APPLICATIONS OF PHARMACOKINETICS IN CLINICAL PSYCHIATRY

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A series of clinical and experimental studies is proposed to evaluate the influence of the aging process on the consequences of chronic sedative-hypnotic drug administration and withdrawal. Healthy young and elderly volunteers will receive single 15-mg nightly doses of flurazepam (or placebo), used to represent the group of long half-life accumulating benzodiazepines. Prior to, during, and following 14 days of therapy, subjects will receive a test-dose challenge with a short half-life benzodiazepine (intravenous midazolam, 0.04 mg/kg, oral triazolam, 0.25 mg, or placebo). Following each test dose, plasma levels and pharmacokinetics of the test drugs are assessed in relation to changes in sedation and mood, impairment of psychomotor performance, impairment of memory, and quantitative alterations in the EEG. In analogous experimental studies, 3 groups of male CD-1 mice (young, middle-aged, and old) receive two weeks of continuous infusion (via implantable osmotic pumps) of lorazepam, clonazepam, or vehicle placebo, with infusion rates chosen to produce steady-state plasma concentrations similar to those achieved in humans. During and after the period of infusion, the following variables are quantitated: plasma and cortex drug levels, behavioral activity based on computerized monitoring, in vivo enzodiazepine receptor binding, and in vitro measures of receptor binding and function. An additional series of studies on young, middle- aged, and old CD-1 mice will assess age effects on chronic exposure to tolerance-producing and dependence-producing does of ethanol, as provided in animals' diet. After 30 days of acute withdrawal, and during long-term recovery. A clinical study of the pharmacotherapy of anxiety in abstinent alcoholics is proposed in male patients up to age 70. The effects of a single test-dose challenge of the medications to be used (halazepam, alprazolam, or buspirone) is followed by a period of long-term double-blind treatment. Plasma levels and clinical effects of the study drugs are monitored during the treatment period and the withdrawal phase.