Comparative bioavailability studies with a new mixed-micelles solution of diazepam utilizing radioreceptor assay,...

In a double-blind, placebo-controlled study the pharmacokinetic and pharmacodynamic properties of a standard solution of diazepam (DZ) (ValiumR) were compared with those of a novel diazepam mixed-micelles solution (DZ MM) (Valium MMR) both after i.v. and i.m. application utilizing radioreceptor assay, quantitative pharmaco-EEG and brain mapping techniques as well as psychometric and psychophysiological methods. The local tolerance was studied as well. The subjects received randomized and, in weekly intervals, following injections: (1) 10 mg DZ i.v. + placebo i.m.; (2) 10 mg DZ MM i.v. + placebo i.m.; (3) placebo i.v. + 10 mg DZ i.m.; (4) placebo i.v. + 10 mg DZ MM i.m.; (5) placebo i.v. + placebo i.m. Blood sampling, EEG-recordings, psychometric and psychophysiological tests as well as tolerance evaluations were carried out at 0, 1/2, 1, 2, 4, 6 and 8 h. Blood level evaluation demonstrated after i.m. application a significantly shortened tmax, a higher Cmax and generally higher plasma concentrations in the first and second hour following the mixed-micelles solution than the standard formulation, which suggests better absorption of the former than the latter in the muscle. Subsequent to i.v. administration, lower blood levels were observed between 30 min and 2 h after DZ MM than DZ. Power spectral density analysis of the EEG resulted in typical anxiolytic-sedative pharmaco-EEG profiles after all 4 active substances as compared with placebo. However, there were significant inter-drug differences as far as topographic aspects (pharmaco-EEG maps) were concerned. DZ MM i.v. induced significantly more initial but also late delta augmentation, alpha attenuation and centroid slowing than DZ i.v. which suggests more sedative effects at those times. Following i.m. application, a significantly more pronounced delta/theta attenuation, beta augmentation and centroid acceleration after DZ MM than DZ suggested more anxiolytic effects of the novel than the standard formulation. Discriminant analysis of changes in 6 thymopsychic, 12 noopsychic and 17 psychophysiological variables demonstrated the best discrimination of the 4 substances based on thymopsychic effects. Considering the latter, all 4 active compounds differed significantly from placebo, with no inter-drug differences after i.v. application but a marked superiority of the novel mixed-micelles solution over the standard solution after i.m. application. Specifically, DZ MM i.m. induced more desactivation and affect-attenuation than DZ i.m.(ABSTRACT TRUNCATED AT 400 WORDS)