EFFECTS OF AGING PROCESS ON DRUG RESPONSIVENESS IN MAN

衰老过程对人类药物反应的影响

• 批准号: 3114198
• 负责人: grant R. wilkinson
• 金额: $ 25.65万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1979
• 资助国家: 美国
• 起止时间: 1979-04-01 至 1991-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3114198
• 关键词: aging; benzodiazepines; beta adrenergic receptor; biological models; biotransformation; blood brain barrier; catecholamines; chemical models; diazepine; drug administration rate /duration; drug administration routes; drug adverse effect; drug metabolism; drug receptors; enzyme induction /repression; gas chromatography; human old age (65+); human subject; laboratory rat; oxidation reduction reaction; propranolol; psychobiology; rifamycins; tobacco abuse; young adult human (21-34)

The number and proportion of elderly (greater than 65 yr) within the U.S. continues to increase, along with the disproportionate use of drugs in this population, The elderly often respond differently to drugs than younger patients, and this is related in a greater incidence of adverse reactions. The overall goal of the proposed research is to gain insight into the role and importance of altered drug disposition/pharmacokinetics and pharmacodynamics in age-related changes in drug responsiveness in man. Such information should lead to more rational and safer drug use in the elderly. Depression is the most common cause of mental illness in the elderly, and tricyclic antidepressant use is high. Doxepin (Sinequan, Adipan) is widely prescribed in the elderly but, in contrast to other commonly used drugs, little is known of the effects of age on its disposition and how such changes contribute to the increased side-effects in older patients. Studies are, therefore, planned to compare the disposition of doxepin and its psychoactive metabolite, N-desmethyl-doxepin, in young and elderly subjects. Because doxepin is administered as a 15:85 mixture of cis and trans isomers, investigations are also planned to determine the mechanism of the apparent inversion of this ratio occurring during formation of the N-demethylated metabolite. Studies will also be performed to determine the contribution of polymorphic oxidative metabolism in the large interindividual variability in the disposition of this antidepressant. Increased CNS sensitivity to drugs is often present in the elderly. Because drug levels in the brain are determined by transport across the blood-brain-barrier-, investigations will be continued to study factors involved in such transport. Of particular interest will be the role of plasma binding and the mechanism whereby dissociation of the bound complex is enhanced in vivo compared to that in vitro. Studies are planned to examine the effect of different binding macro-molecules on this phenomenon and the relationship between unbound drug concentrations in the plasma and those in the brain as measured by technique of in situ intracranial dialysis. Aging leads to a decrease in beta adrenoreceptor responsiveness in animals and humans. Studies with leukocytes sugggest that this involves a functional uncoupling of the receptor adenylate cyclase system without a change in the number of receptors. The elderly also have an impaired ability to regulate this receptor's affinity for agonists in response to physiological stimuli. Studies are planned to determine the mechanism of beta receptor functioning in the elderly and how this differs from that in younger individuals. Investigations will also determine whether the receptor changes seen in the leukocyte are generalizable, especially to the vascular bed, and how this affects hemodynamics.

美国老年人（65岁以上）的数量和比例。 继续增加，沿着不成比例地使用药物， 老年人对药物的反应通常与年轻人不同 患者，这与不良反应的发生率更高有关。 拟议研究的总体目标是深入了解 改变药物处置/药代动力学的重要性， 人体药物反应性年龄相关变化的药效学。 这些信息应有助于在儿童中更合理和更安全地使用药物。 老人 抑郁症是老年人精神疾病最常见的原因， 三环类抗抑郁药的使用率很高。 多塞平（Sinequan，Adipan）广泛用于 但与其他常用药物相比， 很少有人知道年龄对其性格的影响，以及这种影响是如何产生的。 这些变化导致老年患者的副作用增加。 因此，计划进行研究，以比较多塞平和 其精神活性代谢物N-去甲基多塞平在年轻人和老年人中 科目 因为多塞平是作为顺式和式的15：85混合物给药的， 反式异构体，还计划进行调查，以确定机制 这一比例的明显倒置发生在形成的过程中， N-脱甲基代谢物。 还将进行研究，以确定 多态性氧化代谢的贡献， 这种抗抑郁药的处置的个体间差异。 CNS对药物的敏感性增加通常存在于老年人中。 因为大脑中的药物水平是由药物在大脑中的转运决定的， 血脑屏障，调查将继续研究因素 参与这样的运输。 特别令人感兴趣的是 血浆结合和结合复合物解离的机制 与体外相比，在体内增强。 研究计划， 研究不同结合大分子对这种现象的影响 以及血浆中未结合药物浓度与 通过原位颅内测量技术测量脑内的那些 透析 衰老导致动物β肾上腺素受体反应性降低 还有人类 对白细胞的研究表明， 受体腺苷酸环化酶系统的功能性解偶联， 受体数量的变化。 老年人也有一个受损的 调节这种受体对激动剂的亲和力的能力， 生理刺激 计划进行研究，以确定 β受体在老年人中的功能，以及这与老年人的不同之处。 年轻人。 调查还将确定是否 在白细胞中观察到的受体变化是普遍的，特别是对 血管床，以及这如何影响血液动力学。