Pharmacokinetic and dynamic studies with a new anxiolytic imidazo-pyridine alpidem utilizing pharmaco-EEG and psychometry.
In a double-blind, placebo-controlled study the pharmacokinetic and pharmacodynamic effects of a new imidazo-pyridine derivative, alpidem (SL80.0342) and the 1,4 benzodiazepine lorazepam were investigated utilizing quantitative EEG and psychometric testing. Ten normal volunteers received randomized (latin square) single oral doses of placebo, 25 mg, 50 mg and 100 mg alpidem and 2.5 mg lorazepam at weekly intervals. Blood level sampling, EEG recordings, evaluation of pulse, blood pressure and side-effects were carried out at 0, 1, 2, 4, 6 and 8 hours post drug; psychometric and psychophysiological investigations at the same time periods except for the first hour. Computer-assisted spectral-analysis of the EEG demonstrated an anxiolytic profile after both compounds, characterized by an increase of beta activity, decrease of alpha activity and acceleration of the centroid of the total activity and total beta activity. Total power was attenuated, delta activity augmented and the centroid of the combined delta and theta activities decreased. The latter changes were most pronounced after 2.5 mg lorazepam suggesting it is more sedative than alpidem. Dose/treatment efficacy calculations revealed 2.5 mg lorazepam as the most CNS-active compound, followed by 100 mg, 50 mg and 25 mg alpidem. Based on a multivariate analysis 2.5 mg lorazepam could be differentiated from placebo at all times, 100 mg alpidem in the first, second and fourth hours, 50 mg only in the second hour. Time-efficacy calculations showed a marked CNS effect after alpidem in the first hour with a peak in the second hour, a gentle decline to the fourth hour and thereafter a rapid decline up to the eighth hour. In contrast, 2.5 mg lorazepam showed a slower rise in CNS activity which peaked in the fourth hour and declined slowly thereafter. These pharmacodynamic effects paralleled the blood level course of both compounds, as well as the time-course of psychometric changes. The latter were characterized by a deterioration in psychometer function after 2.5 mg lorazepam, which was less pronounced after 100 mg alpidem, while 50 mg and 25 mg showed no significant difference from placebo. Subjective ratings of mood showed a decrement which was most pronounced after 100 mg alpidem, less so after 50 mg, with no difference from placebo after 25 mg or lorazepam. Finally, there were no significant inter-drug differences with regard to psychophysiological variables.
D000328:Adult; D000704:Analysis of Variance; D014151:Anti-Anxiety Agents / Q000009:adverse effects / Q000378:metabolism* / Q000494:pharmacology; D001288:Attention / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000187:drug effects*; D003071:Cognition / Q000187:drug effects; D004311:Double-Blind Method; D004569:Electroencephalography; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000378:metabolism* / Q000494:pharmacology; D007700:Kinetics; D008140:Lorazepam / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008568:Memory / Q000187:drug effects; D008838:Microcomputers; D011594:Psychometrics; D011674:Pulse / Q000187:drug effects; D011725:Pyridines / Q000378:metabolism* / Q000494:pharmacology; D011930:Reaction Time / Q000187:drug effects
D014151:Anti-Anxiety Agents; D007093:Imidazoles; D011725:Pyridines; C052036:alpidem; D008140:Lorazepam