine 50 mg, 61.9% for paroxetine 20 mg and 0% in the placebo group (p < or = 0.0001 agomelatine versus paroxetine). There is a much lower risk of having SD with agomelatine than paroxetine in healthy male volunteers, which confirms the better sexual acceptability profile of agomelatine compared with the SSRIs.

Adverse drug reactions are a significant clinical and economic problem in surgical intensive care units.

The effects of the CYP3A4 inducer, Hypericum perforatum, on the pharmacokinetics of a single oral dose of ivabradine were assessed. An open-label, 2-period, nonrandomized, phase-I, pharmacokinetic interaction design was used. Twelve healthy volunteers received a single oral dose of ivabradine (10 mg) followed by H perforatum (300 mg orally, 3 times a day) for 14 days, combining the last dose with another single dose of ivabradine. Pharmacokinetic data for ivabradine (S16257) and its main active metabolite (S18982) prior to and after the administration of H perforatum were analyzed. After repeated administration of H perforatum, highest observed concentration in plasma (C(max)) and area under the concentration-time curve (AUC) were significantly decreased for ivabradine (32.7 +/- 16.6 vs 15.4 +/- 7.0 ng/mL, P < .01; 114 +/- 39.1 vs 43.7 +/- 12.0 ng x h/mL, P < .01, respectively), and for S18982 (C(max), 6.8 +/- 3.7 vs 5.1 +/- 2.0 ng/mL, P < .05; AUC, 56.2 +/- 23.4 vs 38.3 +/- 25.1 ng x h/mL, P < .01). Tendencies toward shorter time to C(max) and lower apparent terminal half-life values were found. Pharmacokinetic results are consistent with an induction of ivabradine metabolism by H perforatum.

The effects of omeprazole and lansoprazole (CYP3A4 inhibitors) on the pharmacokinetics of a single dose of ivabradine (metabolized via CYP3A4) and its active metabolite (S18982) were assessed. Pharmacodynamics and safety were secondary objectives. An open-label, randomized, crossover, phase I, pharmacokinetic interaction design was used. Volunteers received a single oral dose of ivabradine (10 mg), were randomized to receive either omeprazole (40 mg) or lansoprazole (60 mg) for 5 days, and were administered an ivabradine dose on the sixth day. Crossover was performed after washout. Pharmacokinetic parameters for ivabradine did not vary significantly after omeprazole (C(max): 45.0 +/- 36.6 vs 42.7 +/- 27.6 ng/mL, P = .98; AUC: 128 +/- 87 vs 126 +/- 63 ng/mL, P = .82) or lansoprazole administration (C(max): 45.0 +/- 36.6 vs 41.3 +/- 29.4 ng/mL, P = .70; AUC: 128 +/- 87 vs 123 +/- 50, P = .73). Analyses of S18982 pharmacokinetic parameters showed similar results. Coadministration of either omeprazole or lansoprazole did not significantly affect the pharmacokinetics of a single dose of ivabradine. No pharmacodynamic interaction or safety concerns were evidenced.

Background: Enalapril maleate is the monoethyl ester prodrug of enalapril-