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Roth Thomas - One of the best experts on this subject based on the ideXlab platform.
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Sleep and Pain in Subjects with Fibromyalgia and Comorbid Insomnia: Double-blind, Crossover, Study of Suvorexant 20 mg versus Placebo.
Henry Ford Health System Scholarly Commons, 2020Co-Authors: Roehrs Timothy, Withrow Dana, Koshorek Gail, Verkler Jelena, Bazan Luisa, Roth ThomasAbstract:OBJECTIVES: The chronic pain disorder, fibromyalgia, is associated with sleep disturbance, typically sleep maintenance. No studies have evaluated the effect of sleep medication on pain sensitivity in this population. Suvorexant, an Orexin Antagonist, approved for treatment of insomnia was evaluated for effects on both the sleep and pain of fibromyalgia. METHODS: Women, 21- 65 yrs old, with fibromyalgia and co-morbid insomnia (n=10) were treated, double-blind, for 9 nights each with suvorexant, 20 mg, and placebo in counterbalanced order. All were in good psychiatric and stable physical health and met American College of Rheumatology 2010 criteria for fibromyalgia and DSM-V criteria for insomnia. A screening 8-hr PSG was used to rule out other sleep disorders. On nights 8 and 9 of each treatment 8-hr PSGs were collected and on days 1 and 8 pain sensitivity was assessed at 1100 and 1500 hr by measuring finger withdrawal latency (FWL) to a radiant heat stimulus at 5 randomly presented intensity levels. RESULTS: Suvorexant vs placebo increased total sleep time (7.2 vs 6.7 hrs, p\u3c .05) and reduced wake after sleep onset (37 vs 67 min, p\u3c.04) with no night effects or interaction. Latency to persistent sleep and sleep stage measures were not altered. FWL on both am and pm tests varied as a function of intensity (p\u3c.001). Average FWL (over 5 intensities and both days) was increased relative to placebo on both the am test (13.9 vs 13.1 sec) and pm tests (15.8 vs 14.1 sec, p\u3c.03) following suvorexant the previous night. CONCLUSIONS: Suvorexant 20 mg in patients with fibromyalgia, improved sleep time and reduced next-day pain sensitivity on assessments of FWL to a radiant heat stimulus
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Sleep and pain in humans with fibromyalgia and comorbid insomnia: double-blind, crossover study of suvorexant 20 mg versus placebo.
Henry Ford Health System Scholarly Commons, 2020Co-Authors: Roehrs Timothy, Withrow Dana, Koshorek Gail, Verkler Jelena, Bazan Luisa, Roth ThomasAbstract:STUDY OBJECTIVES: The chronic pain disorder, fibromyalgia, is associated with sleep disturbance, typically sleep maintenance. No studies have evaluated the effect of sleep medication on pain sensitivity in this population. Suvorexant, an Orexin Antagonist approved for treatment of insomnia, was evaluated for effects on both sleep and the pain of fibromyalgia. METHODS: Women age 21 to 65 years with fibromyalgia and comorbid insomnia (n = 10) were treated, double-blind, for 9 nights each with suvorexant, 20 mg and placebo in counterbalanced order. All were in good psychiatric and stable physical health and met American College of Rheumatology 2010 criteria for fibromyalgia and Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition criteria for insomnia. Screening 8-hour polysomnography (PSG) was used to rule out other sleep disorders. On nights 8 and 9 of each treatment 8-hour PSG were collected and on days 1 and 8 pain sensitivity was assessed at 1100 and 1500 hours by measuring finger withdrawal latency (FWL) to a radiant heat stimulus at 5 randomly presented intensity levels. RESULTS: Suvorexant versus placebo increased total sleep time (7.2 versus 6.7 hours, P \u3c .05) and reduced wake after sleep onset (37 versus 67 minutes, P \u3c .04) with no night effects or interaction. Latency to persistent sleep and sleep stage measures were not altered. FWL on both am and pm tests varied as a function of intensity (P \u3c .001). Average FWL (over 5 intensities and both days) was increased relative to placebo on both the am (13.9 versus 13.1 seconds) and pm tests (15.8 versus 14.1 seconds, P \u3c .03) following suvorexant the previous night. CONCLUSIONS: Suvorexant 20 mg in patients with fibromyalgia, improved sleep time and reduced next-day pain sensitivity on assessments of FWL to a radiant heat stimulus
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Arousability of insomnia patients is not impacted by the Orexin Antagonist suvorexant (10 mg and 20 mg)
Henry Ford Health System Scholarly Commons, 2019Co-Authors: Drake, Christopher L, Roth Thomas, Cuamatzi-castelan Andrea, Kalmbach, David A, Cheng Philip, Singh Meeta, Tran M K, Tonnu Christine, Atkinson R L, Fellman-couture CynthiaAbstract:Introduction: Ability to awaken to external or internal stimuli (arousability) has significant clinical implications in patients with a variety of medical disorders (e.g., sleep related breathing disorders, GERD) and life circumstances (e.g. caregiver responsibility, environmental threat). Arousability with an Orexin Antagonist has been demonstrated in an animal model. Yet, arousability has not been assessed with Orexin Antagonists in humans. Thus, we evaluated Auditory Awakening Threshold (AAT) with suvorexant in comparison to placebo. Methods: In a placebo-controlled double-blind 3-way crossover study in 12 (7F) subjects with insomnia, AAT to 1000 Hz tones ∼2-hrs after bedtime was determined following suvorexant 10 and 20 mg (SUV10, 20) compared to placebo (PBO) administered 30 minutes before bedtime. Tones were presented during stable (5 consecutive minutes) stage 2 sleep in 5db increments starting at 30db. The AAT was compared using one-way repeated measures analysis of variance. Standard sleep parameters of latency to persistent sleep (LPS), wake after sleep onset (WASO), and total sleep time (TST) were also assessed for each condition using paired comparisons. Results: Neither the AAT (expressed as dB) for SUV10 (74.18 ± 23.46) nor SUV20 (83.76 ± 20.24) was significantly different from PBO (79.18 ± 22.34; p = .34). SUV was an active dose in these subjects as seen by significantly greater total sleep time following SUV20 (446.35 ± 23.94 minutes; p = 0.024) compared to placebo (401.09 ± 51.29 minutes). In addition, decreased WASO was observed following SUV20 (22.85 ± 18.50 minutes; p = 0.024) compared to placebo (55.69 ± 40.00 minutes). No significant differences were found for effects of condition on LPS likely reflecting the small sample size. Conclusion: The Orexin Antagonist suvorexant improved sleep without decreasing nocturnal arousabilty. These results are in contrast to published reports demonstrating blunting of arousal response with benzodiazepine receptor agonists (e.g., zolpidem). Future studies should investigate whether differential arousal response extends into the post-arousal period thereby impacting other behaviors such as ambulating, memory, and cognitive function
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Effects of suvorexant on sleep in fibromyalgia
Henry Ford Health System Scholarly Commons, 2019Co-Authors: Koshorek Gail, Withrow Dana, Verkler Jelena, Roth Thomas, Roehrs TimothyAbstract:Introduction: The chronic pain disorder, fibromyalgia, is associated with sleep disturbance, typically sleep maintenance. Pharmacological treatment studies have either focused on the pain or the sleep disturbance with equivocal results in that few studies have improved both sleep and pain. No studies have evaluated the effect of sleep medication on pain sensitivity. Suvorexant, an Orexin Antagonist, approved for treatment of insomnia may provide benefit for both the sleep and pain of fibromyalgia. Here we report on suvorexant\u27s sleep effects in patients with fibromyalgia and comorbid insomnia disorder gathered as part of a feasibility study. Methods: Women, 21- 65 yrs old, with fibromyalgia and co-morbid insomnia (n=10) were treated for 9 nights with suvorexant, 20 mg, and placebo with the order of the treatments counterbalanced. They were in good psychiatric and stable physical health and met American College of Rheumatology criteria for fibromyalgia and DSM-V criteria for insomnia. On a screening 8-hr PSG other primary sleep disorders were ruled out. On nights 8 and 9 of each treatment 8-hr PSGs were collected. All PSGs were scored following ASSM criteria and PSG measures were compared using repeated measures ANOVAs with night and drug condition as factors. Results: Suvorexant vs placebo increased total sleep time (7.2 vs 6.7 hrs, p\u3c .05) and reduced wake after sleep onset (37 vs 67 min, p\u3c.04) with no night effects or interaction. Suvorexant also reduced wake during the last half (20 vs 41 min, p\u3c .03) and quarter (13 vs 20 min, p\u3c .03) of the night. Latency to persistent sleep and sleep stage measures were not altered by suvorexant. Conclusion: In patients with fibromyalgia and comorbid insomnia disorder suvorexant, 20 mg, improved total sleep time and reduced wake after sleep onset with sustained effects through the last quarter of the sleep period and no alteration of normal sleep staging
Anthony L. Gotter - One of the best experts on this subject based on the ideXlab platform.
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discovery of 5 chloro n 5 6 dimethoxypyridin 2 yl methyl 2 2 5 3 terpyridine 3 carboxamide mk 1064 a selective Orexin 2 receptor Antagonist 2 sora for the treatment of insomnia
ChemMedChem, 2014Co-Authors: Anthony J Roecker, Susan L Garson, John D. Schreier, Wei Lemaire, Swati P Mercer, Meacham C Harrell, Joseph G Bruno, Mark E Fraley, Justin T Steen, Anthony L. GotterAbstract:The field of small-molecule Orexin Antagonist research has evolved rapidly in the last 15 years from the discovery of the Orexin peptides to clinical proof-of-concept for the treatment of insomnia. Clinical programs have focused on the development of Antagonists that reversibly block the action of endogenous peptides at both the Orexin 1 and Orexin 2 receptors (OX1 R and OX2 R), termed dual Orexin receptor Antagonists (DORAs), affording late-stage development candidates including Merck's suvorexant (new drug application filed 2012). Full characterization of the pharmacology associated with antagonism of either OX1 R or OX2 R alone has been hampered by the dearth of suitable subtype-selective, orally bioavailable ligands. Herein, we report the development of a selective Orexin 2 Antagonist (2-SORA) series to afford a potent, orally bioavailable 2-SORA ligand. Several challenging medicinal chemistry issues were identified and overcome during the development of these 2,5-disubstituted nicotinamides, including reversible CYP inhibition, physiochemical properties, P-glycoprotein efflux and bioactivation. This article highlights structural modifications the team utilized to drive compound design, as well as in vivo characterization of our 2-SORA clinical candidate, 5''-chloro-N-[(5,6-dimethoxypyridin-2-yl)methyl]-2,2':5',3''-terpyridine-3'-carboxamide (MK-1064), in mouse, rat, dog, and rhesus sleep models.
Roehrs Timothy - One of the best experts on this subject based on the ideXlab platform.
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Sleep and Pain in Subjects with Fibromyalgia and Comorbid Insomnia: Double-blind, Crossover, Study of Suvorexant 20 mg versus Placebo.
Henry Ford Health System Scholarly Commons, 2020Co-Authors: Roehrs Timothy, Withrow Dana, Koshorek Gail, Verkler Jelena, Bazan Luisa, Roth ThomasAbstract:OBJECTIVES: The chronic pain disorder, fibromyalgia, is associated with sleep disturbance, typically sleep maintenance. No studies have evaluated the effect of sleep medication on pain sensitivity in this population. Suvorexant, an Orexin Antagonist, approved for treatment of insomnia was evaluated for effects on both the sleep and pain of fibromyalgia. METHODS: Women, 21- 65 yrs old, with fibromyalgia and co-morbid insomnia (n=10) were treated, double-blind, for 9 nights each with suvorexant, 20 mg, and placebo in counterbalanced order. All were in good psychiatric and stable physical health and met American College of Rheumatology 2010 criteria for fibromyalgia and DSM-V criteria for insomnia. A screening 8-hr PSG was used to rule out other sleep disorders. On nights 8 and 9 of each treatment 8-hr PSGs were collected and on days 1 and 8 pain sensitivity was assessed at 1100 and 1500 hr by measuring finger withdrawal latency (FWL) to a radiant heat stimulus at 5 randomly presented intensity levels. RESULTS: Suvorexant vs placebo increased total sleep time (7.2 vs 6.7 hrs, p\u3c .05) and reduced wake after sleep onset (37 vs 67 min, p\u3c.04) with no night effects or interaction. Latency to persistent sleep and sleep stage measures were not altered. FWL on both am and pm tests varied as a function of intensity (p\u3c.001). Average FWL (over 5 intensities and both days) was increased relative to placebo on both the am test (13.9 vs 13.1 sec) and pm tests (15.8 vs 14.1 sec, p\u3c.03) following suvorexant the previous night. CONCLUSIONS: Suvorexant 20 mg in patients with fibromyalgia, improved sleep time and reduced next-day pain sensitivity on assessments of FWL to a radiant heat stimulus
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Sleep and pain in humans with fibromyalgia and comorbid insomnia: double-blind, crossover study of suvorexant 20 mg versus placebo.
Henry Ford Health System Scholarly Commons, 2020Co-Authors: Roehrs Timothy, Withrow Dana, Koshorek Gail, Verkler Jelena, Bazan Luisa, Roth ThomasAbstract:STUDY OBJECTIVES: The chronic pain disorder, fibromyalgia, is associated with sleep disturbance, typically sleep maintenance. No studies have evaluated the effect of sleep medication on pain sensitivity in this population. Suvorexant, an Orexin Antagonist approved for treatment of insomnia, was evaluated for effects on both sleep and the pain of fibromyalgia. METHODS: Women age 21 to 65 years with fibromyalgia and comorbid insomnia (n = 10) were treated, double-blind, for 9 nights each with suvorexant, 20 mg and placebo in counterbalanced order. All were in good psychiatric and stable physical health and met American College of Rheumatology 2010 criteria for fibromyalgia and Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition criteria for insomnia. Screening 8-hour polysomnography (PSG) was used to rule out other sleep disorders. On nights 8 and 9 of each treatment 8-hour PSG were collected and on days 1 and 8 pain sensitivity was assessed at 1100 and 1500 hours by measuring finger withdrawal latency (FWL) to a radiant heat stimulus at 5 randomly presented intensity levels. RESULTS: Suvorexant versus placebo increased total sleep time (7.2 versus 6.7 hours, P \u3c .05) and reduced wake after sleep onset (37 versus 67 minutes, P \u3c .04) with no night effects or interaction. Latency to persistent sleep and sleep stage measures were not altered. FWL on both am and pm tests varied as a function of intensity (P \u3c .001). Average FWL (over 5 intensities and both days) was increased relative to placebo on both the am (13.9 versus 13.1 seconds) and pm tests (15.8 versus 14.1 seconds, P \u3c .03) following suvorexant the previous night. CONCLUSIONS: Suvorexant 20 mg in patients with fibromyalgia, improved sleep time and reduced next-day pain sensitivity on assessments of FWL to a radiant heat stimulus
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Effects of suvorexant on sleep in fibromyalgia
Henry Ford Health System Scholarly Commons, 2019Co-Authors: Koshorek Gail, Withrow Dana, Verkler Jelena, Roth Thomas, Roehrs TimothyAbstract:Introduction: The chronic pain disorder, fibromyalgia, is associated with sleep disturbance, typically sleep maintenance. Pharmacological treatment studies have either focused on the pain or the sleep disturbance with equivocal results in that few studies have improved both sleep and pain. No studies have evaluated the effect of sleep medication on pain sensitivity. Suvorexant, an Orexin Antagonist, approved for treatment of insomnia may provide benefit for both the sleep and pain of fibromyalgia. Here we report on suvorexant\u27s sleep effects in patients with fibromyalgia and comorbid insomnia disorder gathered as part of a feasibility study. Methods: Women, 21- 65 yrs old, with fibromyalgia and co-morbid insomnia (n=10) were treated for 9 nights with suvorexant, 20 mg, and placebo with the order of the treatments counterbalanced. They were in good psychiatric and stable physical health and met American College of Rheumatology criteria for fibromyalgia and DSM-V criteria for insomnia. On a screening 8-hr PSG other primary sleep disorders were ruled out. On nights 8 and 9 of each treatment 8-hr PSGs were collected. All PSGs were scored following ASSM criteria and PSG measures were compared using repeated measures ANOVAs with night and drug condition as factors. Results: Suvorexant vs placebo increased total sleep time (7.2 vs 6.7 hrs, p\u3c .05) and reduced wake after sleep onset (37 vs 67 min, p\u3c.04) with no night effects or interaction. Suvorexant also reduced wake during the last half (20 vs 41 min, p\u3c .03) and quarter (13 vs 20 min, p\u3c .03) of the night. Latency to persistent sleep and sleep stage measures were not altered by suvorexant. Conclusion: In patients with fibromyalgia and comorbid insomnia disorder suvorexant, 20 mg, improved total sleep time and reduced wake after sleep onset with sustained effects through the last quarter of the sleep period and no alteration of normal sleep staging
Debra J. Wallace - One of the best experts on this subject based on the ideXlab platform.
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Reaction development and mechanistic study of a ruthenium catalyzed intramolecular asymmetric reductive amination en route to the dual Orexin inhibitor Suvorexant (MK-4305).
Journal of the American Chemical Society, 2011Co-Authors: Neil A. Strotman, Carl A. Baxter, Karel M. J. Brands, Ed Cleator, Shane W. Krska, Robert A. Reamer, Debra J. Wallace, Timothy J. WrightAbstract:The first example of an intramolecular asymmetric reductive amination of a dialkyl ketone with an aliphatic amine has been developed for the synthesis of Suvorexant (MK-4305), a potent dual Orexin Antagonist under development for the treatment of sleep disorders. This challenging transformation is mediated by a novel Ru-based transfer hydrogenation catalyst that provides the desired diazepane ring in 97% yield and 94.5% ee. Mechanistic studies have revealed that CO2, produced as a necessary byproduct of this transfer hydrogenation reaction, has pronounced effects on the efficiency of the Ru catalyst, the form of the amine product, and the kinetics of the transformation. A simple kinetic model explains how product inhibition by CO2 leads to overall first-order kinetics, but yields an apparent zero-order dependence on initial substrate concentration. The deleterious effects of CO2 on reaction rates and product isolation can be overcome by purging CO2 from the system. Moreover, the rate of ketone hydrogenati...
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the first large scale synthesis of mk 4305 a dual Orexin receptor Antagonist for the treatment of sleep disorder
Organic Process Research & Development, 2011Co-Authors: Carl A. Baxter, Neil A. Strotman, Karel M. J. Brands, Ed Cleator, Robert A. Reamer, John S Edwards, Faye J Sheen, Gavin W Stewart, Debra J. WallaceAbstract:A new synthetic route to drug candidate 1, a potent and selective dual Orexin Antagonist for the treatment of sleep disorders, has been developed. The key acyclic precursor 10 was prepared in a one-step process in 75% isolated yield from commercially available starting materials using novel chemistry to synthesize 2-substituted benzoxazoles. A reductive amination was followed by a classical resolution to afford chiral diazepane (R)-11. Finally, coupling of (R)-11 with acid 5 furnished the desired drug candidate 1.
Michiyuki Suzuki - One of the best experts on this subject based on the ideXlab platform.
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discovery of 1r 2s 2 2 4 dimethylpyrimidin 5 yl oxy methyl 2 3 fluorophenyl n 5 fluoropyridin 2 yl cyclopropanecarboxamide e2006 a potent and efficacious oral Orexin receptor Antagonist
Journal of Medicinal Chemistry, 2015Co-Authors: Yu Yoshida, Yoshimitsu Naoe, Taro Terauchi, Fumihiro Ozaki, Takashi Doko, Takemura Ayumi, Toshiaki Tanaka, Keiichi Sorimachi, Carsten T Beuckmann, Michiyuki SuzukiAbstract:The Orexin/hypocretin receptors are a family of G protein-coupled receptors and consist of Orexin-1 (OX1) and Orexin-2 (OX2) receptor subtypes. Orexin receptors are expressed throughout the central nervous system and are involved in the regulation of the sleep/wake cycle. Because modulation of these receptors constitutes a promising target for novel treatments of disorders associated with the control of sleep and wakefulness, such as insomnia, the development of Orexin receptor Antagonists has emerged as an important focus in drug discovery research. Here, we report the design, synthesis, characterization, and structure-activity relationships (SARs) of novel Orexin receptor Antagonists. Various modifications made to the core structure of a previously developed compound (-)-5, the lead molecule, resulted in compounds with improved chemical and pharmacological profiles. The investigation afforded a potential therapeutic agent, (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide (E2006), an orally active, potent Orexin Antagonist. The efficacy was demonstrated in mice in an in vivo study by using sleep parameter measurements.