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: 3486500
• 负责人: RICHARD I SHADER
• 金额: $ 57.58万
• 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/3486500
• 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.

建议进行一系列的临床和实验研究来评估 衰老过程对慢性阻塞性肺疾病后果的影响 镇静剂-催眠药的给药和戒断。健康的年轻人和 老年志愿者将每晚单次服用15毫克的氟拉西潘 (或安慰剂)，用于表示长半衰期累积的组 苯二氮卓类。在治疗前、治疗中和治疗后14天， 受试者将接受测试剂量的挑战，半衰期很短 苯二氮(静脉注射咪达唑仑0.04 mg/kg，口服三唑仑0.25 Mg，或安慰剂)。在每个测试剂量后，血浆水平和 测试药物的药代动力学根据变化情况进行评估。 镇静和情绪，精神运动能力减退，精神减退 以及脑电波的数量变化。在类比中 实验研究，3组雄性CD-1小鼠(青年、中年、 和老年人)接受两周的持续输液(通过植入物 渗透压泵)劳拉西潘、氯硝西潘或安慰剂 选择输液速度以产生稳定的血浆浓度 类似于在人类身上实现的那些。在...期间和之后 输液时，下列变量被量化：血浆和皮质 药物水平，基于计算机监控的行为活动，在 苯二氮卓类受体的体内结合及受体体外检测 约束性和功能性。另一系列关于年轻、中年和 老年和老年CD-1小鼠将评估年龄对慢性暴露于 产生耐受性和产生依赖性的乙醇剂量，如 在动物的饮食中提供。在30天的急性戒断后， 在长期复苏期间。慢性阻塞性肺疾病药物治疗的临床研究 戒酒者的焦虑被认为是年龄以下男性患者的焦虑 70.药物单次试验剂量挑战对 使用(氟拉西潘、阿普唑仑或丁螺环酮) 长期双盲治疗。血药浓度及临床疗效观察 在治疗期间对研究药物进行监测， 停药阶段。