APPLICATIONS OF PHARMACOKINETICS IN CLINICAL PSYCHIATRY

药代动力学在临床精神病学中的应用

• 批准号: 3486498
• 负责人: RICHARD I SHADER
• 金额: $ 45.17万
• 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 1994-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3486498
• 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.

提出了一系列临床和实验研究来评估 衰老过程对慢性疾病后果的影响 镇静催眠药物的给药和停药。 健康年轻和 老年志愿者将接受单次 15 毫克每晚剂量的氟西泮 （或安慰剂），用于代表长半衰期累积组 苯二氮卓类药物。 在 14 天的治疗之前、期间和之后， 受试者将接受半衰期短的测试剂量挑战 苯二氮卓类药物（静脉注射咪达唑仑，0.04 mg/kg，口服三唑仑，0.25 毫克，或安慰剂）。 每次测试剂量后，血浆水平和 评估测试药物的药代动力学与变化的关系 镇静和情绪、精神运动表现受损、损伤 记忆力和脑电图的定量变化。 类似地 实验研究，3组雄性CD-1小鼠（青年、中年、 和老年人）接受两周的连续输注（通过植入式 劳拉西泮、氯硝西泮或载体安慰剂的渗透泵）， 选择产生稳态血浆浓度的输注速率 与人类所取得的成就相似。 期间及之后 输注时，对以下变量进行定量：血浆和皮质 药物水平、基于计算机监测的行为活动、 体内恩佐二氮卓受体结合以及受体的体外测量 结合和功能。 另一系列针对青年、中青年的研究 老年小鼠和老年 CD-1 小鼠将评估年龄对长期暴露于 产生耐受性和依赖性的乙醇剂量，如 动物饮食中提供。 急性戒断30天后，并且 在长期康复过程中。 药物治疗的临床研究 建议在 1 岁以下的男性患者中戒酒者焦虑 70. 药物的单次试验剂量挑战对 使用（哈拉西泮、阿普唑仑或丁螺环酮）之后是一段时间 长期双盲治疗。 血浆水平和临床效果 在治疗期间对研究药物进行监测，并且 退出阶段。