Effects of the dual orexin receptor antagonist DORA-22 on sleep in 5XFAD mice.
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ABSTRACT:
SUBMITTER: Duncan MJ
PROVIDER: S-EPMC6396100 | biostudies-literature | 2019
REPOSITORIES: biostudies-literature
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Project description:Insomnia is one of the major challenges in medical science nowadays as it leads to great socio-economic burden by impairing daytime function as well as the development of exhaustion, depression, and memory disturbance in affected individuals. Several important classes of drugs have been tried, including the BZDs and non-BZD hypnotics. Available drugs to combat this disease have the limitations of abuse potential, tolerance, and cognitive impairment. In some instances, withdrawal symptoms have been observed upon the abrupt cessation of those drugs. The Orexin system has been very recently targeted as a therapeutic option to overcome those limitations. Treatment of insomnia with Daridorexant as a Dual Orexin Receptor Antagonist (DORA) has been evaluated in several preclinical and clinical studies. Available information obtained from those studies has shown a promising future for this drug in the management of insomnia. Beyond its effectiveness in insomnia, it has been successfully used in patients suffering from obstructive sleep apnoea, chronic obstructed airway disease (COAD), Alzheimer's disease (AD), hypertension, and cardiovascular disorders. Larger studies need to address the safety issues as well as obtain robust pharmacovigilance information to safeguard the risk-benefit aspect of this drug in insomniac adults.
| S-EPMC10325868 | biostudies-literature
Project description:BackgroundThe current standard of care for insomnia includes gamma-aminobutyric acid receptor A (GABAA) activators, which promote sleep as well as general central nervous system depression. Dual orexin receptor antagonists (DORAs) represent an alternative mechanism for insomnia treatment that induces somnolence by blocking the wake-promoting effects of orexin neuropeptides. The current study compares the role and interdependence of these two mechanisms on their ability to influence sleep architecture and quantitative electroencephalography (qEEG) spectral profiles across preclinical species.ResultsActive-phase dosing of DORA-22 induced consistent effects on sleep architecture in mice, rats, dogs, and rhesus monkeys; attenuation of active wake was accompanied by increases in both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. Eszopiclone, a representative GABAA receptor modulator, promoted sleep in rats and rhesus monkeys that was marked by REM sleep suppression, but had inconsistent effects in mice and paradoxically promoted wakefulness in dogs. Active-phase treatment of rats with DORA-12 similarly promoted NREM and REM sleep to magnitudes nearly identical to those seen during normal resting-phase sleep following vehicle treatment, whereas eszopiclone suppressed REM even to levels below those seen during the active phase. The qEEG changes induced by DORA-12 in rats also resembled normal resting-phase patterns, whereas eszopiclone induced changes distinct from normal active- or inactive-phase spectra. Co-dosing experiments, as well as studies in transgenic rats lacking orexin neurons, indicated partial overlap in the mechanism of sleep promotion by orexin and GABA modulation with the exception of the REM suppression exclusive to GABAA receptor modulation. Following REM deprivation in mice, eszopiclone further suppressed REM sleep while DORA-22 facilitated recovery including increased REM sleep.ConclusionDORAs promote NREM and importantly REM sleep that is similar in proportion and magnitude to that seen during the normal resting phase across mammalian animal models. While limited overlap exists between therapeutic mechanisms, orexin signaling does not appear involved in the REM suppression exhibited by GABAA receptor modulators. The ability of DORAs to promote proportional NREM and REM sleep following sleep deprivation suggests that this mechanism may be effective in alleviating recovery from sleep disturbance.
| S-EPMC4261741 | biostudies-literature
Project description:Orexin receptor antagonists are clinically useful for treating insomnia, but thorough blockade of orexin signaling could cause narcolepsy-like symptoms. Specifically, while sleepiness is a desirable effect, an orexin antagonist could also produce cataplexy, sudden episodes of muscle weakness often triggered by strong, positive emotions. In this study, we examined the effects of dual orexin receptor antagonists (DORAs), lemborexant (E2006) and almorexant, on sleep-wake behavior and cataplexy during the dark period in wild-type (WT) mice and prepro-orexin knockout (OXKO) mice. In WT mice, lemborexant at 10 and 30 mg/kg quickly induced NREM sleep in a dose-dependent fashion. In contrast, lemborexant did not alter sleep-wake behavior in OXKO mice. Under the baseline condition, cataplexy was rare in lemborexant-treated WT mice, but when mice were given chocolate as a rewarding stimulus, lemborexant dose-dependently increased cataplexy. Almorexant produced similar results. Collectively, these results demonstrate that DORAs potently increase NREM and REM sleep in mice via blockade of orexin signaling, and higher doses can cause cataplexy when co-administered with a likely rewarding stimulus.
| S-EPMC7294412 | biostudies-literature
Project description:To identify dose(s) of lemborexant that maximize insomnia treatment efficacy while minimizing next-morning residual sleepiness and evaluate lemborexant effects on polysomnography (PSG) measures (sleep efficiency [SE], latency to persistent sleep [LPS], and wake after sleep onset [WASO]) at the beginning and end of treatment.Adults and elderly subjects with insomnia disorder per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition were enrolled in a multicenter, randomized, double-blind, placebo-controlled, Bayesian, adaptive, parallel-group study, receiving lemborexant (1, 2.5, 5, 10, 15, 25 mg) or placebo for 15 nights. Efficacy assessments included a utility function that combined efficacy (SE) and safety (residual morning sleepiness as measured by Karolinska Sleepiness Scale [KSS]), PSG measures, and sleep diary. Safety assessments included KSS, Digit Symbol Substitution Test, computerized reaction time tests, and adverse events (AEs).A total of 616 subjects were screened; 291 were randomized. Baseline characteristics were similar between lemborexant groups and placebo (?63% female, median age: 49.0 years). The study was stopped for early success after the fifth interim analysis when the 15-mg dose met utility index/KSS criteria for success; 3 other doses also met the criteria. Compared with placebo, subjects showed significant improvements in SE, subjective SE, LPS, and subjective sleep onset latency at the beginning and end of treatment for lemborexant doses ? 5 mg (P < .05). WASO and subjective WASO showed numerically greater improvements for doses > 1 mg. AEs, mostly mild to moderate, included dose-related somnolence.Lemborexant doses ranging from 2.5-10 mg provided efficacy for the treatment of insomnia while minimizing next-morning residual sleepiness.Title: A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group, Bayesian Adaptive Randomization Design, Dose Response Study of the Efficacy of E2006 in Adults and Elderly Subjects With Chronic Insomnia; URL: https://clinicaltrials.gov/ct2/show/NCT01995838; Identifier: NCT01995838.
| S-EPMC5656478 | biostudies-literature
Project description:To investigate the respiratory effects of suvorexant, an orexin receptor antagonist for treating insomnia, in patients with obstructive sleep apnea (OSA).This was a randomized, double-blind, placebo-controlled, 2-period (4 days per period), crossover, sleep laboratory study. Twenty-six patients aged 18-65 years with mild (apnea-hypopnea index [AHI] ? 5 and < 15) to moderate (AHI ? 15 and < 30) OSA were randomized to receive suvorexant 40 mg or placebo in period-1 and then crossed over to the other treatment in period-2. Breathing during sleep was measured by AHI (primary endpoint) and oxygen saturation assessed by pulse oximetry (SpO2, secondary endpoint). The study was powered to rule out a mean increase in AHI between suvorexant and placebo of 5 or greater on Day 4.There was a small increase in mean AHI (2.66) in OSA patients after multiple doses of suvorexant relative to placebo, with the upper 90% CI bound slightly exceeding 5.00 (0.22, 5.09). No increase in mean AHI was observed after a single dose of suvorexant versus placebo (mean difference = -0.47 [-3.20, 2.26]), and there was no treatment effect on mean SpO2 during total sleep time after single or multiple doses (Day 1: mean difference = -0.04 [-0.49, 0.42]; Day 4: mean difference = -0.06 [-0.45, 0.33]). There was inter- and intra-individual variability in suvorexant respiratory effects.Suvorexant 40 mg, twice the 20 mg maximum recommended dose for treating insomnia in the USA and Japan, does not appear to have clinically important respiratory effects during sleep in patients with mild to moderate OSA as assessed by mean AHI and SpO2. Due to inter- and intra-individual variability in respiratory effects, suvorexant should be used with caution in patients with compromised respiratory function, and at the lowest effective dose.clinicaltrials.gov, NCT01300455.
| S-EPMC4702197 | biostudies-literature
Project description:To present results from in vivo studies underlying the preclinical development of lemborexant (E2006), a novel dual orexin (hypocretin) receptor antagonist for sleep/wake regulation. Rodent (wild-type rats and wild-type and orexin neuron-deficient [orexin/ataxin-3 Tg/+] mice) studies were performed to evaluate the effects of single-dose oral lemborexant (1-300 mg/kg) on orexin-induced increases in plasma adrenocorticotropic hormone (ACTH), locomotor activity, vigilance state measures (wakefulness, nonrapid eye movement [non-REM] sleep, rapid eye movement [REM] sleep), ethanol-induced anesthesia, and motor coordination, and the effects of multiple-dose oral lemborexant (30 mg/kg) on vigilance state measures. Active comparators were almorexant and zolpidem. Pharmacokinetics were assessed after single-dose lemborexant in mice and rats. Lemborexant prevented the orexin-promoted increase in ACTH in rats, therefore demonstrating inhibition of the orexin signaling pathway. Furthermore, lemborexant promoted sleep in wild-type mice and rats. Lemborexant promoted REM and non-REM sleep at an equal rate (there was no change in the REM sleep ratio). In contrast, zolpidem reduced REM sleep. The sleep-promoting effect of lemborexant was mediated via the orexin-peptide signaling pathway as demonstrated by a lack of sleep promotion in orexin neuron-deficient mice. Chronic dosing was not associated with a change in effect size or sleep architecture immediately postdosing. Lemborexant did not increase the sedative effects of ethanol or impair motor coordination, showing good safety margin in animals. Pharmacokinetic/pharmacodynamic data for mice and rats were well aligned. These findings supported further clinical evaluation (ongoing at this time) of lemborexant as a potential candidate for treating insomnia and other sleep disorders.
| S-EPMC6559177 | biostudies-literature
Project description:Orexins (also known as hypocretins) play critical roles in the regulation of sleep/wakefulness states by activating two G-protein coupled receptors (GPCRs), orexin 1 (OX1R) and orexin 2 receptors (OX2R). In order to understand the differential contribution of both receptors in regulating sleep/wakefulness states we compared the pharmacological effects of a newly developed OX2R antagonist (2-SORA), Compound 1 m (C1 m), with those of a dual orexin receptor antagonist (DORA), suvorexant, in C57BL/6J mice. After oral administration in the dark period, both C1m and suvorexant decreased wakefulness time with similar efficacy in a dose-dependent manner. While C1m primarily increased total non-rapid eye movement (NREM) sleep time without affecting episode durations and with minimal effects on REM sleep, suvorexant increased both total NREM and REM sleep time and episode durations with predominant effects on REM sleep. Fos-immunostaining showed that both compounds affected the activities of arousal-related neurons with different patterns. The number of Fos-IR noradrenergic neurons in the locus coeruleus was lower in the suvorexant group as compared with the control and C1m-treated groups. In contrast, the numbers of Fos-IR neurons in histaminergic neurons in the tuberomamillary nucleus and serotonergic neurons in the dorsal raphe were reduced to a similar extent in the suvorexant and C1m groups as compared with the vehicle-treated group. Together, these results suggest that an orexin-mediated suppression of REM sleep via potential activation of OX1Rs in the locus coeruleus may possibly contribute to the differential effects on sleep/wakefulness exerted by a DORA as compared to a 2-SORA.
| S-EPMC3907770 | biostudies-literature
Project description:Hypothalamic hypocretin (orexin) peptides mediate arousal, attention, and reward processing. Fibers containing orexins project to brain structures that govern motivated behavior, including the ventral tegmental area (VTA). A number of psychiatric conditions, including attention deficit hyperactivity disorder (ADHD) and substance use disorders, are characterized by deficits in impulse control, however the relationship between orexin and impulsive behavior is incompletely characterized. The effects of systemic or centrally administered orexin receptor (OXR) antagonists on measures of impulsive-like behavior in rats were evaluated using the five-choice serial reaction time task (5-CSRTT) and delay discounting procedures. These paradigms were also used to test the capacity of OXR antagonists to attenuate acute cocaine-evoked impulsivity. Finally, immunohistochemistry and calcium imaging were used to assess potential cellular mechanisms by which OXR blockade may influence motor impulsivity. Suvorexant, a dual (OX1/2R) orexin receptor antagonist, reduced cocaine-evoked premature responses in 5-CSRTT when administered systemically or directly into VTA. Neither suvorexant nor OX1R- or OX2R-selective compounds (SB334867 or TCS-OX2-29, respectively) altered delay discounting. Finally, suvorexant did not alter Fos-immunoreactivity within tyrosine hydroxylase-immunolabeled neurons of VTA, but did attenuate cocaine- and orexin-induced increases in calcium transient amplitude within neurons of VTA. Results from the present studies suggest potential therapeutic utility of OXR antagonists in reducing psychostimulant-induced motor impulsivity. These findings also support the view that orexin transmission is closely involved in executive function in normal and pathological conditions.
| S-EPMC5854790 | biostudies-literature
Project description:The analysis aimed at identifying subject-specific characteristics (covariates) influencing exposure to daridorexant and quantification of covariate effects to determine clinical relevance. Data from 13 phase I, two phase II, and two phase III studies were pooled to develop a population pharmacokinetic model describing daridorexant concentration over time. Covariate effects were quantified based on model predictions. A two-compartment model with dose-dependent bioavailability, absorption lag time, linear absorption, and nonlinear elimination described the data best. Statistically significant covariates were food status on absorption (lag time and rate constant), time of drug administration (morning, bedtime) on absorption rate constant, lean body weight on central volume of distribution and elimination, fat mass on peripheral volume of distribution and intercompartmental drug transfer, and age and alkaline phosphatase on elimination. Age, lean body weight, fat mass, and alkaline phosphatase influence exposure (area under the curve, time of maximum concentration after dose administration, maximum plasma concentration, and next-morning concentration) to a limited extent, that is, less than 20% difference from a typical subject. Morning administration is not relevant for daridorexant use by insomnia patients. The food effect with simultaneous intake of a high-fat, high-calorie food is an extreme-case scenario unlikely to occur in clinical practice. Body composition, alkaline phosphatase, and age showed clinically negligible effects on exposure to daridorexant. Lean body weight and fat mass described the pharmacokinetics of daridorexant better than other body size descriptors (body weight, height, body mass index), suggesting a convenient physiological alternative to reduce the number of covariates in population pharmacokinetic models. The results indicate that differences between subjects do not require dose adjustments.
| S-EPMC9835129 | biostudies-literature
Project description:Study objectivesSuvorexant (MK-4305) is an orexin receptor antagonist being developed for the treatment of insomnia. This report describes the effects of nighttime administration of suvorexant on polysomnography (PSG) sleep parameters in healthy young men.DesignRandomized, double-blind, placebo-controlled, 4-period crossover PSG study, followed by an additional 5(th) period to assess pharmacokinetics.SettingSleep laboratory.ParticipantsHealthy young men between 18 and 45 years of age (22 enrolled, 19 completed).InterventionsPeriods 1-4: suvorexant (10 mg, 50 mg, or 100 mg) or placebo 1 h before nighttime PSG recording. Period 5: suvorexant 10 mg, 50 mg, or 100 mg.Measurements and resultsIn Periods 1-4, overnight sleep parameters were recorded by PSG and next-morning residual effects were assessed by psychomotor performance tests and subjective assessments. Statistically significant sleep-promoting effects were observed with all doses of suvorexant compared to placebo. Suvorexant 50 mg and 100 mg significantly decreased latency to persistent sleep and wake after sleep onset time, and increased sleep efficiency. Suvorexant 10 mg significantly decreased wake after sleep onset time. There were no statistically significant effects of suvorexant on EEG frequency bands including delta (slow wave) activity based on power spectral analysis. Suvorexant was well tolerated. There was no evidence of next-day residual effects for suvorexant 10 mg. Suvorexant 50 mg statistically significantly reduced subjective alertness, and suvorexant 100 mg significantly increased reaction time and reduced subjective alertness. There were no statistically significant effects of any suvorexant dose on digit symbol substitution test performance. In Period 5, plasma samples of suvorexant were collected for pharmacokinetic evaluation. The median T(max) was 3 hours and apparent terminal t(½) was 9-13 hours.ConclusionsIn healthy young men without sleep disorders, suvorexant promoted sleep with some evidence of residual effects at the highest doses.
| S-EPMC3542986 | biostudies-literature