EFFECTS OF THE AGING PROCESS ON DRUG RESPONSIVENESS

衰老过程对药物反应的影响

• 批准号: 3114197
• 负责人: grant R. wilkinson
• 金额: $ 25.25万
• 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/3114197
• 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，伴随着不成比例的药物使用在这个 老年人对药物的反应往往与年轻人不同 患者，这与不良反应的发生率较大有关。 拟议研究的总体目标是深入了解 和改变药物处置/药代动力学的重要性和 人体药物反应性随年龄变化的药效学研究。 这样的信息应该导致更合理和更安全的药物使用 老年人。 抑郁症是导致老年人精神疾病的最常见原因， 三环类抗抑郁药使用率较高。多塞平(新泉、阿迪潘)应用广泛 但与其他常用药物不同的是， 关于年龄对其性格的影响以及这种影响是如何发生的，我们知之甚少。 变化导致了老年患者副作用的增加。 因此，研究计划比较多塞平和多塞平的处置情况。 其精神活性代谢物N-脱甲基多塞平在年轻人和老年人中的应用 研究对象。因为多塞平是以15：85的顺式和顺式混合给药的 反式异构体，也计划进行调查以确定其机制 这一比率的表观反转发生在 N-脱甲基代谢物。还将进行研究，以确定 氧化代谢的多态在大体上的贡献 这种抗抑郁药的处置存在个体间的差异。 中枢神经系统对药物的敏感性增加通常出现在老年人中。 因为大脑中的药物水平是由 将继续进行血脑屏障调查，以研究影响因素 参与这种运输的人。特别令人感兴趣的将是 等离子体结合及结合络合物的解离机理 与体外相比，在体内得到了增强。研究计划是为了 考察不同结合大分子对这一现象的影响 血浆中游离药物浓度与血药浓度之间的关系 用原位颅内技术测量脑内的放射性物质 透析。 衰老导致动物的β肾上腺素受体反应性降低 和人类。对白细胞的研究表明，这与一种 受体腺苷环化酶系统的功能解偶联 受体数量的变化。老年人也有一个受损的 调节该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其作用机制。 老年人的β受体功能及其与正常老年人的不同 更年轻的个体。调查还将确定是否 白细胞中的受体变化是可以概括的，尤其是对 血管床，以及这是如何影响血流动力学的。