Sleep disorder melatonin

Melatonin [73-31-4] C 2H N202 (31) has marked effects on circadian rhythm (11). Novel ligands for melatonin receptors such as (32) (12), C2yH2gN202, have affinities in the range of 10 Af, and have potential use as therapeutic agents in the treatment of the sleep disorders associated with jet lag. Such agents may also be usehil in the treatment of seasonal affective disorder (SAD), the depression associated with the winter months. Histamine (see Histamine and histamine antagonists), adenosine (see Nucleic acids), and neuropeptides such as corticotropin-like intermediate lobe peptide (CLIP) and vasoactive intestinal polypeptide (VIP) have also been reported to have sedative—hypnotic activities (7). 

Melatonin secretion is synchronized to the light/dark (LD) cycle, with a nocturnal maximum (in young humans, about 200 pg/ml plasma) and low diurnal baseline levels (about 10 pg/ml plasma). Studies have supported the value of the exogenous administration of melatonin in circadian rhythm sleep disorders, insomnia, cancer, neurodegenerative diseases, disorders of the immune function, and oxidative damage (Karasek et al. 2002 Pandi-Perumal et al. 2005, 2006 Srinivasan et al. 2005a,b, 2006 Hardeland et al. 2006). 

A reduced endogenous melatonin production seems to be a prerequisite for effective exogenous melatonin treatment of sleep disorders. A recent metaanalysis of the effects of melatonin in sleep disturbances, including all age... 

Melatonin receptor agonists in the treatment of sleep disorders... 

Buscemi, N., Vandermeer, B., Hooton, N. et al. (2006). Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction meta-analysis. Br. Med. J. 332, 385-93. 

Melatonin receptor agonists and their relevance for the treatment of sleep disorders and major depression have been previously reviewed in Ann. Rep. Med. Chem., volume 39 [29]. Since then, ramelteon has been approved, representing an important milestone for the proof of concept of this target, and has opened new possibilities for research. 

Antihistamines such as diphenhydramine, a mainstay of OTC sleep preparations, are also used widely by parents for their children at doses of 1 mg/kg. Most of the reports of the use of clonidine for sleep disorders are clinical and anecdotal case reports of use in children with ADFFD (Wilens et ah, 1994 Prince et ah, 1996). There are some safety concerns about using clonidine once a day at bedtime, especially in patients who take a daytime stimulant. Melatonin was studied using a double-blind, placebo-controlled, crossover design (Jan et ah, 1994) on a mixed group of 15 children with sleep disturbances, with some improvement reported. However, caution is warranted in using this agent because melatonin is unregulated, and there are concerns about the purity and safety of some commercially available preparations (Werry and Aman, 1999). 

Chase JF, Gidal BE. Melatonin therapeutic use in sleep disorders. Ann Pharmacother 1997 10 1218-1226. 

Several drugs with novel chemical structures have been introduced more recently for use in sleep disorders. Zolpidem, an imidazopyridine, zaleplon, a pyrazolopyrimidine, and eszopiclone, a cyclopyrrolone (Figure 22-4), although structurally unrelated to benzodiazepines, share a similar mechanism of action, as described below. Eszopiclone is the (S) enantiomer of zopiclone, a hypnotic drug that has been available outside the United States since 1989. Ramelteon, a melatonin receptor agonist, is a new hypnotic drug (see Ramelteon). Buspirone is a slow-onset anxiolytic agent whose actions are quite different from those of conventional sedative-hypnotics (see Buspirone). 

Melatonin has been studied in the treatment of various sleep disorders, including insomnia and delayed sleep-phase syndrome. It has been reported to improve sleep onset, duration, and quality when administered to healthy volunteers, suggesting a pharmacologic hypnotic effect. Melatonin has also been shown to increase rapid-eye-movement (REM) sleep. These observations have been applied to the development of ramel-teon, a prescription hypnotic, which is an agonist at melatonin receptors (see Chapter 22). 

Clinical studies in patients with sleep disorders have shown that oral melatonin supplementation may alter sleep architecture. Subjective improvements in sleep quality and improvements in sleep onset and sleep duration have been reported. However, the significance of these findings is impaired by many study limitations. 

Timing is critical for melatonin to be effective if it is given at the wrong time for sleep disorders or jet lag, it can cause increased daytime sleepiness (5,7) and worsened mental performance (8). Drowsiness and a small fall in body temperature are commonly reported effects (9), particularly after daytime administration, when endogenous concentrations of melatonin are low. 

Researchers used to think that older adults produced very little melatonin. Since the elderly tend to have more problems with insomnia and other sleeping disorders, scientists hypothesized that these lower levels of melatonin were the cause of sleeping problems in this population. 

Melatonin may be an effective treatment for several conditions. Studies suggest that it may be helpful in treating sleep disorders, jet lag, and even cancer. However, research on this topic is still very limited and experts have warned consumers that very little is known about the effectiveness or long-term safety of taking melatonin supplements. 

While the effectiveness of melatonin in treating sleep disorders in most people remains unclear, research shows that it can be helpful for certain individuals. For example, many blind people have sleep disorders, and melatonin has been shown to help promote sleep in this population. Studies have also shown that it is helpful in treating sleep disorders in disabled children. 

No one knows the exact number of people who use melatonin. According to a CNN report, 20 million Americans have taken melatonin to treat jet lag or sleeping disorders. It is legal and therefore easy to buy this hormone in over-the-counter medication in the United States. Several other countries have had a different attitude towards such widespread use of a potentially dangerous hormone several European countries and Canada restrict the sale of melatonin. 

While the results of this trail were negative, it is nonetheless noteworthy, not only for providing comprehensive data indicating that melatonin is inappropriate for managing sleep disorders in AD patients, but also as an exemplar of exactly the type of trails that are necessary if efficacious evidence-based treatments are to be developed. 

Skene DJ, Lockley SW, Arendt J (1999) Melatonin in circadian sleep disorders in the blind. Biol Signals Recept 8 90-95... 

SSRIs can cause insomnia and daytime somnolence however, the symptoms seem to reflect a sleep-wake cycle disorder. It is conceivable that disruptions in the normal pattern of melatonin secretion, particularly a delay in the normal early morning fall in plasma concentrations, could be involved in the pathophysiology of these symptoms. The fact that these sleep disorders were seen only with fluvoxamine would also support a role of melatonin (see the section on Endocrine in this monograph). 

In the course of developing the melatonin agonist 1 (Fig. 1), potentially indicated for the treatment of sleep disorders, we evaluated approaches to the chiral cyclopropane intermediates 2 a and 2 b based on both classical resolution and asymmetric induction. Conceptually, these intermediates could be derived from di-hydrobenzofurans 3, 4 and 5 each of these was used at one stage or another during our research and development work. 

Melatonin Serotonin derivative used for jet-lag and sleep disorders. Purported activity as a contraceptive and in the treatment of cancer, depression, and HIV Drowsiness, sedation, headache. Contraindicated in pregnancy, in woman trying to conceive (4- LH), and in nursing mothers (4- prolactin)... 

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