Huntington's disease is a neurodegenerative disorder resulting from expansion of the polyglutamine region in huntingtin. Although huntingtin is normally cytoplasmic, in affected brain regions proteolytic fragments of mutant huntingtin containing the polyglutamine repeat form intranuclear inclusions. Here, we examine the contribution of nuclear localization to toxicity by transiently transfecting neuro-2a cells with an N-terminal huntingtin fragment similar in size to that believed to be present in patients. The huntingtin fragment, HD-N63, was targeted either to the cytoplasm with a nuclear export signal (NES) or to the nucleus with a nuclear localization signal (NLS). The NES decreased the number of cells with aggregates in the nucleus while an NLS had the opposite effect. By cotransfecting HD-N63 with GFP as a marker, we observed direct cell loss with constructs containing expanded polyglutamine repeats. Compared to unmodified HD-N63-75Q, adding an NES reduced cell loss by 57% while an NLS increased cell loss by 111%. These results indicate that nuclear localization of mutant huntingtin fragments plays an important role in cell toxicity.
Sleep disturbance and insomnia are common in patients with Alzheimer’s disease (AD) but evidence for the efficacy of sleep medications in this population is limited. Suvorexant, a first-in-class orexin receptor antagonist that enables sleep to occur via competitive antagonism of wake-promoting orexins, is approved for treating insomnia in elderly and non-elderly adults. We conducted a clinical trial to evaluate its efficacy and safety for treating insomnia in patients with AD using sleep laboratory polysomnography (PSG) assessments. This randomized, placebo-controlled trial consisted of a 3-week screening period followed by a double-blind 4-week treatment period (ClinicalTrials.gov: NCT02750306). Patients met diagnostic criteria for both AD and insomnia and had a qualified trial partner/caregiver. Participants were randomized to an initial dose of suvorexant 10mg, that could be increased to 20mg based on clinical response, or matching placebo. Assessments included overnight sleep laboratory PSG visits, a sleep diary completed by the trial partner, an activity/sleep watch worn by the patient, and exploratory measures of cognition and neuropsychiatric behavior. The primary objective was to test the hypothesis that suvorexant would be superior to placebo in improving PSG-derived total sleep time (TST) at Week-4. A total of 285 participants (suvorexant N=142, placebo N=143) were randomized from 35 sites in 8 countries worldwide. Of these, 277 (97%) completed the study (suvorexant N=136, placebo N=141). One patient in each group discontinued study treatment due to an adverse event. Mean (SD) TST at baseline was 278 (77) minutes for suvorexant and 274 (84) minutes for placebo. At Week-4, the model-based least squares mean changes-from-baseline were 73 minutes for suvorexant and 45 minutes for placebo (difference = 28 minutes [95% CI:11,45], p<0.005). Regarding safety, 22.5% of suvorexant-treated patients and 16.1% of placebo-treated patients experienced ≥1 adverse events. Somnolence was reported in 4.2% of suvorexant-treated patients and 1.4% of placebo-treated patients. Suvorexant was effective and generally well-tolerated for treating insomnia in patients with AD. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA
Suvorexant, an orexin receptor antagonist, improves sleep in healthy subjects (HS) and patients with insomnia. We compared the electroencephalographic (EEG) power spectral density (PSD) profile of suvorexant with placebo using data from a phase 2 trial in patients with insomnia. We also compared suvorexant's PSD profile with the profiles of other insomnia treatments using data from 3 HS studies Phase 2 trial—randomized, double-blind, two-period (4 w per period) crossover. HS studies—randomized, double-blind, crossover. Sleep laboratories. Insomnia patients (n = 229) or HS (n = 124). Phase 2 trial—suvorexant 10 mg, 20 mg, 40 mg, 80 mg, placebo; HS study 1—suvorexant 10 mg, 50 mg, placebo; HS study 2— gaboxadol 15 mg, zolpidem 10 mg, placebo; HS study 3—trazodone 150 mg, placebo. The PSD of the EEG signal at 1–32 Hz of each PSG recording during nonrapid eye movement (NREM) and rapid eye movement (REM) sleep were calculated. The day 1 and day 28 PSD profiles of suvorexant at all four doses during NREM and REM sleep in patients with insomnia were generally flat and close to 1.0 (placebo) at all frequencies. The day 1 PSD profile of suvorexant in HS was similar to that in insomnia patients. In contrast, the other three drugs had distinct PSD profiles in HS that differed from each other. Suvorexant at clinically effective doses had limited effects on power spectral density compared with placebo in healthy subjects and in patients with insomnia, in contrast to the three comparison insomnia treatments. These findings suggest the possibility that antagonism of the orexin pathway might lead to improvements in sleep without major changes in the patient's neurophysiology as assessed by electroencephalographic.
Abstract Purpose/Background This study was designed as an early assessment of the safety of the orexin receptor antagonist suvorexant, but also included exploratory assessments of balance and psychomotor performance that are the focus of this report. Methods/Procedures This was a double-blind, randomized, 3-period, crossover, phase 1 study. Balance and psychomotor performance were evaluated during the night in 12 healthy elderly participants after bedtime administration of suvorexant 30 mg (a supratherapeutic dose), the GABAergic agonist zolpidem 5 mg (the recommended dose in the elderly), or placebo. Balance (body sway measured by platform stability) and psychomotor performance (measured by choice reaction time) were assessed predose and at 1.5, 4, and 8 hours postdose in each period. Memory (measured by word recall) was assessed predose and at 4 hours postdose. Findings/Results At 1.5 hours after nighttime administration of each drug (the approximate time of their anticipated maximal plasma concentrations), both zolpidem and suvorexant increased body sway versus placebo, with a greater increase for zolpidem than suvorexant. Suvorexant increased choice reaction time compared with placebo or zolpidem at 1.5 hours. There were no treatment differences on body sway or choice reaction time at 4 or 8 hours, or on word recall at 4 hours. Implications/Conclusions These exploratory data suggest that a 30-mg dose of suvorexant (supratherapeutic) and a 5-mg dose of zolpidem (recommended dose in the elderly) impaired balance at 1.5 hours in healthy elderly people, with potentially less impairment for suvorexant relative to zolpidem, but no treatment differences on body sway or psychomotor performance at 4 and 8 hours. Because of their exploratory nature, these findings and their clinical relevance, if any, require confirmation in a prospective study.
Recent research has identified important bidirectional relationships between sleep and Alzheimer's disease (AD). Sleep disturbance and insomnia are common in patients with AD but evidence for the efficacy of sleep medications in this population is limited. Furthermore, potential worsening of cognitive impairment/next-day function is a concern. Suvorexant is an orexin receptor antagonist that enables sleep to occur via competitive antagonism of wake-promoting orexins. We conducted a trial to evaluate its profile for treating insomnia in patients with AD. This randomized, placebo-controlled trial consisted of a 3-week screening period followed by a double-blind 4-week treatment period (ClinicalTrials.gov NCT02750306). Participants were required to meet diagnostic criteria for both AD and insomnia and have a qualified trial partner/caregiver. Eligible participants were randomized to an initial dose of suvorexant 10mg, that could be increased to 20mg based on clinical response, or matching placebo. Sleep was assessed by polysomnography (PSG) during overnight sleep laboratory visits. The primary objective was to test the hypothesis that suvorexant would be superior to placebo in improving PSG-derived total sleep time (TST) at Week-4. PSG-derived wake after sleep onset (WASO) was assessed as a secondary endpoint. A total of 285 participants (suvorexant N=142, placebo N=143) were randomized. Of these, 277 (97%) completed the study (suvorexant N=136, placebo N=141). The percentage of participants who had their dose titrated up was 77% for suvorexant and 73% for placebo. The model-based least squares mean increase from baseline in TST at Week-4 was 73 minutes for suvorexant and 45 minutes for placebo; the increase for suvorexant relative to placebo was 28 minutes [95% CI: 11,45], p<0.005. The model-based least squares mean reduction from baseline in WASO at Week-4 was -45 minutes for suvorexant and -29 minutes for placebo; the reduction for suvorexant relative to placebo was -16 minutes [95% CI: -28,-3], p<0.05. Regarding tolerability, 22.5% and 16.1% of participants experienced one or more adverse events when treated with suvorexant or placebo, respectively. Somnolence was reported in 4.2% of suvorexant-treated participants and 1.4% of those administered placebo. Suvorexant was effective and generally well-tolerated for treating insomnia in patients with AD.
The aim of this randomized, double-blind trial was to evaluate the safety and tolerability profile, including cardiac safety, of sugammadex-mediated recovery from neuromuscular block in participants undergoing surgery who met the American Society of Anesthesiologists (ASA) Physical Class 3 or 4 criteria. Specifically, this study assessed the impact of sugammadex on cardiac adverse events (AEs) and other prespecified AEs of clinical interest.Participants meeting ASA Class 3 and 4 criteria were stratified by ASA Class and NMBA (rocuronium or vecuronium) then randomized to one of the following: 1) Moderate neuromuscular block, sugammadex 2 mg/kg; 2) Moderate neuromuscular block, neostigmine and glycopyrrolate (neostigmine/glycopyrrolate); 3) Deep neuromuscular block, sugammadex 4 mg/kg; 4) Deep neuromuscular block, sugammadex 16 mg/kg (rocuronium only). Primary endpoints included incidences of treatment-emergent (TE) sinus bradycardia, TE sinus tachycardia and other TE cardiac arrhythmias.Of 344 participants randomized, 331 received treatment (61% male, BMI 28.5 ± 5.3 kg/m2, age 69 ± 11 years). Incidence of TE sinus bradycardia was significantly lower in the sugammadex 2 mg/kg group vs neostigmine/glycopyrrolate. The incidence of TE sinus tachycardia was significantly lower in the sugammadex 2 and 4 mg/kg groups vs neostigmine/glycopyrrolate. No significant differences in other TE cardiac arrythmias were seen between sugammadex groups and neostigmine/glycopyrrolate. There were no cases of adjudicated anaphylaxis or hypersensitivity reactions in this study.Compared with neostigmine/glycopyrrolate, incidence of TE sinus bradycardia was significantly lower with sugammadex 2 mg/kg and incidence of TE sinus tachycardia was significantly lower with sugammadex 2 mg/kg and 4 mg/kg. These results support the safety of sugammadex for reversing rocuronium- or vecuronium-induced moderate and deep neuromuscular block in ASA Class 3 or 4 participants.ClinicalTrials.gov Identifier: NCT03346057 .
Abstract Background: This randomized, double-blind trial evaluated sugammadex-mediated recovery time from rocuronium- or vecuronium-induced moderate (M-) or deep neuromuscular block (D-NMB) in morbidly obese adults dosed by actual (ABW) or ideal body weight (IBW). Methods: Adults with BMI ≥40 kg/m 2 were randomized to 1 of 5 groups: M-NMB, sugammadex 2 mg/kg ABW; M-NMB, sugammadex 2 mg/kg IBW; M-NMB, neostigmine 5 mg, and glycopyrrolate 1 mg; D-NMB, sugammadex 4 mg/kg ABW; or D-NMB, sugammadex 4 mg/kg IBW. Supramaximal train of four (TOF) stimulation of the ulnar nerve (TOF-watch SX ® ) monitored recovery. Primary endpoint was time to TOF ratio ≥0.9 for ABW and IBW groups pooled across NMB agent (NMBA)/blocking depth, analyzed by log-rank test stratified for agent and depth. Prespecified safety outcomes included treatment-emergent bradycardia, tachycardia, and other arrhythmias, and adjudicated hypersensitivity and anaphylaxis. Results: Of 207 patients randomized, 188 received treatment (28% male, BMI 47±5.1 kg/m 2 , age 48±13 years). Recovery was 1.5 min faster with ABW vs IBW dosing. The sugammadex 2 mg/kg groups recovered 9-fold faster [time 0.11-fold, 95% CI 0.08 to 0.14] than the neostigmine group. ABW (5.3%) and IBW (2.7%) groups had similar incidences of recovery time >10 min (95% CI of difference: -4.8% to 11.0%); 84% for neostigmine group. Re-curarization occurred in one patient each in the 2 mg/kg IBW and neostigmine groups. Prespecified safety outcomes occurred with similar incidences. Conclusions: ABW-based sugammadex dosing yields faster reversal without re-curarization, supporting ABW-based sugammadex dosing in the morbidly obese, irrespective of the depth of NMB or NMBA used. Trial registration: Registered on November 17, 2017, at ClinicalTrials.gov under number NCT03346070. https://clinicaltrials.gov/ct2/show/results/NCT03346070?term=NCT03346070&draw=2&rank=1
