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

最近的临床时间生物学研究表明，在正常的明暗周期下，视力正常的受试者也观察到慢性睡眠阶段延迟（延迟睡眠阶段综合征（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（non-24））。环境光的强度或时间被怀疑在患有DSPS或非24的视力患者中起病因作用。虽然这些疾病已经被研究了20年，但关于其病理生理或明确的治疗方法的假设很少。研究1：阐明褪黑素的最佳剂量。研究对象为10名无睡眠障碍的健康男性。采用双盲方法研究口服褪黑素对血清褪黑素浓度的影响。在6名受试者中，在13:00 h给药一次0.9 mg褪黑素（治疗1）。在4名受试者中，分别于13:00、15:00和17:00（治疗2）给予0.3 mg褪黑激素3次。处理1后4小时得到有效浓度（100 pg/ml），处理2后6小时得到有效浓度（100 pg/ml）。这些结果表明，0.3 mg的褪黑素可能足以达到有效的血清浓度。研究2：我们之前的研究表明，褪黑素治疗对50%的延迟睡眠阶段综合征或非24小时睡眠-觉醒综合征患者有效，如果在患者期望的就寝时间前1-2小时给药一次（剂量：1-6毫克）。由于假设有昼夜节律睡眠障碍的患者褪黑激素的相位反应的夜间窗口较小，我们从患者通常就寝前6小时开始每两小时给药3次褪黑激素。该方法在5/5的DSPS患者和4/5的非24患者中有效。这些结果表明，持续6小时的高褪黑素期可能更适合患者的夜间褪黑素期反应窗口。

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.