Chronobiotics--drugs that shift rhythms.

A chronobiotic is defined and levels of action within the mammalian circadian pacemaker system, such as the retina, retinohypothalamic tract, geniculohypothalamic tract, suprachiasmatic nuclei, output and feedback systems are identified. Classes of drug that include the indoleamines, cholinergic agents, peptides, and benzodiazepines, which might act as chronobiotics within these levels, are evaluated. Particular emphasis is placed on the indole, melatonin (MLT). The clinical circumstances for use of chronobiotics in sleep disturbances of the circadian kind, such as jet lag, shift work, delayed sleep-phase syndrome, advanced sleep-phase syndrome, irregular and non-24-hr sleep-wake cycles, are described under reorganized headings of disorders of entrainment, partial entrainment, and desynchronization. Specific attention is given to the blind and the aged. Both human and animal studies suggest that MLT has powerful chronobiotic properties. MLT shows considerable promise as a prophylactic and therapeutic alternative or supplement to the use of natural and artificial bright light for resetting the circadian pacemaker. Throughout this discussion, the hypnotic and hypothermic versus the chronobiotic actions of MLT are raised. Finally, problems in the design of delivery systems for MLT are discussed.