Project 5

项目5

• 批准号: 10491096
• 负责人: DAVID ANDREW WELLMAN
• 金额: $ 43.33万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10491096
• 关键词: Affect; Animal Experimentation; Animal Experiments; Apnea; Area; Arousal; Brain Stem; Carbon Dioxide; Cell Nucleus; Cephalic; Clinical Trials; Collaborations; Data; Dilator; Disease; Drug Combinations; Effectiveness; Electroencephalography; Event; Functional disorder; Glean; Goals; Grant; Human; Impaired cognition; Individual; Intention; Light; Measures; Mediating; Methods; Motor; Muscarinics; Muscle; Muscle Tonus; Muscle hypotonia; Neurons; Norepinephrine; Obstructive Sleep Apnea; Outcome; Oxygen; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Pharmacotherapy; Phenotype; Physiological; Placebos; Prevention; REM Sleep; Research; Series; Serotonin; Serotonin Agonists; Serotonin Antagonists; Severities; Sleep; Sleep Apnea Syndromes; Sleep Disorders; Sleep Stages; Stimulant; Testing; Trazodone; Urinary Retention; Withdrawal; Xerostomia; airway muscle; airway obstruction; antagonist; atomoxetine; base; differential expression; druggable target; experience; gabapentin; human data; improved; indexing; inhibitor; member; non rapid eye movement; novel therapeutics; oxybutynin; pharynx muscle; prevent; receptor; receptor expression; respiratory; response; reuptake; sedative; serotonin receptor; side effect; trait; zolpidem

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