Topical Potassium Channel Blockage Improves Pharyngeal Collapsibility

Background Potassium (K+) channel inhibition has been identified in animal models as a potential target to increase pharyngeal dilator muscle activity and to treat OSA. However, these findings have not yet been translated to humans. Research Question Does a novel, potent, tandem of P domains in a weak inward rectifying K+ channel (TWIK)-related acid-sensitive K+ (TASK) 1/3 channel antagonist, BAY2586116, improve pharyngeal collapsibility in pigs and humans, and secondarily, what is the optimal dose and method of topical application? Study Design and Methods In the preclinical study, pharyngeal muscle activity and upper-airway collapsibility via transient negative pressure application was quantified in 13 anesthetized pigs during administration of placebo, 0.3 μg, 3 μg, and 30 μg nasal drops of BAY2586116. In the 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 (160 μg) or placebo nasal spray before sleep via a double-masked, randomized, crossover design. Most participants also returned for three additional overnight visits: (1) nasal drops (160 μg), (2) half-dose nasal spray (80 μg), and (3) direct endoscopic application (160 μg). The upper-airway critical closing pressure (Pcrit) during sleep was quantified at each visit. Results Consistent and sustained improvements in pharyngeal collapsibility to negative pressure were found with 3 and 30 μg of BAY2586116 vs placebo in pigs. Similarly, BAY2586116 improved pharyngeal collapsibility by an average of approximately 2 cm H2O vs placebo, regardless of topical application method and dose (P < .008, mixed model) in participants with OSA. Interpretation Acute topical application of BAY2586116 improves upper-airway collapsibility in anesthetized pigs and sleeping humans with OSA. These novel physiologic findings highlight the therapeutic potential to target potassium channel mechanisms to treat OSA. Trial Registry ClinicalTrials.gov; No.: NCT04236440; URL: www.clinicaltrials.gov Potassium (K+) channel inhibition has been identified in animal models as a potential target to increase pharyngeal dilator muscle activity and to treat OSA. However, these findings have not yet been translated to humans. Does a novel, potent, tandem of P domains in a weak inward rectifying K+ channel (TWIK)-related acid-sensitive K+ (TASK) 1/3 channel antagonist, BAY2586116, improve pharyngeal collapsibility in pigs and humans, and secondarily, what is the optimal dose and method of topical application? In the preclinical study, pharyngeal muscle activity and upper-airway collapsibility via transient negative pressure application was quantified in 13 anesthetized pigs during administration of placebo, 0.3 μg, 3 μg, and 30 μg nasal drops of BAY2586116. In the 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 (160 μg) or placebo nasal spray before sleep via a double-masked, randomized, crossover design. Most participants also returned for three additional overnight visits: (1) nasal drops (160 μg), (2) half-dose nasal spray (80 μg), and (3) direct endoscopic application (160 μg). The upper-airway critical closing pressure (Pcrit) during sleep was quantified at each visit. Consistent and sustained improvements in pharyngeal collapsibility to negative pressure were found with 3 and 30 μg of BAY2586116 vs placebo in pigs. Similarly, BAY2586116 improved pharyngeal collapsibility by an average of approximately 2 cm H2O vs placebo, regardless of topical application method and dose (P < .008, mixed model) in participants with OSA. Acute topical application of BAY2586116 improves upper-airway collapsibility in anesthetized pigs and sleeping humans with OSA. These novel physiologic findings highlight the therapeutic potential to target potassium channel mechanisms to treat OSA. ClinicalTrials.gov; No.: NCT04236440; URL: www.clinicaltrials.gov Task Accomplished: Promising Effects of a New Topical Potassium Channel Antagonist in OSACHESTVol. 163Issue 4PreviewOSA is a common disorder among adults. Although CPAP is highly effective to treat OSA, many patients reject CPAP or other conventional OSA treatments such as oral appliances and surgery.1 Therefore, new treatment approaches for patients with OSA are necessary. Pharyngeal muscle activity is sufficient to maintain airway patency during wakefulness in subjects with OSA. State-dependent reduction of pharyngeal muscle activity during sleep is the hallmark feature of OSA. Until recently, the mechanisms involved in the inhibition of pharyngeal muscle activation during non-rapid eye movement (non-REM) and rapid eye movement (REM) sleep were not understood. Full-Text PDF