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Objective: Ramelteon is an MT(1)/MT(2) melatonin receptor agonist indicated for the treatment of insomnia characterized by difficulty with sleep onset. In previous clinical studies, ramelteon reduced latency to persistent sleep (LPS) in subjects with chronic insomnia. The goal of the current analysis was to determine the average reduction in LPS and overall adverse event profile for subjects taking ramelteon 8 mg.Research Design and Methods: This pooled analysis examined four randomized, double-blind, placebo-controlled clinical trials of ramelteon in subjects with chronic insomnia. The analysis included adults (age 18-83 years) with chronic insomnia who took ramelteon 8 mg or placebo. The primary endpoint of each trial was mean LPS, measured by polysomnography (PSG) on nights 1 and 2. Adverse events were collected for all subjects for the duration of each trial.Results: Efficacy data were available for 566 subjects who took ramelteon 8 mg (mean age 46.7 years) and 556 subjects who took placebo (mean age 47.8 years). Mean LPS at baseline was 66.6 min for the placebo group and 66.9 min for the ramelteon group. At nights 1 and 2, mean LPS for the ramelteon 8 mg group (30.2 min) was significantly less than the mean LPS for the placebo group (43.3 min). The least squares mean difference from placebo was -13.1 min (p < 0.001). Headache (8.9% ramelteon 8 mg, 8.8% placebo) and somnolence (3.5% ramelteon 8 mg, 0.7% placebo) were the most common adverse events.Conclusions: Ramelteon 8 mg, on average, reduced LPS by approximately 13 min more than placebo on nights 1 and 2 of treatment in adults with chronic insomnia. Ramelteon was well tolerated with a low incidence of adverse events. This mean reduction in LPS versus placebo is similar to what has been reported for other classes of insomnia medications. However, these results reflect nights 1 and 2 of treatment and may not be representative of longer treatments. [ABSTRACT FROM AUTHOR]

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 > or = 50% reduction in LPS compared with placebo at weeks 1 (63.0% vs 39.7%; P < 0.001), 3 (63.0% vs 41.2%; P < 0.001), and 5 (65.9% vs 48.9%; P < 0.005). No rebound insomnia or withdrawal effects were observed. Headache (19.4% and 18.3%), fatigue (9.4% and 2.3%), and somnolence (7.9% and 1.5%) were the most common adverse events. CONCLUSIONS: In this post hoc analysis of data from patients with chronic insomnia, a significantly greater percentage experienced a > or = 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. [ABSTRACT FROM AUTHOR]

Objective: To assess the efficacy and safety of ramelteon, a selective melatonin MT1/MT2-receptor agonist, for insomnia treatment in older adults.Methods: In a randomized, 9-week, 3-period crossover trial conducted at 17 sleep centers, older adults (N = 100) with chronic primary insomnia (37 men, 63 women; mean age [range], 70.7 [65-83] years) were administered placebo, ramelteon 4 mg, and ramelteon 8 mg in three treatment phases for two consecutive nights. Each phase was separated by 5- to 12-day washout periods. Sleep was monitored via polysomnography. Subjective sleep parameters, using a Postsleep Questionnaire, were recorded, and residual pharmacologic effects were assessed.Results: Statistically significant reductions in latency to persistent sleep were observed with both ramelteon 4 mg and 8 mg compared to placebo (28.7 min vs. 38.4 min, p < 0.001; 30.8 min vs. 38.4 min, p = 0.005, respectively). Total sleep time (p = 0.036 and p = 0.007, respectively) and sleep efficiency (p = 0.037 and p = 0.007, respectively) were also significantly improved with ramelteon 4 mg and 8 mg compared to placebo. Statistically significant reductions in subjective sleep latency on a Postsleep Questionnaire were reported with ramelteon 4 mg versus placebo (p = 0.037), but not ramelteon 8 mg (p = 0.120); no significant differences on other subjective sleep assessments were reported. A lack of power limits interpretation of self-reported sleep parameters. Incidences of adverse events considered treatment related were placebo (7%), ramelteon 4 mg (11%), and ramelteon 8 mg (5%). No residual pharmacologic effects were observed via Digit Symbol Substitution Test, memory recall tests (immediate and delayed), visual analog scales (feelings and mood), and Postsleep Questionnaire (level of alertness and ability to concentrate).Conclusions: In older adults with chronic primary insomnia, ramelteon produced significant reductions in latency to persistent sleep and increases in total sleep time and sleep efficacy, and showed no evidence of adverse next-day psychomotor or cognitive effects. [ABSTRACT FROM AUTHOR]

Abstract Background Computerized dynamic posturography (CDP) has been used to detect balance and stability impairments in adults of all ages. The goal of the current pilot study was to evaluate balance in healthy older adults after a middle-of-the-night awakening and to assess the ability of CDP to measure effects of bedtime zolpidem administration. Methods Two studies used CDP to evaluate balance in healthy older adults (≥ 65 years) during middle-of-the-night awakenings. The first study used a drug-free, single-period, within-subject, repeated measures study design. Subjects were evaluated during the day, pre-sleep, and 2 hours after bedtime for dynamic standing balance using the NeuroCom EquiTest Sensory Organization Test (SOT). Pairwise comparisons were made using one-way ANOVA. The second study was a single-blind, randomized, placebo-controlled, crossover study evaluating the ability of the SOT to measure medication-induced dynamic standing balance impairments using the commonly prescribed sleep medication, zolpidem 10 mg, as a test medication. Assessments were performed at night before zolpidem administration and then again 2 hours after bedtime. Comparisons were made between the 2 groups using an ANCOVA model. Results Twelve older adults (mean age 68.4 years) were evaluated in the first study. There was no significant difference between pre-sleep and middle-of-the-night assessments for the SOT composite score (P = 0.439). Eleven older adults (mean age 68.9 years) were evaluated in the second study. Zolpidem administration significantly decreased the SOT composite score after a middle-of-the-night awakening compared with placebo (P < 0.001). Conclusion In healthy older adults, getting up in the middle of the night did not have a significant effect on dynamic standing balance; however, bedtime administration of zolpidem 10 mg did lead to significant impairments. Thus, the SOT was able to measure medication-induced dynamic standing balance impairments and may be useful for future studies comparing balance effects of medications.

Background: Computerized dynamic posturography (CDP) has been used to detect balance and stability impairments in adults of all ages. The goal of the current pilot study was to evaluate balance in healthy older adults after a middle-of-the-night awakening and to assess the ability of CDP to measure effects of bedtime zolpidem administration.Methods: Two studies used CDP to evaluate balance in healthy older adults (> or = 65 years) during middle-of-the-night awakenings. The first study used a drug-free, single-period, within-subject, repeated measures study design. Subjects were evaluated during the day, pre-sleep, and 2 hours after bedtime for dynamic standing balance using the NeuroCom EquiTest Sensory Organization Test (SOT). Pairwise comparisons were made using one-way ANOVA. The second study was a single-blind, randomized, placebo-controlled, crossover study evaluating the ability of the SOT to measure medication-induced dynamic standing balance impairments using the commonly prescribed sleep medication, zolpidem 10 mg, as a test medication. Assessments were performed at night before zolpidem administration and then again 2 hours after bedtime. Comparisons were made between the 2 groups using an ANCOVA model.Results: Twelve older adults (mean age 68.4 years) were evaluated in the first study. There was no significant difference between pre-sleep and middle-of-the-night assessments for the SOT composite score (P = 0.439). Eleven older adults (mean age 68.9 years) were evaluated in the second study. Zolpidem administration significantly decreased the SOT composite score after a middle-of-the-night awakening compared with placebo (P < 0.001).Conclusion: In healthy older adults, getting up in the middle of the night did not have a significant effect on dynamic standing balance; however, bedtime administration of zolpidem 10 mg did lead to significant impairments. Thus, the SOT was able to measure medication-induced dynamic standing balance impairments and may be useful for future studies comparing balance effects of medications. [ABSTRACT FROM AUTHOR]

Background: Ramelteon, an MT1/MT2 receptor agonist developed for insomnia treatment, was evaluated for long-term effects on endocrine function.Methods: In a double-blind multicenter trial, 122 patients (aged 18-45 yr) with chronic insomnia received placebo or ramelteon 16 mg nightly for 6 months. Multiple endocrine variables were analyzed at baseline and monthly.Results: There were no consistent statistically significant differences between treatments on measures of thyroid function (total T4, free T4, TSH and total T3), adrenal function (AM cortisol and ACTH), or on most reproductive endocrine measures (LH, FSH, estradiol[women], total and free testosterone[men]). There were small, but statistically significant, differences in prolactin levels between groups: overall mean change from baseline of 2.9 μg/L (22.8% change) with ramelteon and −0.6 μg/L (4.4% change) with placebo. The effect on prolactin appeared to be transient and was only seen in women. No clinical signs of elevated prolactin were reported; average menstrual cycle length, duration of menses, and ovulation probability did not differ between groups. AE incidence was similar between groups; most AEs were mild or moderate (3 patients had SAEs unrelated to study drug).Conclusion: Long-term treatment of chronic insomnia with ramelteon had no appreciable effect on multiple measures of endocrine function compared to placebo. A mild, transient increase in prolactin was observed in women, but it had no significant clinical effect.Clinical Pharmacology & Therapeutics (2005) 79, P68–P68; doi: 10.1016/j.clpt.2005.12.246 [ABSTRACT FROM AUTHOR]

Background & Aims: Firmicutes bacteria produce metabolites that maintain the intestinal barrier and mucosal immunity. Firmicutes are reduced in the intestinal microbiota of patients with ulcerative colitis (UC). In a phase 1b trial of patients with UC, we evaluated the safety and efficacy of SER-287, an oral formulation of Firmicutes spores, and the effects of vancomycin preconditioning on expansion (engraftment) of SER-287 species in the colon., Methods: We conducted a double-blind trial of SER-287 in 58 adults with active mild-to-moderate UC (modified Mayo scores 4-10, endoscopic subscores ≥1). Participants received 6 days of preconditioning with oral vancomycin (125 mg, 4 times daily) or placebo followed by 8 weeks of oral SER-287 or placebo. Patients were randomly assigned (2:3:3:3) to groups that received placebo followed by either placebo or SER-287 once weekly, or vancomycin followed by SER-287 once weekly, or SER-287 once daily. Clinical end points included safety and clinical remission (modified Mayo score ≤2; endoscopic subscores 0 or 1). Microbiome end points included SER-287 engraftment (dose species detected in stool after but not before SER-287 administration). Engraftment of SER-287 and changes in microbiome composition and associated metabolites were measured by analyses of stool specimens collected at baseline, after preconditioning, and during and 4 weeks after administration of SER-287 or placebo., Results: Proportions of patients with adverse events did not differ significantly among groups. A higher proportion of patients in the vancomycin/SER-287 daily group (40%) achieved clinical remission at week 8 than patients in the placebo/placebo group (0%), placebo/SER-287 weekly group (13.3%), or vancomycin/SER-287 weekly group (17.7%) (P = .024 for vancomycin/SER-287 daily vs placebo/placebo). By day 7, higher numbers of SER-287 dose species were detected in stool samples from all SER-287 groups compared with the placebo group (P < .05), but this difference was not maintained beyond day 7 in the placebo/SER-287 weekly group. In the vancomycin groups, a greater number of dose species were detected in stool collected on day 10 and all subsequent time points through 4 weeks post dosing compared with the placebo group (P < .05). A higher number of SER-287 dose species were detected in stool samples on days 7 and 10 from subjects who received daily vs weekly SER-287 doses (P < .05). Changes in fecal microbiome composition and metabolites were associated with both vancomycin/SER-287 groups., Conclusions: In this small phase 1b trial of limited duration, the safety and tolerability of SER-287 were similar to placebo. SER-287 after vancomycin was significantly more effective than placebo for induction of remission in patients with active mild to moderate UC. Engraftment of dose species was facilitated by vancomycin preconditioning and daily dosing of SER-287. ClinicalTrials.gov ID NCT02618187., (Copyright © 2021. Published by Elsevier Inc.)

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 8 mg or placebo was administered 5 min 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 (-10.64 min, 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 < or = 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., (Copyright 2010 Elsevier B.V. All rights reserved.)

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 >or= 3 months received ramelteon nightly for 1 year; a 3-day placebo run out followed. Subjects aged >or=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

Background: Individuals with moderate to severe chronic obstructive pulmonary disease (COPD) have poor sleep quality. This study evaluated the effects of ramelteon, an MT(1)/MT(2) melatonin receptor agonist indicated for insomnia treatment on respiration in this population., Materials and Methods: This double-blind, crossover study enrolled 25 subjects (>or=40 years) with moderate to severe COPD (FEV(1)/FVC <70% and FEV(1) between 50 and 80% of predicted value [moderate], or FEV(1)/FVC <70% and FEV(1) <50% of predicted value [severe]). Subjects received ramelteon 8 mg or placebo for one night 30 min before polysomnographic monitoring, including measurement of oxygen saturation (SaO(2)) and respiratory effort and flow. Subjects crossed to alternate treatment after a 5- to 10-day washout. The primary endpoint was mean SaO(2) for the entire night., Results: No significant difference in SaO(2) for the entire night was observed with ramelteon vs placebo (92.2% vs 92.5%, P = 0.576). Mean SaO(2) was similar between ramelteon and placebo for each hour of the night, each sleep stage, the number of minutes that SaO(2) was <80% and <90%, and mean apnea-hypopnea index. There was a significant difference in total sleep time (389.0 vs 348.4 min, P = 0.019) and sleep efficiency (81.0 vs 72.6%, P = 0.019), and latency to persistent sleep was shorter (23.1 vs 56.9 min, P = 0.051), with ramelteon vs placebo. All adverse events were mild to moderate; none led to study discontinuation., Conclusion: Ramelteon did not produce respiratory depressant effects as measured by oxygenation or abnormal breathing events in subjects with moderate to severe COPD. Ramelteon was well tolerated in this population.

Objective: To evaluate the effects of ramelteon, an MT(1)/MT(2) melatonin receptor agonist used to treat insomnia, on endocrine function in adults with chronic insomnia., Methods: This was a double-blind, placebo-controlled, trial of adults (18-45 years) with chronic insomnia. Subjects received either ramelteon 16 mg or placebo nightly for 6 months. Hormonal measures of the thyroid, reproductive, and adrenal axes were analyzed monthly and compared with baseline and placebo values., Results: While isolated changes were detected at some time points, there were no consistent statistically significant differences between treatments on measures of thyroid function (total T4, free T4, TSH, and total T3), adrenal function (AM cortisol, and ACTH), or on most reproductive endocrine measures [LH, FSH, estradiol (women), total, and free testosterone (men)]. Prolactin concentrations were increased overall in women in the ramelteon group compared with placebo (p = 0.003). No clinical effects of elevated prolactin were reported; average menstrual cycle length, duration of menses, and ovulation probability did not differ between groups., Conclusions: Long-term exposure to ramelteon 16 mg, a potent melatonin receptor agonist, resulted in mild, transient increase in prolactin, in women only, that were not associated with measurable reproductive effects. There were no consistent changes in other endocrine measures.

Study Objectives: To evaluate the effect of ramelteon on middle-of-the-night balance, mobility, and memory in older insomniacs., Methods: Thirty-three older adults (age > or = 65 years) with insomnia were enrolled in a single-dose, 3-way crossover study of balance after bedtime administration of ramelteon, 8 mg; zolpidem, 10 mg (positive control); or placebo. Subjects were administered study medication 30 minutes before bedtime and were awakened 2 hours after dosing to evaluate balance (Sensory Organization Test), turning speed and stability, memory (immediate and delayed word recall), and adverse events. There was a 4- to 10-day washout between treatments., Results: Ramelteon or zolpidem (positive control) was compared with placebo. There were no differences between placebo and ramelteon on the Sensory Organization Test (p = 0.837), turn time (p = 0.776), or turn sway (p = 0.982). The positive control (zolpidem) did reveal significant impairments on the Sensory Organization Test, turn time, and turn sway (p < 0.001, all). Immediate and delayed memory recall were not significantly different with ramelteon (p = 0.683 and p = 0.650, respectively). Immediate recall declined significantly with zolpidem (p = 0.002). Adverse events were infrequent (ramelteon, n = 7; placebo, n = 7; zolpidem, n = 13); none were serious., Conclusion: In older adults, ramelteon did not impair middle-of-the night balance, mobility, or memory relative to placebo.

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 8 mg, 16 mg, 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 8 mg treatment significantly reduced latency to persistent sleep compared with placebo (12.2 min vs. 19.7 min, P=0.004). Total sleep time was significantly increased with both ramelteon 8 mg (436.8 min, P=0.009) and ramelteon 16 mg (433.1 min, P=0.043) compared with placebo (419.7 min). 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 8 mg 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.

Study Objectives: To assess the ability of repeated daily oral ramelteon to facilitate re-entrainment of human circadian rhythms after an imposed phase advance of the sleep-wake cycle., Methods: A total of 75 healthy adult volunteers aged 18-45 years remained in a sleep laboratory for 6 days and 5 nights; a 5-h phase advance in their sleep-wake cycle was imposed under dim-light conditions. Oral ramelteon (1,2, 4, or 8 mg once daily for 4 days) or placebo was administered 30 min before bedtime. The primary endpoint was the phase of the circadian rhythm as assessed by the time at which salivary melatonin concentrations declined below 3 pg/mL after morning awakening (dim-light melatonin offset [DLMoff])., Results: After 4 days of once-daily treatment, participants receiving 1, 2, or 4 mg ramelteon exhibited statistically significant phase shifts in DLMoff of -88.0 (16.6), -80.5 (14.8), and -90.5 (15.2) minutes respectively, versus -7.1 (18.6) minutes for placebo (least-squares mean(SEM), p = 0.002, p = 0.003, p = 0.001, respectively). Change in DLMoff for the 8 mg dose of ramelteon, -27.9 (16.4) minutes, was not significantly different than that for placebo (p = 0.392)., Conclusions: Ramelteon (1, 2, or 4 mg per day) administered before bedtime significantly advanced the phase of the circadian rhythm after a 5-h phase advance in the sleep-wake cycle. These findings suggest that ramelteon has potential as a specific therapy for circadian rhythm sleep disorders.

Ramelteon, a selective MT(1)/MT(2) 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 (SaO(2)) 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 SaO(2) 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 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.

Background: Ramelteon is a selective MT(1)/MT(2) 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] > or =60 minutes) who had received ramelteon 8 mg or placebo were selected from a previously published multicenter outpatient trial of 829 older adults (aged > or =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.

Objective: To evaluate efficacy and safety of ramelteon (MT1/MT2-receptor [corrected] agonist) in subjects with chronic primary insomnia., Methods: Randomized, multicenter, double-blind, placebo-controlled trial of nightly ramelteon treatment (8 mg or 16 mg) in adults (N=405) with primary chronic insomnia (DSM-IV-TR). Latency to persistent sleep (LPS), TST, sleep efficiency, wake time after sleep onset, and number of awakenings were measured by polysomnography. Subject-reported measures were also assessed., Results: LPS at Week 1 (primary measure) was significantly shorter with ramelteon 8 mg (32.2 min) or 16 mg (28.9 min) vs placebo (47.9 min; p <0.001). Significant improvements in LPS were maintained at Weeks 3 and 5. TST was significantly longer with both doses of ramelteon at Week 1 (p <0.001) vs placebo. Subject-reported sleep latency was significantly shorter with ramelteon 8 mg at Weeks 1, 3, and 5 (p <0.001) and ramelteon 16 mg at Weeks 1 and 3 (p < or =0.050) vs placebo. Wake time after sleep onset and number of awakenings were not significantly different with ramelteon 8 mg or 16 mg treatment vs placebo. Subjective TST was significantly longer with ramelteon 8 mg at Weeks 1, 3, and 5 (p < or =0.050) and ramelteon 16 mg at Week 1 (p = 0.003) vs placebo. Ramelteon had no clinically meaningful effect on sleep architecture, next-morning psychomotor tasks, alertness, or ability to concentrate. No withdrawal or rebound effects were observed., Conclusions: Ramelteon reduced LPS over 5 weeks of treatment in subjects with chronic insomnia, with no clinically meaningful sleep architecture alterations, next-morning residual pharmacologic effects, and no evidence of rebound insomnia or withdrawal. No numerical differences were observed between the 2 doses of ramelteon.

Background and Purpose: To assess the efficacy and safety of ramelteon, a selective MT(1)/MT(2) receptor agonist, for chronic insomnia treatment., Patients and Methods: Randomized, double-blind, placebo-controlled 35-night outpatient trial with weekly clinic visits at multiple centers. Patients include older adults (>or=65 years; N=829) with chronic insomnia. Placebo, ramelteon 4mg, or ramelteon 8mg were taken nightly for five weeks, and patient-reported sleep data were collected using sleep diaries. Primary efficacy was sleep latency at week 1. Sustained efficacy was examined at weeks 3 and 5. Rebound insomnia and withdrawal effects were evaluated during a 7-day placebo run-out., Results: Both doses of ramelteon produced statistically significant reductions in sleep latency vs. placebo at week 1 (ramelteon 4mg: 70.2 vs. 78.5min, P=.008; ramelteon 8mg: 70.2 vs. 78.5 min, P=.008). Patients continued to report reduced sleep latency at week 3 with ramelteon 8mg (60.3 vs. 69.3min, P=.003), and at week 5 with ramelteon 4 mg (63.4 vs. 70.6 min, P=.028) and ramelteon 8 mg (57.7 vs. 70.6 min; P<.001). Statistically significant increases in total sleep time were observed with ramelteon 4 mg at week 1 (324.6 vs. 313.9 min, P=.004) and week 3 (336.0 vs. 324.3min, P=.007) compared with placebo. There was no evidence of significant rebound insomnia or withdrawal effects following treatment discontinuation. The incidence of adverse events was similar among all treatment groups; most were mild or moderate., Conclusions: In older adults with chronic insomnia, ramelteon significantly reduced patient reports of sleep latency over five weeks of treatment with no significant rebound insomnia or withdrawal effects.

Skin patch testing of menses and venous blood on the vulva (labia majora) and the upper arm was performed to assess the potential contribution of these biological fluids to vulvar irritation during menstruation. After 24 and 48 hours of occlusive exposure, the skin of the labia majora was relatively unaffected by these fluids compared to the skin of the upper arm: no significant irritation was observed on the labia at either exposure time, but discernible irritation was elicited on the upper arm after 48 hours of exposure. Pre-treatment of the upper arm with a petrolatum-based emollient attenuated the upper arm response. Semi-occlusive conditions also reduced the degree of upper-arm irritation elicited test materials and an irritant control, sodium lauryl sulfate. The relative insensitivity of the vulva to irritation by menses or blood was not predictable a priori because some irritants elicit heightened responses on the vulva relative to the arm (3). These results suggest that the vulva (labia majora) may be adapted to be less sensitive to menses-induced skin irritation than other anatomical sites.

Monoclonal antibody (MAb) technology was used to examine aggrecan metabolites and the role of aggrecanases and matrix metalloproteinases (MMPs) in proteolysis of the interglobular domain (IGD) and C-terminus of aggrecan. An in vitro model of progressive cartilage degradation characterized by early proteoglycan loss and late stage collagen catabolism was evaluated in conjunction with a broad-spectrum inhibitor of MMPs. We have for the first time demonstrated that IGD cleavage by MMPs occurs during this late stage cartilage degeneration, both as a primary event in association with glycosaminoglycan (GAG) release from the tissue and secondarily in trimming of aggrecanase-generated G1 metabolites. Additionally, we have shown that MMPs were responsible for C-terminal catabolism of aggrecan and generation of chondroitin sulfate (CS) deficient aggrecan monomers and that this aggrecan truncation occurred prior to detectable IGD cleavage by MMPs. The onset of this later stage MMP activity was also evident by the generation of MMP-specific link protein catabolites in this model culture system. Recombinant MMP-1, -3 and -13 were all capable of C-terminally truncating aggrecan with at least two cleavage sites N-terminal to the CS attachment domains of aggrecan. Through analysis of aggrecan metabolites in pathological synovial fluids from human, canine and equine sources, we have demonstrated the presence of aggrecan catabolites that appear to have resulted from similar C-terminal processing of aggrecan as that induced in our in vitro culture systems. Finally, by developing a new MAb recognizing a linear epitope in the IGD of aggrecan, we have identified two novel aggrecan metabolites generated by an as yet unidentified proteolytic event. Collectively, these results suggest that C-terminal processing of aggrecan by MMPs may contribute to the depletion of cartilage GAG that leads to loss of tissue function in aging and disease. Furthermore, analysis of aggrecan metabolites resulting from both C-terminal and IGD cleavage by MMPs may prove useful in monitoring different stages in the progression of cartilage degeneration.

Objective: To determine the role of matrix metalloproteinases (MMPs) in retinoic acid (RetA)-induced degradation of type II collagen in cartilage., Methods: Bovine nasal cartilage explants were cultured with 1 microM RetA or in 3 nM interleukin-1alpha (IL-1alpha). Release of proteoglycan and type II collagen into the medium was measured by colorimetric assay and immunoassay, respectively. MMP activity in the medium was determined using a quenched fluorescent substrate assay, while specific collagenases were identified by Western immunoblotting. In some cases the effects of low molecular mass synthetic MMP inhibitors and serum on collagen degradation were studied., Results: RetA promoted maximal breakdown of type II collagen after 4 or 5 weeks in culture, compared with 3 weeks in culture with IL-1alpha. In IL-1alpha-stimulated cultures, collagen degradation was coincident with a large increase in MMP activity in the culture medium, whereas in RetA-stimulated cultures, there was only a small increase. In Western immunoblots of culture media containing RetA, prointerstitial collagenase and active collagenase 3 were sometimes detected, but not in all experiments. In IL-1alpha cultures, active interstitial collagenase was always detected, and active collagenase 3 was detectable in some experiments. Neutrophil collagenase was not detected in any cultures. IL-1alpha-stimulated collagen degradation was effectively inhibited by a potent, broad-spectrum inhibitor of MMPs, whereas it was poorly inhibited by a weak MMP inhibitor. The same 2 compounds were both only weak inhibitors of RetA-induced collagen degradation. When fetal calf serum was included in cartilage cultures, MMP activity in the culture medium was reduced to low levels. This resulted in a marked inhibition of IL-1alpha-induced type II collagen degradation, whereas there was no inhibition of RetA-induced collagen degradation., Conclusion: Unlike IL-1alpha, RetA induces degradation of type II collagen in cartilage explants by a mechanism that is mainly independent of those MMPs that can be detected in the culture medium.