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Levinsohn EA, Radhakrishnan V, Euting H, Kaplan GB. Pharmacological Management of Sleep-Wake Disturbances in Delirium. J Clin Pharmacol 2025; 65:285-302. [PMID: 39415561 DOI: 10.1002/jcph.6151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Accepted: 09/20/2024] [Indexed: 10/18/2024]
Abstract
Delirium is a heterogeneous syndrome primarily characterized by fluctuations in attention and awareness. Sleep-wake disturbances are a common and significant feature of delirium and can manifest as circadian rhythm inversion, sleep fragmentation, and reduced rapid eye movement (REM) and slow-wave sleep. Some literature suggests that the relationship between sleep disruption and delirium is reciprocal wherein the two reinforce one another and may share an underlying etiology. As there are no FDA-approved medications for delirium or delirium-related sleep disturbances, management is primarily focused on addressing underlying medical concerns and promoting physiologic circadian patterns with non-pharmacological behavioral interventions. In practice, however, medications are often used, albeit with limited evidence to support their use. This literature review explores the pharmacology and pharmacokinetics of several medications with literature investigating their use in delirium: melatonin, ramelteon, dual orexin receptor antagonists (DORAs), and dexmedetomidine. Current evidence suggests a possible benefit of ramelteon or melatonin, dexmedetomidine for patients in the ICU setting, and DORAs as therapeutic options for the re-regulation of sleep-wake cycle disruption in delirium. We discuss pertinent pharmacokinetic and pharmacodynamic factors that may influence clinical decision-making regarding these interventions.
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Affiliation(s)
- Erik A Levinsohn
- Department of Psychiatry, University of California San Francisco Medical Center, San Francisco, CA, USA
- Department of Psychiatry and Behavioral Sciences, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA
| | - Varsha Radhakrishnan
- Department of Psychiatry, Tufts Medical Center, Boston, MA, USA
- Department of Psychiatry, Tufts University School of Medicine, Boston, MA, USA
| | - Haley Euting
- Psychiatry Service, VA Boston Healthcare System, West Roxbury, MA, USA
- Department of Psychiatry, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Gary B Kaplan
- Psychiatry Service, VA Boston Healthcare System, West Roxbury, MA, USA
- Department of Psychiatry, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA
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Chen P, Wang W, Ban W, Zhang K, Dai Y, Yang Z, You Y. Deciphering Post-Stroke Sleep Disorders: Unveiling Neurological Mechanisms in the Realm of Brain Science. Brain Sci 2024; 14:307. [PMID: 38671959 PMCID: PMC11047862 DOI: 10.3390/brainsci14040307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 03/15/2024] [Accepted: 03/17/2024] [Indexed: 04/28/2024] Open
Abstract
Sleep disorders are the most widespread mental disorders after stroke and hurt survivors' functional prognosis, response to restoration, and quality of life. This review will address an overview of the progress of research on the biological mechanisms associated with stroke-complicating sleep disorders. Extensive research has investigated the negative impact of stroke on sleep. However, a bidirectional association between sleep disorders and stroke exists; while stroke elevates the risk of sleep disorders, these disorders also independently contribute as a risk factor for stroke. This review aims to elucidate the mechanisms of stroke-induced sleep disorders. Possible influences were examined, including functional changes in brain regions, cerebrovascular hemodynamics, neurological deficits, sleep ion regulation, neurotransmitters, and inflammation. The results provide valuable insights into the mechanisms of stroke complicating sleep disorders.
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Affiliation(s)
- Pinqiu Chen
- Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, School of Pharmacy, Yantai University, Yantai 264005, China; (P.C.)
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China
| | - Wenyan Wang
- Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, School of Pharmacy, Yantai University, Yantai 264005, China; (P.C.)
| | - Weikang Ban
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China
| | - Kecan Zhang
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China
| | - Yanan Dai
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China
| | - Zhihong Yang
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China
| | - Yuyang You
- School of Automation, Beijing Institute of Technology, Beijing 100081, China
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Du L, He X, Fan X, Wei X, Xu L, Liang T, Wang C, Ke Y, Yung WH. Pharmacological interventions targeting α-synuclein aggregation triggered REM sleep behavior disorder and early development of Parkinson's disease. Pharmacol Ther 2023; 249:108498. [PMID: 37499913 DOI: 10.1016/j.pharmthera.2023.108498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 06/24/2023] [Accepted: 07/18/2023] [Indexed: 07/29/2023]
Abstract
Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by elevated motor behaviors and dream enactments in REM sleep, often preceding the diagnosis of Parkinson's disease (PD). As RBD could serve as a biomarker for early PD developments, pharmacological interventions targeting α-synuclein aggregation triggered RBD could be applied toward early PD progression. However, robust therapeutic guidelines toward PD-induced RBD are lacking, owing in part to a historical paucity of effective treatments and trials. We reviewed the bidirectional links between α-synuclein neurodegeneration, progressive sleep disorders, and RBD. We highlighted the correlation between RBD development, α-synuclein aggregation, and neuronal apoptosis in key brainstem regions involved in REM sleep atonia maintenance. The current pharmacological intervention strategies targeting RBD and their effects on progressive PD are discussed, as well as current treatments for progressive neurodegeneration and their effects on RBD. We also evaluated emerging and potential pharmacological solutions to sleep disorders and developing synucleinopathies. This review provides insights into the mechanisms and therapeutic targets underlying RBD and PD, and explores bidirectional treatment effects for both diseases, underscoring the need for further research in this area.
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Affiliation(s)
- Lida Du
- Institute of Molecular Medicine & Innovative Pharmaceutics, Qingdao University, Qingdao, China; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.
| | - Xiaoli He
- Institute of Medical Plant Development, Peking Union Medical College, Beijing, China
| | - Xiaonuo Fan
- Department of Biology, Boston University, Boston, USA
| | - Xiaoya Wei
- Harvard T.H. Chan School of Public Health, Boston, USA
| | - Linhao Xu
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China; Department of Cardiology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Tuo Liang
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China; Institute of Neurological and Psychiatric Disorders, Shenzhen Bay Laboratory, Shenzhen, China
| | - Chunbo Wang
- Institute of Molecular Medicine & Innovative Pharmaceutics, Qingdao University, Qingdao, China
| | - Ya Ke
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Wing-Ho Yung
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China; Department of Neuroscience, City University of Hong Kong, Hong Kong, China.
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Lo YJ, Mishra VK, Lo HY, Dubey NK, Lo WC. Clinical Spectrum and Trajectory of Innovative Therapeutic Interventions for Insomnia: A Perspective. Aging Dis 2023; 14:1038-1069. [PMID: 37163444 PMCID: PMC10389812 DOI: 10.14336/ad.2022.1203] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 12/03/2022] [Indexed: 05/12/2023] Open
Abstract
Increasing incidences of insomnia in adults, as well as the aging population, have been reported for their negative impact on the quality of life. Insomnia episodes may be associated with neurocognitive, musculoskeletal, cardiovascular, gastrointestinal, renal, hepatic, and metabolic disorders. Epidemiological evidence also revealed the association of insomnia with oncologic and asthmatic complications, which has been indicated as bidirectional. Two therapeutic approaches including cognitive behavioral therapy (CBT) and drugs-based therapies are being practiced for a long time. However, the adverse events associated with drugs limit their wide and long-term application. Further, Traditional Chinese medicine, acupressure, and pulsed magnetic field therapy may also provide therapeutic relief. Notably, the recently introduced cryotherapy has been demonstrated as a potential candidate for insomnia which could reduce pain, by suppressing oxidative stress and inflammation. It seems that the synergistic therapeutic approach of cryotherapy and the above-mentioned approaches might offer promising prospects to further improve efficacy and safety. Considering these facts, this perspective presents a comprehensive summary of recent advances in pathological aetiologies of insomnia including COVID-19, and its therapeutic management with a greater emphasis on cryotherapy.
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Affiliation(s)
| | | | | | - Navneet Kumar Dubey
- Victory Biotechnology Co., Ltd., Taipei 114757, Taiwan.
- ShiNeo Technology Co., Ltd., New Taipei City 24262, Taiwan.
| | - Wen-Cheng Lo
- Department of Surgery, Division of Neurosurgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
- Department of Neurosurgery, Taipei Medical University Hospital, Taipei 11031, Taiwan.
- Taipei Neuroscience Institute, Taipei Medical University, Taipei 11031, Taiwan.
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Okuda S, Qureshi ZP, Yanagida Y, Ito C, Homma Y, Tokita S. Hypnotic prescription trends and patterns for the treatment of insomnia in Japan: analysis of a nationwide Japanese claims database. BMC Psychiatry 2023; 23:278. [PMID: 37081408 PMCID: PMC10120113 DOI: 10.1186/s12888-023-04683-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 03/14/2023] [Indexed: 04/22/2023] Open
Abstract
BACKGROUND There is limited consensus regarding the optimal treatment of insomnia. The recent introduction of orexin receptor antagonists (ORA) has increased the available treatment options. However, the prescribing patterns of hypnotics in Japan have not been comprehensively assessed. We performed analyses of a claims database to investigate the real-world use of hypnotics for treating insomnia in Japan. METHODS Data were retrieved for outpatients (aged ≥ 20 to < 75 years old) prescribed ≥ 1 hypnotic for a diagnosis of insomnia between April 1st, 2009 and March 31st, 2020, with ≥ 12 months of continuous enrolment in the JMDC Claims Database. Patients were classified as new or long-term users of hypnotics. Long-term use was defined as prescription of the same mechanism of action (MOA) for ≥ 180 days. We analyzed the trends (2010-2019) and patterns (2018-2019) in hypnotics prescriptions. RESULTS We analyzed data for 130,177 new and 91,215 long-term users (2010-2019). Most new users were prescribed one MOA per year (97.1%-97.9%). In 2010, GABAA-receptor agonists (benzodiazepines [BZD] or z-drugs) were prescribed to 94.0% of new users. Prescriptions for BZD declined from 54.8% of patients in 2010 to 30.5% in 2019, whereas z-drug prescriptions remained stable (~ 40%). Prescriptions for melatonin receptor agonist increased slightly (3.2% to 6.3%). Prescriptions for ORA increased over this time from 0% to 20.2%. Prescriptions for BZD alone among long-term users decreased steadily from 68.3% in 2010 to 49.7% in 2019. Prescriptions for ORA were lower among long-term users (0% in 2010, 4.3% in 2019) relative to new users. Using data from 2018-2019, multiple (≥ 2) MOAs were prescribed to a higher proportion of long-term (18.2%) than new (2.8%) users. The distribution of MOAs according to psychiatric comorbidities, segmented by age or sex, revealed higher proportions of BZD prescriptions in elderly (new and long-term users) and male (new users) patients in all comorbidity segments. CONCLUSION Prescriptions for hypnotics among new and long-term users in Japan showed distinct patterns and trends. Further understanding of the treatment options for insomnia with accumulating evidence for the risk-benefit balance might be beneficial for physicians prescribing hypnotics in real-world settings.
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Affiliation(s)
| | - Zaina P Qureshi
- Center for Observational and Real-World Evidence (CORE), Merck & Co., Inc., Rahway, NJ, USA
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Gupta M, Gupta N, Fradkin Y, Petti T. Sleep Disturbances in Children and Adolescents with Autism
Spectrum Disorder: An Overview for Clinicians. ADOLESCENT PSYCHIATRY 2023; 13:1-24. [DOI: 10.2174/2210676613666230126115646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 09/12/2022] [Accepted: 10/27/2022] [Indexed: 01/28/2023]
Abstract
Background:
Sleep disorders in autism spectrum disorders (ASD/SD) are
distinct, broad, and highly variable clinical entities that ubiquitously affect core
symptomatology, development of comorbid disorders, and overall quality of life for affected
children and families. High genetic predisposition and the presence of co-occurring
disorders present significant challenges in assessment and appropriate interventions.
Objective:
The study aimed to review the best available evidence and address the clinical
gaps in the knowledge about sleep disorders in children and adolescents with autism
spectrum disorders.
Methods:
The review provides a comprehensive literature search of 1622 articles and
summarizes 110 selected for empirical evidence to methodically consider critical aspects of
sleep disorders in ASD for informing clinicians of useful information.
Results:
Clinicians have insufficient guidance and support to effectively manage sleep
disruptions in ASD youth in practice. Prevalence of sleep disruption in ASD, close to 80%, is
characterized by unique subtypes, including but not limited to obstructive sleep apnea,
circadian rhythm disorders, and sleep-related movement disorders. Greater awareness of sleep
disruption, its neurodevelopmental basis, scope, and impact allows for improved treatment and
prevention efforts of these conditions, and is critical for clinical practice and future research.
The bidirectional nature of disruptive sleep and ASD is considered a major area requiring
further clarification.
Conclusion:
Clinician-friendly screening tools are needed for everyday office practice to
identify ASD/SD conditions and interventions, and mitigate harmful effects.
Psychoeducational and cognitive-behavioral approaches for improving and supporting
healthy sleep hygiene, considered the first line of treatment, are detailed. The weak database
for the use of psychopharmacologic agents is summarized, and the strength of prescribing
prolonged-release melatonin for optimal results is described. The promise of other
medications is discussed.
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Affiliation(s)
- Mayank Gupta
- Department of Psychiatry, Clarion Psychiatric Center, Clarion, PA, USA
| | - Nihit Gupta
- Department of Psychiatry,
West Virginia University, Reynolds Memorial Hospital, Glendale, WV, USA
| | - Yuli Fradkin
- Department of
Psychiatry, Rutgers University-Robert Wood Johnson Medical School, Piscataway, NJ, USA
| | - Theodore Petti
- Department of
Psychiatry, Rutgers University-Robert Wood Johnson Medical School, Piscataway, NJ, USA
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Okuda S, Qureshi ZP, Yanagida Y, Ito C, Homma Y, Tokita S. Factors Associated with Prescriptions for an Orexin Receptor Antagonist Among Japanese Patients with Insomnia: Analysis of a Nationwide Japanese Claims Database. Drugs Real World Outcomes 2023:10.1007/s40801-023-00356-4. [PMID: 36867350 PMCID: PMC9982805 DOI: 10.1007/s40801-023-00356-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/30/2023] [Indexed: 03/04/2023] Open
Abstract
BACKGROUND Few studies have examined the prescribing patterns of orexin receptor antagonists (ORAs) in the real-world clinical setting in Japan. OBJECTIVE We sought to analyze the factors associated with ORA prescriptions for patients with insomnia in Japan. METHODS Outpatients (aged ≥ 20 to < 75 years old) prescribed one or more hypnotic for insomnia between April 1, 2018 and March 31, 2020 with continuous enrollment for ≥ 12 months were extracted from the JMDC Claims Database. We performed multivariable logistic regression to identify factors (patient demographics and psychiatric comorbidities) associated with ORA prescription in new or non-new users of hypnotics (patients without or with hypnotics prescription history, respectively). RESULTS Of 58,907 new users, 11,589 (19.7%) were prescribed ORA at the index date. Male sex (odds ratio [OR] 1.17, 95% confidence interval [CI] 1.12-1.22) and presence of bipolar disorders (OR 1.36, 95% CI 1.20-1.55) were associated with greater odds of ORA prescription. Among 88,611 non-new users, 15,504 (17.5%) were prescribed ORA at the index date. Younger age and several psychiatric comorbidities, such as neurocognitive disorders (OR 1.64, 95% CI 1.15-2.35), substance use disorders (OR 1.19, 95% CI 1.05-1.35), bipolar disorders (OR 1.14, 95% CI 1.07-1.22), schizophrenia spectrum disorders (OR 1.07, 95% CI 1.01-1.14), and anxiety disorders (OR 1.05, 95% CI 1.00-1.10), were associated with greater odds of ORA prescription. CONCLUSION This is the first study to determine the factors associated with ORA prescriptions in Japan. Our findings could help guide appropriate insomnia treatment using ORAs.
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Affiliation(s)
| | - Zaina P. Qureshi
- Center for Observational and Real-world Evidence (CORE), Merck & Co., Inc., Rahway, NJ USA
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Han AH, Burroughs CR, Falgoust EP, Hasoon J, Hunt G, Kakazu J, Lee T, Kaye AM, Kaye AD, Ganti L. Suvorexant, a Novel Dual Orexin Receptor Antagonist, for the Management of Insomnia. Health Psychol Res 2023; 10:67898. [PMID: 36726477 PMCID: PMC9886170 DOI: 10.52965/001c.67898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Purpose of Review The present investigation is a comprehensive review regarding the use of Suvorexant for insomnia treatment. It covers the background, pathophysiology, and significance of addressing insomnia, the pharmaceutical details of Suvorexant, and its safety, efficacy, and implications in treating insomnia. We further discuss Suvorexant's role in targeting insomnia with other comorbidities. Recent Findings Insomnia refers to poor quality and/or quantity of sleep. While there are many existing treatments such as benzodiazepines, melatonin agonists, TCAs, and atypical antipsychotics used to target various receptors involved in normal induction and maintenance of sleep, Suvorexant is an antagonist that specifically targets orexin receptors. Recent clinical studies suggest that Suvorexant is both clinically safe and effective. Quantity and quality of sleep are measured in various ways, yet the consensus points towards Suvorexant's effectiveness in improving sleep time, onset, latency, and quality compared to placebo. In addition to helping improve isolated insomnia, Suvorexant helps improve sleep in patients that have other comorbidities such as obstructive sleep apnea, Alzheimer's disease, dementia, acute stroke, and delirium. While Suvorexant is safe, there are still adverse effects associated with the drug that needs to be considered. The most common adverse effects include dizziness, somnolence, headaches, and cognitive impairment. Summary Insomnia is a major public health concern that affects many people worldwide and has been linked to many adverse health outcomes. While there are existing treatments that target different receptors and pathways of normal sleep induction and maintenance, Suvorexant is a novel drug that targets dual orexin receptors. Its safety and efficacy, mechanism of action, pharmacokinetic parameters, and relative lack of rebound and withdrawal effects render suvorexant a reliable choice for the treatment of insomnia.
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Affiliation(s)
- Andrew H. Han
- Georgetown University School of Medicine, Washington, DC
| | | | - Evan P. Falgoust
- AnesthesiologyLouisiana State University Shreveport, Shreveport, LA
| | - Jamal Hasoon
- AnesthesiologyCritical Care, and Pain Medicine, , Beth Israel Deaconess Medical Center, Boston, MA
| | - Grace Hunt
- AnesthesiologyLouisiana State University Shreveport, Shreveport, LA
| | - Juyeon Kakazu
- Georgetown University School of Medicine, Washington, DC
| | - Tim Lee
- NeurologyHCA Florida Osceola Hospital, & University of Central Florida College of Medicine, Orlando, FL
| | - Adam M. Kaye
- Pharmacy PracticeThomas J. Long School of Pharmacy and Health Sciences, University of the Pacific, Stockton, CA
| | - Alan D. Kaye
- AnesthesiologyLouisiana State University Shreveport, Shreveport, LA
| | - Latha Ganti
- NeurologyHCA Florida Osceola Hospital, & University of Central Florida College of Medicine, Orlando, FL
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Qin L, Luo Y, Chang H, Zhang H, Zhu Z, Du Y, Liu K, Wu H. The association between serum orexin-A levels and sleep quality in pregnant women. Sleep Med 2023; 101:93-98. [PMID: 36368074 DOI: 10.1016/j.sleep.2022.10.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 10/07/2022] [Accepted: 10/21/2022] [Indexed: 11/09/2022]
Abstract
OBJECTIVE/BACKGROUND Orexin has been shown to regulate the sleep-wake cycle, and it may play a major role in the pathogenesis of sleep disorders; however, its role in sleep disorders in pregnant women remains unclear. We aimed to assess the relationship between serum orexin-A (OXA) levels and sleep quality in pregnant women. PATIENTS/METHODS This study comprised 214 enrolled pregnant women (poor sleep quality, n = 125; no poor sleep quality, n = 89). We assessed participants' sleep quality and depression and anxiety levels. OXA levels were measured using enzyme-linked immunosorbent assay. RESULTS Women in the poor sleep quality group showed higher serum OXA levels (0.33[0.3] vs. 0.27[0.11], P < 0.001) than those in the no poor sleep quality group. Binary regression analysis showed that the higher the OXA levels (odds ratio [OR] 1.385, 95% CI [confidence interval] 1.160-1.655) and Zung Self-Rating Anxiety Scale scores (OR 1.073, 95% CI 1.009-1.140), the greater the risk of sleep quality in pregnant women. First-trimester OXA levels differed significantly from those in the second and third trimesters (P < 0.05). CONCLUSION Serum OXA levels were higher in pregnant women with poor sleep quality than in those without poor sleep quality. OXA levels were also higher in the second and third trimesters than in the first trimester.
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Affiliation(s)
- Liwei Qin
- Department of Nursing, The First Affiliated Hospital of Xinxiang Medical University, Weihui, 453100, China
| | - Yanyan Luo
- School of Nursing, Xinxiang Medical University, Xingxiang, 453003, China.
| | - Hongjuan Chang
- School of Nursing, Xinxiang Medical University, Xingxiang, 453003, China
| | - Hongxing Zhang
- School of Psychology, Xinxiang Medical University, Xingxiang, 453003, China
| | - Zhiling Zhu
- Department of Nursing, Xinxiang Central Hospital, Xinxiang, 453000, China
| | - Yishen Du
- Department of Nursing, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453003, China
| | - Kaili Liu
- School of Nursing, Xinxiang Medical University, Xingxiang, 453003, China
| | - Huimin Wu
- School of Nursing, Xinxiang Medical University, Xingxiang, 453003, China
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Yoshioka R, Yamamoto S, Nakatani E. Effectiveness of suvorexant versus benzodiazepine receptor agonist sleep drugs in reducing the risk of hip fracture: Findings from a regional population-based cohort study. PLoS One 2023; 18:e0284726. [PMID: 37093840 PMCID: PMC10124872 DOI: 10.1371/journal.pone.0284726] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Accepted: 04/05/2023] [Indexed: 04/25/2023] Open
Abstract
Sleep drugs are often necessary to treat insomnia in older patients. Benzodiazepine receptor agonists (BZRAs) are primarily used for insomnia in these patients, but there are concerns regarding their association with delirium and bone fractures. Among sleep drugs, orexin receptor antagonists such as suvorexant have a lower risk of delirium than BZRAs, but their effectiveness in preventing hip fractures is unknown. Hip fracture is a life-threatening trauma in advanced-age patients and a social problem. Therefore, we investigated the relationship between suvorexant and hip fracture. The Shizuoka Kokuho Database was used to compare the time to hip fracture in patients who had been newly taking suvorexant and other sleep drugs such as benzodiazepines since November 2014. A proportional hazards model for hip fracture as an outcome was used to estimate the hazard ratio. Propensity scores were estimated using a logistic regression model, and the confounding factors were age, sex, several comorbidities, and each oral medication. The suvorexant group comprised 6860 patients (110 with hip fracture), and the BZRA group (benzodiazepines and Z-drugs) comprised 50,203 patients (1487 with hip fracture). In the matched cohort (6855:6855 patients), 259 and 249 patients in the suvorexant and BZRA group developed hip fractures during the observational period, respectively. The hazard ratio of the suvorexant group compared with the BZRA group was 1.48 (95% confidence interval, 1.20-1.82). In the subgroup analysis, patients in the suvorexant group had a higher risk of hip fracture if they were aged >75 years, had no diabetes, had no neurological disease, had no renal failure, had liver disease, had hypertension, were not taking alpha 1 blockers, and were not taking oral steroids. Among people in the Japanese regional population who use sleep drugs, patients taking suvorexant can be at higher risk of hip fracture than patients taking BZRAs.
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Affiliation(s)
- Ryozo Yoshioka
- Graduate School of Public Health, Shizuoka Graduate University of Public Health, Aoi-ku, Shizuoka, Japan
- Department of Emergency Medicine, Shizuoka General Hospital, Aoi-ku, Shizuoka, Japan
| | - Seiichiro Yamamoto
- Graduate School of Public Health, Shizuoka Graduate University of Public Health, Aoi-ku, Shizuoka, Japan
| | - Eiji Nakatani
- Graduate School of Public Health, Shizuoka Graduate University of Public Health, Aoi-ku, Shizuoka, Japan
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11
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Stoops WW, Strickland JC, Hatton KW, Hays LR, Rayapati AO, Lile JA, Rush CR. Suvorexant maintenance enhances the reinforcing but not subjective and physiological effects of intravenous cocaine in humans. Pharmacol Biochem Behav 2022; 220:173466. [PMID: 36152876 PMCID: PMC9588557 DOI: 10.1016/j.pbb.2022.173466] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 09/19/2022] [Accepted: 09/19/2022] [Indexed: 10/14/2022]
Abstract
Preclinical research has sought to understand the role of the orexin system in cocaine addiction given the connection between orexin producing cells in the lateral hypothalamus and brain limbic areas. Exogenous administration of orexin peptides increased cocaine self-administration whereas selective orexin-1 receptor antagonists reduced cocaine self-administration in non-human animals. The first clinically available orexin antagonist, suvorexant (a dual orexin-1 and orexin-2 receptor antagonist), attenuated motivation for cocaine and cocaine conditioned place preference, as well as cocaine-associated impulsive responding, in rodents. This study aimed to translate those preclinical findings and determine whether suvorexant maintenance altered the pharmacodynamic effects of cocaine in humans. Seven non-treatment seeking subjects with cocaine use disorder completed this within-subject human laboratory study, and a partial data set was obtained from one additional subject. Subjects were maintained for at least three days on 0, 5, 10 and 20 mg oral suvorexant administered at 2230 h daily in random order. Subjects completed experimental sessions in which cocaine self-administration of 0, 10 and 30 mg/70 kg of intravenous cocaine was evaluated on a concurrent progressive ratio drug versus money choice task. Subjective and physiological effects of cocaine were also determined. Cocaine functioned as a reinforcer and produced prototypic dose-related subjective and physiological effects (e.g., increased ratings of "Stimulated" and heart rate). Suvorexant (10, 20 mg) increased self-administration of 10 mg/70 kg cocaine and decreased oral temperature but did not significantly alter any other effects of cocaine. Future research may seek to evaluate the effects of orexin-1 selective antagonists in combination with cocaine.
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Affiliation(s)
- William W Stoops
- Department of Behavioral Science, University of Kentucky College of Medicine, 1100 Veterans Drive, Medical Behavioral Science Building, Lexington, KY 40536-0086, USA; Department of Psychiatry, University of Kentucky College of Medicine, 245 Fountain Court, Lexington, KY 40509-1810, USA; Department of Psychology, University of Kentucky College of Arts and Sciences, 171 Funkhouser Drive, Lexington, KY 40506-0044, USA; Center on Drug and Alcohol Research, University of Kentucky College of Medicine, 845 Angliana Avenue, Lexington, KY 40508, USA.
| | - Justin C Strickland
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 5510 Nathan Shock Drive, Baltimore, MD 21224, USA
| | - Kevin W Hatton
- Department of Anesthesiology, University of Kentucky College of Medicine, 800 Rose Street, Lexington, KY 40536, USA
| | - Lon R Hays
- Department of Psychiatry, University of Kentucky College of Medicine, 245 Fountain Court, Lexington, KY 40509-1810, USA
| | - Abner O Rayapati
- Department of Psychiatry, University of Kentucky College of Medicine, 245 Fountain Court, Lexington, KY 40509-1810, USA
| | - Joshua A Lile
- Department of Behavioral Science, University of Kentucky College of Medicine, 1100 Veterans Drive, Medical Behavioral Science Building, Lexington, KY 40536-0086, USA; Department of Psychiatry, University of Kentucky College of Medicine, 245 Fountain Court, Lexington, KY 40509-1810, USA; Department of Psychology, University of Kentucky College of Arts and Sciences, 171 Funkhouser Drive, Lexington, KY 40506-0044, USA
| | - Craig R Rush
- Department of Behavioral Science, University of Kentucky College of Medicine, 1100 Veterans Drive, Medical Behavioral Science Building, Lexington, KY 40536-0086, USA; Department of Psychiatry, University of Kentucky College of Medicine, 245 Fountain Court, Lexington, KY 40509-1810, USA; Department of Psychology, University of Kentucky College of Arts and Sciences, 171 Funkhouser Drive, Lexington, KY 40506-0044, USA
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12
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Okino K, Suzuki H, Kondo S, Tomioka H, Tokumasu T, Yamada H, Iwanami A, Inamoto A. Effectiveness of change from suvorexant to lemborexant drug in the treatment of sleep disorders. Psychogeriatrics 2022; 22:595-604. [PMID: 35689366 DOI: 10.1111/psyg.12858] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 04/28/2022] [Accepted: 05/19/2022] [Indexed: 11/30/2022]
Abstract
BACKGROUND This study aimed to examine the effects of a change in medication from suvorexant to lemborexant among patients with insomnia. METHODS Patients with chronic insomnia who had persistent insomnia for 3 months or longer and who had been taking suvorexant for 3 months or longer were selected. The participants were divided into two groups: the 'modified' group and the 'non-modified' group. Four sub-types of insomnia (i.e., difficulty initiating sleep, difficulty maintaining sleep, early-morning awakening, and non-restorative sleep) were investigated. Logistic regression was used to investigate improvements in both the groups after 12 weeks. RESULTS Among the 77 participants, 43 and 34 patients were in the modified drug group and the non-modified drug group, respectively. Comparing sleep disorders between the two groups, we found significant improvement after 12 weeks in the modified drug group in terms of difficulty initiating sleep, compared with the non-modified drug group (odds ratio = 0.036, P = 0.008, 95% CI = 0.003-0.415). However, no significant differences were found between the two groups in terms of difficulty maintaining sleep, early-morning awakening, and non-restorative sleep. CONCLUSIONS Sleep disorders can be treated by alleviating difficulties in initiating sleep by changing from suvorexant to lemborexant. In addition, it was confirmed that the drug change caused no serious side effects and that it was highly safe and tolerated.
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Affiliation(s)
- Kazumaro Okino
- Mental Care Center, Showa University Northern Yokohama Hospital, Yokohama-shi, Japan.,Department of Neuropsychiatry, Showa University School of Medicine, Shinagawa-ku, Japan
| | - Hirohisa Suzuki
- Department of Neuropsychiatry, Showa University School of Medicine, Shinagawa-ku, Japan.,Neuropsychiatry, Showa University Karasuyama Hospital, Setagaya-ku, Japan
| | | | - Hiroi Tomioka
- Mental Care Center, Showa University Northern Yokohama Hospital, Yokohama-shi, Japan.,Department of Neuropsychiatry, Showa University School of Medicine, Shinagawa-ku, Japan
| | - Takahiro Tokumasu
- Mental Care Center, Showa University Northern Yokohama Hospital, Yokohama-shi, Japan.,Department of Neuropsychiatry, Showa University School of Medicine, Shinagawa-ku, Japan
| | - Hiroki Yamada
- Mental Care Center, Showa University Northern Yokohama Hospital, Yokohama-shi, Japan.,Department of Neuropsychiatry, Showa University School of Medicine, Shinagawa-ku, Japan
| | - Akira Iwanami
- Department of Neuropsychiatry, Showa University School of Medicine, Shinagawa-ku, Japan.,Neuropsychiatry, Showa University Karasuyama Hospital, Setagaya-ku, Japan
| | - Atsuko Inamoto
- Mental Care Center, Showa University Northern Yokohama Hospital, Yokohama-shi, Japan.,Department of Neuropsychiatry, Showa University School of Medicine, Shinagawa-ku, Japan
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13
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Berger AA, Sottosanti ER, Winnick A, Keefe J, Gilbert E, Hasoon J, Thase ME, Kaye AD, Viswanath O, Urits I. Suvorexant in the Treatment of Difficulty Falling and Staying Asleep (Insomnia). PSYCHOPHARMACOLOGY BULLETIN 2022; 52:68-90. [PMID: 35342199 PMCID: PMC8896749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 02/27/2023]
Abstract
Purpose of Review Insomnia affects more than 10% of the population and causes significant discomfort and disability. Suvorexant is an orexin receptor antagonist that specifically targets the wake-sleep cycle. This review summarizes recent and seminal evidence in the biological and physiological evidence of insomnia, the mechanism of action of suvorexant in treating insomnia, and clinical evidence regarding its use. Recent Findings There is no single clear diagnosis for insomnia, and thus prevalence is not entirely clear, but it is estimated to affect 10%-30% of the adult population. Comorbidities include obesity, diabetes, and various psychiatric conditions, and insomnia likely has a contributing role in these conditions. Insomnia, by definition, impacts sleep quality and also wakefulness, including academic success and work efficiency. Insomnia is likely related to genetic susceptibility and a triggering event, leading to hyper-arousal states and functional brain disturbances. This leads to hyperactivity of the hypothalamic-pituitary-adrenal axis, over-secretion of corticotropin-releasing factor, and aberrancy in neurotransmitter release. Though several pharmacological options exist for the treatment of insomnia, there is equivocal data regarding their efficacy or limits to their use due to side effects and contraindications. Suvorexant is a novel dual orexin receptor antagonist, which is shown to improve sleep by reducing arousals. Unlike classical therapeutics, suvorexant does not alter the sleep profile; it prolongs the time spent in each sleep state. Though it may cause some somnolence, it is milder than reported with other drugs. Summary Multiple clinical studies support the use of suvorexant in insomnia. In primary insomnia, suvorexant is effective (over placebo), as measured by polysomnography and reported by patients, in both attaining and maintaining sleep. Similar, albeit to a smaller degree, results were found in secondary insomnia. Suvorexant carries two significant advantages over existing therapies; it has a much better safety profile in approved doses, and it preserves natural sleep architecture, thus promoting more restful sleep and recovery. Unfortunately, data exists mostly for suvorexant versus placebo, and head-to-head trials with common hypnotics are needed to assess the true efficacy of suvorexant over the alternatives. And while tolerance is less likely to develop, close monitoring of post-marketing data is required to evaluate for long term adverse events and efficacy.
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14
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Shibata S, Oda Y, Ohki N, Ikemizu Y, Hayatsu R, Hirose Y, Iyo M. Narcolepsy-like symptoms triggered by lemborexant in the context of hyperactive delirium in a patient with bipolar depression: a case report. J Clin Sleep Med 2022; 18:1459-1462. [PMID: 35022128 PMCID: PMC9059587 DOI: 10.5664/jcsm.9882] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Lemborexant is a dual orexin antagonist (DORA) and is considered a safe and effective hypnotic. DORAs induce physiological sleep by blocking orexin receptors. Although the blockade of orexin signaling has triggered narcolepsy-like symptoms in rodents, there is currently no evidence of lemborexant inducing narcolepsy-like symptoms in humans. We describe the case of a 79-year-old Japanese woman with bipolar depression who experienced lemborexant-induced cataplexy and sleep attack. Her previous results on the Multiple Sleep Latency Test excluded the diagnosis of narcolepsy. She experienced narcolepsy-like symptoms on two occasions after she was administered lemborexant, in the context of hyperactive delirium, but not in a relaxed state. Her case suggests that lemborexant could trigger narcolepsy-like symptoms in patients with hyperactive delirium, even those with no history of narcolepsy. This case also emphasizes that clinicians must be very careful when they prescribe lemborexant to patients who experience hyperactive delirium.
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Affiliation(s)
- Shintaro Shibata
- Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Yasunori Oda
- Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Nozomi Ohki
- Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Yuki Ikemizu
- Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Ryunosuke Hayatsu
- Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Yuki Hirose
- Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Masaomi Iyo
- Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan
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15
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Sleep dysregulation in binge eating disorder and "food addiction": the orexin (hypocretin) system as a potential neurobiological link. Neuropsychopharmacology 2021; 46:2051-2061. [PMID: 34145404 PMCID: PMC8505614 DOI: 10.1038/s41386-021-01052-z] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 05/26/2021] [Accepted: 05/28/2021] [Indexed: 12/12/2022]
Abstract
It has been proposed that binge eating reflects a pathological compulsion driven by the "addictive" properties of foods. Proponents of this argument highlight the large degree of phenomenological and diagnostic overlap between binge eating disorder (BED) and substance use disorders (SUDs), including loss of control over how much is consumed and repeated unsuccessful attempts to abstain from consumption, as well as commonalities in brain structures involved in food and drug craving. To date, very little attention has been given to an additional behavioral symptom that BED shares with SUDs-sleep dysregulation-and the extent to which this may contribute to the pathophysiology of BED. Here, we review studies examining sleep outcomes in patients with BED, which collectively point to a heightened incidence of sleep abnormalities in BED. We identify the orexin (hypocretin) system as a potential neurobiological link between compulsive eating and sleep dysregulation in BED, and provide a comprehensive update on the evidence linking this system to these processes. Finally, drawing on evidence from the SUD literature indicating that the orexin system exhibits significant plasticity in response to drugs of abuse, we hypothesize that chronic palatable food consumption likewise increases orexin system activity, resulting in dysregulated sleep/wake patterns. Poor sleep, in turn, is predicted to exacerbate binge eating, contributing to a cycle of uncontrolled food consumption. By extension, we suggest that pharmacotherapies normalizing orexin signaling, which are currently being trialed for the treatment of SUDs, might also have utility in the clinical management of BED.
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16
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Use of Suvorexant and Antipsychotics in the Treatment of Delirium After Infectious Diseases: A Retrospective Study. J Clin Psychopharmacol 2021; 41:589-593. [PMID: 34411006 DOI: 10.1097/jcp.0000000000001450] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Delirium is often treated on a subjective basis and per the discretion of the attending physician because of a lack of pharmacological evidence in the literature. To address this knowledge gap, we aimed to examine the efficacy of a hypnotic drug, suvorexant, as a therapeutic agent for the treatment of delirium. METHODS Fifty-seven patients were targeted. Of the 57 patients, 39 were in the subolexant group, 17 in the antipsychotic group, and 1 was taking antidepressants. The Delirium Rating Scale-Revised 98 was used to evaluate the symptoms of delirium before and 3 and 7 days after drug administration. In addition, the medical history, occurrence of adverse effects, white blood cell count, and C-reactive protein level of participants were examined. RESULTS Both drugs exhibited therapeutic effects on delirium, but suvorexant had a more pronounced effect. Furthermore, the suvorexant group exhibited decreased levels of C-reactive protein, suggesting an anti-inflammatory effect. Suvorexant seems to improve the symptoms of inflammation-related delirium without any serious adverse effects, suggesting that it can be explored as a safe treatment option for clinical use in future studies. CONCLUSIONS Our findings will be relevant for physicians interested in learning about new pharmacological treatment options and researchers interested in validating our results.
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17
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Subramanian S, Ravichandran M. Orexin receptors: Targets and applications. Fundam Clin Pharmacol 2021; 36:72-80. [PMID: 34464995 DOI: 10.1111/fcp.12723] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 08/18/2021] [Accepted: 08/26/2021] [Indexed: 01/02/2023]
Abstract
Over the years, elucidating targets from the neural circuits that can be used to treat disorders pertaining to the nervous system and extending their scope to other systems have always proved interesting to researchers. The role of various peptides and neurotransmitters has been elucidated and is being developed as therapeutic targets. Out of these, orexins are neuropeptides produced in the hypothalamus that stimulate a specific type of G-Protein coupled receptors (GPCR) called orexin receptors and bring about various physiological and pathological roles. Orexin receptors are of interest not only because of their wide applications such as insomnia, obesity, and inflammatory disorders but also because of their contribution to promising aspects of drug discovery such as optogenetics and their tremendous growth from the stage of being orphans to orexins. This review will discuss in detail the structure of orexin receptors, their physiological role, and various applications in disease states adding a note on agonists and antagonists and finally summarizing the recent drug approvals in the field.
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Affiliation(s)
- Subhiksha Subramanian
- Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
| | - Mirunalini Ravichandran
- Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
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18
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Morley KC, Perry CJ, Watt J, Hurzeler T, Leggio L, Lawrence AJ, Haber P. New approved and emerging pharmacological approaches to alcohol use disorder: a review of clinical studies. Expert Opin Pharmacother 2021; 22:1291-1303. [PMID: 33615945 DOI: 10.1080/14656566.2021.1892641] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
introduction: The number of medications approved for AUD is small and they generally have limited efficacy. We need new pharmacotherapies for the management of AUD.Areas covered: In this review, the authors aim to synthesise literature for new approved and emerging pharmacotherapies for AUD. Recently approved medications include nalmefene, which was approved in Europe and Australia for the purposes of controlled drinking. Baclofen has also been approved in France but not in other countries. Off label medications including topiramate and gabapentin have received significant attention with multiple RCTs and meta-analyses and have widespread use in several countries including the USA. Several novel medications have emerged over the last decade but further work is required to determine their efficacy and safety for the widespread management of AUD.Expert opinion: Despite significant advances in our understanding of the neurobiological basis of factors that contribute to the development and maintenance of AUD, there have been few new AUD medications approved for almost 20 years. There are many challenges to the development and introduction of new pharmacotherapies for AUD. Strategies for improving the translational pipeline include drug repurposing and utilisation of human acute laboratory models.
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Affiliation(s)
- Kirsten C Morley
- Central Clinical School, Sydney School of Medicine, Faculty of Medicine & Health, University of Sydney, NSW, Australia.,Edith Collins Centre (Alcohol, Drugs and Toxicology), Sydney Local Health District, Royal Prince Alfred Hospital, Camperdown, NSW, Australia
| | - Christina J Perry
- University of Melbourne, Mental Health Theme, Florey Institute of Neuroscience and Mental Health, Parkville, Australia
| | - Joshua Watt
- Edith Collins Centre (Alcohol, Drugs and Toxicology), Sydney Local Health District, Royal Prince Alfred Hospital, Camperdown, NSW, Australia
| | - Tristan Hurzeler
- Central Clinical School, Sydney School of Medicine, Faculty of Medicine & Health, University of Sydney, NSW, Australia
| | - Lorenzo Leggio
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Baltimore and Bethesda, USA.,Department of Neuroscience, Georgetown University Medical Center, Washington, USA.,Medication Development Program, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, USA
| | - Andrew J Lawrence
- University of Melbourne, Mental Health Theme, Florey Institute of Neuroscience and Mental Health, Parkville, Australia.,Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, School of Public Health, Brown University, Providence, USA
| | - Paul Haber
- Central Clinical School, Sydney School of Medicine, Faculty of Medicine & Health, University of Sydney, NSW, Australia.,Edith Collins Centre (Alcohol, Drugs and Toxicology), Sydney Local Health District, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.,Division of Addiction Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, USA
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19
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Kaushik MK, Aritake K, Cherasse Y, Imanishi A, Kanbayashi T, Urade Y, Yanagisawa M. Induction of narcolepsy-like symptoms by orexin receptor antagonists in mice. Sleep 2021; 44:6145803. [PMID: 33609365 DOI: 10.1093/sleep/zsab043] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 01/27/2021] [Indexed: 12/19/2022] Open
Abstract
Orexins/hypocretins are hypothalamic neuropeptides that promote and stabilize wakefulness by binding to the orexin receptor type-1 (OX1R) and type-2 (OX2R). Disruption of orexinergic signaling results in the sleep disorder narcolepsy in mice, rats, dogs, and humans. The orexin receptor antagonist suvorexant promotes sleep by blocking both OX1R and OX2R. Whereas suvorexant has been clinically approved for the treatment of insomnia because it is well tolerated in experimental animals as well as in human patients, a logical question remains as to why orexin receptor antagonists do not induce overt narcolepsy-like symptoms. Here we show that acute and chronic suvorexant promotes both rapid eye movement (REM) and non-REM (NREM) sleep without inducing cataplexy in mice. Interestingly, chronic suvorexant increases OX2R mRNA and decreases orexin mRNA and peptide levels, which remain low long after termination of suvorexant administration. When mice are chronically treated with suvorexant and then re-challenged with the antagonist after a 1-week washout, however, cataplexy and sleep-onset REM (SOREM) are observed, which are exacerbated by chocolate administration. Heterozygous orexin knockout mice, with lower brain orexin levels, show cataplexy and SOREM after acute suvorexant administration. Furthermore, we find that acute suvorexant can induce cataplexy and SOREM in wild-type mice when co-administered with chocolate under stress-free (temporally anesthetized) conditions. Taken together, these results suggest that suvorexant can inhibit orexin synthesis resulting in susceptibility to narcolepsy-like symptoms in mice under certain conditions.
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Affiliation(s)
- Mahesh K Kaushik
- International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Japan
| | - Kosuke Aritake
- International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Japan
| | - Yoan Cherasse
- International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Japan
| | - Aya Imanishi
- Department of Neuropsychiatry, Akita University Graduate School of Medicine, Akita, Japan
| | - Takashi Kanbayashi
- International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Japan
| | - Yoshihiro Urade
- International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Japan
- Isotope Science Center, The University of Tokyo, Tokyo, Japan
| | - Masashi Yanagisawa
- International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Japan
- Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, TX
- Life Science Center, Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Japan
- R&D Center for Frontiers of MIRAI in Policy and Technology, University of Tsukuba, Tsukuba, Japan
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20
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Kothari V, Cardona Z, Chirakalwasan N, Anothaisintawee T, Reutrakul S. Sleep interventions and glucose metabolism: systematic review and meta-analysis. Sleep Med 2020; 78:24-35. [PMID: 33383394 DOI: 10.1016/j.sleep.2020.11.035] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 11/22/2020] [Accepted: 11/30/2020] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Sleep disturbances (insufficient or poor sleep quality) have been linked to abnormal glucose metabolism. This systematic review and meta-analysis aimed to explore the effects of behavioral and pharmacological sleep interventions on glucose metabolism. METHODS Medline and Embase were used for systematic search. Studies reporting behavioral or pharmacological interventions in population with sleep disturbances, with measured outcomes of glucose metabolism and sleep parameters were selected. RESULTS Twenty two studies were eligible for review (eight were conducted in people with type 2 diabetes). Studies were grouped into three types of intervention: sleep extension (n = 6), sleep education or cognitive behavioral therapy for insomnia (CBT-I, n = 6) and pharmacological interventions (n = 10). CBT-I and sleep education resulted in significantly improved self-reported sleep quality (Pittsburgh Sleep Quality Index, mean difference, MD, -1.31, 95% confidence interval (CI) -1.83, -0.80), non-significant reduction in hemoglobin A1c level (MD -0.35%, 95% CI -0.84, 0.13), and non-significant reduction in fasting glucose levels (MD -4.76 mg/dL, 95% CI -14.19, 4.67). Other studies were not eligible for meta-analysis due to heterogeneity of interventions or outcomes. Sleep extension was able to increase sleep duration by varying degrees in short sleepers, and five of six studies demonstrated relationships between the intervention and measures of insulin resistance. A majority of pharmacological intervention studies showed improved sleep but the effects on glucose metabolism were mixed. CONCLUSIONS Available sleep interventions were effective in improving sleep but the effects on glucose metabolism were inconclusive. Larger randomized studies with consistent outcome measurements are needed to demonstrate this potential causal relationship.
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Affiliation(s)
- Vallari Kothari
- Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, IL, USA
| | - Zulma Cardona
- Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Naricha Chirakalwasan
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Excellence Center for Sleep Disorders, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
| | - Thunyarat Anothaisintawee
- Department of Family Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; Department of Clinical Epidemiology and Biostatistics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Sirimon Reutrakul
- Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, IL, USA.
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21
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Neylan TC, Richards A, Metzler TJ, Ruoff LM, Varbel J, O’Donovan A, Sivasubramanian M, Motraghi T, Hlavin J, Batki SL, Inslicht SS, Samuelson K, Morairty SR, Kilduff TS. Acute cognitive effects of the hypocretin receptor antagonist almorexant relative to zolpidem and placebo: a randomized clinical trial. Sleep 2020; 43:zsaa080. [PMID: 32303763 PMCID: PMC7551303 DOI: 10.1093/sleep/zsaa080] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 03/06/2020] [Indexed: 12/18/2022] Open
Abstract
STUDY OBJECTIVES 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. METHODS 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). RESULTS 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. CONCLUSIONS 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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Affiliation(s)
- Thomas C Neylan
- Department of Psychiatry, University of California San Francisco, San Francisco, CA
- San Francisco Veterans Affairs Medical Center, San Francisco, CA
- Sierra-Pacific Mental Illness Research Educational and Clinical Center, Department of Veterans Affairs, Palo Alto, CA
- Department of Neurology, University of California San Francisco, San Francisco, CA
| | - Anne Richards
- Department of Psychiatry, University of California San Francisco, San Francisco, CA
- San Francisco Veterans Affairs Medical Center, San Francisco, CA
- Sierra-Pacific Mental Illness Research Educational and Clinical Center, Department of Veterans Affairs, Palo Alto, CA
| | - Thomas J Metzler
- Department of Psychiatry, University of California San Francisco, San Francisco, CA
- San Francisco Veterans Affairs Medical Center, San Francisco, CA
- Sierra-Pacific Mental Illness Research Educational and Clinical Center, Department of Veterans Affairs, Palo Alto, CA
| | - Leslie M Ruoff
- Department of Psychiatry, University of California San Francisco, San Francisco, CA
- San Francisco Veterans Affairs Medical Center, San Francisco, CA
- Sierra-Pacific Mental Illness Research Educational and Clinical Center, Department of Veterans Affairs, Palo Alto, CA
| | - Jonathan Varbel
- Department of Psychiatry, University of California San Francisco, San Francisco, CA
- San Francisco Veterans Affairs Medical Center, San Francisco, CA
- Sierra-Pacific Mental Illness Research Educational and Clinical Center, Department of Veterans Affairs, Palo Alto, CA
| | - Aoife O’Donovan
- Department of Psychiatry, University of California San Francisco, San Francisco, CA
- San Francisco Veterans Affairs Medical Center, San Francisco, CA
- Sierra-Pacific Mental Illness Research Educational and Clinical Center, Department of Veterans Affairs, Palo Alto, CA
| | - Melinda Sivasubramanian
- Department of Psychiatry, University of California San Francisco, San Francisco, CA
- San Francisco Veterans Affairs Medical Center, San Francisco, CA
- Sierra-Pacific Mental Illness Research Educational and Clinical Center, Department of Veterans Affairs, Palo Alto, CA
| | - Terri Motraghi
- Department of Psychiatry, University of California San Francisco, San Francisco, CA
- San Francisco Veterans Affairs Medical Center, San Francisco, CA
- Sierra-Pacific Mental Illness Research Educational and Clinical Center, Department of Veterans Affairs, Palo Alto, CA
| | - Jennifer Hlavin
- Department of Psychiatry, University of California San Francisco, San Francisco, CA
- San Francisco Veterans Affairs Medical Center, San Francisco, CA
- Sierra-Pacific Mental Illness Research Educational and Clinical Center, Department of Veterans Affairs, Palo Alto, CA
| | - Steven L Batki
- Department of Psychiatry, University of California San Francisco, San Francisco, CA
- San Francisco Veterans Affairs Medical Center, San Francisco, CA
- Sierra-Pacific Mental Illness Research Educational and Clinical Center, Department of Veterans Affairs, Palo Alto, CA
| | - Sabra S Inslicht
- Department of Psychiatry, University of California San Francisco, San Francisco, CA
- San Francisco Veterans Affairs Medical Center, San Francisco, CA
- Sierra-Pacific Mental Illness Research Educational and Clinical Center, Department of Veterans Affairs, Palo Alto, CA
| | - Kristin Samuelson
- Department of Psychiatry, University of California San Francisco, San Francisco, CA
- San Francisco Veterans Affairs Medical Center, San Francisco, CA
- Sierra-Pacific Mental Illness Research Educational and Clinical Center, Department of Veterans Affairs, Palo Alto, CA
- Department of Psychology, University of Colorado, Colorado Springs, CO
| | - Stephen R Morairty
- Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, CA
| | - Thomas S Kilduff
- Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, CA
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22
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Mahoney CE, Mochizuki T, Scammell TE. Dual orexin receptor antagonists increase sleep and cataplexy in wild type mice. Sleep 2020; 43:zsz302. [PMID: 31830270 PMCID: PMC7294412 DOI: 10.1093/sleep/zsz302] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 11/26/2019] [Indexed: 11/13/2022] Open
Abstract
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.
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Affiliation(s)
- Carrie E Mahoney
- Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA
| | - Takatoshi Mochizuki
- Graduate School of Science and Engineering, University of Toyama, Gofuku, Japan
| | - Thomas E Scammell
- Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA
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Han Y, Yuan K, Zheng Y, Lu L. Orexin Receptor Antagonists as Emerging Treatments for Psychiatric Disorders. Neurosci Bull 2020; 36:432-448. [PMID: 31782044 PMCID: PMC7142186 DOI: 10.1007/s12264-019-00447-9] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Accepted: 09/27/2019] [Indexed: 12/12/2022] Open
Abstract
Orexins comprise two neuropeptides produced by orexin neurons in the lateral hypothalamus and are released by extensive projections of these neurons throughout the central nervous system. Orexins bind and activate their associated G protein-coupled orexin type 1 receptors (OX1Rs) and OX2Rs and act on numerous physiological processes, such as sleep-wake regulation, feeding, reward, emotion, and motivation. Research on the development of orexin receptor antagonists has dramatically increased with the approval of suvorexant for the treatment of primary insomnia. In the present review, we discuss recent findings on the involvement of the orexin system in the pathophysiology of psychiatric disorders, including sleep disorders, depression, anxiety, and drug addiction. We discuss the actions of orexin receptor antagonists, including selective OX1R antagonists (SORA1s), selective OX2R antagonists (SORA2s), and dual OX1/2R antagonists (DORAs), in the treatment of these disorders based on both preclinical and clinical evidence. SORA2s and DORAs have more pronounced efficacy in the treatment of sleep disorders, whereas SORA1s may be promising for the treatment of anxiety and drug addiction. We also discuss potential challenges and opportunities for the application of orexin receptor antagonists to clinical interventions.
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Affiliation(s)
- Ying Han
- National Institute of Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, 100191, China
| | - Kai Yuan
- Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, 100191, China
- Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, 100871, China
| | - Yongbo Zheng
- Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, 100191, China
| | - Lin Lu
- National Institute of Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, 100191, China.
- Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, 100191, China.
- Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, 100871, China.
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24
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He D, Jiang B, Guo Z, Mu Q, Mcclure MA. Biphasic feature of placebo response in primary insomnia: pooled analysis of data from randomized controlled clinical trials of orexin receptor antagonists. Sleep 2020; 43:5583906. [PMID: 31593985 DOI: 10.1093/sleep/zsz238] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Revised: 09/13/2019] [Indexed: 11/14/2022] Open
Abstract
OBJECTIVES The placebo response to orexin receptor antagonists in primary insomnia is little-known. Our aim was, therefore, to conduct a systematic review of placebo-controlled randomized clinical trials to characterize placebo response. METHODS We performed a comprehensive literature search for randomized, placebo-controlled, double-blind clinical trials evaluating the efficacy of orexin receptor antagonists addressing primary insomnia. To pool effect size estimates (Cohen's d) of placebo and orexin receptor antagonists across trials for outcome measures, a meta-analysis was done according to the Cochrane guideline. RESULTS The placebo response was significant and robust to improve the symptoms of insomnia in terms of objective and subjective measures, and the effects (0.70 ± 0.51) in subjective measures were smaller than that (1.10 ± 1.14) in objective measures (p = 0.027). The biphasic feature of placebo response showed an initial short-term increase of placebo effect and subsequent changeless long-term effect. CONCLUSION The biphasic feature of placebo response is clinically useful, and neuroimaging is essential to clarify the long-term mechanism in the future.
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Affiliation(s)
- Dongmei He
- Department of Neurology, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, Sichuan, China
| | - Binghu Jiang
- Imaging Institute of Brain Function, Department of Radiology, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, Sichuan, China
| | - Zhiwei Guo
- Imaging Institute of Brain Function, Department of Radiology, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, Sichuan, China
| | - Qiwen Mu
- Imaging Institute of Brain Function, Department of Radiology, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, Sichuan, China
| | - Morgan A Mcclure
- Imaging Institute of Brain Function, Department of Radiology, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, Sichuan, China
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25
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Yang M, Ma H, Jia M, Li Y, Miao D, Cui C, Wu L. The role of the nucleus accumbens OXR1 in cocaine-induced locomotor sensitization. Behav Brain Res 2019; 379:112365. [PMID: 31743729 DOI: 10.1016/j.bbr.2019.112365] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 11/13/2019] [Accepted: 11/14/2019] [Indexed: 11/15/2022]
Abstract
Re-exposure to drug or drug-associated cues after withdrawal can induce behavioral sensitization expression in animals or increase in the expected effect to drug in humans, which mean an enhanced drug seeking/taking motivation to trigger relapse after abstinence. The Nucleus accumbens (NAc) is known to play a key role in mediating this motivation. Recently, it has been shown that systemic administration of orexin receptor 1 (OXR1) antagonist attenuates animals' motivation behavior to take drug by self-administration paradigm, which is more effectively than orexin receptor 2 (OXR2) antagonist. However, the effect of OXR1 in the NAc on drug-induced locomotor sensitization remains elusive. The present study was designed to investigate the effect of OXR1 in the NAc on chronic cocaine-induced locomotor sensitization. Rats were given 10 mg/kg cocaine intraperitoneal injection (i.p.) for five consecutive days, followed by 10 mg/kg cocaine re-exposure (challenge) on the 14th day of withdrawal. Results showed that re-exposure to cocaine after withdrawal could induce locomotor sensitization expression in cocaine-sensitized rats. Simultaneously, the number of OXR1 positive neurons and OXR1 membrane protein level in the NAc core but not the shell were significantly increased following the cocaine re-exposure. Further, micro-infusion of SB-334867, an OXR1 selective antagonist, into the NAc core but not the shell before cocaine re-exposure, significantly attenuated the expression of locomotor sensitization in rats. The findings demonstrate that OXR1 in the NAc core partially mediates the expression of chronic cocaine-induced locomotor sensitization.
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Affiliation(s)
- Mingda Yang
- Department of Neurobiology, School of Basic Medical Sciences, Key Laboratory for Neuroscience of the Ministry of Education and National Health Commission, Neuroscience Research Institute, Peking University, Beijing, China
| | - Hui Ma
- Department of Neurobiology, School of Basic Medical Sciences, Key Laboratory for Neuroscience of the Ministry of Education and National Health Commission, Neuroscience Research Institute, Peking University, Beijing, China
| | - Meng Jia
- Department of Neurobiology, School of Basic Medical Sciences, Key Laboratory for Neuroscience of the Ministry of Education and National Health Commission, Neuroscience Research Institute, Peking University, Beijing, China
| | - Yijing Li
- Department of Neurobiology, School of Basic Medical Sciences, Key Laboratory for Neuroscience of the Ministry of Education and National Health Commission, Neuroscience Research Institute, Peking University, Beijing, China
| | - Degen Miao
- Department of Neurobiology, School of Basic Medical Sciences, Key Laboratory for Neuroscience of the Ministry of Education and National Health Commission, Neuroscience Research Institute, Peking University, Beijing, China
| | - Cailian Cui
- Department of Neurobiology, School of Basic Medical Sciences, Key Laboratory for Neuroscience of the Ministry of Education and National Health Commission, Neuroscience Research Institute, Peking University, Beijing, China.
| | - Liuzhen Wu
- Department of Neurobiology, School of Basic Medical Sciences, Key Laboratory for Neuroscience of the Ministry of Education and National Health Commission, Neuroscience Research Institute, Peking University, Beijing, China.
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26
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Kario K, Yamasaki K, Yagi K, Tsukamoto M, Yamazaki S, Okawara Y, Tomitani N, Kanegae H. Effect of suvorexant on nighttime blood pressure in hypertensive patients with insomnia: The SUPER‐1 study. J Clin Hypertens (Greenwich) 2019; 21:896-903. [DOI: 10.1111/jch.13505] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Revised: 12/26/2018] [Accepted: 12/28/2018] [Indexed: 12/14/2022]
Affiliation(s)
- Kazuomi Kario
- Jichi Medical University School of Medicine Tochigi Japan
| | | | | | | | - Shoji Yamazaki
- Jichi Medical University School of Medicine Tochigi Japan
| | - Yukie Okawara
- Jichi Medical University School of Medicine Tochigi Japan
| | - Naoko Tomitani
- Jichi Medical University School of Medicine Tochigi Japan
| | - Hiroshi Kanegae
- Jichi Medical University School of Medicine Tochigi Japan
- Genki Plaza Medical Center for Health Care Tokyo Japan
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27
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Arrigoni E, Chee MJS, Fuller PM. To eat or to sleep: That is a lateral hypothalamic question. Neuropharmacology 2018; 154:34-49. [PMID: 30503993 DOI: 10.1016/j.neuropharm.2018.11.017] [Citation(s) in RCA: 77] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Revised: 11/08/2018] [Accepted: 11/12/2018] [Indexed: 12/15/2022]
Abstract
The lateral hypothalamus (LH) is a functionally and anatomically complex brain region that is involved in the regulation of many behavioral and physiological processes including feeding, arousal, energy balance, stress, reward and motivated behaviors, pain perception, body temperature regulation, digestive functions and blood pressure. Despite noteworthy experimental efforts over the past decades, the circuit, cellular and synaptic bases by which these different processes are regulated by the LH remains incompletely understood. This knowledge gap links in large part to the high cellular heterogeneity of the LH. Fortunately, the rapid evolution of newer genetic and electrophysiological tools is now permitting the selective manipulation, typically genetically-driven, of discrete LH cell populations. This, in turn, permits not only assignment of function to discrete cell groups, but also reveals that considerable synergistic and antagonistic interactions exist between key LH cell populations that regulate feeding and arousal. For example, we now know that while LH melanin-concentrating hormone (MCH) and orexin/hypocretin neurons both function as sensors of the internal metabolic environment, their roles regulating sleep and arousal are actually opposing. Additional studies have uncovered similarly important roles for subpopulations of LH GABAergic cells in the regulation of both feeding and arousal. Herein we review the role of LH MCH, orexin/hypocretin and GABAergic cell populations in the regulation of energy homeostasis (including feeding) and sleep-wake and discuss how these three cell populations, and their subpopulations, may interact to optimize and coordinate metabolism, sleep and arousal. This article is part of the Special Issue entitled 'Hypothalamic Control of Homeostasis'.
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Affiliation(s)
- Elda Arrigoni
- Department of Neurology, Beth Israel Deaconess Medical Center, Division of Sleep Medicine, Harvard Medical School, Boston, MA, 02215, USA.
| | - Melissa J S Chee
- Department of Neuroscience, Carleton University, Ottawa, ON, K1S 5B6, Canada
| | - Patrick M Fuller
- Department of Neurology, Beth Israel Deaconess Medical Center, Division of Sleep Medicine, Harvard Medical School, Boston, MA, 02215, USA
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28
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Herring WJ, Roth T, Krystal AD, Michelson D. Orexin receptor antagonists for the treatment of insomnia and potential treatment of other neuropsychiatric indications. J Sleep Res 2018; 28:e12782. [DOI: 10.1111/jsr.12782] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 09/06/2018] [Accepted: 09/22/2018] [Indexed: 01/06/2023]
Affiliation(s)
| | - Thomas Roth
- Sleep Disorders and Research Center Henry Ford Hospital Detroit MI USA
| | - Andrew D. Krystal
- Department of Psychiatry University of California San Francisco California USA
| | - David Michelson
- Clinical ResearchMerck & Co., Inc. Kenilworth New Jersey USA
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29
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Vigil JM, Stith SS, Diviant JP, Brockelman F, Keeling K, Hall B. Effectiveness of Raw, Natural Medical Cannabis Flower for Treating Insomnia under Naturalistic Conditions. MEDICINES 2018; 5:medicines5030075. [PMID: 29997343 PMCID: PMC6164964 DOI: 10.3390/medicines5030075] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Revised: 07/07/2018] [Accepted: 07/09/2018] [Indexed: 11/16/2022]
Abstract
Background: We use a mobile software application (app) to measure for the first time, which fundamental characteristics of raw, natural medical Cannabis flower are associated with changes in perceived insomnia under naturalistic conditions. Methods: Four hundred and nine people with a specified condition of insomnia completed 1056 medical cannabis administration sessions using the Releaf AppTM educational software during which they recorded real-time ratings of self-perceived insomnia severity levels prior to and following consumption, experienced side effects, and product characteristics, including combustion method, cannabis subtypes, and/or major cannabinoid contents of cannabis consumed. Within-user effects of different flower characteristics were modeled using a fixed effects panel regression approach with standard errors clustered at the user level. Results: Releaf AppTM users showed an average symptom severity reduction of -4.5 points on a 0⁻10 point visual analogue scale (SD = 2.7, d = 2.10, p < 0.001). Use of pipes and vaporizers was associated with greater symptom relief and more positive and context-specific side effects as compared to the use of joints, while vaporization was also associated with lower negative effects. Cannabidiol (CBD) was associated with greater statistically significant symptom relief than tetrahydrocannabinol (THC), but the cannabinoid levels generally were not associated with differential side effects. Flower from C. sativa plants was associated with more negative side effects than flower from C. indica or hybrid plant subtypes. Conclusions: Consumption of medical Cannabis flower is associated with significant improvements in perceived insomnia with differential effectiveness and side effect profiles, depending on the product characteristics.
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Affiliation(s)
- Jacob M Vigil
- Department of Psychology, University of New Mexico, Albuquerque, NM 87131, USA.
| | - Sarah S Stith
- Department of Economics, University of New Mexico, Albuquerque, NM 87131, USA.
| | - Jegason P Diviant
- Department of Psychology, University of New Mexico, Albuquerque, NM 87131, USA.
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30
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Patel D, Steinberg J, Patel P. Insomnia in the Elderly: A Review. J Clin Sleep Med 2018; 14:1017-1024. [PMID: 29852897 PMCID: PMC5991956 DOI: 10.5664/jcsm.7172] [Citation(s) in RCA: 313] [Impact Index Per Article: 44.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Revised: 02/03/2018] [Accepted: 02/15/2018] [Indexed: 01/11/2023]
Abstract
BACKGROUND Insomnia remains one of the most common sleep disorders encountered in the geriatric clinic population, frequently characterized by the subjective complaint of difficulty falling or maintaining sleep, or nonrestorative sleep, producing significant daytime symptoms including difficulty concentrating and mood disturbances. METHODS A search of the literature was conducted to review the epidemiology, definition, and age-related changes in sleep, as well as factors contributing to late-life insomnia and scales utilized for the assessment of insomnia in older people. The aim is to summarize recent diagnostic guidelines and both nonpharmacological and pharmacological strategies for the management of insomnia in the older population. RESULTS Insomnia remains a clinical diagnosis. There are several demographic, psychosocial, biologic, and behavioral factors that can contribute to late-life insomnia. Older adults are at higher risk for the medical and psychiatric effects of insomnia. CONCLUSIONS The most important aspect in evaluation of insomnia is detailed history taking and thorough physical examination. Nonpharmacological treatment options have favorable and enduring benefits compared to pharmacological therapy.
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Affiliation(s)
- Dhaval Patel
- Department of Geriatrics, Wayne State University School of Medicine, Detroit, Michigan
| | - Joel Steinberg
- Department of Geriatrics, Wayne State University School of Medicine, Detroit, Michigan
| | - Pragnesh Patel
- Department of Geriatrics, Wayne State University School of Medicine, Detroit, Michigan
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31
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Pagel JF, Pandi-Perumal SR, Monti JM. Treating insomnia with medications. SLEEP SCIENCE AND PRACTICE 2018. [DOI: 10.1186/s41606-018-0025-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
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32
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Hatano M, Kamei H, Inagaki R, Matsuzaki H, Hanya M, Yamada S, Iwata N. Assessment of Switching to Suvorexant versus the Use of Add-on Suvorexant in Combination with Benzodiazepine Receptor Agonists in Insomnia Patients: A Retrospective Study. CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE 2018; 16:184-189. [PMID: 29739132 PMCID: PMC5953018 DOI: 10.9758/cpn.2018.16.2.184] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Revised: 04/05/2017] [Accepted: 04/07/2017] [Indexed: 11/18/2022]
Abstract
Objective Suvorexant is a novel hypnotic drug that does not interact with the conventional γ-aminobutyric acid (GABA)-A receptor. We investigated the method by which suvorexant was introduced in insomnia patients who were taking benzodiazepine receptor agonists (BzRA). Methods This was a retrospective study. We extracted clinical data for patients who were prescribed suvorexant and were already using BzRA. The patients were assigned to two groups, the switching and add-on groups. We assessed the suvorexant discontinuation rate at one month after the prescription of the drug. Results One hundred and nineteen patients were assigned to the switching group, and 109 were assigned to the add-on group. The add-on group exhibited a significantly higher all-cause discontinuation rate than the switching group (odds ratio, 2.7; 95% confidence interval, 1.5 to 5.0; adjusted p<0.001). Intolerability was a significantly stronger risk factor for suvorexant discontinuation in the add-on group (22.0% vs. 7.6%, p<0.002), and the most common adverse effect was oversedation. Conclusion Our results show that the add-on of suvorexant increases the frequency of oversedation compared with switching in insomnia patients that are taking BzRA. However, this was only a preliminary retrospective study, and further studies will be required to confirm our findings.
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Affiliation(s)
- Masakazu Hatano
- Department of Psychiatry, Fujita Health University School of Medicine, Aichi, Japan.,Department of Clinical Pharmacy, Fujita Health University School of Medicine, Aichi, Japan.,Office of Clinical Pharmacy Practice and Health Care Management, Faculty of Pharmacy, Meijo University, Nagoya, Japan
| | - Hiroyuki Kamei
- Office of Clinical Pharmacy Practice and Health Care Management, Faculty of Pharmacy, Meijo University, Nagoya, Japan
| | - Risa Inagaki
- Department of Clinical Pharmacy, Fujita Health University School of Medicine, Aichi, Japan
| | - Haruna Matsuzaki
- Department of Clinical Pharmacy, Fujita Health University School of Medicine, Aichi, Japan
| | - Manako Hanya
- Office of Clinical Pharmacy Practice and Health Care Management, Faculty of Pharmacy, Meijo University, Nagoya, Japan
| | - Shigeki Yamada
- Department of Clinical Pharmacy, Fujita Health University School of Medicine, Aichi, Japan
| | - Nakao Iwata
- Department of Psychiatry, Fujita Health University School of Medicine, Aichi, Japan
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Mukerjee S, Lazartigues E. Sympathetic nerve activity and neuro-inflammation: Who is in the driver's seat? Acta Physiol (Oxf) 2018; 222. [PMID: 29210184 DOI: 10.1111/apha.13011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Affiliation(s)
- S. Mukerjee
- Department of Pharmacology and Experimental Therapeutics and Cardiovascular Center of Excellence; Louisiana State University Health Sciences Center; New Orleans LA USA
| | - E. Lazartigues
- Department of Pharmacology and Experimental Therapeutics and Cardiovascular Center of Excellence; Louisiana State University Health Sciences Center; New Orleans LA USA
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34
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Dayot S, Speisky D, Couvelard A, Bourgoin P, Gratio V, Cros J, Rebours V, Sauvanet A, Bedossa P, Paradis V, Ruszniewski P, Couvineau A, Voisin T. In vitro, in vivo and ex vivo demonstration of the antitumoral role of hypocretin-1/orexin-A and almorexant in pancreatic ductal adenocarcinoma. Oncotarget 2018; 9:6952-6967. [PMID: 29467942 PMCID: PMC5805528 DOI: 10.18632/oncotarget.24084] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2017] [Accepted: 01/02/2018] [Indexed: 02/05/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is still the poorest prognostic tumor of the digestive system. We investigated the antitumoral role of orexin-A and almorexant in PDAC. We analyzed the orexin receptor type 1 (OX1R) expression by immunohistochemistry in human normal pancreas, PDAC and its precursor dysplastic intraepithelial lesions. We used PDAC-derived cell lines and fresh tissue slices to study the apoptotic role of hypocretin-1/orexin-A and almorexant in vitro and ex vivo. We analyzed in vivo the hypocretin-1/orexin-A and almorexant effect on tumor growth in mice xenografted with PDAC cell lines expressing, or not, OX1R. Ninety-six percent of PDAC expressed OX1R, while adjacent normal exocrine pancreas did not. OX1R was expressed in pre-cancerous lesions. In vitro, under hypocretin-1/orexin-A and almorexant, the OX1R-positive AsPC-1 cells underwent apoptosis, abolished by the tyrosine phosphatase SHP2 inhibitor, NSC-87877, whereas the OX1R-negative HPAF-II cell line did not. These effects were mediated by phosphorylation of OX1R and recruitment of SHP2. Ex vivo, caspase-3 positive tumor cells were significantly higher in fresh tumour slices treated 48h with hypocretin-1/orexin-A, as compared to control, whereas cellular proliferation, assessed by Ki-67 index, was not modified. In vivo, when AsPC-1 cells or patient-derived cells were xenografted in nude mice, hypocretin-1/orexin-A or almorexant, administrated both starting the day of cell line inoculation or after tumoral development, strongly slowed tumor growth. Hypocretin-1/orexin-A and almorexant induce, through OX1R, the inhibition of PDAC cellular growth by apoptosis. Hypocretins/orexins and almorexant might be powerful candidates for the treatment of PDAC.
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Affiliation(s)
- Stéphanie Dayot
- INSERM UMR1149 Centre de Recherche sur l’Inflammation (CRI), Université Paris-Diderot, Sorbonne Paris Cité, DHU UNITY, Faculté de Médecine Xavier Bichat, Huchard, 75018 Paris, France
| | - Daniela Speisky
- INSERM UMR1149 Centre de Recherche sur l’Inflammation (CRI), Université Paris-Diderot, Sorbonne Paris Cité, DHU UNITY, Faculté de Médecine Xavier Bichat, Huchard, 75018 Paris, France
| | - Anne Couvelard
- INSERM UMR1149 Centre de Recherche sur l’Inflammation (CRI), Université Paris-Diderot, Sorbonne Paris Cité, DHU UNITY, Faculté de Médecine Xavier Bichat, Huchard, 75018 Paris, France
- Département de Pathologie Beaujon-Bichat, AP-HP, Hôpital Bichat, Huchard, 75018 Paris, France
| | - Pierre Bourgoin
- INSERM UMR1149 Centre de Recherche sur l’Inflammation (CRI), Université Paris-Diderot, Sorbonne Paris Cité, DHU UNITY, Faculté de Médecine Xavier Bichat, Huchard, 75018 Paris, France
| | - Valérie Gratio
- INSERM UMR1149 Centre de Recherche sur l’Inflammation (CRI), Université Paris-Diderot, Sorbonne Paris Cité, DHU UNITY, Faculté de Médecine Xavier Bichat, Huchard, 75018 Paris, France
| | - Jérôme Cros
- INSERM UMR1149 Centre de Recherche sur l’Inflammation (CRI), Université Paris-Diderot, Sorbonne Paris Cité, DHU UNITY, Faculté de Médecine Xavier Bichat, Huchard, 75018 Paris, France
- Département de Pathologie Beaujon-Bichat, AP-HP, Hôpital Beaujon, 92118 Clichy, France
| | - Vinciane Rebours
- INSERM UMR1149 Centre de Recherche sur l’Inflammation (CRI), Université Paris-Diderot, Sorbonne Paris Cité, DHU UNITY, Faculté de Médecine Xavier Bichat, Huchard, 75018 Paris, France
- Service de Pancréatologie-Gastroentérologie PMAD, Pôle des Maladies de l’Appareil Digestif, AP-HP, Hôpital Beaujon, 92118 Clichy, France
| | - Alain Sauvanet
- INSERM UMR1149 Centre de Recherche sur l’Inflammation (CRI), Université Paris-Diderot, Sorbonne Paris Cité, DHU UNITY, Faculté de Médecine Xavier Bichat, Huchard, 75018 Paris, France
- Service de Pancréatologie-Gastroentérologie PMAD, Pôle des Maladies de l’Appareil Digestif, AP-HP, Hôpital Beaujon, 92118 Clichy, France
| | - Pierre Bedossa
- INSERM UMR1149 Centre de Recherche sur l’Inflammation (CRI), Université Paris-Diderot, Sorbonne Paris Cité, DHU UNITY, Faculté de Médecine Xavier Bichat, Huchard, 75018 Paris, France
- Département de Pathologie Beaujon-Bichat, AP-HP, Hôpital Beaujon, 92118 Clichy, France
| | - Valérie Paradis
- INSERM UMR1149 Centre de Recherche sur l’Inflammation (CRI), Université Paris-Diderot, Sorbonne Paris Cité, DHU UNITY, Faculté de Médecine Xavier Bichat, Huchard, 75018 Paris, France
- Département de Pathologie Beaujon-Bichat, AP-HP, Hôpital Beaujon, 92118 Clichy, France
| | - Philippe Ruszniewski
- INSERM UMR1149 Centre de Recherche sur l’Inflammation (CRI), Université Paris-Diderot, Sorbonne Paris Cité, DHU UNITY, Faculté de Médecine Xavier Bichat, Huchard, 75018 Paris, France
- Service de Pancréatologie-Gastroentérologie PMAD, Pôle des Maladies de l’Appareil Digestif, AP-HP, Hôpital Beaujon, 92118 Clichy, France
| | - Alain Couvineau
- INSERM UMR1149 Centre de Recherche sur l’Inflammation (CRI), Université Paris-Diderot, Sorbonne Paris Cité, DHU UNITY, Faculté de Médecine Xavier Bichat, Huchard, 75018 Paris, France
| | - Thierry Voisin
- INSERM UMR1149 Centre de Recherche sur l’Inflammation (CRI), Université Paris-Diderot, Sorbonne Paris Cité, DHU UNITY, Faculté de Médecine Xavier Bichat, Huchard, 75018 Paris, France
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Milligan G. G protein-coupled receptors not currently in the spotlight: free fatty acid receptor 2 and GPR35. Br J Pharmacol 2017; 175:2543-2553. [PMID: 28940377 PMCID: PMC6003633 DOI: 10.1111/bph.14042] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Revised: 08/17/2017] [Accepted: 08/30/2017] [Indexed: 01/05/2023] Open
Abstract
It is widely appreciated that G protein‐coupled receptors have been the most successfully exploited class of targets for the development of small molecule medicines. Despite this, to date, less than 15% of the non‐olfactory G protein‐coupled receptors in the human genome are the targets of a clinically used medicine. In many cases, this is likely to reflect a lack of understanding of the basic underpinning biology of many G protein‐coupled receptors that are not currently in the spotlight, as well as a paucity of pharmacological tool compounds and appropriate animal models to test in vivo function of such G protein‐coupled receptors in both normal physiology and in the context of disease. ‘Open Innovation’ arrangements, in which pharmaceutical companies and public–private partnerships provide wider access to tool compounds identified from ligand screening programmes, alongside enhanced medicinal chemistry support to convert such screening ‘hits’ into useful ‘tool’ compounds will provide important routes to improved understanding. However, in parallel, novel approaches to define and fully appreciate the selectivity and mode of action of such tool compounds, as well as better understanding of potential species orthologue variability in the pharmacology and/or signalling profile of a wide range of currently poorly understood and understudied G protein‐coupled receptors, will be vital to fully exploit the therapeutic potential of this large target class. I consider these themes using as exemplars two G protein‐coupled receptors, free fatty acid receptor 2 and GPR35.
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Affiliation(s)
- Graeme Milligan
- Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK
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Jiang J, Gan Z, Li Y, Zhao W, Li H, Zheng JP, Ke Y. REM sleep deprivation induces endothelial dysfunction and hypertension in middle-aged rats: Roles of the eNOS/NO/cGMP pathway and supplementation with L-arginine. PLoS One 2017; 12:e0182746. [PMID: 28809932 PMCID: PMC5557538 DOI: 10.1371/journal.pone.0182746] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Accepted: 07/23/2017] [Indexed: 11/18/2022] Open
Abstract
Sleep loss can induce or aggravate the development of cardiovascular and cerebrovascular diseases. However, the molecular mechanism underlying this phenomenon is poorly understood. The present study was designed to investigate the effects of REM sleep deprivation on blood pressure in rats and the underlying mechanisms of these effects. After Sprague-Dawley rats were subjected to REM sleep deprivation for 5 days, their blood pressures and endothelial function were measured. In addition, one group of rats was given continuous access to L-arginine supplementation (2% in distilled water) for the 5 days before and the 5 days of REM sleep deprivation to reverse sleep deprivation-induced pathological changes. The results showed that REM sleep deprivation decreased body weight, increased blood pressure, and impaired endothelial function of the aortas in middle-aged rats but not young rats. Moreover, nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) concentrations as well as endothelial NO synthase (eNOS) phosphorylation in the aorta were decreased by REM sleep deprivation. Supplementation with L-arginine could protect against REM sleep deprivation-induced hypertension, endothelial dysfunction, and damage to the eNOS/NO/cGMP signaling pathway. The results of the present study suggested that REM sleep deprivation caused endothelial dysfunction and hypertension in middle-aged rats via the eNOS/NO/cGMP pathway and that these pathological changes could be inhibited via L-arginine supplementation. The present study provides a new strategy to inhibit the signaling pathways involved in insomnia-induced or insomnia-enhanced cardiovascular diseases.
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Affiliation(s)
- Jiaye Jiang
- Experimental Center for Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, PR China
| | - Zhongyuan Gan
- Experimental Center for Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, PR China
| | - Yuan Li
- Experimental Center for Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, PR China
| | - Wenqi Zhao
- Experimental Center for Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, PR China
| | - Hanqing Li
- Experimental Center for Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, PR China
| | - Jian-Pu Zheng
- Experimental Center for Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, PR China
- * E-mail: (YK); (JPZ)
| | - Yan Ke
- Experimental Center for Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, PR China
- * E-mail: (YK); (JPZ)
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Lawson K. Emerging pharmacological strategies for the treatment of fibromyalgia. World J Pharmacol 2017; 6:1-10. [DOI: 10.5497/wjp.v6.i1.1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2016] [Revised: 01/06/2017] [Accepted: 02/13/2017] [Indexed: 02/06/2023] Open
Abstract
Fibromyalgia (FM) has been described as a chronic clinical condition related to multisensory hypersensitivity presenting with a complex of symptoms dominated by chronic widespread pain associated with the existence of a range of co-morbidities, such as fatigue, sleep disturbance, cognitive impairment, anxiety and depression. Current treatments include drugs that target serotonin and noradrenaline levels within the central nervous system, e.g., tricyclic antidepressants, serotonin noradrenaline reuptake inhibitors, and voltage-gated calcium channel subunit ligands, e.g., gabapentin and pregabalin. Investigation of a range of novel targets, such as melatoninergic, cannabinoid, dopamine, NMDA, angiotensin, orexin and opioid receptors, and ion channels, in addition revisiting bioamine modulation and subunits has provided efficacy outcomes that improve the health status of patients with FM. Nevertheless, modest and limited efficacy is often observed reflecting the heterogeneity of FM with existence of subpopulations of patients, the contribution of peripheral and central components to the pathophysiology, and the extensive range of accompanying co-morbidities. The complexity and multidimensional nature of FM is emphasized by the diversity of pharmacological targets gaining interest. Clues to underlying mechanisms which offer themselves as novel and potential targets for new medications are being provided by advances in the understanding of the pathophysiology of FM.
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Schneider P, Schneider G. De-orphaning the marine natural product (±)-marinopyrrole A by computational target prediction and biochemical validation. Chem Commun (Camb) 2017; 53:2272-2274. [DOI: 10.1039/c6cc09693j] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
A machine-learning method led to the discovery of the macromolecular targets of the natural anticancer compound marinopyrrol A.
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Affiliation(s)
- P. Schneider
- Department of Chemistry and Applied Biosciences
- Swiss Federal Institute of Technology (ETH)
- Zurich
- Switzerland
- inSili.com LLC
| | - G. Schneider
- Department of Chemistry and Applied Biosciences
- Swiss Federal Institute of Technology (ETH)
- Zurich
- Switzerland
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Kohyama J. Possible neuronal mechanisms of sleep disturbances in patients with autism spectrum disorders and attention-deficit/hyperactivity disorder. Med Hypotheses 2016; 97:131-133. [PMID: 27876121 DOI: 10.1016/j.mehy.2016.11.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Accepted: 11/02/2016] [Indexed: 12/28/2022]
Affiliation(s)
- Jun Kohyama
- Tokyo Bay Urayasu Ichikawa Medical Center, Japan.
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