A Novel Pharmacological Therapy for Obstructive Sleep Apnea

项目摘要/摘要 阻塞性睡眠呼吸暂停(OSA)是一种非常普遍的疾病，对 神经认知功能和心血管健康。然而，领先的治疗方法是持续正压气道 压力(CPAP)，是许多人难以忍受的。因此，发展新的治疗策略是 这是急需的。阻塞性睡眠呼吸暂停综合征的药物治疗仍然难以捉摸。 导致阻塞性睡眠呼吸暂停的一个关键因素是咽部扩张器、肌肉张力和睡眠时的反应性降低。动物 研究支持两种机制：去甲肾上腺素的丧失和毒鼠强的丧失。 对舌下运动池的抑制。因此，在一项针对人类阻塞性睡眠呼吸暂停综合征患者的小型研究中，我们 给予现有药物的新组合-去甲肾上腺素再摄取抑制剂托莫西汀和 抗血吸虫药物奥昔布宁-在一个晚上，发现阻塞性睡眠呼吸暂停综合症的严重程度降低了约75%，是迄今为止最大的 先前观察到的任何药物干预的强大效果。我们目前的提案充分利用了我们的 在阻塞性睡眠呼吸暂停综合征的药物治疗方面取得重大进展的初步发现。 在目标1中，我们试图证明托莫西汀联合奥昔布宁的重复给药疗效和耐受性。 48名男性和女性阻塞性睡眠呼吸暂停患者的随机、安慰剂对照、交叉研究，为期1个月。我们会 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、频率的影响 从睡眠、困倦和疾病特有的生活质量中唤醒。坚持治疗和不良事件 也将受到仔细的监控。在目标2中，我们将研究阿莫西汀和阿莫西汀的作用机制。 奥昔布宁单独或联合应用可改善阻塞性睡眠呼吸暂停的严重程度。使用黄金标准的“深度表型” 机制研究，我们将分别检验这两种制剂提高肌肉反应性的假设。 和协同作用，奥昔布宁抵消了托莫西汀的作用，提高了唤醒能力。 这些结果将对正在进行的这一药理学方法的开发产生关键影响。在AIM 3，我们将同时使用深度表型和非侵入性(临床适用)方法来确定哪位患者 表型对阿莫西汀和奥昔布宁的反应最好。初步数据强烈表明，患有 不太严重的崩解表现出对治疗的更大反应，这可以通过代用品检测到。 来自常规临床睡眠研究的测量。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。 总体而言，我们的建议有望证明联合用药有可能治疗阻塞性睡眠呼吸暂停低通气综合征。 通过恢复睡眠时肌肉的反应性。如果管理得当，这种干预可能会 为许多患者提供了一个有效的CPAP替代方案。这样的结果具有重大意义，因为它们 对改善未经治疗的阻塞性睡眠呼吸暂停综合征患者的生活质量和健康结果具有巨大潜力。

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.