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)

TAK-375 (Ramelteon), a melatonin ML1/MT1 receptor agonist for the potential treatment of primary insomnia, is being developed by Takeda. Takeda submitted an NDA to the FDA for TAK-375 in September 2004.
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PMID:TAK-375 Takeda. 1567 11

Ramelteon (TAK-375) is a novel melatonin receptor agonist currently under investigation for the treatment of insomnia. This study describes the neurochemical and receptor binding characteristics of ramelteon in vitro. Ramelteon showed very high affinity for human MT1 (Mel1a) and MT2 (Mel1b) receptors (expressed in Chinese hamster ovary [CHO] cells), and chick forebrain melatonin receptors (consisting of Mel1a and Mel1c receptors) with Ki values of 14.0, 112, and 23.1 pM, respectively, making the affinities of ramelteon for these receptors 3-16 times higher than those of melatonin. The affinity of ramelteon for hamster brain MT3 binding sites was extremely weak (Ki: 2.65 microM) compared to melatonin's affinity for the MT3 binding site (Ki: 24.1 nM). In addition, ramelteon showed no measurable affinity for a large number of ligand binding sites (including benzodiazepine receptors, dopamine receptors, opiate receptors, ion channels, and transporters) and no effect on the activity of various enzymes. Ramelteon inhibited forskolin-stimulated cAMP production in the CHO cells that express the human MT1 or MT2 receptors. Taken together, these results indicate that ramelteon is a potent and highly selective agonist of MT1/MT2 melatonin receptors.
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PMID:Neurochemical properties of ramelteon (TAK-375), a selective MT1/MT2 receptor agonist. 1569 69

Ramelteon [TAK 375] is a melatonin (MT1/MT2) receptor agonist that is being developed by Takeda as a treatment for sleep disorders. It is undergoing regulatory review in the US, phase III trials in Europe, and phase II trials in Japan for the treatment of insomnia. Phase II trials are also being conducted in the US for the treatment of circadian rhythm sleep disordersIn September 2004, Takeda submitted an NDA to the US FDA for ramelteon for the treatment of insomnia. In May 2003, data presented at the 156th Annual Meeting of the American Psychiatric Association report that ramelteon is highly selective for the MT1 receptor, and has greater affinity, selectivity and potency than melatonin.
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PMID:Ramelteon: TAK 375. 1586 23

Ramelteon, approved in the US for the treatment of insomnia characterised by difficulty with sleep onset, is a highly selective agonist for the melatonin MT1/MT2 receptors, which are believed to mediate the circadian rhythm in mammals. Ramelteon has negligible affinity for the MT3 binding sites and other receptors in the brain, including the opiate, dopamine, benzodiazepine and serotonin receptors, which may explain the lack of significant adverse events and lack of abuse or dependence potential observed with ramelteon. In three clinical trials in patients with chronic insomnia, ramelteon 8mg was effective in reducing sleep latency, without being associated with any significant or clinically relevant residual effects. It also generally increased total sleep time and, where assessed, sleep efficiency. In a first-night-effect model of transient insomnia, ramelteon 8mg was significantly more effective than placebo at reducing sleep latency and increasing total sleep time. Ramelteon was generally well tolerated; the most commonly reported adverse events occurring in more ramelteon than placebo recipients were somnolence (5% vs 3%), fatigue (4% vs 2%) and dizziness (5% vs 3%). Adverse events were mostly mild or moderate in nature. Ramelteon has been shown to have no potential for abuse or dependence.
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PMID:Ramelteon. 1633 46

To date the mainstay of the pharmacological treatment of insomnia has involved the modulation of the gabaminergic system via benzodiazepines or the Z-drugs, zolpidem, zopiclone or zaleplon. A new approach has explored the melatoninergic system, namely activation of MT1 and MT2 receptors in the suprachiasmatic nucleus of the hypothalamus. Ramelteon (TAK-375) is a novel sleep-promoting agent that acts as an agonist at these receptors; its preclinical pharmacology, mode of action, pharmacokinetics, drug interactions, clinical efficacy, and safety and tolerability are reviewed here.
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PMID:Ramelteon: profile of a new sleep-promoting medication. 1670 22

Ramelteon, a potent agonist for the melatonin MT1 and MT2 brain receptors, has recently been granted approval by the US FDA for the treatment of insomnia associated with sleep onset. The drug has not exhibited potential for abuse or dependency in laboratory tests, nor does it interact with neurotransmitter receptors most associated with these phenomena, hence it has the great advantage of being a nonscheduled drug. Few data have been published in peer-reviewed journals describing its efficacy and side effects in patients with insomnia; however, side effects noted to date appear minor. No comparison study has been performed to determine whether the recommended dose of ramelteon 8 mg has any advantage over physiologic doses of melatonin (0.3 mg), particularly for long-term use.
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PMID:Ramelteon: a novel treatment for the treatment of insomnia. 1683 Nov 11

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

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

Several novel melatonin receptor agonists, in addition to various formulations of melatonin itself, are either available or in development for the treatment of insomnia. Melatonin is thought to exert its effects principally through two high affinity, G-protein coupled receptors, MT1 and MT2, though it is not known which subtype is responsible for the sleep-promoting action. The present study used radiotelemetry to record EEG and EMG in un-restrained freely moving rats to monitor the sleep-wake behaviour and examined the acute sleep-promoting activity of an MT2 receptor subtype selective melatonin analog, IIK7. IIK7 is a full agonist at the MT2 receptor subtype but a partial agonist at the MT1 receptor and has approximately 90-fold higher affinity for MT2 than MT1. Like melatonin, IIK7 (10mg/kg i.p.) significantly reduced NREM sleep onset latency and transiently increased the time spent in NREM sleep, but did not alter REM sleep latency or the amount of REM sleep. An analysis of the EEG power spectrum showed no change in delta (1-4 Hz) or theta activity (5-8 Hz) following IIK7 administration. Core body temperature was slightly decreased ( approximately 0.3 degrees C) by IIK7 compared to vehicle-treated rats. The acute and transient changes in the sleep-wake cycle mimic the changes seen with melatonin and suggest that its sleep-promoting activity is mediated by activation of the MT2 receptor subtype.
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PMID:Sleep-promoting action of IIK7, a selective MT2 melatonin receptor agonist in the rat. 1942 70

Current treatment of insomnia with hypnotics, GABA(A) receptor modulators, induces various side effects, including cognitive impairment, motor disturbance, dependence, tolerance, hang-over, and rebound insomnia. Ramelteon (Rozerem) is an orally active, highly selective melatonin MT1/MT2 receptor agonist. Unlike the sedative hypnotics that target GABA(A) receptor complexes, ramelteon is a chronohypnotic that acts on the melatonin MT1 and MT2 receptors, which are primarily located in the suprachiasmatic nucleus. 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:[A novel therapeutic drug: ramelteon]. 1976 47


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