Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917801 (insomnia)
 10,606 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Melatonin is synthesized and secreted during the dark period of the light-dark cycle. The rhythmic nocturnal melatonin secretion is directly generated by the circadian clock, located in mammals within the suprachiasmatic nucleus (SCN), and is entrained to a 24-hour period by the light-dark cycle. The periodic secretion of melatonin may be used as a circadian mediator to any system that can 'read' the message. In addition, direct effects of the hormone on the SCN could explain some of the melatonin effects on the circadian system. Duration of the melatonin nocturnal secretion is directly proportional to the length of the night and it has experimentally been demonstrated to be the critical parameter for photoperiod integration. The sites and mechanisms of action of melatonin for circadian and photoperiodic responses are far from being elucidated, but action through specific membrane receptor sites starts to emerge. A possible bicompartmental model of distribution for melatonin, the first compartment in plasma acting on peripheral organs and the second in the cerebrospinal fluid affecting neurally mediated functions at a much higher concentration, has recently been proposed. From earlier studies it was concluded that melatonin administration to humans reduces sleep latency and induces sleepiness and fatigue. More recently, the effect of lower pharmacologic or physiologic doses of melatonin was examined in different laboratories. These studies included young normal volunteers and patients with chronic insomnia, as well as dementia patients exhibiting sundowning syndrome. Irrespective of the method of assessment, melatonin showed effects in insomniac patients in most studies. With some exceptions, melatonin administration reduced sleep latency and/or increased total sleep time and sleep efficiency. Furthermore, melatonin was more effective when given to elderly insomniacs, or Alzheimer disease patients, although sleep improvement was not strictly correlated with prior levels of the hormone.
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PMID:A critical assessment of the melatonin effect on sleep in humans. 1102 39

The first-night effect (FNE) is the tendency for individuals to sleep worse than normal during their first night of polysomnographic sleep evaluation. FNE reflects the adaptive increase of alertness and perhaps the stress resulting from an unfamiliar sleeping environment. This effect is usually absent in patients with chronic schizophrenia. Melatonin (N-acetyl-5-methoxy-tryptamine), the hormone secreted by the pineal gland at night, has been found to improve sleep in elderly patients with insomnia and recently in patients with chronic schizophrenia. The authors used FNE as a marker to explore the neurobehavioral responses of patients with chronic schizophrenia to melatonin treatment. In a randomized, double-blind, crossover trial, 14 patients with chronic schizophrenia were administered melatonin (2 mg in a controlled-release formulation) or placebo for 3 weeks with a 1-week washout between treatment periods. Polysomnography was performed during the last two consecutive nights of each treatment period. The following significant FNEs were observed with melatonin treatment: (1) rapid eye movement sleep latency was longer; (2) sleep efficiency was lower; and (3) the duration of wakefulness during sleep was lower on the first night than on the second night. These effects were not found when the patients received a placebo. The FNE was manifested regardless of whether melatonin was administered before or after the placebo treatment period. For the first time, these results show that melatonin treatment exaggerates FNE in patients with chronic schizophrenia, thereby suggesting an improved ability of these patients to mobilize alertness in unfamiliar surroundings.
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PMID:First-night effect of melatonin treatment in patients with chronic schizophrenia. 1110 43

Melatonin is a hormone synthesized in the pineal gland from tryptophan. It participates in several biological processes in the human being, such as circadian sleep rhythm, mood, reproductive processes and aging. Melatonin serum levels are increased in childhood and diminish importantly in older people. Serum levels are diminished in patients with insomnia and depressive mood. Experimentally, the melatonin inhibits the growth of mammary tumors in animals. With respect to endometrial cancer and Alzheimer's disease, the information is not conclusive. No changes have been found in melatonin levels in climacterical women. So its use has not fundament in postmenopausal women, however it can only be administered for short periods of time for the treatment of some sleep disturbances.
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PMID:Melatonin and climactery. 1120 81

For the treatment of insomnia/sleep disturbances, drugs are indicated only if non-drug-procedures alone are not sufficiently successful or not successful at all. To facilitate sleep, sedative-hypnotic agents are used clinically. Because of favorable risk-benefit ratio, non-benzodiazepines with benzodiazepine-like action (zolpidem, zopiclon) or benzodiazepines themselves (dependent on their pharmacokinetic profil) are administered in the most cases. Sedative-hypnotic drugs reducing the electric activity of the CNS sufficiently to produce coma and even death are not recommended at present. To assess the clinical relevance of amino acid L-tryptophan for the treatment of insomnia/sleep disturbances, more controlled clinical studies are necessary. The nonprescription antihistamines (Doxylamin, Diphenhydramin) are only suitable for short-term administration in adults. Under certain conditions, antidepressant and antipsychotic drugs can be taken. Because of potential risks, the intake demands caution. Different herbal remedies are recommended, but only for extracts of valerian a sleep-inducing effect can be assumed. Melatonin, an endogenous hormone and tryptophan-metabolite is thought to be involved with the sleep-wake cycle. Therefore the exogenous intake of melatonin may influence vigilance and sleep. This is particularly true for patients with jet-lag symptoms.
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PMID:[Drug for the treatment of sleep disorders--review]. 1123 87

An intrinsic body clock residing in the suprachiasmatic nucleus (SCN) within the brain regulates a complex series of rhythms in humans, including sleep/wakefulness. The individual period of the endogenous clock is usually >24 hours and is normally entrained to match the environmental rhythm. Misalignment of the circadian clock with the environmental cycle may result in sleep disorders. Among these are chronic insomnias associated with an endogenous clock which runs slower or faster than the norm [delayed (DSPS) or advanced (ASPS) sleep phase syndrome, or irregular sleep-wake cycle], periodic insomnias due to disturbances in light perception (non-24-hour sleep-wake syndrome and sleep disturbances in blind individuals) and temporary insomnias due to social circumstances (jet lag and shift-work sleep disorder). Synthesis of melatonin (N-acetyl-5-methoxytryptamine) within the pineal gland is induced at night, directly regulated by the SCN. Melatonin can relay time-of-day information (signal of darkness) to various organs, including the SCN itself. The phase-shifting effects of melatonin are essentially opposite to those of light. In addition, melatonin facilitates sleep in humans. In the absence of a light-dark cycle, the timing of the circadian clock, including the timing of melatonin production in the pineal gland, may to some extent be adjusted with properly timed physical exercise. Bright light exposure has been demonstrated as an effective treatment for circadian rhythm sleep disorders. Under conditions of entrainment to the 24-hour cycle, bright light in the early morning and avoidance of light in the evening should produce a phase advance (for treatment of DSPS), whereas bright light in the evening may be effective in delaying the clock (ASPS). Melatonin, given several hours before its endogenous peak at night, effectively advances sleep time in DSPS and adjusts the sleep-wake cycle to 24 hours in blind individuals. In some blind individuals, melatonin appears to fully entrain the clock. Melatonin and light, when properly timed, may also alleviate jet lag. Because of its sleep-promoting effect, melatonin may improve sleep in night-shift workers trying to sleep during the daytime. Melatonin replacement therapy may also provide a rational approach to the treatment of age-related insomnia in the elderly. However, there is currently no melatonin formulation approved for clinical use, neither are there consensus protocols for light or melatonin therapies. The use of bright light or melatonin for circadian rhythm sleep disorders is thus considered exploratory at this stage.
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PMID:Circadian rhythm sleep disorders: pathophysiology and potential approaches to management. 1146 35

Melatonin is being increasingly promoted as a therapeutic agent for the treatment of jet lag and insomnia, and is an efficient free radical scavenger. We have recently characterized a product for the reaction of melatonin with nitric oxide (NO), N-nitrosomelatonin. In the present work, reaction pathways with N1, C2, C4, C6 and C7 as possible targets for its reaction with NO that yield the respective nitroso derivatives have been investigated using semiempirical AM1 computational tools, both in vacuo and aqueous solution. Specifically, two different pathways were studied: a radical mechanism involving the hydrogen atom abstraction to yield a neutral radical followed by NO addition, and an ionic mechanism involving addition of nitrosonium ion to the indolic moiety. Our results show that the indolic nitrogen is the most probable site for nitrosation by the radical mechanism, whereas different targets are probable considering the ionic pathway. These results are in good agreement with previous experimental findings and provide a coherent picture for the interaction of melatonin with NO.
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PMID:Nitrosation of melatonin by nitric oxide: a computational study. 1155 63

Melatonin (N-acetyl-5-methoxytryptamine) has a diverse range of functions, including the control of neuroendocrine events. A number of studies have shown that melatonin may be of potential benefit for the treatment of insomnia, as well as neurodegenerative disorders. At present, there are numerous dosage forms of melatonin, with the oral route of administration being most popular. Presently, there is little information on the stability of melatonin over a pH range. With the changes in pH in the gastro-intestinal tract, as well as in different experimental conditions, information on the stability of melatonin would be important. We used a high-performance liquid chromatography method to determine the stability of melatonin solutions over a pH range (1.2-12) at room temperature and at 37 degrees C over a period of 21 days. The results show that no melatonin degradation occurred in the first 2 days. From days 3 to 21, there was a gradual decline in melatonin at all pHs, with the decline not exceeding 30%. No decline in melatonin levels occurred in the first 2 days at 37 degrees C. From days 3 to 21, melatonin levels declined gradually, with the decline not exceeding 29%.
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PMID:The effect of variations in pH and temperature on stability of melatonin in aqueous solution. 1155 71

Patients with end-stage renal disease (ESRD) suffer from a number of related disorders. These include endocrine abnormalities, sleep disturbances, and depression. Melatonin is involved in the synchronization of exogenous zeitgebers with the endogenous rhythms, and it has effects on various psychological factors. As the concentrations of melatonin and the effects of dialysis have only occasionally been investigated in ESRD, we performed a study involving 35 patients, measuring the serum concentrations of melatonin, and of its major metabolite 6-sulfatoxymelatonin (aMT6s), before and after hemodialysis. Serum samples taken during morning hours from a control group (n=11) with intact kidneys served as controls. Patients were dialyzed for approximately 4 hr between 07:00 and 13:00 hr (S1), between 13:00 and 20:00 hr (S2), or between 18:30 and 22:30 hr (S3). Mean melatonin concentrations before hemodialysis were highly elevated when compared with the controls (40.6 vs. 6.7 pg/mL; P<0.001). Although melatonin levels were decreased to 20.3 pg/mL after dialysis, they were still well above the control levels. Likewise, aMT6s concentrations before dialysis were highly elevated in ESRD patients before dialysis when compared with controls (39.5 vs. 2.0 pg/mL; P<0.001), and also decreased by dialysis to levels still well above control levels (25.3 pg/mL). Clearance efficacy was better for melatonin (48.9%) than for aMT6s (36.6%; P<0.05). In ESRD patients, a diurnal rhythm for melatonin was observed (S1, 45.1 pg/mL; S2, 31.5 pg/mL; S3, 48.7 pg/mL; P<0.05), indicating that the normal synthesis rhythm is maintained. None of the following secondary disorders were correlated with melatonin concentrations: insomnia, delayed sleep onset, night-time arousals, and restless-leg syndrome. The reason for this observation is probably the melatonin concentrations, which were so high that no sub-classification could be identified. It is concluded that in ESRD patients, hemodialysis is unable to decrease elevated levels of melatonin and aMT6s to normal values. It is speculated that some of the secondary disorders in ESRD are caused by supraphysiological concentrations of melatonin.
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PMID:Clearance of melatonin and 6-sulfatoxymelatonin by hemodialysis in patients with end-stage renal disease. 1158 56

Melatonin is an indole hormone that is produced by the pineal gland, mainly at night, with a peak around 3.00 a.m. under normal environmental conditions. This endogenic secretion cycle is generated by the suprachiasmatic nuclei in response to the day/night alternation. Light either suppresses or entrains melatonin production according to the time of light exposure. Melatonin can be viewed as the "hand" of the internal clock and is regulated via the central nervous and sympathetic systems. Melatonin synchronizes biological cycles, particularly the temperature and sleep/wake cycles. Exogenous melatonin can influence the endogenous secretion of melatonin according to a phase response curve, an effect that provides a rationale for the use of melatonin to treat disorders of biological rhythms (rapid time-zone change syndrome, delayed sleep phase syndrome, desynchronization in blind subjects or shift workers, insomnia in the elderly).
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PMID:[Melatonin and circadian rhythm]. 1192 23

To develop a new therapeutic agent for sleep disorders, we synthesized a novel series of tricyclic indan derivatives and evaluated them for their binding affinity to melatonin receptors. In our previous paper, we proposed a conformation of the methoxy group favorable for the binding of the MT(1) receptor. To fix the methoxy group in an active conformation, we decided to synthesize conformationally restricted tricyclic indan analogues with the oxygen atom in the 6-position incorporated into a furan, 1,3-dioxane, oxazole, pyran, morpholine, or 1,4-dioxane ring system. Among these compounds, indeno[5,4-b]furan analogues were found to be the most potent and selective MT(1) receptor ligands and to have superior metabolic stability. The optimization of substituents led to (S)-(-)-22b, which showed very strong affinity for human MT(1) (K(i) = 0.014 nM), but no significant affinity for hamster MT(3)() (K(i) = 2600 nM) or other neurotransmitter receptors. The pharmacological effects of (S)-(-)-22b were studied in experimental animals, and it was found that a dose of 0.1 mg/kg, po promoted a sleep in freely moving cats, as demonstrated by a decrease in wakefulness and increases in slow wave sleep and rapid eye movement sleep, which lasted for 6 h after administration. Melatonin (1 mg/kg, po) also had a sleep-promoting effect, though it lasted only 2 h. A new chiral method for the synthesis of (S)-(-)-22b starting from 60, which was prepared from 59 employing asymmetric hydrogenation with the (S)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl-Ru complex, was developed. (S)-(-)-22b (TAK-375) is currently under clinical trial for the treatment of insomnia and circadian rhythm disorders.
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PMID:Synthesis of a novel series of tricyclic indan derivatives as melatonin receptor agonists. 1221 63


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