scholarly journals Effects of the selective orexin-2 receptor antagonist JNJ-48816274 on sleep initiated in the circadian wake maintenance zone: a randomised trial

2021 ◽  
Author(s):  
Victoria L. Revell ◽  
Ciro della Monica ◽  
Jeewaka Mendis ◽  
Hana Hassanin ◽  
Robin J. Halter ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Rem Sleep ◽  
Spectral Power ◽  
Randomised Trial ◽  
Sleep Onset ◽  
Residual Effects ◽  
Phase Advance ◽  
Sleep Onset Latency ◽  
Placebo Condition ◽  
Double Blind

AbstractThe effects of orexinergic peptides are diverse and are mediated by orexin-1 and orexin-2 receptors. Antagonists that target both receptors have been shown to promote sleep initiation and maintenance. Here, we investigated the role of the orexin-2 receptor in sleep regulation in a randomised, double-blind, placebo-controlled, three-period crossover clinical trial using two doses (20 and 50 mg) of a highly selective orexin-2 receptor antagonist (2-SORA) (JNJ-48816274). We used a phase advance model of sleep disruption where sleep initiation is scheduled in the circadian wake maintenance zone. We assessed objective and subjective sleep parameters, pharmacokinetic profiles and residual effects on cognitive performance in 18 healthy male participants without sleep disorders. The phase advance model alone (placebo condition) resulted in disruption of sleep at the beginning of the sleep period compared to baseline sleep (scheduled at habitual time). Compared to placebo, both doses of JNJ-48816274 significantly increased total sleep time, REM sleep duration and sleep efficiency, and reduced latency to persistent sleep, sleep onset latency, and REM latency. All night EEG spectral power density for both NREM and REM sleep were unaffected by either dose. Participants reported significantly better quality of sleep and feeling more refreshed upon awakening following JNJ-48816274 compared to placebo. No significant residual effects on objective performance measures were observed and the compound was well tolerated. In conclusion, the selective orexin-2 receptor antagonist JNJ-48816274 rapidly induced sleep when sleep was scheduled earlier in the circadian cycle and improved self-reported sleep quality without impact on waking performance.

scholarly journals 0146 Efficacy and Safety of Single Dose of TS-142, a Novel and Potent Dual Orexin Receptor Antagonist, in Insomnia Patients

SLEEP ◽  
2020 ◽  
Vol 43 (Supplement_1) ◽  
pp. A58-A58
Author(s):  
M Uchiyama ◽  
D Kambe ◽  
Y Imadera ◽  
H Sunaga ◽  
S Hasegawa ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Healthy Subjects ◽  
Phase 1 ◽  
Sleep Onset ◽  
Pharmacokinetic Profile ◽  
Residual Effects ◽  
Digit Symbol Substitution Test ◽  
Efficacy And Safety ◽  
Serious Adverse Events ◽  
Double Blind

Abstract Introduction TS-142 is a novel dual orexin receptor antagonist (DORA) developed for the treatment of insomnia. Here we report its pharmacokinetic profile in the healthy subjects and its efficacy and safety in patients with insomnia. Methods A phase1 study was conducted to clarify pharmacokinetic profile, in which various doses of TS-142 (1–30 mg) were orally administered once to thirty two healthy subjects. Subsequently, a phase 2a study utilizing polysomnography (PSG) was carried out in patients with primary insomnia, in which 5, 10, or 30 mg of TS-142, or placebo was randomly administered in a double-blind manner. Karolinska Sleepiness Scale (KSS) and Digit Symbol Substitution Test (DSST) were also examined in the morning after PSG. Results Following single administration of TS-142, plasma concentration of unchanged compound reached maximum within 2.50 h (median), and then eliminated rapidly, giving mean elimination half-life between 1.32 and 3.25 h. Twenty-three patients with insomnia completed the Phase2a study. Both latency to persistent sleep (LPS) and wake after sleep onset (WASO) were significantly improved with TS-142 at all doses, in comparison with placebo (-42, -42 and -45 for LPS [min] and -28, -35 and -55 for WASO [min] in 5, 10, 30 mg, respectively). KSS and DSST administered in the morning indicated no serious hangover effects. No serious adverse events were observed in these trials. Conclusion The phase 1 trial showed favorable pharmacokinetic profiles. The phase 2a trial demonstrated that TS-142 was efficacious in objective sleep onset and maintenance with minimal next-day residual effects. TS-142 was generally well tolerated in both studies. Support Taisho Pharmaceutical. Co., Ltd.

The Acceptability of a Non-Benzodiazepine Hypnotic (Zopiclone) in General Practice

1983 ◽  
Vol 11 (6) ◽  
pp. 333-337 ◽  
Author(s):  
P J Chaudoir ◽  
N C Jarvie ◽  
G J Wilcox
Keyword(s):  
General Practice ◽  
Adverse Reactions ◽  
Sleep Onset ◽  
Residual Effects ◽  
Sleep Onset Latency ◽  
Onset Latency ◽  
Quality Of Sleep ◽  
Double Blind ◽  
Randomized Crossover Study

The hypnotic effects of Zopiclone, a novel cyclopyrrolone derivative, were compared with placebo in a double-blind randomized crossover study in insomniac patients. Subjective morning assessments by the patients showed that Zopiclone 7·5 mg improved the quality of sleep, with a reduction in the sleep onset latency and the number of nocturnal awakenings. Zopiclone was judged by the physicians to be superior to placebo and was preferred by the patients. Subjective residual effects and adverse reactions were minimal.

scholarly journals 0004 TS-142: A Novel and Potent Dual Orexin Receptor Antagonist with Sleep-Promoting Effects in Rats

SLEEP ◽  
2020 ◽  
Vol 43 (Supplement_1) ◽  
pp. A2-A2
Author(s):  
D Kambe ◽  
H Hikichi ◽  
Y Tokumaru ◽  
M Ohmichi ◽  
Y Konno ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Half Life ◽  
Sleep Onset ◽  
Sleep Time ◽  
Sleep Onset Latency ◽  
Orexin A ◽  
Pharmacokinetic Profiles ◽  
Orexin Receptors ◽  
Elimination Half ◽  
Emg Electrodes

Abstract Introduction The orexin system plays a pivotal role in regulating sleep and wakefulness, thus, orexin receptors (OX1 and OX2 receptors) have gained much attention as promising therapeutic targets for the treatment of insomnia. We synthesized a novel and potent dual orexin receptor antagonist (DORA), ORN0829 (investigation code name as TS-142), which was designed to have short-acting effects. Here we report pharmacological and pharmacokinetic profiles of ORN0829 in rats. Methods The antagonistic activities of ORN0829 were assessed using calcium mobilization assays. Ala-orexin A-induced [Ca2+]i response was measured with CHO-K1 cells stably expressing human/rat orexin receptor. Rats implanted the EEG/EMG electrodes were orally administrated ORN0829 at doses of 1, 3 or 10 mg/kg at the dark onset and sleep-wake stages were inspected visually. In addition, pharmacokinetic profiles of ORN0829 were investigated in rats. Results ORN0829 inhibited Ala-orexin A-increased [Ca2+]i response with a Kb of 0.67/0.44 nmol/L (for human/rat OX1 receptor), and with a Kb of 0.84/0.80 nmol/L (for human/rat OX2 receptor), respectively, indicating that ORN0829 is a potent DORA with no species differences. ORN0829 dose-dependently increased total sleep time and reduced sleep onset latency at doses of 1, 3 and 10 mg/kg. Importantly, the ORN0829 levels in plasma and cerebrospinal fluid rapidly reached a maximum concentration, and decreased with an elimination half-life of less than 1 h. Conclusion The present study indicates that ORN0829 is a novel and potent DORA with sleep-promoting effects, and that it exhibits ideal pharmacokinetic profiles (rapid absorption and short half-life) in rats. A phase 2a study of TS-142 using patients with insomnia has been completed, which is presented in a separate poster. Support Taisho Pharmaceutical. Co., Ltd.

scholarly journals Cryotherapy associated with tailored land-based exercises for knee osteoarthritis: a protocol for a double-blind sham-controlled randomised trial

BMJ Open ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. e035610 ◽  
Author(s):  
Lucas Ogura Dantas ◽  
Ana Elisa Serafim Jorge ◽  
Paula Regina Mendes da Silva Serrão ◽  
Francisco Aburquerque-Sendín ◽  
Tania de Fatima Salvini
Keyword(s):  
Knee Osteoarthritis ◽  
Short Form ◽  
Randomised Trial ◽  
Unmet Need ◽  
Residual Effects ◽  
Control Group ◽  
Therapeutic Exercise ◽  
Exercise Protocol ◽  
Double Blind ◽  
Intention To Treat

IntroductionThere is an unmet need to develop tailored therapeutic exercise protocols applying different treatment parameters and modalities for individuals with knee osteoarthritis (KOA). Cryotherapy is widely used in rehabilitation as an adjunct treatment due to its effects on pain and the inflammatory process. However, disagreement between KOA guidelines remains with respect to its recommendation status. The aim of this study is to verify the complementary effects of cryotherapy when associated with a tailored therapeutic exercise protocol for patients with KOA.Methods and analysisThis study is a sham-controlled randomised trial with concealed allocation and intention-to-treat analysis. Assessments will be performed at baseline and immediately following the intervention period. To check for residual effects of the applied interventions, 3-month and 6-month follow-up assessments will be performed. Participants will be community members living with KOA divided into three groups: (1) the experimental group that will receive a tailored therapeutic exercise protocol followed by a cryotherapy session of 20 min; (2) the sham control group that will receive the same regimen as the first group, but with sham packs filled with dry sand and (3) the active treatment control group that will receive only the therapeutic exercise protocol. The primary outcome will be pain intensity according to a Visual Analogue Scale. Secondary outcomes will be the Western Ontario & McMaster Universities Osteoarthritis Index; the Short-Form Health Survey 36; the 30-s Chair Stand Test; the Stair Climb test; and the 40-m fast-paced walk test.Ethics and disseminationThe trial was approved by the Institutional Ethics Committee of Federal University of São Carlos, São Paulo, Brazil. Registration approval number: CAAE: 65966617.9.0000.5504. The results will be published in peer-reviewed journals.Trial registration numberNCT03360500

scholarly journals 0468 A Multiple Dose, Placebo-Controlled, Randomized Double-Blind, Multicenter Study to Investigate Triprolidine in the Treatment of Temporary Sleep Disturbance

SLEEP ◽  
2020 ◽  
Vol 43 (Supplement_1) ◽  
pp. A179-A180
Author(s):  
L Reyner ◽  
J E Miller ◽  
T Shea
Keyword(s):  
Sleep Disturbance ◽  
Daytime Sleepiness ◽  
Multiple Dose ◽  
Dose Range ◽  
Randomized Study ◽  
Sleep Onset ◽  
Primary Diagnosis ◽  
Optimum Dose ◽  
Sleep Onset Latency ◽  
Double Blind

Abstract Introduction American Association of Sleep Medicine guidelines states that the primary goals of the treatment of insomnia are to improve sleep quality and related daytime function. While H1 antihistamines have sedative effects, they are associated with residual daytime sleepiness and an effective dose range for hypnotic effect has hitherto not been established. Triprolidine a first generation antihistamine used to treat allergic rhinitis and the common cold has a mean half-life of 3.2 hours. We evaluated the effect of two doses of triprolodine compared with placebo on sleep onset latency and daytime sleepiness to determine the optimum dose in subjects with temporary sleep disturbance. Methods Multicenter, placebo-controlled, parallel group, double blind, multiple dose, randomized study of 178 patients aged 18 years or above with a primary diagnosis of temporary sleep disturbance. Patients were randomized to one of three groups. Group 1: 2 x placebo tablets; Group 2: 1 x placebo tablet + 1 x 2.5mg triprolidine tablet; Group 3: 2 x 2.5mg triprolodine tablets, taken 20 minutes before intended sleep on three consecutive evenings. Efficacy was measured objectively using the Sleep Disturbance Index using a wrist actimeter and subjectively using the Loughborough Sleep Log and Karolinska Sleepiness Scale. Results Both doses were statistically significantly superior to placebo in terms of quality and duration of sleep and sleep interruptions. No hangover effects or daytime sleepiness were observed with either dose compared to placebo. Patients on the 2.5 mg dose awoke more refreshed than the 5 mg dose. No serious adverse effects observed in any group and anticholinergic events i.e. dry mouth were very low. Conclusion Tripolidine is effective and safe in the treatment of temporary sleep disturbance. The optimum dose is 2.5mg. Support The study was sponsored by Boots Healthcare International.

Internet-delivered cognitive behaviour therapy for adolescents with insomnia comorbid to psychiatric conditions: A non-randomised trial

2020 ◽  
pp. 135910452097846
Author(s):  
Vendela Zetterqvist ◽  
Charlotte Lundén ◽  
Anders Herrmann ◽  
Linda Hasbar ◽  
Najah Khalifa ◽  
...  
Keyword(s):  
Cognitive Behaviour Therapy ◽  
Psychiatric Symptoms ◽  
Randomised Trial ◽  
Sleep Onset ◽  
Sleep Onset Latency ◽  
Behaviour Therapy ◽  
Paranoid Ideation ◽  
Comorbid Insomnia ◽  
Cognitive Behaviour ◽  
Psychiatric Conditions

Insomnia is highly prevalent among adolescents with psychiatric conditions and is known to aggravate psychiatric symptoms. Research on cognitive behaviour therapy for adolescents with comorbid insomnia (CBT-I) is still limited. The aim of this study was to investigate feasibility and preliminary effects of internet-delivered CBT for adolescents with insomnia comorbid to a psychiatric condition. Twenty-one patients (13–17 years) with comorbid insomnia were recruited from Child and Adolescent Psychiatry. All patients received 7 weeks of internet-delivered CBT-I with therapist support. Outcomes were assessed at baseline, post-treatment, and at a 4-month follow-up. The proportion of completed assessments was overall acceptable. Participants on average completed 4.48 ( sd = 1.97) of the seven treatment modules and therapists on average spent 12.80 minutes ( sd = 6.23) per patient and week. Results showed large statistically significant improvements on insomnia severity, sleep efficiency, sleep onset latency and sleep quality. Medium to large improvements were also seen on the psychiatric symptoms of depression, obsessive-compulsive symptoms, interpersonal sensitivity, paranoid ideation and psychoticism. These findings indicate that internet-delivered CBT is feasible and potentially promising for improving sleep and reducing psychiatric symptoms in adolescent psychiatric patients with insomnia and co-morbid psychiatric disorders. A larger randomised trial is warranted to verify these preliminary results.

scholarly journals Study protocol for a randomised controlled trial evaluating the effects of the orexin receptor antagonist suvorexant on sleep architecture and delirium in the intensive care unit

BMJ Open ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. e038474
Author(s):  
Omid Azimaraghi ◽  
Maximilian Hammer ◽  
Peter Santer ◽  
Katharina Platzbecker ◽  
Friederike C Althoff ◽  
...  
Keyword(s):  
Intensive Care Unit ◽  
Intensive Care ◽  
Receptor Antagonist ◽  
Medical Center ◽  
Controlled Trial ◽  
Sleep Onset ◽  
Secondary Outcome ◽  
Night Time ◽  
Subjective Sleep Quality ◽  
Double Blind

IntroductionInsomnia frequently occurs in patients admitted to an intensive care unit (ICU). Sleep-promoting agents may reduce rapid eye movement sleep and have deliriogenic effects. Suvorexant (Belsomra) is an orexin receptor antagonist with Food and Drug Administration (FDA) approval for the treatment of adult insomnia, which improves sleep onset and maintenance as well as subjective measures of quality of sleep. This trial will evaluate the efficacy of postoperative oral suvorexant treatment on night-time wakefulness after persistent sleep onset as well as the incidence and duration of delirium among adult cardiac surgical patients.Methods and analysisIn this single-centre, randomised, double-blind, placebo-controlled trial, we will enrol 120 patients, aged 60 years or older, undergoing elective cardiac surgery with planned postoperative admission to the ICU. Participants will be randomised to receive oral suvorexant (20 mg) or placebo one time a day starting the night after extubation. The primary outcome will be wakefulness after persistent sleep onset. The secondary outcome will be total sleep time. Exploratory outcomes will include time to sleep onset, incidence of postoperative in-hospital delirium, number of delirium-free days and subjective sleep quality.Ethics and disseminationEthics approval was obtained through the ‘Committee on Clinical Investigations’ at Beth Israel Deaconess Medical Center (protocol number 2019P000759). The findings will be published in peer-reviewed journals.Trial registration numberThis trial has been registered at clinicaltrials.gov on 17 September 2019 (NCT04092894).

scholarly journals Preliminary finding of a randomized, double-blind, placebo-controlled, crossover study to evaluate the safety and efficacy of 5-hydroxytryptophan on REM sleep behavior disorder in Parkinson’s disease

2021 ◽  
Author(s):  
Mario Meloni ◽  
Michela Figorilli ◽  
Manolo Carta ◽  
Ludovica Tamburrino ◽  
Antonino Cannas ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Rem Sleep ◽  
Rating Scale ◽  
Sleep Onset ◽  
Rem Sleep Behavior Disorder ◽  
Behavior Disorder ◽  
Double Blind ◽  
Sleep Behavior ◽  
Double Blind Placebo

Abstract Purpose Altered serotonergic neurotransmission may contribute to the non-motor features commonly associated with Parkinson’s disease (PD) such as sleep disorders. The 5-hydroxytryptophan (5-HTP) is the intermediate metabolite of l-tryptophan in the production of serotonin and melatonin. The purpose of this study was to compare the effects of 5-HTP to placebo on REM sleep behavior disorder (RBD) status in patients with PD. Methods A single-center, randomized, double-blind placebo-controlled crossover trial was performed in a selected population of 18 patients with PD and RBD. The patients received a placebo and 50 mg of 5-HTP daily in a crossover design over a period of 4 weeks. Results 5-HTP produced an increase in the total percentage of stage REM sleep without a related increase of RBD episodes, as well as a marginal, non-significant reduction in both arousal index and wake after sleep onset. The self-reported RBD frequency and clinical global impression (CGI) were improved during 5-HTP and placebo treatment in comparison to baseline. 5-HTP significantly improved our patients’ motor experiences of daily living as rated by the Unified Parkinson’s Disease Rating Scale (UPDRS) part II. Conclusions This study provides evidence that 5-HTP is safe and effective in improving sleep stability in PD, contributing to ameliorate patients’ global sleep quality. Larger studies with higher doses and longer treatment duration are needed to corroborate these preliminary findings.

scholarly journals Regular Caffeine Intake Delays REM Sleep Promotion and Attenuates Sleep Quality in Healthy Men

2021 ◽  
pp. 074873042110139
Author(s):  
Janine Weibel ◽  
Yu-Shiuan Lin ◽  
Hans-Peter Landolt ◽  
Christian Berthomier ◽  
Marie Brandewinder ◽  
...  
Keyword(s):  
Sleep Quality ◽  
Rem Sleep ◽  
Sleep Time ◽  
Caffeine Intake ◽  
Sleep Regulation ◽  
Caffeine Consumption ◽  
Subjective Sleep Quality ◽  
Placebo Condition ◽  
Double Blind ◽  
Sleep Episode

Acute caffeine intake can attenuate homeostatic sleep pressure and worsen sleep quality. Caffeine intake—particularly in high doses and close to bedtime—may also affect circadian-regulated rapid eye movement (REM) sleep promotion, an important determinant of subjective sleep quality. However, it is not known whether such changes persist under chronic caffeine consumption during daytime. Twenty male caffeine consumers (26.4 ± 4 years old, habitual caffeine intake 478.1 ± 102.8 mg/day) participated in a double-blind crossover study. Each volunteer completed a caffeine (3 × 150 mg caffeine daily for 10 days), a withdrawal (3 × 150 mg caffeine for 8 days then placebo), and a placebo condition. After 10 days of controlled intake and a fixed sleep-wake cycle, we recorded electroencephalography for 8 h starting 5 h after habitual bedtime (i.e., start on average at 04:22 h which is around the peak of circadian REM sleep promotion). A 60-min evening nap preceded each sleep episode and reduced high sleep pressure levels. While total sleep time and sleep architecture did not significantly differ between the three conditions, REM sleep latency was longer after daily caffeine intake compared with both placebo and withdrawal. Moreover, the accumulation of REM sleep proportion was delayed, and volunteers reported more difficulties with awakening after sleep and feeling more tired upon wake-up in the caffeine condition compared with placebo. Our data indicate that besides acute intake, also regular daytime caffeine intake affects REM sleep regulation in men, such that it delays circadian REM sleep promotion when compared with placebo. Moreover, the observed caffeine-induced deterioration in the quality of awakening may suggest a potential motive to reinstate caffeine intake after sleep.

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