DOSE-RESPONSE CURVE FOR MELATONIN IN THE ELDERLY

描述：（改编自研究者摘要）：褪黑激素是一种 松果体只在夜间黑暗时产生的一种激素。 它 就像一个黑暗的信号，因此重置生物钟，特别是如果 在白天管理。 通过内源性褪黑激素起效进行评估，如果 褪黑激素是在早上给予的，它会引起内源性昼夜节律 起搏器（ECP）相位延迟（移到稍后的时间），就好像ECP是 看到了迟来的黎明。 如果在下午或晚上服用， 使ECP相位提前（移到较早的时间），就好像ECP 感觉到了更早的黄昏。 这些响应由相位描述 响应曲线（PRC）。 我们在这一领域的第一笔赠款是确定中国 在正常人身上。 我们发现褪黑激素PRC的形状确实 不随年龄而变化;也就是说，老年人可能会受益于 褪黑激素以同样的方式做年轻人。 然而， 我们知道最佳剂量，尤其是老年人。 如上所述，褪黑激素PRC提供正确的给药 治疗昼夜节律相位紊乱的时间，包括在 老年人，尤其是晚期睡眠综合征。 褪黑素PRC 也是了解内源性褪黑激素功能的基础， 人类 考虑到褪黑激素PRC与 光PRC，内源性褪黑素的功能似乎是 通过光/暗循环增强ECP的夹带。 研究人员现在建议确定诱导的最佳剂量。 老年人的相位变化 具体来说，他们将确定 在0.05-30.0 mg宽范围内的剂量-反应曲线。 他们假设， 该曲线在低剂量下是对数线性的，在低剂量以上达到平台。 如果 因此，褪黑素可被推荐用于治疗昼夜节律时相 低剂量的药物会导致疾病，因此也是非常安全的。 在一些（重复） 试验，研究人员计划评估整个褪黑激素曲线，以及 作为昼夜节律的其他标志。 在本申请中，他们计划 来研究65岁到90岁人群的剂量反应曲线。 于任何补助 最近提交给NIMH，他们希望研究剂量反应曲线 在年轻人身上。 这些基础科学研究应该形成 为今后褪黑激素的临床疗效和安全性研究奠定基础。 以来 大量的人已经在用褪黑激素治疗自己， 认为拟议的调查是关键和及时的，实际上是紧迫的 needed. 基于这些研究，褪黑激素可能被证明是一种安全的， 有效治疗昼夜节律紊乱。 具体而言，本研究的受试者将包括20至24名老年人。 10 - 12例受试者将分别提前（A）或延迟参加 (D)剂量反应实验。 每个主题将有三种类型的 评估：一天的昼夜节律相位基线评估;七个 用不同剂量的褪黑激素或安慰剂进行评估;以及重复研究 安慰剂和褪黑激素10.0 mg，以评估对24小时测量的影响， 其他昼夜节律标记。 每项剂量反应研究将包括为期三天的 实验室方案与DLMO的基线评估，单 在第2天施用褪黑激素剂量，然后重复测量 第3天的DLMO。 昼夜节律时相的主要依赖测量是第3天 DLMO。 对相移的剂量反应效应将具有统计学意义。 使用具有七个水平（安慰剂加6个剂量的褪黑激素）的ANOVA评估。 将采用双因素ANOVA分析7个治疗组的体温 条件和11个重复测量时间点。

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.