المؤلفون: Wu, Ming-Fung, Li, Songlin, Lai, Yuan-Yang, Siegel, Jerome, Thannickal, Thomas, Mcgregor, Ronald

المصدر: Sleep. 46(9)

مصطلحات موضوعية: Xyrem, hypocretin, locus coeruleus, narcolepsy, orexin, sodium oxybate, tyrosine hydroxylase, Humans, Mice, Animals, Dogs, Orexins, Sodium Oxybate, Cataplexy, Locus Coeruleus, Narcolepsy, Neurons, Opiate Alkaloids

الوصف: Long-term use of sodium oxybate (SXB), (also called gamma-hydroxybutyrate [GHB]) attenuates the cataplexy and sleepiness of human narcolepsy. We had previously found that chronic opiate usage in humans and long-term opiate administration to mice significantly increased the number of detected hypocretin/orexin (Hcrt) neurons, decreased their size, and increased Hcrt level in the hypothalamus. We also found that opiates significantly decreased cataplexy in human narcoleptics as well as in narcoleptic mice and that cessation of locus coeruleus neuronal activity preceded and was tightly linked to cataplectic attacks in narcoleptic dogs. We tested the hypothesis that SXB produces changes similar to opiates and now report that chronic SXB administration significantly increased the size of Hcrt neurons, the reverse of what we had seen with opiates in humans and mice. Levels of Hcrt in the hypothalamus were nonsignificantly lower, in contrast to the significant increase in hypothalamic Hcrt level after opiates. SXB decreased tyrosine hydroxylase levels in the locus coeruleus, the major descending projection of the hypocretin system, also the reverse of what we saw with opioids. Therefore despite some similar effects on narcoleptic symptomatology, SXB does not produce anatomical changes similar to those elicited by opiates. Analysis of changes in other links in the cataplexy pathway might further illuminate SXBs mechanism of action on narcolepsy.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/1685v0b7Test

المؤلفون: Besterman, Aaron D, Jeste, Shafali S

المصدر: European Child & Adolescent Psychiatry. 32(3)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Psychology, Clinical Trials and Supportive Activities, Pediatric, Brain Disorders, Neurosciences, Intellectual and Developmental Disabilities (IDD), Mental Health, Behavioral and Social Science, Sleep Research, Clinical Research, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Child, Humans, Adolescent, Sleep Initiation and Maintenance Disorders, Orexin Receptor Antagonists, Sleep, Neurodevelopmental Disorders, Research, Insomnia, Neurodevelopmental disorders, Dual orexin receptor antagonists, Sleep disorders, Developmental & Child Psychology, Clinical sciences, Applied and developmental psychology, Clinical and health psychology

الوصف: Insomnia is a common, impairing, and difficult-to-treat comorbidity in children with neurodevelopmental disorders (NDDs). Behavioral interventions can be challenging because of developmental and behavioral features that interfere with treatment. Medication management also can be difficult due to a high burden of side effects, a high rate of paradoxical responses, and frequent treatment resistance. Therefore, new treatment options for insomnia in children with NDDs are needed. Dual orexin receptor antagonists (DORAs) are a relatively new class of pharmacotherapeutics that induce sleep by inhibiting the orexin signaling pathway. To date, there is little safety or efficacy data on the use of DORAs in children with NDDs. We present four patients with NDDs and insomnia that we treated with the DORA, suvorexant. We found that patients had a wide range of responses, with one patient displaying a robust improvement in sleep onset and maintenance, while another had significant improvement in insomnia symptoms on combination therapy with trazodone. Our final two patients had mild or no benefit from suvorexant therapy. Further research is necessary to establish the safety and efficacy of DORAs in this population and to identify predictive factors, such as specific neurogenetic diagnoses or clinical features, of a positive treatment response.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/8769g7sfTest

المؤلفون: Neylan, Thomas C, Richards, Anne, Metzler, Thomas J, Ruoff, Leslie M, Varbel, Jonathan, O’Donovan, Aoife, Sivasubramanian, Melinda, Motraghi, Terri, Hlavin, Jennifer, Batki, Steven L, Inslicht, Sabra S, Samuelson, Kristin, Morairty, Stephen R, Kilduff, Thomas S

المصدر: Sleep. 43(10)

مصطلحات موضوعية: Clinical Trials and Supportive Activities, Behavioral and Social Science, Neurosciences, Clinical Research, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Acetamides, Animals, Cognition, Double-Blind Method, Female, Humans, Hypnotics and Sedatives, Isoquinolines, Male, Orexin Receptors, Orexins, Psychomotor Performance, Pyridines, Young Adult, Zolpidem, hypnotics and sedatives, cognitive dysfunction, psychomotor performance, zolpidem, almorexant, humans, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery

الوصف: Hypnotic medications can adversely affect behavior during unanticipated awakenings during the night. Animals treated with the hypocretin (Hcrt) receptor antagonist almorexant (ALM) have less acute cognitive impairment compared to the GABAA receptor modulator zolpidem (ZOL). This study aimed to determine whether ALM produces less acute cognitive impairment than ZOL in human subjects. Healthy, young adult, unmedicated male and female subjects participated in a controlled trial of a single dose of ALM 100 mg (N = 48), ALM 200 mg (N = 53), ZOL 10 mg (N = 49), and placebo (PBO, N = 52). ZOL and both doses of ALM produced similar levels of subjective sleepiness and impaired the ability of subjects to remain awake in a dark, low-stimulus setting relative to PBO. For most cognitive measures, performance under ZOL was significantly worse than ALM or PBO. For tasks involving verbal memory or visual-motor coordination, ZOL impaired performance, whereas the two doses of ALM were no different than PBO. For tasks involving higher-order executive function, ZOL produced impairment in processing speed and inhibitory control, whereas the two doses of ALM were no different than PBO. Performance decrements for ALM were less than ZOL but greater than PBO for some reaction time measures. The data provide support for the hypothesis that Hcrt receptor antagonists produce less functional impairment than a benzodiazepine receptor agonist (BzRA). These observations are particularly relevant to patients treated with sedative-hypnotics who are at elevated risk for falls and other untoward events during the intended hours for sleep.

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الوصول الحر: https://escholarship.org/uc/item/6s7854trTest

المؤلفون: Azimaraghi, Omid, Hammer, Maximilian, Santer, Peter, Platzbecker, Katharina, Althoff, Friederike C, Patrocinio, Maria, Grabitz, Stephanie D, Wongtangman, Karuna, Rumyantsev, Sandra, Xu, Xinling, Schaefer, Maximilian S, Fuller, Patrick M, Subramaniam, Balachundhar, Eikermann, Matthias

المصدر: BMJ open. 10(7)

مصطلحات موضوعية: Humans, Delirium, Azepines, Triazoles, Stroke Volume, Treatment Outcome, Double-Blind Method, Sleep, Pregnancy, Ventricular Function, Left, Adult, Middle Aged, Intensive Care Units, Female, Randomized Controlled Trials as Topic, Orexin Receptor Antagonists, anaesthetics, cardiac surgery, clinical trials, delirium & cognitive disorders, sleep medicine, Sleep Research, Neurosciences, Aging, Clinical Trials and Supportive Activities, Mental Health, Patient Safety, Clinical Research, Behavioral and Social Science, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Clinical Sciences, Public Health and Health Services, Other Medical and Health Sciences

الوصف: 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).

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/3tw9796rTest

المؤلفون: Oh, Jun, Eser, Rana A, Ehrenberg, Alexander J, Morales, Dulce, Petersen, Cathrine, Kudlacek, Jessica, Dunlop, Sara R, Theofilas, Panos, Resende, Elisa DPF, Cosme, Celica, Alho, Eduardo JL, Spina, Salvatore, Walsh, Christine M, Miller, Bruce L, Seeley, William W, Bittencourt, Jackson C, Neylan, Thomas C, Heinsen, Helmut, Grinberg, Lea T

المصدر: Alzheimer's & Dementia. 15(10)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Biological Psychology, Clinical Sciences, Neurosciences, Psychology, Dementia, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, Rare Diseases, Neurodegenerative, Aging, Alzheimer's Disease, Acquired Cognitive Impairment, Sleep Research, 2.1 Biological and endogenous factors, Aetiology, Neurological, Aged, Alzheimer Disease, Autopsy, Brain, Female, Humans, Male, Middle Aged, Neurons, Sleep Wake Disorders, Supranuclear Palsy, Progressive, Tauopathies, Alzheimer's disease, Human, Progressive supranuclear palsy, Corticobasal degeneration, Wake-promoting, Locus coeruleus, Orexin, Histamine, Sleep, Wakefulness, Unbiased stereology, Geriatrics, Clinical sciences, Biological psychology

الوصف: IntroductionSleep-wake disturbances are a common and early feature in Alzheimer's disease (AD). The impact of early tau pathology in wake-promoting neurons (WPNs) remains unclear.MethodsWe performed stereology in postmortem brains from AD individuals and healthy controls to identify quantitative differences in morphological metrics in WPNs. Progressive supranuclear palsy (PSP) and corticobasal degeneration were included as disease-specific controls.ResultsThe three nuclei studied accumulate considerable amounts of tau inclusions and showed a decrease in neurotransmitter-synthetizing neurons in AD, PSP, and corticobasal degeneration. However, substantial neuronal loss was exclusively found in AD.DiscussionWPNs are extremely vulnerable to AD but not to 4 repeat tauopathies. Considering that WPNs are involved early in AD, such degeneration should be included in the models explaining sleep-wake disturbances in AD and considered when designing a clinical intervention. Sparing of WPNs in PSP, a condition featuring hyperinsomnia, suggest that interventions to suppress the arousal system may benefit patients with PSP.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/2ks7q6xcTest

المؤلفون: Connor, Kathryn M, Ceesay, Paulette, Hutzlemann, Jill, Snavely, Duane, Krystal, Andrew D, Trivedi, Madhukar H, Thase, Michael, Lines, Christopher, Herring, W Joseph, Michelson, David

المصدر: The International Journal of Neuropsychopharmacology. 20(8)

مصطلحات موضوعية: Clinical Trials and Supportive Activities, Depression, Mental Health, Brain Disorders, Clinical Research, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Mental health, Adult, Antidepressive Agents, Depressive Disorder, Major, Double-Blind Method, Female, Humans, Male, Middle Aged, Orexin Receptor Antagonists, Piperidines, Proof of Concept Study, Pyrimidines, Treatment Failure, Young Adult, depression, filorexant, MK-6096, orexin receptor antagonist, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry

الوصف: BackgroundWe evaluated the orexin receptor antagonist filorexant (MK-6096) for treatment augmentation in patients with major depressive disorder.MethodsWe conducted a 6-week, double-blind, placebo-controlled, parallel-group, Phase II, proof-of-concept study. Patients with major depressive disorder (partial responders to ongoing antidepressant therapy) were randomized 1:1 to once-daily oral filorexant 10 mg or matching placebo.ResultsDue to enrollment challenges, the study was terminated early, resulting in insufficient statistical power to detect a prespecified treatment difference; of 326 patients planned, 129 (40%) were randomized and 128 took treatment. There was no statistically significant difference in the primary endpoint of change from baseline to week 6 in Montgomery Asberg Depression Rating Scale total score; the estimated treatment difference for filorexant-placebo was -0.7 (with negative values favoring filorexant) (P=.679). The most common adverse events were somnolence and suicidal ideation.ConclusionsThe interpretation of the results is limited by the enrollment, which was less than originally planned, but the available data do not suggest efficacy of orexin receptor antagonism with filorexant for the treatment of depression. (Clinical Trial Registry: clinicaltrials.gov: NCT01554176).

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/8f82d87gTest

المؤلفون: Jeremy A. Bigalke, Zhiying Shan, Jason R. Carter

المصدر: Hypertension (Dallas, Tex. : 1979). 79(12)

مصطلحات موضوعية: Orexins, Sympathetic Nervous System, Orexin Receptors, Sleep Initiation and Maintenance Disorders, Internal Medicine, Animals, Humans, Orexin Receptor Antagonists, Sleep

الوصف: Inadequate sleep duration and quality are associated with reduced cardiovascular health and increased mortality. Experimental evidence points to the sympathetic nervous system as a key mediator in the observed relationship between poor sleep and cardiovascular dysfunction. However, brain mechanisms underpinning the impaired sympathetic function associated with poor sleep remain unclear. Recent evidence suggests the central orexin system, particularly orexins A and B and their receptors, have a key regulatory role for sleep in animal and human models. While orexin system activity has been observed to significantly impact sympathetic regulation in animals, the extension of these findings to humans has been difficult due to an inability to directly assess orexin system activity in humans. However, direct measures of sympathetic activity in populations with narcolepsy and chronic insomnia, 2 sleep disorders associated with deficient and excessive orexin neural activity, have allowed indirect assessment of the relationships between orexin, sleep, and sympathetic regulation. Further, the recent pharmaceutical development of dual orexin receptor antagonists for use in clinical insomnia populations offers an unprecedented opportunity to examine the mechanistic role of orexin in sleep and cardiovascular health in humans. The current review assesses the role of orexin in both sleep and sympathetic regulation from a translational perspective, spanning animal and human studies. The review concludes with future research directions necessary to fully elucidate the mechanistic role for orexin in sleep and sympathetic regulation in humans.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::fc82e34be38c66d3e4d8b03cead9e225Test
https://pubmed.ncbi.nlm.nih.gov/36148653Test

المؤلفون: James, Morgan H, Mahler, Stephen V, Moorman, David E, Aston-Jones, Gary

المصدر: Current topics in behavioral neurosciences. 33

مصطلحات موضوعية: Animals, Humans, Behavior, Addictive, Orexins, Addiction, Alcohol, Behavioral economics, Cocaine, Dopamine, Drugs of abuse, Glutamate, Heroin, Hypocretin, Motivation, Orexin, Reward, VTA

الوصف: One decade ago, our laboratory provided the first direct evidence linking orexin/hypocretin signaling with drug seeking by showing that activation of these neurons promotes conditioned morphine-seeking behavior. In the years since, contributions from many investigators have revealed roles for orexins in addiction for all drugs of abuse tested, but only under select circumstances. We recently proposed that orexins play a fundamentally unified role in coordinating "motivational activation" under numerous behavioral conditions, and here we unpack this hypothesis as it applies to drug addiction. We describe evidence collected over the past 10 years that elaborates the role of orexin in drug seeking under circumstances where high levels of effort are required to obtain the drug, or when motivation for drug reward is augmented by the presence of external stimuli like drug-associated cues/contexts or stressors. Evidence from studies using traditional self-administration and reinstatement models, as well as behavioral economic analyses of drug demand elasticity, clearly delineates a role for orexin in modulating motivational, rather than the primary reinforcing aspects of drug reward. We also discuss the anatomical interconnectedness of the orexin system with wider motivation and reward circuits, with a particular focus on how orexin modulates prefrontal and other glutamatergic inputs onto ventral tegmental area dopamine neurons. Last, we look ahead to the next decade of the research in this area, highlighting the recent FDA approval of the dual orexin receptor antagonist suvorexant (Belsomra®) for the treatment of insomnia as a promising sign of the potential clinical utility of orexin-based therapies for the treatment of addiction.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/0b22856gTest

المؤلفون: Herring, W Joseph, Connor, Kathleen M, Snyder, Ellen, Snavely, Duane B, Zhang, Ying, Hutzelmann, Jill, Matzura-Wolfe, Deborah, Benca, Ruth M, Krystal, Andrew D, Walsh, James K, Lines, Christopher, Roth, Thomas, Michelson, David

المصدر: Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine. 12(9)

مصطلحات موضوعية: Humans, Sleep Initiation and Maintenance Disorders, Azepines, Triazoles, Treatment Outcome, Double-Blind Method, Dose-Response Relationship, Drug, Adolescent, Adult, Aged, Middle Aged, Female, Male, Young Adult, Sleep Aids, Pharmaceutical, insomnia, orexin, pharmacotherapy, randomized controlled trial, sleep, suvorexant, Aging, Clinical Trials and Supportive Activities, Neurosciences, Sleep Research, Clinical Research, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Clinical Sciences, Other Medical and Health Sciences, Psychology, Neurology & Neurosurgery

الوصف: Study objectivesSuvorexant is an orexin receptor antagonist approved for treating insomnia at a maximum dose of 20 mg. Phase-3 trials evaluated two age-adjusted (non-elderly/elderly) dose-regimes of 40/30 mg and 20/15 mg with the primary focus on 40/30 mg. We report here results from pooled analyses of the 20/15 mg dose-regime, which was evaluated as a secondary objective in the trials.MethodsPrespecified analysis of pooled data from two identical randomized, double-blind, placebo-controlled, parallel-group, 3-month trials in non-elderly (18-64 years) and elderly (≥ 65 years) patients with insomnia. Patients were randomized to suvorexant 20/15 mg (non-elderly/elderly), suvorexant 40/30 mg (non-elderly/elderly), or placebo; by design, fewer patients were randomized to 20/15 mg. Efficacy was assessed by self-reported and polysomnography (PSG; subset of patients) sleep maintenance and onset endpoints.ResultsSuvorexant 20/15 mg (N = 493 treated) was effective compared to placebo (N = 767 treated) on patient-reported and PSG sleep maintenance and onset endpoints at Night-1 (PSG endpoints) / Week-1 (subjective endpoints), Month-1 and Month-3, except for effects on PSG sleep onset at Month-3. Suvorexant 20/15 mg was generally well tolerated, with 3% of patients discontinuing due to adverse events over 3 months vs. 5.2% on placebo. Somnolence was the most common adverse event (6.7% vs. 3.3% for placebo). There was no systematic evidence of rebound or withdrawal signs or symptoms when suvorexant was discontinued after 3 months of nightly use.ConclusionsSuvorexant 20/15 mg improved sleep onset and maintenance over 3 months of nightly treatment and was generally safe and well tolerated.Clinical trial registrationClinicalTrials.gov trial registration numbers: NCT01097616, NCT01097629.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/9jw0n75rTest

المؤلفون: van der Hoeven, Adrienne Elisabeth, van Waaij, Kevin, Bijlenga, Denise, Roelandse, Frederik Willem Cornelis, Overeem, Sebastiaan, Bakker, Jaap Adriaan, Fronczek, Rolf, Lammers, Gert-Jan

المصدر: van der Hoeven , A E , van Waaij , K , Bijlenga , D , Roelandse , F W C , Overeem , S , Bakker , J A , Fronczek , R & Lammers , G-J 2022 , ' Hypocretin-1 measurements in cerebrospinal fluid using radioimmunoassay : within and between assay reliability and limit of quantification ' , Sleep , vol. 45 , no. 7 , zsac103 . https://doi.org/10.1093/sleep/zsac103Test

مصطلحات موضوعية: Humans, Iodine Radioisotopes, Narcolepsy/cerebrospinal fluid, Orexins/cerebrospinal fluid, Pharmaceutical Preparations, Radioimmunoassay/methods, Reproducibility of Results, Retrospective Studies, orexin-A, narcolepsy, inter-assay coefficient of variation, intra-assay coefficient of variation

الوصف: STUDY OBJECTIVES: The most sensitive and specific investigative method for the diagnosis of narcolepsy type 1 (NT1) is the determination of hypocretin-1 (orexin-A) deficiency (≤110 pg/mL) in cerebrospinal fluid using a radioimmunoassay (RIA). We aimed to assess the reliability of the Phoenix Pharmaceuticals hypocretin-1 RIA, by determining the lower limit of quantification (LLOQ), the variability around the cutoff of 110 pg/mL, and the inter- and intra-assay variability. METHODS: Raw data of 80 consecutive hypocretin-1 RIAs were used to estimate the intra- and inter-assay coefficient of variation (CV). The LLOQ was established and defined as the lowest converted concentration with a CV <25%; the conversion is performed using a harmonization sample which is internationally used to minimize variation between RIAs. RESULTS: The mean intra-assay CV was 4.7%, while the unconverted inter-assay CV was 28.3% (18.5% excluding 2 outliers) and 7.5% when converted to international values. The LLOQ was determined as 27.9 pg/mL. The intra-assay CV of RIAs with lower specific radioactive activity showed a median of 5.6% (n = 41, range 1.6%-17.0%), which was significantly higher than in RIAs with higher specific activity (n = 36; median 3.2%, range 0.4%-11.6%, p = .013). The CV around the 110 pg/mL cutoff was <7%. CONCLUSIONS: Hypocretin-1 RIAs should always be harmonized using standard reference material. The specific activity of an RIA has a significant impact on its reliability, because of the decay of 125I radioactivity. Values around the hypocretin-1 cut-off can reliably be measured. Hypocretin-1 concentrations below 28 pg/mL should be reported as "undetectable" when measured with the Phoenix Pharmaceuticals RIA. CLINICAL TRIAL INFORMATION: This study is not registered in a clinical trial register, as it has a retrospective database design.

وصف الملف: application/pdf

العلاقة: https://research.tue.nl/en/publications/2e7b6004-f3fd-4eae-aa19-58d9a7374e76Test

الإتاحة: https://doi.org/10.1093/sleep/zsac103Test
https://research.tue.nl/en/publications/2e7b6004-f3fd-4eae-aa19-58d9a7374e76Test
https://pure.tue.nl/ws/files/209876487/zsac103.pdfTest
http://www.scopus.com/inward/record.url?scp=85134425919&partnerID=8YFLogxKTest