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|Title:||One Month Dosing of Atomoxetine plus Oxybutynin in Obstructive Sleep Apnea: A Randomized, Placebo-controlled Trial.|
|Citation:||Annals of the American Thoracic Society, 2022; 20(4):584-595|
|Publisher:||American Thoracic Society|
|Atqiya Aishah, Kelly A. Loffler, Barbara Toson, Sutapa Mukherjee, Robert J. Adams, Thomas J. Altree, Henry W. Ainge-Allen, Brendon J. Yee, Ronald R. Grunstein, Jayne C. Carberry, and Danny J. Eckert|
|Abstract:||RATIONALE: The combination of noradrenergic and anti-muscarinic agents has recently been shown to improve upper-airway function and reduce obstructive sleep apnea (OSA) severity in short-term (≤1 week) proof-of-concept studies. OBJECTIVE: To determine the safety, tolerability, and potential efficacy of longer-term use of different doses of the noradrenergic agent atomoxetine combined with the anti-muscarinic oxybutynin. METHODS: Thirty-nine people with predominantly severe OSA received either 80mg atomoxetine/5mg oxybutynin (ato-oxy), 40/5mg ato-oxy, 40/2.5mg ato-oxy or placebo nightly for 30 days in a double-blind, randomized, parallel design. Participants completed three in-laboratory sleep studies (baseline, night 1, night 30) to assess efficacy. Vital signs and objective measures of alertness and memory were assessed. In men, potential effects on prostate function were assessed using the International Prostate Symptom Score (IPSS) at baseline and night 30. Potential adverse events were assessed during in-lab visits and via weekly phone calls. RESULTS: Side effects were generally mild and consistent with known side-effect profiles of each individual drug (i.e., dose-dependent increases in dry mouth with oxybutynin). Heart rate increased by night 30 in two active drug arms (mean±SD: 8±10 beats/min, p=0.01, 80/5mg; 9±14 beats/min, p=0.02, 40/2.5mg; versus placebo). No clinically relevant changes to blood pressure, IPSS and measures of alertness and memory were observed between conditions. Apnoea-hypopnea index (4% oxygen desaturation: AHI4) and hypoxic burden decreased by ~50% with 80/5mg ato-oxy from baseline but not versus placebo (e.g., AHI3 and AHI4 difference [95%CI] at night 30= -8.2 [-22.5, 6.2] and -8.5 [-18.3, 1.3] events/h, respectively). CONCLUSIONS: 1 month of nightly noradrenergic and anti-muscarinic combination therapy was generally well-tolerated with a side effect profile consistent with each agent alone and was associated with an ~50% reduction from baseline in a key OSA severity metric, the hypoxic burden with the highest dose combination. These findings highlight the potential to target noradrenergic and anti-muscarinic mechanisms for OSA pharmacotherapy development. CLINICAL TRIAL REGISTRATION: ACTRN12619001153101.|
|Keywords:||sleep-disordered breathing; noradrenergic; antimuscarinic; pharmacotherapy; upper airway|
|Rights:||Copyright status unknown|
|Appears in Collections:||Medicine publications|
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