Project 5

摘要/摘要：项目5 OSA是一种常见的、使人虚弱的疾病，目前还没有有效的药物治疗。在上一次 PPG，我们发现了一种药物组合(托莫西汀+奥昔布宁)，可以通过以下方式降低呼吸暂停低通气指数 74%，最低血氧饱和度由84%提高到94%。尽管有这些令人鼓舞的结果，但一些人 患者经历了奥昔布宁的抗肌肉毒副作用。此外，随后的机械论 研究表明，奥昔布宁主要作为镇静剂(对抗托莫西汀)，而不是 咽肌兴奋剂。因此，目前拨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、非肌肉松弛的 镇静剂(目标1)。然后，在目标2中，我们将测试项目1-4中确定的镇静剂，这些镇静剂专门阻止二氧化碳- 介导的唤醒(但不是二氧化碳介导的呼吸/咽部肌肉反应)。如中所述 PPG项目2和4附带的其他赠款预计将确定5-羟色胺亚受体 臂旁CGRP神经元(PBCGRP)可被拮抗以阻止EEG对升高的反应觉醒 二氧化碳。此外，项目3和4将专注于识别一组单独的 臂旁神经元(PBFoxP2)可被药物操纵以增强上呼吸道扩张器 语气。值得注意的是，初步研究表明，PBCGRP神经元被不同的5-羟色胺亚群激活 受体多于PBFoxP2神经元，从而使我们能够潜在地靶向这两个臂旁区域 独立的。因此，Aim 2将测试特定的5-羟色胺激动剂/拮抗剂，使用或不使用托莫西汀。 (根据需要)，激活呼吸道肌肉而不引起唤醒。最后，在目标3中，进行了为期一个月的临床试验 将对目标1和目标2中出现的最有效的药物执行(如果没有发现此类药物，则 将研究最初的阿莫西汀+奥昔布宁组合)。作为该PPG、项目的人工组件 5将利用从动物实验中收集的信息来建立令人兴奋的结果 之前的PPG，并使该领域更接近于OSA的潜在药物疗法。

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.