title: Coadministration of the AMPAKINE CX717 with propofol reduces respiratory depression and fatal apneas.
abstract: BACKGROUND
  Propofol (2,6-diisopropylphenol) is used for the induction and maintenance of anesthesia in human and veterinary medicine. Propofol's disadvantages include the induction of respiratory depression and apnea. Here, the authors report a clinically feasible pharmacological solution for reducing propofol-induced respiratory depression via a mechanism that does not interfere with anesthesia. Specifically, they test the hypothesis that the AMPAKINE CX717, which has been proven metabolically stable and safe for human use, can prevent and rescue from propofol-induced severe apnea.
  
  
  METHODS
  The actions of propofol and the AMPAKINE CX717 were measured via (1) ventral root recordings from newborn rat brainstem-spinal cord preparations, (2) phrenic nerve recordings from an adult mouse in situ working heart-brainstem preparation, and (3) plethysmographic recordings from unrestrained newborn and adult rats.
  
  
  RESULTS
  In vitro, respiratory depression caused by propofol (2 μM, n = 11, mean ± SEM, 41 ± 5% of control frequency, 63 ± 5% of control duration) was alleviated by CX717 (n = 4, 50-150 μM). In situ, a decrease in respiratory frequency (44 ± 9% of control), phrenic burst duration (66 ± 7% of control), and amplitude (78 ± 5% of control) caused by propofol (2 μM, n = 5) was alleviated by coadministration of CX717 (50 μM, n = 5). In vivo, pre- or coadministration of CX717 (20-25mg/kg) with propofol markedly reduced propofol-induced respiratory depression (n = 7; 20mg/kg) and propofol-induced lethal apnea (n = 6; 30 mg/kg).
  
  
  CONCLUSIONS
  Administration of CX717 before or in conjunction with propofol provides an increased safety margin against profound apnea and death.
authors.affiliation: Department of Physiology, Centre for Neuroscience, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
authors.forename: Floriane
authors.initials: F
authors.lastname: Lenal
authors.forename: Michael
authors.initials: M
authors.lastname: Yang
authors.forename: Xiuqing
authors.initials: X
authors.lastname: Ding
authors.forename: John J
authors.initials: JJ
authors.lastname: Greer
mesh_terms: D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D001049:Apnea / Q000150:complications* / Q000517:prevention & control*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination / Q000379:methods; D007555:Isoxazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D010991:Plethysmography / Q000379:methods; D015742:Propofol / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012131:Respiratory Insufficiency / Q000150:complications / Q000517:prevention & control*
chemical_list: D018686:Anesthetics, Intravenous; C542518:CX717; D007555:Isoxazoles; D015742:Propofol