ASSESSMENT OF THE INTERACTION BETWEEN A PARTIAL AGONIST AND A FULL AGONIST OF BENZODIAZEPINE RECEPTORS, BASED ON PSYCHOMOTOR PERFORMANCE AND MEMORY, IN HEALTHY-VOLUNTEERS

Potential interactions between the imidazopyridine anxiolytic alpidem and the full benzodiazepine agonist lorazepam were assessed in a rando mized, double-blind, four-way cross-over, placebo-controlled study in 16 healthy young male volunteers. Each volunteer received alpidem, 50 mg, or a placebo twice daily for 8 days with a 1-week wash-out interva l. The interaction between alpidem, at the steady state, and a single oral dose of lorazepam 2 mg or a placebo was assessed after concomitan t administration on days 7 or 9 of each treatment period. Psychomotor performance and cognitive function were evaluated before and 2, 4, 6 a nd 8 h post-dose, using objective tests [critical flicker fusion thres hold (CFF), choice reaction time (CRT), digit-symbol substitution (DSS T), body sway and short-term memory (Sternberg memory scanning)] and s elf-ratings [line analogue rating scales: (LARS)]. Long-term memory (d elayed free recall and recognition of pictures) was assessed before th e dose and 2 and 4 h post-dose. Pharmacodynamic interactions were eval uated by applying repeated measures ANOVA to a 2x2 factorial interacti on model. Alpidem, 50 mg twice daily at the steady state, was free of any clinically relevant detrimental effects on skilled performance, in formation processing or memory. In contrast, a single 2 mg dose of lor azepam induced marked impairment of psychomotor performance and cognit ive function (significant reductions in CFF and DSST and increases in CRT and body sway), as well as subjective sedation from 2 to 8 h post- dose, depending on the test used. In addition, lorazepam induced anter ograde amnesia, characterized by a decrease in delayed free recall and recognition, and a deficit in short-term memory. Finally, alpidem 50 mg did not potentiate the detrimental effects of lorazepam 2 mg. On th e contrary, alpidem significantly antagonized the lorazepam-induced CR T increase and anterograde amnesia, and produced similar trends on mos t of the other cognitive parameters; thus, the results obtained with t he combination of alpidem and lorazepam consistently indicated less im pairment than those measured after lorazepam alone. These results are consistent with the suggested partial agonsist properties of alpidem a t the benzodiazepine receptor and indicate that such properties can be assessed in humans based on antagonism of the effects of a full agoni st.