Project 5- BWH Wellman

项目摘要/摘要 大约一半的阻塞性睡眠呼吸暂停(OSA)患者不能耐受持续的正压通气 加压(CPAP)疗法。因此，迫切需要新的治疗方案。一个潜在的治疗目标 是呼吸唤醒的阈值。最近的证据表明，对呼吸刺激的过早唤醒 (容易被二氧化碳唤醒)可以防止重要的神经肌肉代偿机制稳定 上呼吸道。然而，有效的镇静剂在提高觉醒阈值的同时又不会减少咽喉 肌张力(传统苯二氮卓类药物的局限性)，缺乏。因此，这笔赠款的一个主要目标是 就是寻找镇静剂，在不影响咽部肌肉张力的情况下提高唤醒阈值。另一个 阻塞性睡眠呼吸暂停综合征的潜在治疗靶点是咽肌本身。新的动物数据表明， 咽肌在睡眠中变得低张，主要是因为去甲肾上腺素的逐渐退出- 在快速眼动睡眠中，舌下核的错误音，以及毒碱抑制。然而，由于 对这些机制的认识相对较新，具有这些神经递质特征的药物尚未 在人体上进行了充分的测试。因此，这笔赠款的另一个主要目标是确定去甲肾上腺素能和抗去甲肾上腺素能 可在人类睡眠时刺激咽部肌肉的毒鼠碱类药物。最后，对其进行了假设 同时治疗这两种特征，即联合治疗，可能比单一药物更有效 心理治疗。这样做的理由是非CPAP疗法(口腔矫治器、外科手术、体位疗法) 一般情况下，这些药物的影响都很小，认为这些药物也会有影响是现实的。因此，COM- 联合用药可以最大限度地发挥药效，增强咽部的神经肌肉代偿。 肌肉。具体地说，目标1将测试以下药物在睡眠中刺激咽肌的效果 人类：1)地昔帕明(一种具有去甲肾上腺素和抗肌肉碱双重作用的三环抗抑郁药)；和2) 托莫西汀(一种去甲肾上腺素再摄取抑制剂)与奥昔布宁(一种抗肿瘤药物)联合使用。目标 2将测试埃佐匹克隆或替加宾在提高呼吸觉醒阈值方面的有效性。埃佐匹克隆 是一种非苯二氮类镇静剂，与旧的镇静剂相比，它产生的咽部低眼压较少，而替加宾 是一种能引起慢波睡眠的抗惊厥药。慢波睡眠相对不受阻塞性睡眠呼吸暂停的影响， 总而言之，这是因为它与更高的唤醒阈值和更活跃的咽肌有关。最后， 目标3将联合来自目标1的刺激咽部的药物和来自目标2的镇静剂来治疗阻塞性睡眠呼吸暂停综合征。 低觉醒阈值和非严重解剖损害(约占OSA的1/3) 蒂恩斯)。长期目标是改善阻塞性睡眠呼吸暂停患者的依从性、生活质量和健康结局。 这笔赠款是实现这一目标的重要第一步，可能会改变OSA的管理方式 很多病人。

PROJECT SUMMARY/ABSTRACT Approximately half of all obstructive sleep apnea (OSA) patients cannot tolerate continuous positive airway pressure (CPAP) therapy. Therefore, new treatment options are badly needed. One potential treatment target is the respiratory arousal threshold. Recent evidence suggests that premature arousals to respiratory stimuli (wake up easily to CO2) can prevent important neuromuscular compensatory mechanisms from stabilizing the upper airway. However, effective sedatives for raising the arousal threshold without also reducing pharyngeal muscle tone (a limitation of traditional benzodiazepines), are lacking. Therefore, a major objective of this grant is to find sedatives that will raise the arousal threshold without compromising pharyngeal muscle tone. Another potential treatment target for OSA is the pharyngeal muscles themselves. New animal data suggests that the pharyngeal muscles become hypotonic during sleep primarily because of progressive withdrawal of noradren- ergic tone at the hypoglossal nucleus, as well as muscarinic inhibition during REM sleep. However, due to the relatively recent awareness of these mechanisms, drugs with these neurotransmitter profiles have not been adequately tested in humans. Thus, another major objective of this grant is to identify noradrenergic and anti- muscarinic drugs that can stimulate the pharyngeal muscles during sleep in humans. Lastly, it is hypothesized that treating both traits simultaneously, i.e. combination therapy, may achieve more success than single drug therapy. The rationale for doing this is that non-CPAP therapies (oral appliances, surgery, positional therapy) generally tend to have small effect sizes, and it is realistic to think that these drugs will also. Therefore, com- bining them could maximize their effectiveness and enhance neuromuscular compensation of the pharyngeal muscles. Specifically, Aim 1 will test how well the following drugs stimulate the pharyngeal muscles in sleeping humans: 1) desipramine (a tricyclic antidepresseant with dual noradrenergic and antimuscarinic effects); and 2) atomoxetine (a norepinephrine reuptake inhibitor) in combination with oxybutynin (an antimuscarnic drug). Aim 2 will test the effectiveness of eszopiclone or tiagabine at raising the respiratory arousal threshold. Eszopiclone is a non-benzodiazepine sedative that produces less pharyngeal hypotonia than older sedatives, and tiagabine is and anticonvulsant that induces slow wave sleep. Slow wave sleep is relatively protected from OSA, pre- sumably because it is associated with a higher arousal threshold and more active pharyngeal muscles. Finally, Aim 3 will combine a pharyngeal stimulating drug from Aim 1 with a sedative from Aim 2 to treat OSA in pa- tients with a low arousal threshold and non-severe anatomical compromise (approximately 1/3 of OSA pa- tients). The long term goal is to improve compliance, quality of life, and health outcomes in patients with OSA. This grant is a major first step in achieving this goal and could potentially change the way OSA is managed for many patients.