Update on emerging drugs for insomnia

Sullivan, Shannon

doi:10.1517/14728214.2012.693158

Cited by 19 publications

(11 citation statements)

References 8 publications

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“…However, these drugs are associated with several side effects including morning sedation, amnesia, confusion, dependence/tolerance, and rebound insomnia at discontinuation. [4][5][6][7] Thus, developing new effective drugs that selectively increase nonrapid eye movement (NREM) sleep without altering entire sleep architecture remains a priority. One potentially promising candidate is melatonin.…”

Section: Introductionmentioning

confidence: 99%

Melatonin promotes sleep in mice by inhibiting orexin neurons in the perifornical lateral hypothalamus

Sharma

Sahota

Thakkar

2018

Journal of Pineal Research

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Melatonin promotes sleep. However, the underlying mechanisms are unknown. Orexin neurons in the perifornical lateral hypothalamus (PFH) are pivotal for wake promotion. Does melatonin promote sleep by inhibiting orexin neurons? We used C57BL/6J mice and designed 4 experiments to address this question. Experiment 1 used double-labeled immunofluorescence and examined the presence of melatonin receptors on orexin neurons. Second, mice, implanted with bilateral guides targeted toward PFH and sleep-recording electrodes, were infused with melatonin (500 pmole/50 nL/side) at dark onset (onset of active period), and spontaneous bouts of sleep-wakefulness were examined. Third, mice, implanted with bilateral guides into the PFH, were infused with melatonin (500 pmole/50 nL/side) at dark onset and euthanized 2 hours later, to examine the activation of orexin neurons using c-Fos expression in orexin neurons. Fourth, mice, implanted with PFH bilateral guides and sleep-recording electrodes, were infused with melatonin receptor antagonist, luzindole (10 pmol/50 nL/side), at light onset (onset of sleep period), and spontaneous bouts of sleep-wakefulness were examined. Our results suggest that orexin neurons express MT1, but not MT2 receptors. Melatonin infusion into the PFH, at dark onset, site-specifically and significantly increased NREM sleep (43.7%, P = .003) and reduced wakefulness (12.3%, P = .013). Local melatonin infusion at dark onset inhibited orexin neurons as evident by a significant reduction (66%, P = .0004) in the number of orexin neurons expressing c-Fos. Finally, luzindole infusion-induced blockade of melatonin receptors in PFH at sleep onset significantly increased wakefulness (44.1%, P = .015). Based on these results, we suggest that melatonin may act via the MT1 receptors to inhibit orexin neurons and promote sleep.

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Section: Introductionmentioning

confidence: 99%

Melatonin promotes sleep in mice by inhibiting orexin neurons in the perifornical lateral hypothalamus

Sharma

Sahota

Thakkar

2018

Journal of Pineal Research

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“…The orexin peptides A and B bind selectively to the orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R) , and drugs that bind to both OX1R and OX2R are referred to as dual orexin receptor antagonists (DORAs) . Several DORAs have been investigated as potential treatments for insomnia , and one of them, suvorexant (MK4305), received approval by the US Food and Drug Administration (FDA) on 13 August 2014 for the treatment of insomnia, as defined by difficulties with sleep onset and/or sleep maintenance . This was followed on 28 August 2014 by action by the US Drug Enforcement Administration (DEA), placing suvorexant into Schedule IV of the Controlled Substances Act .…”

Section: Introductionmentioning

confidence: 99%

Suvorexant for insomnia: a systematic review of the efficacy and safety profile for this newly approved hypnotic - what is the number needed to treat, number needed to harm and likelihood to be helped or harmed?

Citrome

2014

Int J Clin Pract

239

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Suvorexant for insomnia: a systematic review of the efficacy and safety profile for this newly approved hypnotic -what is the number needed to treat, number needed to harm and likelihood to be helped or harmed?L. Citrome SUMMA RYObjective: To describe the efficacy and safety of suvorexant for the treatment of insomnia. Data sources: The pivotal registration trials were accessed by querying http://www.ncbi.nlm.nih.gov/pubmed/ and http://www.clinicaltrials.gov for the search terms 'suvorexant' and 'MK4305'. Briefing documents from the US Food and Drug Administration Peripheral & Central Nervous System Drugs Advisory Committee and product labelling, provided additional information. Study selection: All available clinical reports of studies were identified. Data extraction: Descriptions of the principal results and calculation of number needed to treat (NNT) and number needed to harm (NNH) for relevant dichotomous outcomes were extracted from the available study reports and other sources of information. Data synthesis: Suvorexant (MK4305) is the first orexin receptor antagonist approved for the treatment of insomnia. This approval was based in part on a Phase 3 clinical development programme that included two similarly designed, 3-month, randomised, double-blind, placebo-controlled, parallel-group studies examining suvorexant 40 and 20 mg in non-elderly adults (age < 65 years) and 30 and 15 mg in elderly patients (age ≥ 65 years). Suvorexant was superior to placebo for sleep latency as assessed both objectively by polysomnography and subjectively by patient-estimated sleep latency; suvorexant was also superior to placebo for sleep maintenance, as assessed both objectively by polysomnography and subjectively by patient-estimated total sleep time. NNT vs. placebo for response as measured by a ≥ 6 point improvement on the Insomnia Severity Index at month 3 was 8 (95% CI 6-14) for both the higher and lower dose regimens. The most commonly encountered adverse event (incidence ≥ 5% and at least twice the rate of placebo) as identified in product labelling is somnolence, with NNH values vs. placebo of 13 (95% CI 11-18) for suvorexant 40 and 30 mg, and 28 (95% CI 17-82) for suvorexant 20 and 15 mg. The efficacy and tolerability profile of suvorexant is similar for those < 65 and ≥ 65 years of age. Rebound insomnia and withdrawal effects were not observed when suvorexant was discontinued after 3 months or after 12 months of nightly use. Because of concerns about dose-related, next-day effects, including sedation, the recommended dose range is 10-20 mg. Conclusions: Suvorexant appears efficacious and relatively tolerable. Its different mechanism of action and potentially different safety and tolerability profile compared with currently available hypnotics represents a new option for the pharmacological treatment of insomnia. Review criteriaThe pivotal registration trials were accessed by querying http://www.ncbi.nlm.nih.gov/pubmed/ and

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“…86 Studies of diverse new agents and receptors have reported numerous compounds and targets for developing novel insomnia treatments, among them we mention central nervous system (CNS) histamine receptors, GABA(A), melatonin and serotonin modulators. 87 However, sedative-hypnotics that target GABA receptors represent the main current therapy for insomnia. 18 Starting from the hypothesis that the new compounds that are potentially effective in various types of insomnia, which is associated with some disease, can, via the alleviation of insomnia, directly result in the improvement of those diseases, we suppose that treating insomnia using novel approaches might have three main consequences: {1} Reduce the incidence of the above mentioned disorders, 1 {2}improve the prognosis of insomniarelated pathologies and {3} provide an alternative to the agents that target GABA receptors and thus, avoid the side effects of such class of drugs (see: Fig.…”

Section: Mechanisms/effects Referencesmentioning

confidence: 99%

Targeting the orexinergic system: Mainly but not only for sleep-wakefulness therapies

Ghanemi

2015

Alexandria Journal of Medicine

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Orexin receptors belong to the big family of G protein coupled receptors (GPCRs) that constitute the main targets in the modern pharmacological approaches. Although the orexinergic system is involved in a variety of processes, treating sleep-wakefulness disorders such as narcolepsy and insomnia, remains the main therapeutic implication of targeting orexinergic receptors. After novel advances, such as the description of the binding pockets, and ligand developments, more researchers are focusing on orexin receptors as promising targets. Furthermore, targeting these receptors may provide therapeutic solutions for some health problems, other than sleep-wakefulness disorders including some psychiatric disorders and neurodegenerative diseases. Within this paper, we put a spotlight on the orexins' physiology, pathophysiology and pharmacology of mainly sleep-wakefulness. We have also reviewed examples about other orexinergic system-related disorders. We further illustrated recent development in orexin receptors' agonists and antagonists. In addition, we discussed selected progresses in orexinergic receptors' ligands.

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Update on emerging drugs for insomnia

Cited by 19 publications

References 8 publications

Melatonin promotes sleep in mice by inhibiting orexin neurons in the perifornical lateral hypothalamus

Melatonin promotes sleep in mice by inhibiting orexin neurons in the perifornical lateral hypothalamus

Suvorexant for insomnia: a systematic review of the efficacy and safety profile for this newly approved hypnotic - what is the number needed to treat, number needed to harm and likelihood to be helped or harmed?

Targeting the orexinergic system: Mainly but not only for sleep-wakefulness therapies

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