Project 5

项目5

• 批准号: 10674892
• 负责人: DAVID ANDREW WELLMAN
• 金额: $ 42.88万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10674892
• 关键词: Affect; Animal Experimentation; Animal Experiments; Apnea; Area; Arousal; Brain Stem; Carbon Dioxide; Cell Nucleus; Cephalic; Clinical Trials; Collaborations; Data; Dilator; Disease; Drug Combinations; Effectiveness; Electroencephalography; Event; Functional disorder; Glean; Goals; Grant; Human; Impaired cognition; Individual; Intention; Light; Measures; Mediating; Methods; Motor; Muscarinics; Muscle; Muscle Tonus; Muscle hypotonia; Neurons; Norepinephrine; Obstructive Sleep Apnea; Outcome; Oxygen; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacotherapy; Pharyngeal structure; Phenotype; Physiological; Placebos; Predisposition; Prevention; REM Sleep; Research; Series; Serotonin; Serotonin Agonists; Serotonin Antagonists; Severities; Sleep; Sleep Apnea Syndromes; Sleep Disorders; Sleep Stages; Stimulant; Testing; Trazodone; Urinary Retention; Withdrawal; Xerostomia; airway muscle; airway obstruction; antagonist; atomoxetine; differential expression; druggable target; experience; gabapentin; human data; improved; indexing; inhibitor; member; non rapid eye movement; novel therapeutics; oxybutynin; pharmacologic; pharynx muscle; prevent; receptor; receptor expression; respiratory; response; reuptake; sedative; serotonin receptor; side effect; trait; zolpidem

Abstract/ Summary: Project 5 OSA is a common and debilitating condition that currently has no effective pharmacotherapy. In the previous PPG, we identified a drug combination (atomoxetine + oxybutynin) that lowered the apnea-hypopnea index by 74% and raised the nadir oxygen saturation from 84% to 94%. Despite these encouraging results, some patients experienced antimuscarinic side effects from oxybutynin. Furthermore, subsequent mechanistic studies revealed that oxybutynin was acting primarily as a sedative (counteracting atomoxetine), rather than a pharyngeal muscle stimulant. Therefore, the goal of the current grant is to find a better sedative than oxybutynin to add to atomoxetine. This will be accomplished by first testing common, non-myorelaxing sedatives (Aim 1). Then, in Aim 2 we will test sedatives identified from Projects 1-4 that specifically block CO2- mediated arousals (but not CO2-mediated respiratory/pharyngeal muscle responses). As described in the other grants accompanying this PPG, Projects 2 and 4 are expected to identify serotonin subreceptors on parabrachial CGRP neurons (PBCGRP) that can be antagonized to prevent EEG arousal in response to elevated CO2. Additionally, Projects 3 and 4 will focus on identifying serotonin subreceptors on a separate group of parabrachial neurons (PBFoxP2) that could be manipulated pharmacologically to augment upper airway dilator tone. Of note, preliminary studies suggest that PBCGRP neurons are activated by a different subset of serotonin receptors than the PBFoxP2 neurons, thus allowing us to potentially target these two parabrachial regions independently. Therefore, Aim 2 will test specific serotonin agonists/antagonists, with or without atomoxetine (as necessary), to activate airway muscles without inducing arousals. Finally, in Aim 3 a one-month clinical trial will be performed on the most effective drugs emerging from Aims 1 and 2 (if no such drugs are found, then the original atomoxetine + oxybutynin combination will be studied). As the human component to this PPG, Project 5 will utilize the information gleaned from the animal experiments to build upon the exciting results of the previous PPG and move the field closer towards a potential pharmacotherapy for OSA.

摘要/总结：项目5 OSA是一种常见的使人衰弱的疾病，目前还没有有效的药物治疗。上一 PPG，我们确定了一种药物组合（托莫西汀+奥昔布宁），降低呼吸暂停低通气指数， 74%，并将最低血氧饱和度从84%提高到94%。尽管取得了这些令人鼓舞的成果， 患者经历了奥昔布宁的抗毒蕈碱副作用。此外，随后的机械 研究表明，奥昔布宁主要作为镇静剂（抵消托莫西汀），而不是一种抗抑郁药。 咽肌兴奋剂因此，目前赠款的目标是找到一种比 奥昔布宁加入托莫西汀。这将通过首先测试常见的，非myorelaxing 镇静剂（目标1）。然后，在目标2中，我们将测试从项目1-4中确定的专门阻断CO2的镇静剂。 介导的觉醒（但不是CO2介导的呼吸/咽肌反应）。中所述 伴随着这个PPG的其他赠款，项目2和4预计将确定血清素亚受体， 臂旁CGRP神经元（PBCGRP），其可以被拮抗以防止响应于升高的 二氧化碳。此外，项目3和4将集中在确定血清素亚受体在一个单独的组， 臂旁神经元（PBFoxP 2），可以被操纵的背侧增加上气道扩张 语气值得注意的是，初步研究表明，PBCGRP神经元被不同的血清素亚群激活， 受体比PBFoxP 2神经元，从而使我们能够潜在地靶向这两个臂旁区域 独立地。因此，Aim 2将检测特定的5-羟色胺激动剂/拮抗剂，伴或不伴托莫西汀 (as必要的），以激活气道肌肉而不诱导觉醒。最后，在目标3中， 将对目标1和目标2中最有效的药物进行研究（如果没有发现此类药物， 将研究最初的托莫西汀+奥昔布宁组合）。作为本PPG的人类组件，项目 5将利用从动物实验中收集到的信息，建立在令人兴奋的结果的基础上， 以前的PPG和移动领域更接近一个潜在的药物治疗OSA。