ABSTRACT
What is the right time to administer a drug? Although this question was put forth as early as 1814 by JJ Virey, its answers began to be unraveled 150 years later based on the fact that the median lethal dose (LD50) of a chemical or physical agent varied on a diurnal basis. This gave rise to chronopharmacology as a new discipline. The molecular mechanisms that underlie the function of the biological clocks are universally present in all cells and consist of geneprotein-gene feedback loops in which proteins can down-regulate their own transcription and stimulate the transcription of other clock proteins. The existence of 24-hour rhythms in gastrointestinal absorption, binding to plasma proteins, liver metabolism, and renal excretion explain why the plasma levels of a drug change predictably in time (chronopharmacokinetics). A constant level of a drug in blood does not imply that the response of effector cells will be the same throughout time. The presence of 24-hour rhythms in receptors and cell metabolism explain why in the face of a constant concentration of a drug the cell response changes (chronoesthesy). Further complicating the view, any drug has desired and undesired effects that may also vary on a circadian basis (chronotoxicology). Therefore, to design a protocol of administration for a given drug the desired and undesired effects must be weighed (chronergy) for an optimal chronotherapy. A substance capable of shifting the phase of the circadian time system and thus re-entraining circadian rhythms is called a chronobiotic. Melatonin administration synchronizes the sleep-wake cycle in blind people and in individuals suffering from delayed sleep phase syndrome or jet lag, as well as in shift workers. The effect of melatonin on sleep is probably the consequence of increasing sleep propensity (by inducing a fall in body temperature) and of a synchronizing effect on the circadian clock (chronobiotic effect). Daily melatonin production decreases with age and, in several pathologies, attains its lowest values in Alzheimer’s dementia patients. About 45% of dementia patients have severe disruptions in their sleep-wakefulness cycle. In both
aged subjects having very minimal sleep disorders, as well as in demented patients with a very severe disorganization of the sleep-wake cycle, melatonin treatment reduced the variability of sleep onset and restored sleep.
