Melatonin Entrainment of Elderly Blind Free-runners

描述（由申请人提供）：在我们刚刚完成的项目中，我们已经证明，每晚口服10毫克褪黑激素可以使9名年轻盲人中的8名进入（同步）自由运行的昼夜节律，从而改善夜间睡眠和白天的警觉性。1名未上车的人在治疗前自由跑步时间最长（24.9小时）。此外，我们已经证明，当盲人的自由运行的昼夜节律被颠倒时，给他们10毫克褪黑激素有直接的催眠作用。最近，我们发现这三个人中有三个人的剂量可以“降低”到0.5毫克。我们进一步发现，它们也可以被携带到0.5 mg的新生剂量（它们的最长自由运行时间为24.4 h）。预处理期似乎可以预测褪黑素的携带可能性和携带的稳态阶段，这与动物研究中建立的几个重要原则是一致的。因此，我们的项目具有临床和科学的重要性。在美国大约有20万完全失明的人，其中50%的人有自由运行的昼夜节律。这些人中有许多是老年人。该项目的目标是确定三种剂量（0.5 mg， 10 mg和20 mg）褪黑素治疗的疗效，并预测0.5 mg剂量仅对相对较短的时间（<24.5 h）有效。如果0.5 mg剂量治疗失败，我们将测试更高剂量的疗效。成功接受褪黑素治疗的盲人受试者将被随访一年，以评估褪黑素治疗的长期益处和风险。研究老年盲人尤为重要，因为与年轻盲人相比，他们可能更容易受到褪黑激素副作用的影响，对褪黑激素治疗的反应也可能不同。在我们将要讨论的许多基础科学问题中，有一个是年龄对昼夜节律的影响。对盲人的研究提供了一个机会来理解不受光/暗周期干扰的人类昼夜节律系统的生理学。

DESCRIPTION (provided by applicant): In our just completed project, we have shown that nightly oral administration of 10 mg melatonin can entrain (synchronize) free-running circadian rhythms in eight of nine younger blind people to the 24.0-hour day, resulting in improved nighttime sleep and daytime alertness. The one person who did not entrain had the longest pre-treatment free-running period (24.9 h). In addition, we have shown that 10 mg of melatonin has a direct soporific action when given to blind subjects when their free-running circadian rhythms are inverted. Most recently, we have found that the dose can be "stepped down" to 0.5 mg in three out of three of these people. We have further found that they could also be entrained to a de novo 0.5 mg dose (their longest free-running period was 24.4 h). The pre-treatment period appears to predict the likelihood of entrainment to melatonin and the steady-state phase of entrainment, which is consistent with several important principles established in animal studies. Therefore, our projects are of both clinical and scientific importance. There are approximately 200,000 totally blind people in the U.S. About 50 percent of these people have free-running circadian rhythms. Many of these people are elderly. The goal of this project will be to determine the efficacy of melatonin treatment at three doses (0.5 mg, 10 mg and 20 mg), with the prediction that the 0.5 mg dose will work only in people with relatively short periods (<24.5 h). In treatment failures with the 0.5 mg dose, we will test the efficacy of higher doses. Blind subjects who successfully entrain with melatonin will be followed for one year to assess the long-term benefits and risks of melatonin administration. It is particularly important to study the elderly blind, because - compared to younger blind people - they may be more susceptible to side effects of melatonin and they may respond differently to melatonin treatment. Among the many basic science questions that we will be addressing is the effect of age on circadian period. The study of blind people provides an opportunity to understand the physiology of the circadian system in humans unperturbed by the light/dark cycle.