A comprehensive investigation of plasma and brain regional pharmacokinetics of imipramine and its metabolites during and after chronic administration in the rat.

The relationship between the serum imipramine concentration and its antidepressant effects remain undefined despite > 30 years of clinical investigation. No study to date has assessed the kinetic relationships between the concentrations of imipramine and its metabolites in plasma and in various brain structures. In this study, we examine the pharmacokinetics of imipramine (IMI) and its desmethylated and hydroxylated metabolites in rats given IMI chronically (20 mg/kg, intraperitoneally twice a day for 14 days). The concentrations in serum, cerebrospinal fluid, and six brain structures were measured by high-performance liquid chromatography at 13 different times from 0.5 to 120 h after the end of treatment. The concentrations of IMI, desipramine (DMI), and didesmethylimipramine (DDMI) in brain tissue were much higher than in the serum; concentrations were maximal at 1-2 h in the serum and the brain, which is indicative of the rapid metabolism of IMI with immediate and massive entry of the metabolites into the brain. The elimination halflives of desmethylated compounds increased with the degree of desmethylation, and DDMI was still present in brain tissue 96 h after the end of treatment. These results suggest that DDMI should be taken into account in clinical investigations of the effects of serum concentrations of IMI. The hydroxylated metabolites 2-OH imipramine (2-OH IMI) and 2-OH desipramine (2-OH DMI) were detected in serum, but not in cerebral tissue. The 10-OH metabolites were detected in both serum and brain, but the antidepressant action of these metabolites have not been clearly established. Finally, there were significant differences in the distributions of IMI and several of its metabolites in brain structures. Such differences may have clinical relevance if they also occur in humans.

[Recent progresses in the biology of schizophrenia]. / Progrès récents dans la biologie de la schizophrénie.

Investigations designed to improve our understanding of the physiopathology of schizophrenia are progressing along various, but no necessarily exclusive, lines. The most important aspects of the recently established biological data and their potential value are discussed and compared to classical hypotheses and results.

[Buspirone: pharmacological and clinical properties of the first member of a new anxiolytic drug family]. / La buspirone: propriétés pharmacologiques et cliniques du premier représentant d'une famille nouvelle d'anxiolytiques.

Buspirone is a new anxiolytic agent with an original chemical structure. Its activity in doses of 15 to 30 mg per day has been demonstrated in patients presenting with manifestations of generalized anxiety. Its mode of action is still imperfectly known; in animals, it influences several neuromediator systems but does not act on benzodiazepine receptors. Its main pharmacokinetic features are: complete absorption when given orally, short half-life (4 to 8 h), reduced plasma clearance in patients with hepatic cirrhosis or renal impairment and no major interaction with most of the other psychotropic drugs. Controlled clinical studies have provided evidence of its anxiolytic properties; against anxiety symptoms buspirone has proved more effective than placebo and as effective as several reference benzodiazepine derivatives, with a lesser incidence of sedative effects. However, it is not effective in the treatment of benzodiazepine withdrawal. Gastrointestinal disorders and moderate headache have been reported in less than 10 p. 100 of the patients treated. Administered acutely, buspirone does not seem to alter cognitive mechanisms. Unlike benzodiazepines, it does not potentiate the effects of alcohol and does not lead to drug-dependence. Its usefulness in panic disorders, anxious-depressive states and obsessional symptoms remains to be determined.