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Query: UMLS:C0917801 (insomnia)
 10,606 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Drug Insight: the use of melatonergic agonists for the treatment of insomnia-focus on ramelteon. 1741 Jan 9

Ramelteon is a novel MT1 and MT2 melatonin receptor selective agonist recently approved for the treatment of insomnia characterized by difficulty in sleep onset. It is a nonscheduled drug since it lacks the potential for abuse and does not interact with neurotransmitter receptors most associated with these phenomena. Although the effects of ramelteon use > 5 weeks are unknown, the available data confirms its safety and efficacy for short-term use. Clinical use and future research should uncover more information about ramelteon's properties.
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PMID:Ramelteon: a melatonin receptor agonist for the treatment of insomnia. 1829 8

Each year millions of travelers undertake long distance flights over one or more continents. These multiple time zone flights produce a constellation of symptoms known as jet lag. Familiar to almost every intercontinental traveler is the experience of fatigue upon arrival in a new time zone, but almost as problematic are a number of other jet lag symptoms. These include reduced alertness, nighttime insomnia, loss of appetite, depressed mood, poor psychomotor coordination and reduced cognitive skills, all symptoms which are closely affected by both the length and direction of travel. The most important jet lag symptoms are due to disruptions to the body's sleep/wake cycle. Clinical and pathophysiological studies also indicate that jet lag can exacerbate existing affective disorders. It has been suggested that dysregulation of melatonin secretion and occurrence of circadian rhythm disturbances may be the common links which underlie jet lag and affective disorders. Largely because of its regulatory effects on the circadian system, melatonin has proven to be highly effective for treating the range of symptoms that accompany transmeridian air travel. Additionally, it has been found to be of value in treating mood disorders like seasonal affective disorder. Melatonin acts on MT(1) and MT(2) melatonin receptors located in the hypothalamic suprachiasmatic nuclei, the site of the body's master circadian clock. Melatonin resets disturbed circadian rhythms and promotes sleep in jet lag and other circadian rhythm sleep disorders, including delayed sleep phase syndrome and shift-work disorder. Although post-flight melatonin administration works efficiently in transmeridian flights across less than 7-8 times zones, in the case longer distances, melatonin should be given by 2-3 days in advance to the flight. To deal with the unwanted side effects which usually accompany this pre-departure treatment (acute soporific and sedative effects in times that may not be wanted), the suppression of circadian rhythmicity by covering symmetrically the phase delay and the phase advance portions of the phase response curve for light, together with the administration of melatonin at local bedtime to resynchronize the circadian oscillator, have been proposed. The current view that sleep loss is a major cause of jet lag has focused interest on two recently developed pharmacological agents. Ramelteon and agomelatine are melatonin receptor agonists which, compared to melatonin itself, have a longer half-life and greater affinity for melatonin receptors and consequently are thought to hold promise for treating a variety of circadian disruptions.
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PMID:Jet lag: therapeutic use of melatonin and possible application of melatonin analogs. 1834 69

Melatonin (CAS 73-31-4) has both hypnotic and sleep/wake rhythm regulating properties. These sleep promoting actions, which are already demonstrable in healthy humans, have been found useful in subjects suffering from circadian rhythm sleep disorders (CRSD) like delayed sleep phase syndrome (DSPS), jet lag and shift-work sleep disorder. Low nocturnal melatonin production and secretion have been documented in elderly insomniacs, and exogenous melatonin has been shown to be beneficial in treating sleep disturbances of these patients. In comparison to a number of sleep-promoting compounds that are usually prescribed, such as benzodiazepines and z-drugs (zolpidem and zopiclon belonging to the latter ones), melatonin has several advantages of clinical value: it does not cause hangover nor withdrawal effects and is devoid of any addictive potential. However, recent meta-analyses revealed that melatonin is not sufficiently effective in treating most primary sleep disorders. Some of the reasons for a limited efficacy of this natural hormone are related to its extremely short half-life in the circulation, and to the fact that sleep maintenance is also regulated by mechanisms downstream of primary melatonergic actions. Hence, there is an urgent need for the development of melatonin receptor agonists with a longer half-life, which could be suitable for a successful treatment of insomnia. Such requirements are fulfilled by ramelteon (CAS 196597-26-9), which possesses a high affinity for the melatonin receptors MT1 and MT2 present in the circadian pacemaker, the suprachiasmatic nucleus (SCN). Ramelteon also has a substantially longer half-life than melatonin. This new drug has been successfully used in treating elderly insomniacs without any adverse effects reported, and is promising for treating patients with primary insomnia and also those suffering from CRSD. Since sleep disturbances constitute the most prevalent symptoms of various forms of depression, the need for the development of an ideal antidepressant was felt, which would both improve sleep and mitigate depressive symptoms. Since most of the currently used antidepressants, including the selective serotonin re-uptake inhibitors worsen the sleep disturbances of depressive patients, another novel melatonergic drug, agomelatine (CAS 138112-76-2), holds some promise because of its particular combination of actions: it has a high affinity for MT1 and MT2 receptors in the SCN, but it acts additionally as a 5-HT(2C) antagonist [5-hydroxytryptamine (serotonin) receptor 2C antagonist]. The latter property, which is decisive for the antidepressive action, would not favor but potentially antagonize sleep, but this is overcome during night by the melatonergic, sleep-promoting effect. This drug has been found beneficial in treating patients with major depressive and seasonal affective disorders. Unlike the other antidepressants, agomelatine improves both sleep and clinical symptoms of depressive illness and does not have any of the side effects on sleep seen with other compounds in use. This property seems to be of particular value because of the aggravating effects of disturbed sleep in the development of depressive symptoms. Based on these facts, agomelatine seems to be a drug of superior efficacy with a promising future in the treatment of depressive disorders. However, long-term safety studies are required for both ramelteon and agomelatine, with a consideration of the pharmacology of their metabolites, their effects on redox metabolism, and of eventual undesired melatonergic effects, e. g., on reproductive functions. According to current data, both compounds seem to be safe during short-term treatment
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PMID:Melatonergic drugs in clinical practice. 1836 44

Ramelteon is a novel hypnotic compound that is FDA-approved for the treatment of sleep-onset difficulty. It is a melatonin 1/2 receptor agonist with rapid absorption, extensive first-pass metabolism and an elimination half-life of just over 1h. Clinical efficacy data indicate moderate efficacy in reduction of sleep latency in adults of all ages with chronic insomnia, with estimated effect sizes roughly comparable to other standard hypnotic agents. Objective studies show minimal increases in total sleep time and no significant impact on wake after sleep-onset or sleep-stage distribution. Subjective reports demonstrate comparable, if slightly smaller, improvements. The recommended dosage is 8mg but studies suggest a flat response across dosage ranges from 4 to 32mg. Safety data indicate no evidence of clinically significant next-day performance effects and a reasonably low side effect profile. Animal studies, and a single human study suggest low abuse potential. Single-blind run-out from clinical trials have demonstrated no evidence of rebound insomnia.
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PMID:Efficacy and clinical safety of ramelteon: an evidence-based review. 1860 21

Ramelteon is a selective melatonin receptor (MT(1) and MT(2)) agonist that has been approved by the US Food and Drug Administration for the treatment of insomnia characterized by difficulty with sleep onset. It is the only approved sleep-promoting medication that does not have a direct sedating effect, but rather enhances sleep through effects on sleep regulatory mechanisms within the suprachiasmatic nucleus. Ramelteon has been shown to have no abuse liability and therefore is not scheduled by the U.S. Drug Enforcement Agency as a controlled substance. It is available as an 8 mg tablet, which should be taken approximately 30 minutes prior to bedtime. The FDA approval contains no limitation on how long the medication may be prescribed.
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PMID:A review of ramelteon in the treatment of sleep disorders. 1872 8

Ramelteon (Rozerem) is the first melatonin receptor agonist to be approved for the treatment of insomnia; it is not classified as a controlled substance. In patients with chronic insomnia, objectively assessed latency to persistent sleep (LPS) at week 1 was improved with oral ramelteon 8 mg administered 30 minutes before bedtime, compared with placebo, and this effect was maintained throughout the duration of 5-week and 6-month clinical studies. Subjectively assessed sleep latency (sSL) improved in some, but not all, studies. When a statistically significant improvement in sSL occurred at week 1, the effect was maintained throughout the duration of the 5-week studies, but not at all timepoints throughout a 6-month study. Improvements in objectively assessed total sleep time (TST) and sleep efficiency (SE) were only reported during the first week of treatment. Improvements in other objective or subjective measures of sleep were not consistent. Ramelteon was generally well tolerated, did not impair next-day cognitive or motor performance and was not associated with withdrawal symptoms, rebound insomnia or abuse potential. Thus, ramelteon provides a well tolerated option for the treatment of patients with insomnia characterized by difficulty in sleep onset.
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PMID:Ramelteon: a review of its use in insomnia. 1872 42

An estimated one-third of the general population is affected by insomnia, and this number is increasing due to more stressful working conditions and the progressive aging of society. However, current treatment of insomnia with hypnotics, gamma-aminobutyric acid A (GABA(A)) receptor modulators, induces various side effects, including cognitive impairment, motor disturbance, dependence, tolerance, hangover, and rebound insomnia. Ramelteon (Rozerem; Takeda Pharmaceutical Company Limited, Osaka, Japan) is an orally active, highly selective melatonin MT(1)/MT(2) receptor agonist. Unlike the sedative hypnotics that target GABA(A) receptor complexes, ramelteon is a chronohypnotic that acts on the melatonin MT(1) and MT(2) receptors, which are primarily located in the suprachiasmatic nucleus, the body's "master clock." As such, ramelteon possesses the first new therapeutic mechanism of action for a prescription insomnia medication in over three decades. Ramelteon has demonstrated sleep-promoting effects in clinical trials, and coupled with its favorable safety profile and lack of abuse potential or dependence, this chronohypnotic provides an important treatment option for insomnia.
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PMID:Pharmacology of ramelteon, a selective MT1/MT2 receptor agonist: a novel therapeutic drug for sleep disorders. 1922 78

Pineal melatonin is synthesized and secreted in close association with the light/dark cycle. The temporal relationship between the nocturnal rise in melatonin secretion and the "opening of the sleep gate" (i.e., the increase in sleep propensity at the beginning of the night), coupled with the sleep-promoting effects of exogenous melatonin, suggest that melatonin is involved in the regulation of sleep. The sleep-promoting and sleep/wake rhythm regulating effects of melatonin are attributed to its action on MT(1) and MT(2) melatonin receptors present in the suprachiasmatic nucleus (SCN) of the hypothalamus. Animal experiments carried out in rats, cats, and monkeys have revealed that melatonin has the ability to reduce sleep onset time and increase sleep duration. However, clinical studies reveal inconsistent findings, with some of them reporting beneficial effects of melatonin on sleep, whereas in others only marginal effects are documented. Recently a prolonged-release 2-mg melatonin preparation (Circadin(TM)) was approved by the European Medicines Agency as a monotherapy for the short-term treatment of primary insomnia in patients who are aged 55 or above. Several melatonin derivatives have been shown to increase nonrapid eye movement (NREM) in rats and are of potential pharmacological importance. So far only one of these melatonin derivatives, ramelteon, has received approval from the U.S. Food and Drug Administration to be used as a sleep promoter. Ramelteon is a novel MT(1) and MT(2) melatonergic agonist that has specific effects on melatonin receptors in the SCN and is effective in promoting sleep in experimental animals such as cats and monkeys. In clinical trials, ramelteon reduced sleep onset latency and promoted sleep in patients with chronic insomnia, including an older adult population. Both melatonin and ramelteon promote sleep by regulating the sleep/wake rhythm through their actions on melatonin receptors in the SCN, a unique mechanism of action not shared by any other hypnotics. Moreover, unlike benzodiazepines, ramelteon causes neither withdrawal effects nor dependence. Agomelatine, another novel melatonergic antidepressant in its final phase of approval for clinical use, has been shown to improve sleep in depressed patients and to have an antidepressant efficacy that is partially attributed to its effects on sleep-regulating mechanisms.
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PMID:Melatonin and melatonergic drugs on sleep: possible mechanisms of action. 1932 88

(1) Patients complaining of insomnia should first be treated with non-drug measures (information, advice). Short-course benzodiazepine therapy can be tried if non-drug measures and established herbal remedies fail; (2) Ramelteon, a drug that antagonises receptors for melatonin, a hormone involved in circadian rhythms, is being considered for European marketing authorization in the treatment of insomnia; (3) Ramelteon has only been compared with placebo in clinical trials. Only one of three trials in which the patients were studied in their normal environment showed that ramelteon reduced the time to sleep onset, only by about 10 minutes. A similar reduction was observed in the artificial conditions of a sleep laboratory. There was no effect on sleep duration or on the number of night-time awakenings; (4) Ramelteon does not appear to have the disadvantages of benzodiazepines, such as residual daytime drowsiness, rebound insomnia on drug withdrawal, and dependence. But ramelteon provokes hyperprolactinaemia and was carcinogenic in experimental animals; (5) In practice, when a drug is needed for a patient complaining of insomnia, the best options are phytotherapy or short-course benzodiazepine treatment.
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PMID:Ramelteon: new drug. Insomnia: no role for risky placebos. 1953 18


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