DOSE-RESPONSE CURVE FOR MELATONIN IN THE ELDERLY

老年人褪黑激素的剂量反应曲线

• 批准号: 2465249
• 负责人: ALFRED J LEWY
• 金额: $ 29.73万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-15 至 2000-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2465249
• 关键词: aging; blood chemistry; body temperature; circadian rhythms; clinical research; clinical trials; dosage; drug administration rate /duration; drug screening /evaluation; emotions; human old age (65+); human subject; human very old age (85+); longitudinal human study; melatonin; neuroendocrine system; performance; placebos; sleep; statistics /biometry; wakefulness

DESCRIPTION: (adapted from investigator's abstract): Melatonin is a hormone produced by the pineal gland only during nighttime darkness. It acts like a dark signal and therefore resets the body clock, especially if administered during the day. Assessed by the endogenous melatonin onset, if melatonin is given in the morning, it causes the endogenous circadian pacemaker (ECP) to phase delay (shift to a later time), as if the ECP were perceiving a later dawn. If administered in the afternoon or evening, it causes the ECP to phase advance (shift to an earlier time), as if the ECP were perceiving an earlier dusk. These responses are described by a phase response curve (PRC). Our first grant in this area was to determine the PRC in normal subjects. We have found that the shape of the melatonin PRC does not vary with age; that is, older people are likely to benefit from melatonin in the same way as do younger individuals. However, little is known about optimal doses, particularly in the elderly. As described above, the melatonin PRC provides the correct administration times for treating circadian phase disturbances, including those found in the elderly, particularly advanced sleep phase syndrome. The melatonin PRC is also the basis for understanding the function of endogenous melatonin in humans. Given that the melatonin PRC is about 12 hours out of phase with the light PRC, the function of endogenous melatonin appears to be augmentation of entrainment of the ECP by the light/dark cycle. The investigators now propose to determine the optimal doses for inducing phase shifts in elderly humans. Specifically, they will determine the dose-response curve over a broad range, 0.05-30.0 mg. They hypothesize that this curve is log linear at low doses, above which a plateau is reached. If so, melatonin can be recommended for the treatment of circadian phase disorders at low -- and therefore extremely safe -- doses. In some (repeat) trials, the investigators plan to assess the entire melatonin curve, as well as other markers for circadian phase. In the present application, they plan to study the dose-response curve in people between 65 and 90. In a grant recently submitted to the NIMH, they hope to study the dose-response curve in younger individuals. These basic science investigations should form the basis for future clinical efficacy and safety studies of melatonin. Since people in vast numbers are already treating themselves with melatonin, we regard the proposed investigations as critical and timely, indeed, urgently needed. Based on these studies, melatonin may prove to be a safe and efficacious treatment for circadian phase disorders. Specifically, subjects for this study will include 20 to 24 elderly adults. Ten to 12 subjects each will participate in either in advance (A) or delay (D) set of dose response experiments. Each subject will have three types of evaluations: a one-day baseline evaluation of circadian phase; seven evaluations with different doses of melatonin or placebo; and repeat studies with placebo and melatonin 10.0 mg to assess effects on 24-hour measures of other circadian markers. Each dose-response study will include a three-day laboratory protocol with a baseline assessment of DLMO, a single administration of the melatonin dose on Day 2, followed by repeat measure of DLMO on Day 3. The major dependent measure of circadian phase is Day 3 DLMO. The dose response effect on phase shifting will be statistically assessed with ANOVA with seven levels (placebo plus 6 doses of melatonin). Body temperature will be analyzed with a two-way ANOVA for seven treatment conditions and eleven repeated measures time points.

描述：(改编自研究人员摘要)：褪黑素是一种 松果体只在夜间黑暗时产生的荷尔蒙。它 其作用类似于暗信号，因此会重置生物钟，尤其是在 白天给药。根据内源性褪黑素的开始情况进行评估，如果 褪黑激素在早上服用，会引起内源性昼夜节律 起搏器(ECP)到相位延迟(移到稍后的时间)，就像ECP是 感觉到更晚的黎明。如果在下午或晚上给药，它 使ECP进相(移到更早的时间)，就好像ECP 感觉到了一个更早的黄昏。这些响应由一个阶段来描述 响应曲线(PRC)。我们在这方面的第一笔拨款是确定中华人民共和国 在正常受试者中。我们发现褪黑激素PRC的形状 不随年龄变化；也就是说，老年人可能受益于 褪黑激素的作用方式与年轻人相同。然而，几乎没有什么是 知道最佳剂量，特别是在老年人中。 如上所述，褪黑素PRC提供了正确的给药方式 治疗昼夜节律相位扰动的时间，包括在 老年人，尤其是晚期睡眠相综合症。褪黑素中华人民共和国 也是理解内源性褪黑素在体内的作用的基础。 人类。鉴于褪黑素PRC与褪黑素的时间相差12小时 光PRC，内源性褪黑素的功能似乎是 光/暗周期对ECP的夹带作用增强。 研究人员现在提议确定诱导的最佳剂量 老年人的相变。具体来说，他们将确定 剂量-反应曲线的范围很广，0.05-30.0 mg。他们假设 这条曲线在低剂量时是对数线性的，超过这一点就会达到平台期。如果 因此，褪黑激素可推荐用于治疗昼夜节律期。 低剂量--因此非常安全--的疾病。在一些(重复)中 在试验中，研究人员还计划评估整个褪黑素曲线 作为昼夜节律的其他标志。在本申请中，他们计划 研究65岁至90岁人群的剂量-反应曲线。在一笔赠款中 最近提交给NIMH的，他们希望研究剂量-反应曲线 在更年轻的个体中。这些基础科学研究应该形成 为今后褪黑素的临床疗效和安全性研究奠定基础。自.以来 大量的人已经在用褪黑素治疗自己了，我们 认为拟议的调查是关键的、及时的、确实是紧急的 需要的。根据这些研究，褪黑素可能被证明是一种安全和 对昼夜节律紊乱的有效治疗。 具体地说，这项研究的对象将包括20至24名老年人。 10至12名受试者将分别提前(A)或推迟参加 (D)一套剂量反应实验。每个科目将有三种类型的 评估：昼夜节律阶段的一天基线评估；七 使用不同剂量的褪黑素或安慰剂进行评估；以及重复研究 使用安慰剂和褪黑素10.0毫克评估24小时测量的效果 其他昼夜节律标记。每项剂量反应研究将包括为期三天的 对DLMO进行基线评估的实验室方案，单个 在第2天给药褪黑激素剂量，然后重复测量 DLMO在第三天。昼夜节律的主要依赖度量是第三天 DLMO。相移的剂量响应效应将是统计上的 用七个水平的方差分析进行评估(安慰剂加6剂褪黑素)。 体温分析采用双因素方差分析进行七种处理 条件和11个重复测量时间点。