KA 672-HCL, A NEURONAL ACTIVATOR AGAINST DEMENTIA - TOLERABILITY, SAFETY, AND PRELIMINARY PHARMACOKINETICS AFTER SINGLE AND MULTIPLE ORAL DOSES IN HEALTHY MALE AND FEMALE VOLUNTEERS

In vitro and animal experiments have characterized KA 672-HCl as a pot ent functional antagonist of excitatory amino acid-induced convulsions and mortality. In receptor-binding studies, the compound displayed hi gh affinities to several serotoninergic, adrenergic, and dopaminergic receptors and to the sigma receptor. The potential for short- and long -term toxicity of KA 672-HCl in rats and dogs was found to be low. Dou ble-blind, randomized, placebo-controlled studies were undertaken in h ealthy volunteers ranging from 52 to 74 years of age to determine tole rability, safety, and preliminary pharmacokinetics of single and repea ted doses in humans. Single doses up to 40 mg were well tolerated, wit h no difference in effect from placebo. At 60 mg, approximately half o f the volunteers experienced a moderate drug-related orthostatic syndr ome. After repeated doses of 10 or 20 mg KA 672-HCl for 14 days only m inor adverse events of mild intensity were reported with no clear rela tion to dose or a clinically relevant difference from placebo. A mild decrease in semisupine and standing blood pressure 4 hours after admin istration was observed in the 20 mg group with no occurrence of orthos tasis. Linear pharmacokinetics were observed after repeated doses. How ever, this was not the case after single-dose administration, as gener ally higher plasma concentrations were observed after the 20-mg dose t han would have been predicted from the 10-mg data. The mean terminal p hase half-life after the 20 mg dose was 11.1 hours and 13.7 hours afte r repeated and single doses, respectively. The safety and tolerability data support a continuation of therapeutic trials. KA 672-HCl is curr ently entering phase II development. (C)1998 The American College of C linical Pharmacology.