This report describes the first evaluation in humans of CL 284,846, a non-benzodiazepine compound with a preclinical profile indicative of sedative/hypnotic properties. Healthy, normal male volunteers were assigned randomly to receive single oral doses of 1, 5, 15, 30, or 60 mg of CL 284,846 or placebo on a double-blind basis. Observations were made over the subsequent 25 hours to determine the safety, pharmacokinetic profile, and psychometric effects of the test compound. CL 284,846 was well tolerated in the normal volunteers, causing no significant changes in vital signs, EEG, ECG, hematologic, or clinical chemistry laboratory parameters. Although few adverse events were noted at doses less than 60 mg, at the highest dose (60 mg), all volunteers reported transient neurologically related adverse events (e.g., impaired concentration, difficulty focusing, and impaired coordination), reflecting the central nervous system action of the compound. Although determination of hypnotic efficacy was not an objective in this Phase I study, daytime treatment with 60 mg of CL 284,846 was associated with greater reports of drowsiness and impaired performance on psychomotor tests. However, memory, as assessed by a word recall test, was not affected at any dose of the compound. Pharmacokinetic analyses revealed CL 284,846 to be absorbed and eliminated rapidly (Tmax = 0.9-1.5 hr, T 1/2 = 0.9-1.1 hr), with a dose-proportional AUC (area under cure). Plasma levels of CL 284,859, the primary desethylated metabolite of CL 284,846, were much lower in humans than in other species, indicating that the metabolism of CL 284,846 in humans may differ from that of rodents and dogs. Overall, CL 284,846 was well tolerated, and the authors recommend repeating dose safety and pharmacokinetic studies in healthy volunteers.

The clinical pharmacology of the new reversible monoamine oxidase (MAO) inhibitor, moclobemide, was examined in three separate studies in healthy male volunteers. In a single oral dose study, moclobemide (25-150 mg) was rapidly absorbed from the gastrointestinal tract and had a relatively short plasma half-life (mean 1.3 h after 150 mg). A decrease in the plasma concentrations of the noradrenaline metabolite 4- hydroxy-3-methoxyphenylglycol (HMPG), however, indicated a longer time to peak pharmacodynamic effect and longer duration of activity. Assay of platelet MAO activity did not reveal any evidence of irreversible inhibition of the B form of the isoenzyme. Single oral doses of moclobemide (150 and 300 mg) significantly lowered the threshold to the cardiovascular effects ('cheese reaction') of intravenous tyramine. However, after repeated administration of 100 mg three times daily for over 2 weeks, moclobemide caused significantly less potentiation than did phenelzine (15 mg three times per day) on the cardiovascular effects of oral tyramine, a clinically more relevant model. The MAO-B inhibitor, selegiline (5 mg once daily), also lowered the oral tyramine threshold significantly. Moclobemide was generally well tolerated by these healthy volunteers.