Basic Ancillary Study

基础辅助研究

• 批准号: 8730212
• 负责人: MIODRAG G RADULOVACKI
• 金额: $ 13.23万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8730212
• 关键词: Address; Agonist; Ancillary Study; Animal Model; Animals; Apnea; Arousal; Asphyxia; Basic Science; Behavioral; Behavioral Symptoms; Blood Pressure; Brain; Brain Stem; Breathing; CNR2 gene; Cardiovascular system; Central Nervous System Agents; Cessation of life; Clinical; Clinical Research; Clinical Trials; Cognitive; Conscious; Crossover Design; Data; Development; Devices; Diabetes Mellitus; Disease; Dose; Endocannabinoids; Future; Goals; Health; Hypertension; Hypotension; Injection of therapeutic agent; Instruction; Kidney; Measures; Mechanics; Mediating; Medical; Metabolic; Modality; Morbidity - disease rate; Muscle; Myocardial Infarction; Nerve; Neurologic; Nodose Ganglion; Norepinephrine; Obstructive Sleep Apnea; Pathogenesis; Pathway interactions; Patients; Pattern; Peripheral Nervous System; Pharmaceutical Preparations; Pharmacotherapy; Placebo Control; Placebos; Population; Public Health; REM Sleep; Randomized; Rattus; Reflex action; Risk; Safety; Serotonin; Severities; Severity of illness; Site; Sleep; Sleep Apnea Syndromes; Source; Stimulus; Stroke; Symptoms; Synapses; Testing; Tetrahydrocannabinol; Time; Treatment Efficacy; United States National Institutes of Health; Vagotomy; Wakefulness; alertness; base; blood pressure regulation; cannabinoid receptor; clinical practice; clinically significant; excitotoxicity; human data; improved; indexing; innovation; insight; instrument; monoamine; mortality; neuroprotection; non rapid eye movement; novel; novel therapeutics; oleylamide; promoter; receptor; respiratory; respiratory reflex; sleep regulation; treatment effect; vehicular accident

Sleep related breathing disorders (SRBD), especially obstructive sleep apnea (OSA), represent an important health problem, conferring substantial cognitive/behavioral symptoms and increased risk of motor vehicle accident, hypertension, myocardial infarction, stroke, diabetes and death on at least 3% ofthe US population. Identifying novel treatments for OSA would be of great public health significance, because fully effective and acceptable OSA treatments are lacking. A critical need remains for NIH supported, mechanistically driven proof-of-concept clinical studies to evaluate novel therapeutic strategies. Despite basic research advances regarding the pathogenesis of OSA, generally effective drug treatments have not been identified. Based on our animal and preliminary human data, we propose to test the innovative hypothesis that cannabimimetic drugs are both effective in reducing sleep apnea severity and disease modifying in protecting against cardiovascular and neurological sequelae of OSA. Project 1 will be a randomized, placebo-controlled parallel groups proof-of-concept clinical trial of dronabinol in patients with OSA. Subjects will be randomized to receive either placebo or dronabinol for a period of 6 weeks. The overarching goal will be to establish the safety, tolerability and therapeutic efficacy of dronabinol in OSA, with co-primary efficacy endpoints including: reduced in apnea/hypopnea index (AHI) and improved subjective and objective daytime alertness at the end of treatment. Secondary endpoints will include improved oxygenation, sleep quality, blood pressure control and time-on-treatments effects. Project 2 will employ anesthetized and chronically instrumented conscious behaving animals to directly test the mechanisms of dronabinol action schematized in figure 1. For example, we will characterize dronabinol's dose-dependent inhibition of afferent vagal reflexes elicited by pharmacological and mechanical stimuli. We will use CBi and CB2 antagonists to confirm the receptor targets for reduced apnea propensity and we will establish the CNS versus vagal-reflex impact of dronabinol on upper airway muscle activity during sleep. We will test the hypothesis that cannabimimetics lower blood pressure by reducing sympathetic activity. Taken together, these projects will provide critical evidence regarding the potential efficacy and mechanisms of action for cannabimimetic treatment of OSA. By providing a path toward the first viable OSA pharmacotherapeutic, the proposed studies could have a tremendous impact on clinical practice.

与睡眠有关 健康问题，赋予大量认知/行为症状和汽车风险增加 美国至少3％的事故，高血压，心肌梗死，中风，糖尿病和死亡 人口。确定OSA的新型治疗方法将具有很大的公共卫生意义，因为 缺乏完全有效和可接受的OSA治疗方法。 NIH受支持的关键需求， 机械驱动的概念验证临床研究，以评估新的治疗策略。尽管 有关OSA发病机理的基础研究进展，通常没有有效的药物治疗 已确定。根据我们的动物和初步人类数据，我们建议测试创新 假设大麻药在降低睡眠呼吸暂停严重程度和 疾病在预防OSA的心血管和神经系统后遗症方面改变了疾病。 项目1将是一个随机的，安慰剂对照组的平行组，概念证明Dronabinol的临床试验 在OSA患者中。受试者将被随机地接受安慰剂或dronabinol 6 几周。总体目标是建立Dronabinol的安全性，耐受性和治疗功效 在OSA中，具有共同主要效力终点，包括：减少呼吸暂停/呼吸呼吸症指数（AHI）并改进 治疗结束时主观和客观的白天警觉性。次要终点将包括 改善氧合，睡眠质量，血压控制和治疗时间的影响。 项目2将采用麻醉和长期有意识的行为动物直接测试 在图1中示式的Dronabinol作用的机制。例如，我们将表征Dronabinol的 药理学和机械刺激引起的剂量依赖性抑制对传入迷走神经反射的抑制作用。我们 将使用CBI和CB2拮抗剂来确认受体靶标的呼吸趋势降低，我们将 在睡眠期间，建立Dronabinol对上气道肌肉活动的中枢神经系统与迷走神经反射的影响。我们 将检验以下假设，即大麻通过减少交感神经活动降低血压。 综上所述，这些项目将提供有关潜在功效和机制的关键证据 OSA大麻治疗的作用。通过为第一个可行的OSA提供一条途径 拟议的研究可能会对临床实践产生巨大影响。