A single physiological dose of melatonin (20 µg for 3 h given intravenously at different times of the day (04.00–12.00, 16.00 and 20.00 h) was able to shift the endogenous plasma melatonin profile of healthy volunteers under entrained conditions according to a phase-response curve (PRC). ANOVA showed an effect of the time of administration on the onset, the acrophase or the offset of the melatonin profiles. These profiles were significantly delayed when the infusion was administered at 12.00 h and advanced when the infusion was given at 20.00 h. Further, the AUCs evaluated on the nocturnal melatonin profiles were increased after the 04.00 h infusion (+20.5%, p < 0.05), whereas they were decreased after the 12.00 h infusion (–20%, p < 0.05). Lastly, no alteration was observed for cortisol rhythm, whatever the time of melatonin administration. These results, which show that according to a PRC the system regulating melatonin secretion is sensitive to a single short-term administration of the hormone given at a low dose, support the paradigm of the endogenous synchronizer melatonin.
The plasma melatonin profile was significantly disturbed (phase-shift of the maximum melatonin level) in four out of six female sufferers from status migrainosus, compared with nine healthy controls. The number of secretion peaks was similar in both groups. A nocturnal 20 micrograms melatonin infusion (from 21.00 to 01.00 h) evoked plasma melatonin levels slightly higher than a physiological secretion peak. During infusion, the episodes of secretion were reinforced and the endogenous plasma profile was phase-advanced in two patients displaying a phase-delay. These data suggest impaired pineal function in migraine. In the absence of side effects of melatonin infusion, the relief of certain migraine symptoms described by our patients might support a controlled trial of melatonin in migraine.
Melatonin (MLT) is a methoxyindole secreted principally by the pineal gland. It is synthesized at night under normal environmental conditions. The endogenous rhythm of secretion is generated by the suprachiasmatic nuclei and entrained by the light/dark cycle. Light is able to both suppress or entrain MLT production on light schedule. The nyctohemeral rhythm of this hormone can be determined by repeated measurement of plasma or saliva MLT or urine sulfatoxy-MLT, the main hepatic metabolite. MLT can be considered as the output (the hand) of the endogenous clock. Since the regulating system follows a central and sympathetic nervous pathway, an abnormality at any level could unspecifically modify the MLT secretion, especially in patients with sympathalgia or dysautonomia. MLT plays the role of an endogenous zeitgeber on core temperature or sleep-wake cycle. Exogenous MLT is able to influence the endogenous secretion of the hormone according to a phase-response curve. There are practical implications for this property in situations when biological rhythms are disturbed (jet-lag syndrome, delayed sleep phase syndrome, insomnia in blind people, shift-work, insomnia in elderly people). Improvement of pharmaceutical forms (controlled release preparations) or development of MLT analogs could lead to decisive progress.
The effect of oral controlled-release (CR), oral transmucosal (buccal; TMD) and transdermal (TDD) drug delivery systems on plasma concentrations of melatonin (MT) and its principal metabolite in human subjects using a crossover, single dose design was evaluated. Twelve adult male volunteers participated in the study and received all three dosage forms on three separate occasions. All patch dosage forms were removed after 10 h of wear. Plasma concentrations of the parent drug and its metabolite, 6-sulfatoxymelatonin (MT6s) were measured by radioimmunoassay. Between-subject plasma concentrations of MT were very variable following both oral CR and TDD. Use of the oral CR system gave plasma MT profiles in some subjects that were initially similar to physiological levels, but then differed substantially from physiological in the rate of MT offset; in a few subjects, plasma MT levels remained consistently much below normal nocturnal physiological levels. Also, the ratio of metabolite to parent drug by the oral CR route was many times greater than physiological. TDD resulted in a significant delay in systemic drug levels and a gradual decline in drug delivery after patch removal, possibly due to deposition of melatonin in the skin. TDD failed to simulate the physiological plasma profile of MT (rapid achievement of steady-state blood levels and rapid decline after removal of the patch; i.e., so-called "square-wave" profile). TMD provided prompt systemic drug levels with less variability than oral CR or TDD delivery. Also, plasma MT levels fell promptly and rapidly after removal of the patch. No indication of mucosal deposition was observed. TMD was able to mimic the physiological plasma profiles of both MT and its principal metabolite.
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