Drug Insight: the use of melatonergic agonists for the treatment of insomnia-focus on ramelteon.
ABSTRACT Melatonin, a chronobiotic that participates in the control of the circadian system, is known for its sleep-promoting effects, which include shortening of sleep latency and lengthening of sleep duration. As a result of its short half-life, melatonin does not exhibit undesirable side effects, and its broad applicability for a variety of sleep problems has been the focus of numerous scientific studies. Melatonin has not, however, received regulatory approval from the US FDA as a drug, because it can be sold freely as a food supplement. Consequently, there has been an active search for patentable melatonin receptor ligands in recent years. Ramelteon, an agonist that acts solely on melatonin MT(1) and MT(2) receptors, is of particular interest, and preliminary research indicates that it holds considerable promise for clinical applications. Ramelteon has been shown to induce sleep initiation and maintenance in various animal models and in clinical trials. In chronic insomnia, ramelteon decreases sleep latency and increases total sleep time and sleep efficiency, without causing hangover, addiction or withdrawal effects. Ramelteon is thought to promote sleep by influencing homeostatic sleep signaling mediated by the suprachiasmatic nucleus. Although ramelteon's metabolism and pharmacokinetics differ from those of melatonin, its safety seems to be sufficient for short-term application. Its long-term effects remain to be determined.
- SourceAvailable from: Pablo Antonio Scacchi Bernasconi[Show abstract] [Hide abstract]
ABSTRACT: Normal circadian rhythms are synchronized to a regular 24 hr environmental light/dark cycle. Both the su-prachiasmatic nucleus (SCN) and melatonin are essential for this adaptation. Melatonin exerts its chronophysiological action in part by acting through specific receptors (MT 1 , MT 2) which have been identified in the plasma membrane of SCN as well as in several neural and non-neural tissues. Both receptors have been cloned and share general features with other G protein linked receptors. Melatonin also exerts direct effects on intracellular proteins such as calmodulin or tubu-lin and has strong free radical scavenger properties which are non-receptor mediated. Within the SCN, melatonin reduces neuronal activity in a time-dependent manner. SCN MT 1 and MT 2 receptors appear to be insensitive during the day, but sensitive at dusk and dawn (MT 2 ; causes phase shifts) or during early night period (MT 1 ; decreases neuronal firing rate). Melatonin secreted during nighttime provides enough inertia to resist minor perturbations of the circadian timing system. The disruption of these circadian mechanisms cause a number of sleep disorders named according to the International Classification of Sleep Disorders as circadian rhythm sleep disorders (CRSDs). CRSDs include delayed or advanced sleep phase syndromes, non 24 hr sleep/wake rhythm disorder, time zone change syndrome ("jet lag") and shift work sleep dis-order. Disturbances in the circadian phase position of plasma melatonin levels have been found in all these disorders. In addition, co-morbility of severe circadian alterations with neurodegenerative diseases like Alzheimer´disease (AD) has been documented. Although further research involving larger number of patients suffering CRSDs is required, currently there is sufficient evidence to implicate endogenous melatonin as an important mediator in CRSD pathophysiology. Mela-tonin and its analogs can constitute useful therapeutic tools to treat disturbed sleep-wake rhythms in CRSDs. Melatonin secretion decreases in AD patients and its administration improves sleep efficiency, sundowning and cognitive function. This effect can be particularly important in mild cognitive impairment, an etiologically heterogeneous syndrome charac-terized by cognitive impairment preceding dementia.
- The Open Physiology Journal 04/2008; 1(1):1-22. DOI:10.2174/1874360900801010001
- Proceedings of the Combustion Institute 01/2000; 28(1):1203-1209. DOI:10.1016/S0082-0784(00)80331-8 · 3.83 Impact Factor