Project 5
项目5
基本信息
- 批准号:10674892
- 负责人:
- 金额:$ 42.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-01 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:AffectAnimal ExperimentationAnimal ExperimentsApneaAreaArousalBrain StemCarbon DioxideCell NucleusCephalicClinical TrialsCollaborationsDataDilatorDiseaseDrug CombinationsEffectivenessElectroencephalographyEventFunctional disorderGleanGoalsGrantHumanImpaired cognitionIndividualIntentionLightMeasuresMediatingMethodsMotorMuscarinicsMuscleMuscle TonusMuscle hypotoniaNeuronsNorepinephrineObstructive Sleep ApneaOutcomeOxygenPatientsPharmaceutical PreparationsPharmacological TreatmentPharmacotherapyPharyngeal structurePhenotypePhysiologicalPlacebosPredispositionPreventionREM SleepResearchSeriesSerotoninSerotonin AgonistsSerotonin AntagonistsSeveritiesSleepSleep Apnea SyndromesSleep DisordersSleep StagesStimulantTestingTrazodoneUrinary RetentionWithdrawalXerostomiaairway muscleairway obstructionantagonistatomoxetinedifferential expressiondruggable targetexperiencegabapentinhuman dataimprovedindexinginhibitormembernon rapid eye movementnovel therapeuticsoxybutyninpharmacologicpharynx musclepreventreceptorreceptor expressionrespiratoryresponsereuptakesedativeserotonin receptorside effecttraitzolpidem
项目摘要
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.
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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DAVID ANDREW WELLMAN其他文献
DAVID ANDREW WELLMAN的其他文献
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{{ truncateString('DAVID ANDREW WELLMAN', 18)}}的其他基金
Predicting response to non-PAP therapies in OSA using PSG-derived endotypes
使用 PSG 衍生的内型预测 OSA 对非 PAP 疗法的反应
- 批准号:
10440108 - 财政年份:2022
- 资助金额:
$ 42.88万 - 项目类别:
Predicting response to non-PAP therapies in OSA using PSG-derived endotypes
使用 PSG 衍生的内型预测 OSA 对非 PAP 疗法的反应
- 批准号:
10705062 - 财政年份:2022
- 资助金额:
$ 42.88万 - 项目类别:
Determination of the site of pharyngeal collapse in Obstructive Sleep Apnea patients from snoring sounds
从鼾声判断阻塞性睡眠呼吸暂停患者咽部塌陷部位
- 批准号:
10515474 - 财政年份:2016
- 资助金额:
$ 42.88万 - 项目类别:
A method for measuring and modeling the physiologic traits causing sleep apnea
一种测量和模拟导致睡眠呼吸暂停的生理特征的方法
- 批准号:
8040823 - 财政年份:2011
- 资助金额:
$ 42.88万 - 项目类别:
A method for measuring and modeling the physiologic traits causing sleep apnea
一种测量和模拟导致睡眠呼吸暂停的生理特征的方法
- 批准号:
8449678 - 财政年份:2011
- 资助金额:
$ 42.88万 - 项目类别:
Validation of a Phenotype Model to Predict Response to Alternative OSA Treatments
验证表型模型以预测替代 OSA 治疗的反应
- 批准号:
9239787 - 财政年份:2011
- 资助金额:
$ 42.88万 - 项目类别:
A method for measuring and modeling the physiologic traits causing sleep apnea
一种测量和模拟导致睡眠呼吸暂停的生理特征的方法
- 批准号:
8664909 - 财政年份:2011
- 资助金额:
$ 42.88万 - 项目类别:
A method for measuring and modeling the physiologic traits causing sleep apnea
一种测量和模拟导致睡眠呼吸暂停的生理特征的方法
- 批准号:
8245082 - 财政年份:2011
- 资助金额:
$ 42.88万 - 项目类别:
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