Project 5- BWH Wellman

项目总结/摘要 大约一半的阻塞性睡眠呼吸暂停（OSA）患者不能耐受持续气道正压通气 压力（CPAP）治疗。因此，迫切需要新的治疗选择。一个潜在治疗靶点 是呼吸唤醒阈值最近的证据表明，对呼吸刺激的过早觉醒 (wake容易上升到CO2）可以阻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，提高唤醒阈值，而不减少咽 肌肉张力（传统苯二氮卓类药物的局限性）。因此，这笔赠款的一个主要目标是， 是找到既能提高唤醒阈值又不会影响咽肌张力的镇静剂。另一 OSA的潜在治疗目标是咽肌本身。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减少， 在舌下神经核的神经张力，以及在REM睡眠期间的毒蕈碱抑制。但由于 相对最近的认识，这些机制，药物与这些神经递质的档案还没有 在人类中进行了充分的测试。因此，该基金的另一个主要目标是鉴定去甲肾上腺素能和抗- 毒蕈碱类药物，可以在人类睡眠期间刺激咽部肌肉。最后，假设 同时治疗这两种特征，即联合治疗，可能比单一药物取得更大的成功。 疗法这样做的理由是，非CPAP治疗（口腔矫治器，手术，体位治疗） 一般倾向于有小的影响大小，这是现实的认为，这些药物也将。因此，COM- 比宁它们可以最大限度地发挥它们的作用，并增强咽部的神经肌肉代偿。 肌肉.具体来说，目标1将测试以下药物在睡眠中刺激咽部肌肉的效果如何 人类：1）地昔帕明（一种具有去甲肾上腺素能和抗毒蕈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（一种抗毒蕈碱药物）联合。目的 2将测试右佐匹克隆或噻加宾在提高呼吸觉醒阈值方面的有效性。右佐匹克隆 是一种非苯二氮卓类镇静剂，与较老的镇静剂相比， 是一种能引起慢波睡眠的抗惊厥药。慢波睡眠是相对保护，从阻塞性睡眠呼吸暂停综合征，前 这可能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将目标1中的咽部刺激药物与目标2中的镇静剂结合联合收割机，以治疗重度阻塞性睡眠呼吸暂停。 低唤醒阈值和非严重解剖学损害的患者（约1/3的OSA患者） tients）。长期目标是改善OSA患者的依从性、生活质量和健康结果。 这笔赠款是实现这一目标的重要的第一步，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.