APPLICATION OF PHARMACOKINETICS IN CLINICAL PSYCHIATRY

药代动力学在临床精神病学中的应用

• 批准号: 2244374
• 负责人: RICHARD I SHADER
• 金额: $ 62.96万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 1979
• 资助国家: 美国
• 起止时间: 1979-09-15 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2244374
• 关键词: drug metabolism; human subject; mental disorder chemotherapy; psychopharmacology

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.

一系列的临床和实验研究建议，以评估 衰老过程对慢性病后果的影响 镇静催眠药的给药和停药。 健康的年轻人， 老年志愿者将接受单次15毫克的泮夜间剂量 (or安慰剂），用于代表长半衰期累积组 苯二氮卓类 在14天治疗之前、期间和之后， 受试者将接受半衰期短的试验剂量激发 苯二氮卓类（静脉注射咪达唑仑，0.04 mg/kg，口服三唑仑，0.25 mg/kg mg或安慰剂）。 每次试验给药后， 根据变化评估试验药物的药代动力学 镇静和情绪，精神表现受损， 以及脑电图的定量变化。 以类似 实验研究将3组雄性CD-1小鼠（年轻，中年， 和老年人）接受两周的连续输注（通过植入式 渗透泵）的氯硝西泮、氯硝西泮或载体安慰剂， 选择输注速率以产生稳态血浆浓度 类似于在人类中实现的。 期间及之后， 输注后，对以下变量进行定量：血浆和皮质 药物水平，基于计算机监控的行为活动， 体内苯二氮卓受体结合和受体的体外测量 约束力和功能。 一系列关于年轻人的研究， 老年和老年CD-1小鼠将评估年龄对慢性暴露于 产生耐受性和依赖性的乙醇剂量， 提供的食物。 急性停药30天后， 在长期的恢复过程中。 药物治疗原发性高血压的临床研究 在男性戒酒患者中， 70. 单次试验剂量的药物挑战对 使用（哈拉西泮，阿普唑仑或丁螺环酮）后， 长期双盲治疗。 血浆水平和临床效果 在治疗期间监测研究药物， 戒断阶段