Basic Ancillary Study

基础辅助研究

基本信息

批准号：
8467050
负责人：
MIODRAG G RADULOVACKI
金额：
$ 12.85万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8467050
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

项目摘要

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.

睡眠相关呼吸障碍 (SRBD)，尤其是阻塞性睡眠呼吸暂停 (OSA)，是一种重要的健康问题，导致严重的认知/行为症状并增加机动车辆的风险美国至少有 3% 的人因事故、高血压、心肌梗死、中风、糖尿病而死亡人口。确定 OSA 的新疗法具有重大的公共卫生意义，因为缺乏完全有效且可接受的 OSA 治疗方法。仍然迫切需要 NIH 的支持，机械驱动的概念验证临床研究，以评估新的治疗策略。尽管关于OSA发病机制的基础研究进展，普遍有效的药物治疗尚未取得进展已被识别。根据我们的动物和初步人体数据，我们建议测试创新的假设大麻模拟药物既能有效减轻睡眠呼吸暂停的严重程度，改变疾病以预防 OSA 的心血管和神经系统后遗症。项目 1 将是屈大麻酚的随机、安慰剂对照平行组概念验证临床试验 OSA 患者。受试者将随机接受安慰剂或屈大麻酚，为期 6 年几周。总体目标是确定屈大麻酚的安全性、耐受性和治疗效果在 OSA 中，共同主要疗效终点包括：呼吸暂停/呼吸不足指数 (AHI) 降低和改善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效果。项目 2 将使用麻醉并长期使用有意识行为的动物来直接测试屈大麻酚的作用机制如图1所示。例如，我们将描述屈大麻酚的作用机制药物和机械刺激引起的传入迷走神经反射的剂量依赖性抑制。我们将使用 CBi 和 CB2 拮抗剂来确认降低呼吸暂停倾向的受体靶标，我们将确定屈大麻酚对睡眠期间上呼吸道肌肉活动的中枢神经系统与迷走神经反射的影响。我们将检验大麻模拟物通过减少交感神经活动来降低血压的假设。总的来说，这些项目将提供有关潜在功效和机制的关键证据大麻模拟治疗 OSA 的作用。通过提供通向第一个可行的 OSA 的途径药物治疗方面，拟议的研究可能会对临床实践产生巨大影响。