Effects of Melatonin on Circadian System in patients with Circadian Rhythm Disorders

临床时间生物学的最新研究表明，在正常光暗周期下生活的视力受试者中也观察到慢性睡眠相位延迟（延迟睡眠相位综合征（DSPS））或慢性自由运行的睡眠-觉醒节律（非24小时睡眠-觉醒综合征（非24小时））。环境光的强度或时间被怀疑在患有DSPS或非24的视力正常的患者中起病因作用。虽然这些疾病已经被研究了大约20年，有很少的假设，他们的病理生理或明确的治疗。研究对象为10名无睡眠障碍的健康男性。采用双盲法研究了两种不同方式口服褪黑素后血清褪黑素浓度的时间过程。在6名受试者中，在13：00 h给予一次0.9 mg的褪黑素（治疗1）。在4名受试者中，在13：00 h、15：00 h和17：00 h（治疗2）给予3次0.3 mg褪黑激素。处理1后，4小时内获得有效浓度（100 pg/ml），而处理2后6小时内获得有效浓度。研究2：我们先前的研究表明，在患者睡前1-2小时给予褪黑素（剂量：1-6 mg），对50%的睡眠时相延迟综合征或非24小时睡眠-觉醒综合征患者有效。由于褪黑激素的相位响应的夜间窗口被认为是昼夜节律睡眠障碍患者的较小，我们从患者通常就寝前6小时开始每隔一小时给予褪黑激素3次。5/5例DSPS患者和4/5例非24小时患者的这一程序是有效的。这些结果表明，持续6小时的高褪黑激素期可能更适合于患者的夜间褪黑激素相位响应窗口。

Recent studies in clinical chronobiology have revealed that a chronic sleep phase delay (delayd sleep phase syndrome (DSPS)), or a chronic free-running sleep-wake rhythm (non-24 hour sleep-wake syndrome (non-24)) was also observed in sighted subjects living under a normal light-dark cycle. The intesity or timing of environmental light is suspected to play an etiologic role in sighted patients suffering from DSPS or non-24. Though these disorders have been studied for about 20 years, there have been few hypotheses on their pathophysiology or defintive treatments.Study 1 : To clarify an optimal dose of melatonin. 10 healthy male subjects without sleep disorders were studied. Time course of serum melatonin concentration following orally administered melatonin in two different manners were investigated double-blindly. In 6 subjects, 0.9 mg of elatonin was administered once at 13 : 00h (treatment 1). In 4 subjects, 0.3 mg of melatonin was administered 3 times at 13 : 00h, 15 : 00h, and 17 : 00h (treatment 2). After the treatment1, an effective concentration (100 pg/ml) was obtained for 4 hours, while it was obtained for 6 hours after the treatment 2. These results indicated that 0.3 mg of melaonin may be enough for achieving the effective serum concentration.Study 2 : Our prior study indicated that melatonin treatment was effective in 50% of patients with delayd sleep phase syndrome or non-24-hour sleep-wake syndrome when it was administerd once 1-2 hours before the patient's desired bedtime (dose : 1-6 mg). Since evening window for phase response by melatonin was assumed to be smaller in patients with circadian thythm sleep disorders, we administered melatonin 3 times bi-houly from 6 hours before the patient's usual bedtime. This procedure was effective in 5/5 patients with DSPS and 4/5 patients with non-24, These results suggest that high melatonin period lasting for 6 hours may coincide more properly on the patient's evening window for phase response by melatonin.