A Novel Pharmacological Therapy for Obstructive Sleep Apnea

阻塞性睡眠呼吸暂停的新型药物疗法

• 批准号: 10673863
• 负责人: Scott A Sands
• 金额: $ 68.17万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10673863
• 关键词: Adherence; Adverse event; Animals; Anti-Cholinergics; Apnea; Arousal; Cell Nucleus; Clinical; Continuous Positive Airway Pressure; Cross-Over Studies; Data; Development; Dilator; Disease; Dose; Double-Blind Method; Drowsiness; Effectiveness; Electric Stimulation; Exhibits; Female; Frequencies; Health; Human; Hypoglossal nerve structure; Individual; Intervention; Investigation; Knowledge; Measurement; Measures; Methods; Monitor; Motor; Muscarinic Antagonists; Muscarinics; Muscle; Muscle Tonus; Muscular Atrophy; Neurocognitive; Obstructive Sleep Apnea; Outcome; Patient Selection; Patient Self-Report; Patients; Pharmaceutical Preparations; Pharyngeal structure; Phenotype; Physiological; Physiology; Placebo Control; Placebos; Quality of life; Randomized; Reducing Agents; Research; Rest; Severities; Sleep; Sleep Apnea Syndromes; Techniques; Testing; Withdrawal; atomoxetine; cardiovascular health; clinical application; improved; indexing; inhibitor; instrumentation; male; noradrenergic; novel; novel therapeutic intervention; oxybutynin; personalized medicine; pharmacologic; pharynx muscle; primary outcome; response; restoration; reuptake; trait; treatment response

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.

项目总结/文摘

项目成果

Physiological Determinants of Snore Loudness.

打鼾响度的生理决定因素。

• DOI: 10.1513/annalsats.202305-438oc
• 发表时间: 2024
• 期刊: Annals of the American Thoracic Society
• 影响因子: 8.3
• 作者: Vena,Daniel;Gell,Laura;Messineo,Ludovico;Mann,Dwayne;Azarbarzin,Ali;Calianese,Nicole;Wang,Tsai-Yu;Yang,Hyungchae;Alex,Raichel;Labarca,Gonzalo;Hu,Wen-Hsin;Sumner,Jeffrey;White,DavidP;Wellman,Andrew;Sands,ScottA
• 通讯作者: Sands,ScottA

Pro: can physiological risk factors for obstructive sleep apnea be determined by analysis of data obtained from routine polysomnography?

赞成：可以通过分析常规多导睡眠图获得的数据来确定阻塞性睡眠呼吸暂停的生理危险因素吗？

• DOI: 10.1093/sleep/zsac310
• 发表时间: 2023
• 期刊: Sleep
• 影响因子: 5.6
• 作者: Sands,ScottA;Edwards,BradleyA
• 通讯作者: Edwards,BradleyA

Continuous positive airway pressure and adherence in patients with different endotypes of obstructive sleep apnea.

不同内型阻塞性睡眠呼吸暂停患者的持续气道正压通气和依从性。

• DOI: 10.1111/jsr.13999
• 发表时间: 2024
• 期刊: Journal of sleep research
• 影响因子: 4.4
• 作者: Cheng,Wan-Ju;Finnsson,Eysteinn;Ágústsson,JónS;Sands,ScottA;Hang,Liang-Wen
• 通讯作者: Hang,Liang-Wen

Quantification of airway conductance from noninvasive ventilatory drive in patients with sleep apnea.

睡眠呼吸暂停患者无创通气驱动气道传导的量化。

• DOI: 10.1152/japplphysiol.00387.2021
• 发表时间: 2021
• 期刊: Journal of applied physiology (Bethesda, Md. : 1985)
• 作者: Tolbert,ThomasM;Parekh,Ankit;Sands,ScottA;Mooney,AnneM;Ayappa,Indu;Rapoport,DavidM
• 通讯作者: Rapoport,DavidM

Association of cortical arousals with sleep-disordered breathing events.

皮质唤醒与睡眠呼吸障碍事件的关联。

• DOI: 10.5664/jcsm.10492
• 发表时间: 2023
• 期刊: Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine
• 作者: Zitting,Kirsi-Marja;Lockyer,BrandonJ;Azarbarzin,Ali;Sands,ScottA;Wang,Wei;Wellman,Andrew;Quan,StuartF
• 通讯作者: Quan,StuartF