• Luigi Taranto-Montemurro, Scott A Sands, Ali Azarbarzin, Melania Marques, Camila M de Melo, Bradley A Edwards, Danny J Eckert, Ludovico Messineo, David P White, and Andrew Wellman.
• 1 Department of Medicine and Department of Neurology, Division of Sleep and Circadian Disorders, Brigham & Women's Hospital & Harvard Medical School, Boston, Massachusetts.
• Ann Am Thorac Soc. 2017 Jul 1; 14 (7): 1177-1183.

RationaleThe reduction in upper airway muscle activity from wakefulness to sleep plays a key role in the development of obstructive sleep apnea. Potassium (K+) channels have been recently identified as the downstream mechanisms through which hypoglossal motoneuron membrane excitability is reduced both in non-rapid eye movement (NREM) sleep and REM sleep. In animal models, the administration of 4-aminopyridine (4-AP), a voltage-gated K+ channel blocker, increased genioglossus activity during wakefulness and across all sleep stages.ObjectivesWe tested the hypothesis that administration of a single dose of 4-AP 10 mg extended release would increase genioglossus activity (electromyography of the genioglossus muscle [EMGGG]) during wakefulness and sleep, and thereby decrease pharyngeal collapsibility.MethodsWe performed a randomized controlled crossover proof-of-concept trial in 10 healthy participants. Participants received active treatment or placebo in randomized order 3 hours before bedtime in the physiology laboratory.ResultsEMGGG during wakefulness and NREM sleep and upper airway collapsibility measured during NREM sleep were unchanged between placebo and 4-AP nights. Tonic but not phasic EMGGG during REM sleep was higher on the 4-AP night when measured as a percentage of maximal voluntary activation (median [interquartile range] 0.3 [0.5] on placebo vs. 0.8 [1.9] %max on 4 AP; P = 0.04), but not when measured in μV or as a percentage of wakefulness value.ConclusionsA single dose of 4-AP 10 mg extended release showed only a small increase in tonic EMGGG during REM sleep in this group of healthy subjects. We speculate that a higher dose of 4-AP may further increase EMGGG. However, given the potentially severe, dose-related adverse effects of this drug, including seizures, the administration of 4-AP does not appear to be an effective strategy to increase genioglossus activity during sleep in humans. Clinical Trial registered with clinicaltrials.gov (NCT02656160).

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