title: Effect of 4-Aminopyridine on Genioglossus Muscle Activity during Sleep in Healthy Adults.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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
  EMGGGduring wakefulness and NREM sleep and upper airway collapsibility measured during NREM sleep were unchanged between placebo and 4-AP nights. Tonic but not phasic EMGGGduring 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] %maxon 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 EMGGGduring 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).
authors.affiliation: 1 Department of Medicine and Department of Neurology, Division of Sleep and Circadian Disorders, Brigham & Women's Hospital & Harvard Medical School, Boston, Massachusetts.
authors.forename: Luigi
authors.initials: L
authors.lastname: Taranto-Montemurro
authors.affiliation: 1 Department of Medicine and Department of Neurology, Division of Sleep and Circadian Disorders, Brigham & Women's Hospital & Harvard Medical School, Boston, Massachusetts.|2 Department of Allergy, Immunology and Respiratory Medicine and Central Clinical School, The Alfred and Monash University, Melbourne, Victoria, Australia.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Sands
authors.affiliation: 1 Department of Medicine and Department of Neurology, Division of Sleep and Circadian Disorders, Brigham & Women's Hospital & Harvard Medical School, Boston, Massachusetts.
authors.forename: Ali
authors.initials: A
authors.lastname: Azarbarzin
authors.affiliation: 1 Department of Medicine and Department of Neurology, Division of Sleep and Circadian Disorders, Brigham & Women's Hospital & Harvard Medical School, Boston, Massachusetts.|3 Pulmonary Division, Heart Institute, Hospital das Clínicas, University of São Paulo School of Medicine, São Paulo, Brazil.
authors.forename: Melania
authors.initials: M
authors.lastname: Marques
authors.affiliation: 1 Department of Medicine and Department of Neurology, Division of Sleep and Circadian Disorders, Brigham & Women's Hospital & Harvard Medical School, Boston, Massachusetts.|4 Department of Psychobiology, Federal University of São Paulo, São Paulo, Brazil.
authors.forename: Camila M
authors.initials: CM
authors.lastname: de Melo
authors.affiliation: 5 Sleep and Circadian Medicine Laboratory, Department of Physiology, Monash University, Melbourne, Victoria, Australia.|6 School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences, Monash University, Melbourne, Victoria, Australia.
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Edwards
authors.affiliation: 7 Neuroscience Research Australia and the University of New South Wales, Randwick, Sydney, Australia; and.
authors.forename: Danny J
authors.initials: DJ
authors.lastname: Eckert
authors.affiliation: 1 Department of Medicine and Department of Neurology, Division of Sleep and Circadian Disorders, Brigham & Women's Hospital & Harvard Medical School, Boston, Massachusetts.|8 Respiratory Medicine and Sleep Laboratory, Department of Internal Medicine, Spedali Civili di Brescia, University of Brescia, Brescia, Italy.
authors.forename: Ludovico
authors.initials: L
authors.lastname: Messineo
authors.affiliation: 1 Department of Medicine and Department of Neurology, Division of Sleep and Circadian Disorders, Brigham & Women's Hospital & Harvard Medical School, Boston, Massachusetts.
authors.forename: David P
authors.initials: DP
authors.lastname: White
authors.affiliation: 1 Department of Medicine and Department of Neurology, Division of Sleep and Circadian Disorders, Brigham & Women's Hospital & Harvard Medical School, Boston, Massachusetts.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wellman
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology*; D000328:Adult; D004576:Electromyography; D006801:Humans; D018482:Muscle, Skeletal / Q000187:drug effects; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D012890:Sleep / Q000502:physiology*
chemical_list: D026902:Potassium Channel Blockers; D015761:4-Aminopyridine
keywords: drug therapy; obstructive sleep apnea; potassium channel blockers