Luigi Taranto-Montemurro1, Scott A Sands1,2, Ali Azarbarzin1, Melania Marques1,3, Camila M de Melo1,4, Bradley A Edwards5,6, Danny J Eckert7, Ludovico Messineo1,8, David P White1, Andrew Wellman1. 1. 1 Department of Medicine and Department of Neurology, Division of Sleep and Circadian Disorders, Brigham & Women's Hospital & Harvard Medical School, Boston, Massachusetts. 2. 2 Department of Allergy, Immunology and Respiratory Medicine and Central Clinical School, The Alfred and Monash University, Melbourne, Victoria, Australia. 3. 3 Pulmonary Division, Heart Institute, Hospital das Clínicas, University of São Paulo School of Medicine, São Paulo, Brazil. 4. 4 Department of Psychobiology, Federal University of São Paulo, São Paulo, Brazil. 5. 5 Sleep and Circadian Medicine Laboratory, Department of Physiology, Monash University, Melbourne, Victoria, Australia. 6. 6 School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences, Monash University, Melbourne, Victoria, Australia. 7. 7 Neuroscience Research Australia and the University of New South Wales, Randwick, Sydney, Australia; and. 8. 8 Respiratory Medicine and Sleep Laboratory, Department of Internal Medicine, Spedali Civili di Brescia, University of Brescia, Brescia, Italy.
Abstract
RATIONALE: The 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. OBJECTIVES: We 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. METHODS: We 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. RESULTS: EMGGG 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. CONCLUSIONS: A 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).
RCT Entities:
RATIONALE: The 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. OBJECTIVES: We 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. METHODS: We 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. RESULTS: EMGGG 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. CONCLUSIONS: A 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).
Entities:
Keywords:
drug therapy; obstructive sleep apnea; potassium channel blockers
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