tasimelteon and Sleep-Initiation-and-Maintenance-Disorders

Alzheimer's disease (AD) is an age-dependent neurodegenerative disease with progressive cognition and memory loss, insomnia, and other abnormal behavioral changes. Amongst various hypotheses for AD pathophysiology, occupational stress-induced Alzheimer's has recently been reported in many AD cases.. Studies pertaining to the same suggest that stress leads to insomnia or sleep disruption, which further leads to neuroinflammation due to oxidative stress, both of which are major harbingers of AD. Additionally, overall sleep deficit is associated with progressive cognitive and memory decline, which adds more inconvenience to Alzheimer's disease. Based on this, any triumphant AD management needs a pharmacological intervention that can not only antagonize the amyloid betainduced neurotoxicity but also correct the sleep-wake cycle disruption. Chronobiotic therapeutics like melatonin offer vital neuroprotective effects by eliciting its action through more than one of the pathologies of AD. This is also bolstered by the finding that endogenous melatonin levels are lower in AD patients. This melatonin replacement therapy can be especially useful in AD treatment, but only in the early phases of the disease and in cases where the melatonin receptors are intact and functioning.. To negate such limitations and extend the action and therapeutic efficacy of melatonin- mediated actions towards AD treatment, melatonin analogue like tasimelteon can pose a high therapeutic value in AD treatment superior to that provided by melatonin. This review encapsulates all details about how AD is believed to occur and how current situations influence it, along with how melatonin and tasimelteon act towards treating Alzheimer's.

Topics: Alzheimer Disease; Humans; Melatonin; Neurodegenerative Diseases; Sleep Initiation and Maintenance Disorders

Geriatric patients often experience insomnia because of physiological and neurological changes that occur during the aging process. Use of benzodiazepines, nonbenzodiazepine hypnotics, and diphenhydramine for the treatment of insomnia pose an increased risk of cognitive impairment, falls, and fractures in this patient population. Therapeutic alternatives approved by the Food and Drug Administration include suvorexant, doxepin, ramelteon, and tasimelteon, which have shown efficacy and safety in various studies. This paper explores and outlines the available safety and efficacy data associated with these medications and reviews their potential place in therapy in treating insomnia in the geriatric population.

Topics: Aged; Aged, 80 and over; Azepines; Benzofurans; Cyclopropanes; Doxepin; Humans; Hypnotics and Sedatives; Indenes; Randomized Controlled Trials as Topic; Sleep Initiation and Maintenance Disorders; Triazoles

Tasimelteon, a novel circadian regulator, is the first product for the treatment of Non-24-hour Sleep-Wake Disorder (Non-24) approved by either the FDA or the European Medicines Agency (EMA). Tasimelteon is a potent and specific melatonin (MT1 and MT2) receptor agonist with 2 - 4 times greater affinity for the MT2 receptor.. Safety was assessed in two controlled and two open-label studies in blind individuals with Non-24 and in two controlled studies of primary insomnia. Periodic assessments included collection of adverse events (AEs), laboratory testing, electrocardiograms (ECGs), vital sign monitoring, physical examinations and assessment for the potential for suicide. One study included additional assessments for endocrine function.. A total of 184 blind individuals with Non-24 received tasimelteon nightly with a median exposure > 1 year. In placebo-controlled studies, 387 patients with insomnia and 42 patients with Non-24 received tasimelteon nightly for 4 - 26 weeks. The total patient years exposure for the six studies assessed here is 258.64 patient years. Discontinuations due to AEs were similar across treatment groups. Overall in the clinical studies described here, AEs attributable to tasimelteon treatment were headache, diarrhea, dry mouth, alanine aminotransferase increased, somnolence, dizziness and nightmare/abnormal dreams. There were no clinically significant differences in treatment group with ECGs, vital signs, withdrawal, endocrine function and suicidality assessments.. Long-term tasimelteon administration was safe and well-tolerated. This is supported by placebo-controlled data in both Non-24 and insomnia patients.

Topics: Benzofurans; Cyclopropanes; Humans; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Sleep Disorders, Circadian Rhythm; Sleep Initiation and Maintenance Disorders; Time Factors

To examine the efficacy of tasimelteon for the treatment of non-24-hour sleep-wake disorder using evidence from controlled clinical trials.. Citations in Google Scholar and PubMed from January 1, 2008, to May 31, 2014, were identified using tasimelteon as the search term.. Results were limited to human trials published in English. Trials that compared tasimelteon with placebo were included.. A phase II trial (n = 39) evaluated the effects of tasimelteon versus placebo on improvements in sleep efficiency and the ability to shift circadian rhythms over 3 days. Significant shifts in circadian rhythm were only observed for 100-mg tasimelteon. A phase III trial (n = 412) evaluated the effects of tasimelteon versus placebo on assessment of latency to persistent sleep and wake after sleep onset; significant advantages were observed in tasimelteon recipients. The SET (Safety and Efficacy of Tasimelteon) trial (n = 84) enrolled blind men and women with Non-24. They received placebo or tasimelteon 20 mg daily. Tasimelteon recipients had significantly (P = 0.0025) better entrainment and N24CRS scores. The RESET (Randomized Withdrawal Study of the Efficacy and Safety of Tasimelteon) trial (n = 20) enrolled entrained participants from the SET trial who received 20 mg of tasimelteon or placebo daily for 8 weeks. The primary objective was to evaluate the maintenance of effect of tasimelteon to entrain circadian rhythms. Tasimelteon was associated with significantly (P = 0.0055) greater entrainment than placebo.. Tasimelteon improves sleep initiation and maintenance in patients with Non-24 who have a shift in endogenous circadian rhythms. However, the cost of this agent limits its use.

Topics: Benzofurans; Circadian Rhythm; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Cyclopropanes; Humans; Randomized Controlled Trials as Topic; Receptors, Melatonin; Sleep; Sleep Initiation and Maintenance Disorders

Current pharmacological treatment of insomnia involves the use of sedative-hypnotic benzodiazepine and non-benzodiazepine drugs. Although benzodiazepines improve sleep, their multiple adverse effects hamper their application. Adverse effects include impairment of memory and cognitive functions, next-day hangover and dependence. Non-benzodiazepines are effective for initiating sleep but are not as effective as benzodiazepines for improving sleep quality or efficiency. Furthermore, their prolonged use produces adverse effects similar to those observed with benzodiazepines. Inasmuch as insomnia may be associated with decreased nocturnal melatonin, administration of melatonin is a strategy that has been increasingly used for treating insomnia. Melatonin can be effective for improving sleep quality without the adverse effects associated with hypnotic-sedatives. Ramelteon, a synthetic analog of melatonin which has a longer half life and a stronger affinity for MT1 and MT2 melatonergic receptors, has been reportedly effective for initiating and improving sleep in both adult and elderly insomniacs without showing hangover, dependence, or cognitive impairment. Insomnia is also a major complaint among patients suffering from depressive disorders and is often aggravated by conventional antidepressants especially the specific serotonin reuptake inhibitors. The novel antidepressant agomelatine, a dual action agent with affinity for melatonin MT1 and MT2 receptors and 5-HT2c antagonistic properties, constitutes a new approach to the treatment of major depressive disorders. Agomelatine ameliorates the symptoms of depression and improves the quality and efficiency of sleep. Taken together, the evidence indicates that MT1/MT2 receptor agonists like ramelteon or agomelatine may be valuable pharmacological tools for insomnia and for depression-associated insomnia.

Topics: Acetamides; Animals; Benzodiazepines; Benzofurans; Clinical Trials as Topic; Cyclopropanes; Depressive Disorder; Humans; Hypnotics and Sedatives; Indenes; Indoles; Melatonin; Sleep Initiation and Maintenance Disorders

Insomnia is a prevalent disorder with nearly 50% of the US adult population reporting insomnia symptoms during the past year and 10 - 15% reporting chronic insomnia. In addition, insomnia is a frequent comorbidity with depression, anxiety and pain, as well as other medical and psychiatric disorders. Tasimelteon is a melatonin receptor agonist developed by Bristol-Myers Squibb Co. and later licensed to Vanda Pharmaceuticals in 2004. It is being developed for the treatment of sleep disorders, including insomnia and mood disorders.. The nature and prevalence of insomnia are described in this review, along with the current pharmacological treatments for the disorder. Summaries of the available pharmacological and clinical data for tasimelteon are also provided. A Medline search using the terms tasimelteon, melatonin and insomnia was undertaken to assess the current literature on these topics.. While the few clinical trials of the medication have been promising, much more extensive testing, along with more detailed reporting of the drug's pharmacokinetics and pharmacodynamics, is needed before tasimelteon can be considered a worthwhile addition to the available treatments for insomnia. In particular, testing of the drug's effectiveness in treating maintenance insomnia, as well as tests of its long-term effectiveness and safety, is much needed.

Topics: Animals; Benzofurans; Clinical Trials as Topic; Cyclopropanes; Humans; Melatonin; Receptors, Melatonin; Sleep Initiation and Maintenance Disorders

The ability of melatonin to shift biological rhythms is well known. As a result, melatonin has been used in the treatment of various circadian rhythm sleep disorders, such as advanced and delayed sleep phase disorders, jet lag and shiftwork disorder. The current evidence for melatonin being efficacious in the treatment of primary insomnia is less compelling. The development of agents that are selective for melatonin receptors provides opportunity to further elucidate the actions of melatonin and its receptors and to develop novel treatments for specific types of sleep disorders. The agonists reviewed here - ramelteon, tasimelteon and agomelatine - all appear to be efficacious in the treatment of circadian rhythm sleep disorders and some types of insomnia. However, further studies are required to understand the mechanisms of action, particularly for insomnia. Clinical application of the agonists requires a good understanding of their phase-dependent properties. Long-term effects of melatonin should be evaluated in large-scale, independent randomized controlled trials.

Topics: Acetamides; Animals; Benzofurans; Circadian Rhythm; Cyclopropanes; Humans; Hypnotics and Sedatives; Indenes; Melatonin; Sleep Initiation and Maintenance Disorders

An impairment in next day driving performance has been reported for almost every drug currently United States Food and Drug Administration (FDA) approved for improvement of sleep in chronic and transient insomnia. Tasimelteon, a melatonin receptor agonist, demonstrated significant improvements in night-time sleep, daytime naps, and sleep timing in non-24-hr sleep-wake disorder (Non-24) by entraining these patients to a 24-hr day as measured by melatonin and cortisol rhythms. Given this new mechanism of action of entraining the biological clock, we conducted a study to evaluate the potential effect tasimelteon may have on the ability to operate a motor vehicle. The study was conducted in 48 healthy adult subjects using a randomised, double-blind, placebo and active (zopiclone 7.5 mg) controlled study with a 3-period cross-over design. Driving performance was assessed by measuring standard deviation of lateral position (SDLP) using the validated Cognitive Research Corporation Driving Simulator-MiniSim. The difference in least square mean SDLP for tasimelteon was 1.22 cm reflecting a non-significant increase in SDLP change from placebo (p = .1119). In contrast, treatment with the active control, zopiclone 7.5 mg, was associated with a meaningful and significant increase in SDLP, change from placebo for zopiclone was 4.14 cm (p < .0001). The lack of clinically meaningful and statistically significant finding with tasimelteon was further supported by the symmetry analysis, which showed the distribution of within-subject differences between tasimelteon and placebo was symmetric about zero. At the FDA-approved 20 mg dose to treat Non-24, tasimelteon did not impair next-day driving performance compared to placebo in adult healthy volunteers.

Topics: Adult; Automobile Driving; Benzofurans; Cross-Over Studies; Cyclopropanes; Double-Blind Method; Humans; Sleep; Sleep Initiation and Maintenance Disorders

We present a totally blind adolescent with refractory insomnia due to a combination of Non-24 hour sleep-wake disorder and restless leg syndrome that was successfully treated with tasimelteon, iron replacement, and gabapentin. To our knowledge, this is the first published report of treatment of N24 with tasimelteon in an adolescent. In addition, this case highlights the importance of recognizing and treating multifactorial causes of insomnia.

Topics: Adolescent; Benzofurans; Blindness; Cyclopropanes; Drug Resistance; Drug Therapy, Combination; Female; Gabapentin; Humans; Iron; Restless Legs Syndrome; Sleep Disorders, Circadian Rhythm; Sleep Initiation and Maintenance Disorders

Tasimelteon, developed by Vanda Pharmaceuticals Inc under license from Bristol-Myers Squibb Co, is a melatonin receptor agonist. Because of the high density of melatonin receptors in the circadian pacemaker, the suprachiasmatic nucleus, melatonergic actions can phase-shift circadian rhythms and promote sleep. Tasimelteon was effective in reducing sleep onset latency (in phase II and III clinical trials) and in resetting the circadian melatonin rhythm (in phase II trials), which indicated its potential suitability as treatment for jet lag, shift work and circadian rhythm sleep disorders. Statistically significant improvements in sleep maintenance have also been observed with the drug. Tasimelteon has been claimed to be useful in the treatment of depression, and preclinical evidence in this respect is to be confirmed in a phase II clinical trial, which was ready to be initiated at the time of publication. It is plausible that the drug may be effective in the treatment of depressive disorders, at least those that are related to circadian dysfunction, and that it may attenuate sleep problems in depressed patients of different subtypes. A general suitability in mitigating other symptoms of major depressive disorder cannot be deduced from the actions of tasimelteon via the melatonin receptors MT1 and MT2. The drug is well tolerated, does not induce impairment of next-day functioning or dependence, and seems to be safe in short-term treatment; however, toxicological data would be required for assessing its long-term safety.

Topics: Animals; Benzofurans; Clinical Trials as Topic; Cyclopropanes; Drugs, Investigational; Humans; Melatonin; Molecular Structure; Patents as Topic; Receptors, Melatonin; Sleep Disorders, Circadian Rhythm; Sleep Initiation and Maintenance Disorders; Structure-Activity Relationship