Furthermore, melatonin deficiency may contribute to insomnia because levels generally decrease with age while sleep fragmentation increases with age, and sleep latency increases with melatonin suppression or delayed melatonin onset. There has been a particular interest in the potential role of melatonin for the treatment of insomnia in older adults because, unlike most hypnotic medications, melatonin has minimal effects on psychomotor function. Exogenous melatonin has been used as a chronobiotic (to shift circadian phase), as an antioxidant, and as an oncostatic agent. Melatonin is a secretory product produced in the pineal gland and in several extrapineal sites, which has a wide variety of functions. The linear pharmacokinetic behavior of melatonin observed in the elderly can form the basis for future studies exploring a wider range of dosing scenarios to establish exposure-response relationships for melatonin-mediated sleep outcomes. Renal and liver function parameters remained stable after 6 weeks of treatment. In addition, subjects in the high dose arm maintained melatonin levels >50 pg/ml for an average of 10 hours, which could result in elevated melatonin levels beyond the typical sleep period. The maximum concentration was 405☙3 pg/ml for the low dose arm and 3999☗00 pg/ml for the high dose arm, both of which are substantially higher than physiologic melatonin levels for this age group. The time to maximum level (1.3 hrs vs 1.5 hrs), elimination half-life (1.8 hrs vs 2.1 hrs), and apparent total clearance (379 l/hr vs 478 l/hr) did not differ significantly between the low and high dose arms, respectively. To assess this, we conducted a randomized, double-blind, placebo-controlled study of low (0.4 mg) and high (4.0 mg) dose melatonin (25% immediate release+75% controlled release) in 27 older adults with insomnia complaints and low endogenous melatonin levels to determine if melatonin pharmacokinetic properties differ between these two doses. However, relatively little is known about the pharmacokinetic properties of low dose (2 mg) melatonin in a combined immediate release/controlled release dose, especially in older adults who may also exhibit altered melatonin disposition. Surge-sustained formulations consisting of combined immediate release and controlled release dosing may mimic the endogenous melatonin physiologic profile. Melatonin is increasingly used for the treatment of sleep disorders.
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