A Novel Pharmacological Therapy for Obstructive Sleep Apnea

阻塞性睡眠呼吸暂停的新型药物疗法

• 批准号: 10445052
• 负责人: Scott A Sands
• 金额: $ 67.54万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10445052
• 关键词: Address; Adherence; Adverse event; Animals; Anti-Cholinergics; Apnea; Arousal; Clinical; Continuous Positive Airway Pressure; Cross-Over Studies; Data; Development; Dilator; Disease; Dose; Double-Blind Method; Drowsiness; Effectiveness; Electric Stimulation; Exhibits; Female; Frequencies; Gold; Health; Human; Hypoglossal nerve structure; Individual; Intervention; Investigation; Knowledge; Measurement; Measures; Methods; Monitor; Motor; Muscarinic Antagonists; Muscarinics; Muscle; Muscle Tonus; Muscular Atrophy; Neurocognitive; Obstructive Sleep Apnea; Outcome; Patient Self-Report; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiological; Physiology; Placebo Control; Placebos; Quality of life; Randomized; Reducing Agents; Research; Rest; Severities; Sleep; Sleep Apnea Syndromes; Techniques; Testing; Withdrawal; atomoxetine; base; cardiovascular health; clinical application; improved; indexing; inhibitor; instrumentation; male; noradrenergic; novel; novel therapeutic intervention; oxybutynin; personalized medicine; pharynx muscle; primary outcome; response; restoration; reuptake; trait; treatment response; treatment strategy

PROJECT SUMMARY/ABSTRACT Obstructive sleep apnea (OSA) is a highly prevalent disorder with numerous deleterious effects on neurocognitive function and cardiovascular health. However, the leading treatment, continuous positive airway pressure (CPAP), is poorly tolerated by many individuals. Thus, the development new treatment strategies are critically needed. A pharmacological therapy for OSA remains elusive. A key contributor to OSA is reduced pharyngeal dilator muscle tone and responsiveness during sleep. Animal studies support the view that two mechanisms are responsible: a loss of noradrenergic drive and muscarinic inhibition to the hypoglossal motor pool. Accordingly, in a small study in human patients with OSA, we administered a novel combination of existing agents—a noradrenergic reuptake inhibitor atomoxetine plus an antimuscarinic oxybutynin—on a single night, and found a reduction in OSA severity by ~75%, by far the most powerful effect of any pharmacological intervention observed previously. Our current proposal leverages our preliminary findings to make major headway on pharmacological therapy for OSA. In Aim 1, we seek to demonstrate the repeated-dose efficacy and tolerance of atomoxetine-plus-oxybutynin in a randomized, placebo-controlled, crossover study in 48 male and female patients with OSA for 1 month. We will assess effects on OSA severity (apnea-hypopnea index, primary outcome), nocturnal oxygenation, the frequency of arousals from sleep, sleepiness and disease-specific quality of life. Adherence to therapy and adverse events will also be carefully monitored. In Aim 2, we will investigate the mechanisms by which atomoxetine and oxybutynin improve OSA severity, alone and in combination. Using gold-standard “deep phenotyping” mechanistic studies, we will test the hypotheses that both agents increase muscle responsiveness, separately and synergistically, and that oxybutynin counterbalances the effect of atomoxetine to increase arousability. These results will have key implications for the ongoing development of this pharmacological approach. In Aim 3, we will use both deep phenotyping and non-invasive (clinically-applicable) methods to determine which patient phenotypes respond best to atomoxetine and oxybutynin. Preliminary data strongly suggested that patients with less-severe collapsibility exhibit a greater response to therapy, and that this can be detected with a surrogate measurement from a routine clinical sleep study. This personalized medicine approach will provide the scientific knowledge needed to progress towards larger studies in selected patients. Overall, our proposal is expected to demonstrate that a combination of agents has the potential to treat OSA through reinstatement of muscle responsiveness during sleep. If judiciously administered, this intervention could provide many patients with an effective alternative to CPAP. Such results are of major importance because they have great potential to improve the quality of life and health outcomes of untreated patients with OSA.

项目总结/摘要 阻塞性睡眠呼吸暂停（OSA）是一种高度流行的疾病，对睡眠呼吸暂停有许多有害影响。 神经认知功能和心血管健康。然而，领先的治疗，持续气道正压通气， 压力（CPAP），许多人耐受性差。因此，开发新的治疗策略是 急需的。OSA的药物治疗仍然难以捉摸。 阻塞性睡眠呼吸暂停综合症的一个关键因素是睡眠期间咽扩张肌张力和反应性降低。动物 研究支持两种机制负责的观点：去甲肾上腺素能驱动和毒蕈碱的损失 抑制舌下神经运动池因此，在一项针对OSA患者的小型研究中，我们 给予现有药物的新组合-去甲肾上腺素能再摄取抑制剂托莫西汀加 抗毒蕈碱奥昔布宁-在一个晚上，并发现减少OSA的严重程度约75%，迄今为止最 之前观察到的任何药物干预的强大效果。我们目前的建议利用我们的 初步发现，使OSA的药物治疗取得重大进展。 在目的1中，我们试图证明阿托莫西汀加奥昔布宁的重复剂量疗效和耐受性， 在48名男性和女性OSA患者中进行了为期1个月的随机、安慰剂对照、交叉研究。我们将 评估对OSA严重程度（呼吸暂停低通气指数，主要结局）、夜间氧合、 从睡眠中觉醒，嗜睡和疾病特异性生活质量。治疗依从性和不良事件 也将受到密切关注。在目的2中，我们将研究托莫西汀和 奥昔布宁单独和联合使用可改善OSA的严重程度。使用黄金标准的“深度表型分析” 机制的研究，我们将测试的假设，这两种药物增加肌肉反应，分别 并且奥昔布宁抵消了托莫西汀增加唤醒能力的作用。 这些结果将对这种药理学方法的持续发展产生重要影响。在Aim中 3、我们将同时使用深度表型和非侵入性（临床适用）方法来确定哪个患者 表型对托莫西汀和奥昔布宁的反应最好。初步数据强烈表明， 不太严重的过敏性对治疗的反应更大，这可以用替代品检测到 从常规临床睡眠研究测量。这种个性化的医疗方法将提供科学的 在选定的患者中进行更大规模研究所需的知识。 总的来说，我们的建议有望证明药物组合具有治疗OSA的潜力 通过恢复睡眠时的肌肉反应。如果管理得当，这种干预可以 为许多患者提供了CPAP的有效替代方案。这些结果非常重要，因为它们 具有改善未经治疗的OSA患者的生活质量和健康结果的巨大潜力。