Ramelteon

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Thomas Roth - One of the best experts on this subject based on the ideXlab platform.

  • effects of Ramelteon on insomnia symptoms induced by rapid eastward travel
    Sleep Medicine, 2010
    Co-Authors: Phyllis C Zee, Sherry Wangweigand, Kenneth P Wright, Xuejun Peng, Thomas Roth
    Abstract:

    Abstract Objective Ramelteon, an MT 1 /MT 2 melatonin receptor agonist, was evaluated for its ability to reduce sleep-onset difficulties associated with eastward jet travel. Methods Healthy adults ( n =110) with a history of jet lag sleep disturbances were flown eastward across five time zones from Hawaii to the east coast of the US. Ramelteon 1, 4, or 8mg or placebo was administered 5min before bedtime (local time) for four nights. Sleep parameters were measured using polysomnography (PSG) on Nights 2, 3, and 4. Next-day residual effects were assessed using psychomotor and memory function tests. Results Compared to placebo, there was a significant decrease in mean latency to persistent sleep (LPS) on Nights 2–4 with Ramelteon 1mg (−10.64min, P =0.030). No consistent significant differences were observed with Ramelteon vs. placebo on measures of next-day residual effects except on Day 4 where participants in all Ramelteon groups performed significantly worse on the immediate memory recall test compared with placebo ( P ⩽0.05). The incidence of adverse events was similar for Ramelteon and placebo. Conclusion After a 5-h phase advance due to eastward jet travel, Ramelteon 1mg taken before bedtime for four nights reduced mean LPS relative to placebo in healthy adults.

  • the effects of Ramelteon in a first night model of transient insomnia
    Sleep Medicine, 2009
    Co-Authors: Gary Zammit, Thomas Roth, Stephen Sainati, Sherry Wangweigand, Howard Schwartz, Jeffrey Zhang
    Abstract:

    Abstract Objective To evaluate the efficacy and safety of Ramelteon, a highly selective MT 1 /MT 2 melatonin receptor agonist, for the treatment of transient insomnia in adults. Methods In a randomized, double-blind, placebo-controlled, multi-center study, 289 adults naive to a sleep laboratory environment were randomized to receive a single nighttime dose of Ramelteon 8mg, 16mg, or placebo. The primary variable was latency to persistent sleep measured by polysomnography. Additional objective and subjective sleep parameters as well as next-morning residual effects were assessed. Results Ramelteon 8mg treatment significantly reduced latency to persistent sleep compared with placebo (12.2min vs. 19.7min, P =0.004). Total sleep time was significantly increased with both Ramelteon 8mg (436.8min, P =0.009) and Ramelteon 16mg (433.1min, P =0.043) compared with placebo (419.7min). Ramelteon did not alter sleep architecture, and no significant next-morning residual effects were detected. The incidence of adverse events was similar for the Ramelteon and placebo groups and most were considered mild or moderate. Conclusion Ramelteon 8mg significantly decreased latency to persistent sleep and increased total sleep time, with no significant next-morning psychomotor, memory, or cognitive effects in this first-night model of transient insomnia.

  • effect of Ramelteon a selective mt 1 mt 2 receptor agonist on respiration during sleep in mild to moderate copd
    Sleep and Breathing, 2008
    Co-Authors: Meir H Kryger, Jeffrey Zhang, Sherry Wangweigand, Thomas Roth
    Abstract:

    Ramelteon, a selective MT1/MT2 melatonin receptor agonist, was evaluated in subjects with mild to moderate chronic obstructive pulmonary disease (COPD) to determine whether it would have a negative effect on measures of safety and respiration. This randomized, double-blind, crossover study in 26 subjects with mild to moderate COPD compared the effects of a single bedtime dose of Ramelteon 16 mg and placebo on sleep, oxygenation, and sleep-related abnormal breathing events. Compared with placebo, Ramelteon had no statistically significant effect on mean arterial oxygen percent saturation (SaO2) for the entire night (92.9 vs 92.9%; 95% confidence interval [CI], −0.6 to 0.6; P = 0.972), for each of the 8 h of the night, for each sleep stage (awake, rapid eye movement, nonrapid eye movement) or for the percentage of the night that SaO2 was less than 85 and 90%. The mean apnea–hypopnea index was similar between Ramelteon and placebo groups (9.0 vs 8.3; 95% CI, −1.5 to 3.0; P = 0.515). Polysomnography documented a significant increase in total sleep time (380.6 vs 353.6, P = 0.015), sleep efficiency (79.3 vs 73.7, P = 0.017), and number of awakenings (11.1 vs 9.5, P = 0.036) with Ramelteon vs placebo. Other polysomnography and subject-reported sleep measures were comparable between groups. Only one adverse event was reported; it was not considered treatment related. No clinically meaningful changes in laboratory test results, vital signs, electrocardiogram, and physical examination were observed. In this study, Ramelteon 16 mg (two times the recommended therapeutic dose) showed no clinically meaningful or statistically significant effects on oxygenation or abnormal breathing events, was well tolerated, and improved sleep duration and efficiency in subjects with mild to moderate COPD.

  • Safety of Ramelteon in individuals with mild to moderate obstructive sleep apnea
    Sleep and Breathing, 2007
    Co-Authors: Meir Kryger, Sherry Wang-weigand, Thomas Roth
    Abstract:

    Ramelteon is a selective MT_1/MT_2-receptor agonist indicated for insomnia treatment. Because it has no depressant effects on the nervous system, it is not expected to affect the control of breathing. The potential effects of Ramelteon on apneic and hypopneic events and arterial oxygen saturation (SaO_2) in individuals with obstructive sleep apnea were assessed. In this double-blind, randomized, crossover study, 26 adults with mild to moderate obstructive sleep apnea received Ramelteon 16 mg and placebo for one night each, with a 5- to 12-day washout period between treatments. Treatments were administered 30 min before habitual bedtime. Respiratory effort was monitored using respiratory inductance plethysmography, SaO_2 was measured by pulse oximetry, and sleep onset and duration were measured by polysomnography and post-sleep questionnaire. Post-sleep questionnaire also measured next-day residual effects. The primary measure was apnea–hypopnea index. Apnea–hypopnea index was similar in Ramelteon and placebo groups (11.4 vs 11.1, respectively; CI = −2.1, 2.6, P  = 0.812). Ramelteon had no effect on the number of central, obstructive, or mixed apnea episodes. No significant differences were observed in SaO_2 for the entire night between Ramelteon and placebo (95.1 vs 94.7%; P  = 0.070). Ramelteon did not meaningfully affect sleep when evaluated by polysomnography and post-sleep questionnaire. Compared with placebo, Ramelteon had no significant effect on next-day residual effects. Adverse events were reported by three subjects in the Ramelteon group: headache ( n  = 2) and urinary tract infection ( n  = 1). No adverse events were reported with placebo. Ramelteon was well-tolerated and, as expected, did not worsen sleep apnea when administered to subjects with mild to moderate obstructive sleep apnea.

  • evaluation of the efficacy and safety of Ramelteon in subjects with chronic insomnia
    Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine, 2007
    Co-Authors: Gary Zammit, Stephen Sainati, Sherry Wangweigand, Jeffrey Zhang, Milton K Erman, Thomas Roth
    Abstract:

    Objective: To evaluate efficacy and safety of Ramelteon (MT1/MT2-receptor agonist) in subjects with chronic primary insomnia.

Masaomi Miyamoto - One of the best experts on this subject based on the ideXlab platform.

  • 10.1177/0748730404269890JOURNALOF BIOLOGICALRHYTHMS / February 2005Hirai et al. / EFFECTS OF RAMEL EON ON PHASE SHIFTS IN RATS Ramelteon (TAK-375) Accelerates Reentrainment of Circadian Rhythm after a Phase Advance of the Light-Dark Cycle in Rats
    2016
    Co-Authors: Shigenori Ohkawa, Masaomi Miyamoto
    Abstract:

    Abstract In vivo pharmacological effects of Ramelteon (TAK-375), a novel, highly MT1/MT2-selective receptor agonist, were studied in rats to determine Ramelteon’s ability to reentrain the circadian rhythm after an abrupt phase advance. Experiments were also conducted to assess the potential cognitive side effects of Ramelteon and its potential to become a drug of abuse. After an abrupt 8-h phase shift, Ramelteon (0.1 and 1 mg/kg, p.o.) and melatonin (10 mg/kg, p.o.) accelerated reentrainment of running wheel activity rhythm to the new light-dark cycle. Ramelteon (3-30 mg/kg, p.o.) and melatonin (10-100 mg/kg, p.o.) did not affect learning or memory in rats tested by the water maze task and the delayed match to position task, although diazepam and triazolam impaired both of the tasks. Neither Ramelteon (3-30 mg/kg, p.o.) nor melatonin (10-100 mg/kg, p.o.) demonstrated a rewarding property in the conditioned place-preference test, implying that MT1/MT2 receptor agonists have no abuse potential. In con-trast, benzodiazepines and morphine showed rewarding properties in this test. The authors ’ results suggest that Ramelteon may be useful for treatment of circa

  • pharmacology of Ramelteon a selective mt1 mt2 receptor agonist a novel therapeutic drug for sleep disorders
    CNS Neuroscience & Therapeutics, 2009
    Co-Authors: Masaomi Miyamoto
    Abstract:

    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 (GABAA) 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 MT1/MT2 receptor agonist. Unlike the sedative hypnotics that target GABAA receptor complexes, Ramelteon is a chronohypnotic that acts on the melatonin MT1 and MT2 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.

  • neurochemical properties of Ramelteon tak 375 a selective mt1 mt2 receptor agonist
    Neuropharmacology, 2005
    Co-Authors: Koki Kato, Keisuke Hirai, Osamu Uchikawa, Shigenori Ohkawa, Keiji Nishiyama, Kohji Fukatsu, Yuji Kawamata, Shuji Hinuma, Masaomi Miyamoto
    Abstract:

    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.

  • Ramelteon tak 375 accelerates reentrainment of circadian rhythm after a phase advance of the light dark cycle in rats
    Journal of Biological Rhythms, 2005
    Co-Authors: Keisuke Hirai, Hisao Nishikawa, Shigenori Ohkawa, Muneto Kita, Hiroyuki Ohta, Yuu Fujiwara, Masaomi Miyamoto
    Abstract:

    In vivo pharmacological effects of Ramelteon (TAK-375), a novel, highly MT1/MT2-selective receptor agonist, were studied in rats to determine Ramelteon's ability to reentrain the circadian rhythm after an abrupt phase advance. Experiments were also conducted to assess the potential cognitive side effects of Ramelteon and its potential to become a drug of abuse. After an abrupt 8-h phase shift, Ramelteon (0.1 and 1 mg/kg, p.o.) and melatonin (10 mg/kg, p.o.) accelerated reentrainment of running wheel activity rhythm to the new lightdark cycle. Ramelteon (3-30 mg/kg, p.o.) and melatonin (10-100 mg/kg, p.o.) did not affect learning or memory in rats tested by the water maze task and the delayed match to position task, although diazepam and triazolam impaired both of the tasks. Neither Ramelteon (3-30 mg/kg, p.o.) nor melatonin (10-100 mg/kg, p.o.) demonstrated a rewarding property in the conditioned place-preference test, implying that MT1/MT2 receptor agonists have no abuse potential. In contrast, benzodiazepines and morphine showed rewarding properties in this test. The authors' results suggest that Ramelteon may be useful for treatment of circadian rhythm sleep disorders without adverse effects typically associated with benzodiazepine use, such as learning and memory impairment, and drug dependence.

  • effects of Ramelteon tak 375 on nocturnal sleep in freely moving monkeys
    Brain Research, 2004
    Co-Authors: Nobuhito Yukuhiro, Hisao Nishikawa, Shigenori Ohkawa, Hiroyuki Kimura, Shinichi Yoshikubo, Masaomi Miyamoto
    Abstract:

    We investigated the effects of (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4]furan-8-yl)ethyl]propionamide (Ramelteon, TAK-375), a novel MT1/MT2 receptor agonist, on nocturnal sleep in freely moving monkeys and compared these results with those of melatonin and zolpidem. Treatment with Ramelteon (0.03 and 0.3 mg/kg, p.o.) significantly shortened latency to sleep onset and significantly increased total duration of sleep. Treatment with melatonin (0.3, 1, and 3 mg/kg, p.o.) also decreased sleep latency, but the effect was weak; the only significant reduction was seen with the 0.3 mg/kg dose on latency to light sleep. Melatonin had no significant effects on the duration of sleep. Zolpidem had no significant effects on latency to sleep onset in this study at any dose (1, 3, 10, and 30 mg/kg, p.o.). The highest dose (30 mg/kg) of zolpidem had a tendency to increase slow wave sleep; however, it also induced apparent sedation and myorelaxation. Treatment with Ramelteon and melatonin had no evident effect on the general behavior of the monkeys. Spectral analysis (fast Fourier transform, FFT) of both Ramelteon and melatonin revealed sleep patterns that were indistinguishable from those of naturally occurring sleep. The EEG power spectra of zolpidem were qualitatively different from that of naturally occurring physiological sleep. Results of the present study support the investigation of Ramelteon as a sleep-promoting agent in humans.

Jeffrey Zhang - One of the best experts on this subject based on the ideXlab platform.

  • safety and subjective sleep effects of Ramelteon administration in adults and older adults with chronic primary insomnia a 1 year open label study
    The Journal of Clinical Psychiatry, 2009
    Co-Authors: Gary S. Richardson, Sherry Wangweigand, Gary Zammit, Jeffrey Zhang
    Abstract:

    Objective: To evaluate the long-term safety and subjective sleep effects of Ramelteon in adults with chronic insomnia. Method: Subjects with primary insomnia (DSM-IV-TR criteria) for ≥ 3 months received Ramelteon nightly for 1 year; a 3-day placebo run out followed. Subjects aged ≥ 65 years received open-label Ramelteon 8 mg (N = 248); those aged 18 to 64 years received Ramelteon 16 mg (N = 965). Subjects completed sleep diaries and returned to the clinic at week 1 and at months 1, 2, 3, 4, 6, 8, 10, and 12 for safety assessments and investigator-performed Clinical Global Impressions. The study was conducted from February 2003 through September 2004. Results: There were no noteworthy changes in vital signs, physical examinations, clinical chemistry, hematology, or urinalysis values and no electrocardiogram changes to suggest adverse cardiac effects. Endocrine values remained within normal range throughout treatment. Consistent statistically significant (p ≤.05) decreases in free thyroxine (in adults) and free testosterone (in older men) were detected. Duration of menses increased by approximately 1 day. A total of 40.8% of subjects reported at least 1 adverse event possibly associated with Ramelteon use. The adverse events reported varied considerably, the incidence of individual adverse events was low, and the frequencies of adverse events were similar at months 6 and 12. In both groups, subjective sleep latency and total sleep time improved by month 1 and was sustained during the 1-year period. At 6 months and 1 year, Clinical Global Impressions indices were improved. During placebo run out, subjective sleep latency did increase but did not return to baseline. Conclusion: Year-long administration of Ramelteon was well tolerated. Ramelteon was associated with sustained improvements in subjective sleep latency, subjective total sleep time, and Clinical Global Impressions.

  • the effects of Ramelteon in a first night model of transient insomnia
    Sleep Medicine, 2009
    Co-Authors: Gary Zammit, Thomas Roth, Stephen Sainati, Sherry Wangweigand, Howard Schwartz, Jeffrey Zhang
    Abstract:

    Abstract Objective To evaluate the efficacy and safety of Ramelteon, a highly selective MT 1 /MT 2 melatonin receptor agonist, for the treatment of transient insomnia in adults. Methods In a randomized, double-blind, placebo-controlled, multi-center study, 289 adults naive to a sleep laboratory environment were randomized to receive a single nighttime dose of Ramelteon 8mg, 16mg, or placebo. The primary variable was latency to persistent sleep measured by polysomnography. Additional objective and subjective sleep parameters as well as next-morning residual effects were assessed. Results Ramelteon 8mg treatment significantly reduced latency to persistent sleep compared with placebo (12.2min vs. 19.7min, P =0.004). Total sleep time was significantly increased with both Ramelteon 8mg (436.8min, P =0.009) and Ramelteon 16mg (433.1min, P =0.043) compared with placebo (419.7min). Ramelteon did not alter sleep architecture, and no significant next-morning residual effects were detected. The incidence of adverse events was similar for the Ramelteon and placebo groups and most were considered mild or moderate. Conclusion Ramelteon 8mg significantly decreased latency to persistent sleep and increased total sleep time, with no significant next-morning psychomotor, memory, or cognitive effects in this first-night model of transient insomnia.

  • effect of Ramelteon a selective mt 1 mt 2 receptor agonist on respiration during sleep in mild to moderate copd
    Sleep and Breathing, 2008
    Co-Authors: Meir H Kryger, Jeffrey Zhang, Sherry Wangweigand, Thomas Roth
    Abstract:

    Ramelteon, a selective MT1/MT2 melatonin receptor agonist, was evaluated in subjects with mild to moderate chronic obstructive pulmonary disease (COPD) to determine whether it would have a negative effect on measures of safety and respiration. This randomized, double-blind, crossover study in 26 subjects with mild to moderate COPD compared the effects of a single bedtime dose of Ramelteon 16 mg and placebo on sleep, oxygenation, and sleep-related abnormal breathing events. Compared with placebo, Ramelteon had no statistically significant effect on mean arterial oxygen percent saturation (SaO2) for the entire night (92.9 vs 92.9%; 95% confidence interval [CI], −0.6 to 0.6; P = 0.972), for each of the 8 h of the night, for each sleep stage (awake, rapid eye movement, nonrapid eye movement) or for the percentage of the night that SaO2 was less than 85 and 90%. The mean apnea–hypopnea index was similar between Ramelteon and placebo groups (9.0 vs 8.3; 95% CI, −1.5 to 3.0; P = 0.515). Polysomnography documented a significant increase in total sleep time (380.6 vs 353.6, P = 0.015), sleep efficiency (79.3 vs 73.7, P = 0.017), and number of awakenings (11.1 vs 9.5, P = 0.036) with Ramelteon vs placebo. Other polysomnography and subject-reported sleep measures were comparable between groups. Only one adverse event was reported; it was not considered treatment related. No clinically meaningful changes in laboratory test results, vital signs, electrocardiogram, and physical examination were observed. In this study, Ramelteon 16 mg (two times the recommended therapeutic dose) showed no clinically meaningful or statistically significant effects on oxygenation or abnormal breathing events, was well tolerated, and improved sleep duration and efficiency in subjects with mild to moderate COPD.

  • Ramelteon 8 mg d versus placebo in patients with chronic insomnia post hoc analysis of a 5 week trial using 50 or greater reduction in latency to persistent sleep as a measure of treatment effect
    Clinical Therapeutics, 2008
    Co-Authors: Louis Mini, Sherry Wangweigand, Jeffrey Zhang
    Abstract:

    Abstract Background: Ramelteon is a selective MT1/MT2 melatonin receptor agonist approved by the US Food and Drug Administration for insomnia treatment. Objective: The aim of this post hoc analysis was to compare the efficacy and tolerability of Ramelteon 8 mg/d versus placebo in adults with chronic insomnia. Methods: This study analyzed data from a previously published 5-week, randomized, double-blind, placebo-controlled study. Patients aged 18 to 64 years with chronic insomnia were randomly assigned to receive Ramelteon 8 or 16 mg/d or placebo QD for 5 weeks. Sleep parameters were evaluated using polysomnography at weeks 1, 3, 5, and 6 (placebo runout). In this post hoc analysis, patients who received Ramelteon 8 mg (approved dose) or placebo in the original study were evaluated using a primary end point of a=50% reduction from baseline in latency to persistent sleep (LPS). Results: A total of 270 adults (Ramelteon 8 mg, 139 patients, mean age, 38.0 years; placebo, 131 patients, mean age, 39.7 years) met the criteria for inclusion in this analysis. One patient from the original study (Ramelteon 8-mg/d group) was excluded from the post hoc analysis based on a lack of evaluable LPS data. Ramelteon was associated with significantly greater proportions of patients who achieved a=50% reduction in LPS compared with placebo at weeks 1 (63.0% vs 39.7%; P Conclusions: In this post hoc analysis of data from patients with chronic insomnia, a significantly greater percentage experienced a=50% reduction in LPS with Ramelteon 8 mg/d versus placebo. This improvement was evident at week 1 and was sustained through 5 weeks of treatment. Ramelteon 8 mg was well tolerated in this study, with no evidence of withdrawal or rebound insomnia.

  • self reported efficacy and tolerability of Ramelteon 8 mg in older adults experiencing severe sleep onset difficulty
    American Journal of Geriatric Pharmacotherapy, 2007
    Co-Authors: Louis Mini, Sherry Wangweigand, Jeffrey Zhang
    Abstract:

    Background: Ramelteon is a selective MT1/MT2 melatonin receptor agonist indicated for the treatment of insomnia characterized by difficulty with sleep onset. Objective: The current analysis was conducted to determine the effectiveness of Ramelteon 8 mg in reducing the time to fall asleep in older adults with severe baseline sleep-onset difficulties. Methods: Patients with severe sleep-onset difficulty (defined as subjective sleep latency [sSL] ≥60 minutes) who had received Ramelteon 8 mg or placebo were selected from a previously published multicenter outpatient trial of 829 older adults (aged ≥65 years) with primary, chronic insomnia (according to Diagnostic and Statistical Manual of Mental Disorders [Fourth Edition, Text Revision] criteria). Patients received single-blind placebo for 7 days (baseline) before receiving double-blind Ramelteon 8 mg or placebo nightly for 5 weeks (35 nights). A 7-day, single-blind, placebo washout period followed. The primary end point was mean sSL for nights 1 through 7 (week 1). The mean changes in sSL from baseline at weeks 3 and 5 were evaluated to assess sustained efficacy. Adverse events (AEs) were collected in this analysis for both the Ramelteon 8-mg and placebo groups. Results: A total of 157 patients from the rameltcon 8-mg group (mean age, 72.7 years; 87 women, 70 men) and 170 patients from the placebo group (mean age, 72.3 years; 111 women, 59 men) met the entry criteria for this post hoc analysis. Ramelteon 8 mg significantly reduced sSL at week 1 compared with placebo (change from baseline, -23.2 vs -7.5 minutes; P = 0.002). This statistically significant improvement was sustained at week 3 (-33.7 vs -19.8 minutes; P = 0.005) and week 5 (-37.4 vs -17.1 minutes; P < 0.001). The incidence of AEs was low. The most commonly reported treatment-emergent AEs were dizziness (ramclteon, 8.9%; placebo, 7.1%), dysgeusia (Ramelteon, 7.0%; placebo, 2.9%), myalgia (Ramelteon, 6.4%; placebo, 3.5%), and headache (Ramelteon, 5.1%; placebo, 5.9%). Conclusions: In this subset analysis of older adults with severe baseline sleep-onset difficulties, Ramelteon 8 mg significantly and persistently reduced subjective reports of time to sleep onset during 5 weeks of nightly treatment. Ramelteon appeared to be an effective and well-tolerated treatment for these older adults with primary, chronic insomnia.

James K Walsh - One of the best experts on this subject based on the ideXlab platform.

  • Ramelteon tak 375 a selective mt1 mt2 receptor agonist reduces latency to persistent sleep in a model of transient insomnia related to a novel sleep environment
    Sleep, 2005
    Co-Authors: Thomas Roth, Charlene Stubbs, James K Walsh
    Abstract:

    Objective: Evaluate the efficacy of Ramelteon, an MT 1 /MT 2 -receptor agonist, for the treatment of transient insomnia in healthy adults. Design: Randomized, double-blind, placebo-controlled design using a model of transient insomnia related to sleeping in a novel environment. Setting: Fourteen sleep research centers. Participants: Healthy adults (N = 375; 228 women), aged 35 to 60 years, who had never previously slept in a sleep laboratory and had a reported usual sleep duration of 6.5 to 8.5 hours and usual bedtime between 8:30 PM and midnight. Interventions: Single administration of Ramelteon (16 or 64 mg) or placebo 30 minutes before bedtime. Outcome Measures: Primary efficacy measure was latency to persistent sleep. Also evaluated were total sleep time, wake after sleep onset, percentage of each sleep stage, subjective estimates of sleep from postsleep questionnaire, number of awakenings, and subjective number of awakenings. Residual effects were assessed via Digit Symbol Substitution Test and postsleep questionnaire. Results: Participants in Ramelteon-treated groups had significantly shorter latency to persistent sleep relative to placebo. They also were associated with significantly longer total sleep time. Wake after sleep onset and time spent in each sleep stage were not significantly different from placebo. The use of Ramelteon (16 mg) was associated with a shorter subjective sleep latency compared to placebo. Other subjective measures of sleep did not differ significantly from placebo. Digit Symbol Substitution Test scores did not differ significantly among the 3 groups, but the use of the 16-mg dose was associated with subjective reports of impairment in the morning. Conclusions: Ramelteon significantly improved latency to persistent sleep and total sleep time in this model of transient insomnia in healthy adults. No dose-related differences in latency to persistent sleep were observed, and both doses were well tolerated.

  • Ramelteon tak 375 a selective mt1 mt2 receptor agonist reduces latency to persistent sleep in a model of transient insomnia related to a novel sleep environment
    Sleep, 2005
    Co-Authors: Thomas Roth, Charlene Stubbs, James K Walsh
    Abstract:

    Objective Evaluate the efficacy of Ramelteon, an MT/1MT2-receptor agonist, for the treatment of transient insomnia in healthy adults. Design Randomized, double-blind, placebo-controlled design using a model of transient insomnia related to sleeping in a novel environment. Setting Fourteen sleep research centers. Participants Healthy adults (N=375; 228 women), aged 35 to 60 years, who had never previously slept in a sleep laboratory and had a reported usual sleep duration of 6.5 to 8.5 hours and usual bedtime between 8:30 PM and midnight. Interventions Single administration of Ramelteon (16 or 64 mg) or placebo 30 minutes before bedtime. Outcome measures Primary efficacy measure was latency to persistent sleep. Also evaluated were total sleep time, wake after sleep onset, percentage of each sleep stage, subjective estimates of sleep from postsleep questionnaire, number of awakenings, and subjective number of awakenings. Residual effects were assessed via Digit Symbol Substitution Test and postsleep questionnaire. Results Participants in Ramelteon-treated groups had significantly shorter latency to persistent sleep relative to placebo. They also were associated with significantly longer total sleep time. Wake after sleep onset and time spent in each sleep stage were not significantly different from placebo. The use of Ramelteon (16 mg) was associated with a shorter subjective sleep latency compared to placebo. Other subjective measures of sleep did not differ significantly from placebo. Digit Symbol Substitution Test scores did not differ significantly among the 3 groups, but the use of the 64-mg [corrected] dose was associated with subjective reports of impairment in the morning. Conclusions Ramelteon significantly improved latency to persistent sleep and total sleep time in this model of transient insomnia in healthy adults. No dose-related differences in latency to persistent sleep were observed, and both doses were well tolerated.

Keisuke Hirai - One of the best experts on this subject based on the ideXlab platform.

  • the melatonin agonist Ramelteon induces duration dependent clock gene expression through camp signaling in pancreatic ins 1 β cells
    PLOS ONE, 2014
    Co-Authors: Keiji Nishiyama, Keisuke Hirai
    Abstract:

    Prolonged exposure to melatonin improves glycemic control in animals. Although glucose metabolism is controlled by circadian clock genes, little is known about the role of melatonin signaling and its duration in the regulation of clock gene expression in pancreatic β-cells. Activation of MT1 and MT2 melatonin receptors inhibits cAMP signaling, which mediates clock gene expression. Therefore, this study investigated exposure duration-dependent alterations in cAMP element-binding protein (CREB) phosphorylation and clock gene expression that occur during and after exposure to Ramelteon, a selective melatonin agonist used to treat insomnia. In rat INS-1 cells, a pancreatic β-cell line endogenously expressing melatonin receptors, Ramelteon persistently decreased CREB phosphorylation during the treatment period (2–14 h), whereas the subsequent washout induced an enhancement of forskolin-stimulated CREB phosphorylation in a duration- and concentration-dependent manner. This augmentation was blocked by forskolin or the melatonin receptor antagonist luzindole. Similarly, gene expression analyses of 7 clock genes revealed the duration dependency of the effects of Ramelteon on Rev-erbα and Bmal1 expression through melatonin receptor-mediated cAMP signaling; longer exposure times (14 h) resulted in greater increases in the expression and signaling of Rev-erbα, which is related to β-cell functions. Interestingly, this led to amplified oscillatory Rev-erbα and Bmal1 expression after agonist washout and forskolin stimulation. These results provide new insights into the duration-dependent effects of Ramelteon on clock gene expression in INS-1 cells and may improve the understanding of its effect in vivo. The applicability of these results to pancreatic islets awaits further investigation.

  • Duration-dependent changes in CREB phosphorylation during Ramelteon treatment and after washout.
    2014
    Co-Authors: Keiji Nishiyama, Keisuke Hirai
    Abstract:

    (A) INS-1 cells were treated with Ramelteon (10 nM) for 2, 4, 8, or 14 h. (B) Concentration-dependent decreases in CREB phosphorylation were assessed after Ramelteon (0.1–100 nM) treatment for 2 and 14 h. (C) After Ramelteon (10 nM) treatment for 2, 4, 8, or 14 h, the cells were washed twice and stimulated with forskolin (0.1 µM) for 30 min in the absence of Ramelteon. (D) Concentration-dependent potentiation of forskolin-stimulated CREB phosphorylation was assessed after Ramelteon (0.1–100 nM) treatment for 2 and 14 h. Values are expressed as the ratio of phosphorylated CREB to total CREB in the vehicle-pretreated control (100%). Data are presented as means ± SEM (n = 3) and were analyzed using 2-way analysis of variance followed by Dunnett's test. ***P

  • Duration-dependent changes in insulin secretion during Ramelteon treatment and after drug washout.
    2014
    Co-Authors: Keiji Nishiyama, Keisuke Hirai
    Abstract:

    (A) INS-1 cells were treated with Ramelteon (0.1–100 nM) for 2 or 14 h. (B) After Ramelteon treatment for 2 or 14 h, the cells were washed twice and stimulated with forskolin (10 µM) for 2 h in the absence of Ramelteon. (C) The cells were incubated with Ramelteon (10 nM) in the absence or presence of luzindole (30 µM) for 14 h. After drug washout, the cells were stimulated with forskolin (10 µM) for 2 h. Values are expressed as the percentage of the vehicle- (A) or forskolin (10 µM; B and C)-stimulated insulin release in vehicle-pretreated controls. Data are presented as means ± SEM (n = 6) and were analyzed using 2-way analysis of variance followed by Dunnett's test. ***P

  • The Melatonin Agonist Ramelteon Induces Duration- Dependent Clock Gene Expression through cAMP Signaling in Pancreatic INS-1 b-Cells
    2014
    Co-Authors: Keiji Nishiyama, Keisuke Hirai
    Abstract:

    Prolonged exposure to melatonin improves glycemic control in animals. Although glucose metabolism is controlled by circadian clock genes, little is known about the role of melatonin signaling and its duration in the regulation of clock gene expression in pancreatic b-cells. Activation of MT1 and MT2 melatonin receptors inhibits cAMP signaling, which mediates clock gene expression. Therefore, this study investigated exposure duration-dependent alterations in cAMP element-binding protein (CREB) phosphorylation and clock gene expression that occur during and after exposure to Ramelteon, a selective melatonin agonist used to treat insomnia. In rat INS-1 cells, a pancreatic b-cell line endogenously expressing melatonin receptors, Ramelteon persistently decreased CREB phosphorylation during the treatment period (2–14 h), whereas the subsequent washout induced an enhancement of forskolin-stimulated CREB phosphorylation in a duration-and concentration-dependent manner. This augmentation was blocked by forskolin or the melatonin receptor antagonist luzindole. Similarly, gene expression analyses of 7 clock genes revealed the duration dependency of the effects of Ramelteon on Rev-erba and Bmal1 expression through melatonin receptor-mediated cAMP signaling; longer exposure times (14 h) resulted in greater increases in the expression and signaling of Rev-erba, which is related to b-cell functions. Interestingly, this led to amplified oscillatory Rev-erba and Bmal1 expression after agonist washout and forskolin stimulation. These results provide new insights into the duration-dependent effects of Ramelteon on clock gene expression in INS-1 cells and ma

  • neurochemical properties of Ramelteon tak 375 a selective mt1 mt2 receptor agonist
    Neuropharmacology, 2005
    Co-Authors: Koki Kato, Keisuke Hirai, Osamu Uchikawa, Shigenori Ohkawa, Keiji Nishiyama, Kohji Fukatsu, Yuji Kawamata, Shuji Hinuma, Masaomi Miyamoto
    Abstract:

    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.