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Rationale: The combination of noradrenergic and antimuscarinic agents has recently been shown to improve upperairway function and reduce obstructive sleep apnea (OSA) severity in short-term (<1 wk) proof-of-concept studies. Objectives: To determine the safety, tolerability, and potential efficacy of longer term use of different doses of the noradrenergic agent atomoxetine combined with the antimuscarinic oxybutynin (ato-oxy). Methods: Thirty-nine people with predominantly severe OSA received 80/5 mg ato-oxy, 40/5 mg ato-oxy, 40/2.5 mg 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, and 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 at baseline and Night 30. Potential adverse events were assessed during in-laboratory 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 (mean6standard deviation 8610 beats/min [P= 0.01] with 80/5 mg and 9614 beats/min [P=0.02] with 40/2.5 mg vs. placebo). No clinically relevant changes in blood pressure, International Prostate Symptom Score, and measures of alertness and memory were observed between conditions. Apnea–hypopnea index (AHI) with 4% oxygen desaturation and hypoxic burden decreased by (50% with 80/5 mg ato-oxy from baseline but not versus placebo (e.g., AHI with 3% oxygen desaturation and AHI with 4% oxygen desaturation difference at Night 30 was 28.2 [95% confidence interval, 222.5 to 6.2] and 28.5 [95% confidence interval, 218.3 to 1.3] events/h, respectively). Conclusions: One month of nightly noradrenergic and antimuscarinic 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 antimuscarinic mechanisms for OSA pharmacotherapy development. [ABSTRACT FROM AUTHOR]

Background: K+ channel inhibition has been identified in animal models as a potential target to increase pharyngeal dilator muscle activity and treat obstructive sleep apnea (OSA). However, these findings have not yet been translated to humans.Research Question: Does a novel, potent, TASK 1/3 channel antagonist, BAY2586116, improve pharyngeal collapsibility in pigs and humans and secondarily, what is the optimal dose and mode of topical application?Study Design and Methods: Pre-clinical study: Pharyngeal muscle activity and upper-airway collapsibility via transient negative pressure application was quantified in 13 anesthetized pigs during placebo, 0.3, 3 and 30μg nasal drops of BAY2586116.Clinical Study: 12 people with OSA instrumented with polysomnography equipment, an epiglottic pressure catheter, pneumotachograph and nasal mask to monitor sleep and breathing performed up to four detailed upper airway sleep physiology studies. Participants received BAY2586116 or placebo nasal spray (160μg) prior to sleep via a double-blind, randomized, crossover design. Most participants also returned for three additional overnight visits: 1) nasal drops (160μg), 2) half dose nasal spray (80μg), and 3) direct endoscopic application (160μg). The upper-airway critical closing pressure (Pcrit) during sleep was quantified at each visit.Results: There were consistent and sustained improvements in pharyngeal collapsibility to negative pressure with 3 and 30μg of BAY2586116 versus placebo in pigs. Similarly, BAY2586116 improved pharyngeal collapsibility by an average of ∼2cmH2O versus placebo regardless of topical application mode and dose (mixed model p<0.008) in participants with OSA.Interpretation: Acute topical application of BAY2586116 improves upper-airway collapsibility in anesthetized pigs and sleeping humans with OSA. These novel physiology findings highlight the therapeutic potential to target K+ channel mechanisms to treat OSA.Clinical Trial Registration: NCT04236440. [ABSTRACT FROM AUTHOR]

Rationale: Regular, low-dose, sustained-release morphine is frequently prescribed for persistent breathlessness in chronic obstructive pulmonary disease (COPD). However, effects on daytime sleepiness, perceived sleep quality and daytime function have not been rigorously investigated., Objectives: Determine the effects of regular, low-dose, sustained-release morphine on sleep parameters in COPD., Methods: Pre-specified secondary analyses of validated sleep questionnaire data from a randomized trial of daily, low-dose, sustained -release morphine versus placebo over four weeks commencing at 8mg or 16mg/day with blinded up-titration over two weeks to a maximum of 32mg/day. Primary outcomes for these analyses were week-1 Epworth Sleepiness Scale (ESS) and Karolinska Sleepiness Scale (KSS) responses on morphine versus placebo. Secondary outcomes included Leeds Sleep Evaluation Questionnaire (LSEQ) scores (end of weeks 1 and 4), KSS and ESS beyond week-1 and associations between breathlessness, morphine, and questionnaire scores., Measurements and Main Results: 156 people were randomized. Week-1 sleepiness scores were not different on morphine versus placebo (∆ESS [95%CI] versus placebo: 8mg group: -0.59 [-1.99, 0.81], p=0.41; 16mg group: -0.72 [-2.33, 0.9], p=0.38; ∆KSS versus placebo: 8mg group: 0.11 [-0.7, 0.9], p=0.78; 16mg group: -0.41 [-1.31, 0.49], p=0.37). This neutral effect persisted at later timepoints. In addition, participants who reported reduced breathlessness with morphine at 4 weeks also had improvement in LSEQ domain scores including perceived sleep quality and daytime function., Conclusions: Regular, low-dose morphine does not worsen sleepiness when used for breathlessness in COPD. Individual improvements in breathlessness with morphine may be related to improvements in sleep.