# Project 5 > **NIH NIH P01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2022 · $433,250 ## Abstract 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. ## Key facts - **NIH application ID:** 10491096 - **Project number:** 5P01HL149630-03 - **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER - **Principal Investigator:** DAVID ANDREW WELLMAN - **Activity code:** P01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2022 - **Award amount:** $433,250 - **Award type:** 5 - **Project period:** 2020-07-01 → 2025-06-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10491096 ## Citation > US National Institutes of Health, RePORTER application 10491096, Project 5 (5P01HL149630-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10491096. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*