title: Sensitization of upper airway mechanoreceptors as a new pharmacologic principle to treat obstructive sleep apnea: investigations with AVE0118 in anesthetized pigs.
abstract: OBJECTIVE
  Drug treatment for obstructive sleep apnea (OSA) is desirable because at least 30% of patients do not tolerate continuous positive airway pressure (CPAP) treatment. The negative pressure reflex (NPR) involving superficially located mechanoreceptors in the upper airway (UA) is an important mechanism for UA patency inhibitable by topical UA anesthesia (lidocaine). The NPR may serve as a target for pharmacological intervention for a topical treatment of OSA. The objective was to determine the effect of pharmacological augmentation of the NPR on UA collapsibility.
  
  
  METHODS
  We developed a model of UA collapsibility in which application of negative pressures caused UA collapses in spontaneously breathing α-chloralose-urethane anesthetized pigs as indicated by characteristic tracheal pressure and air flow changes.
  
  
  METHODS
  N/A.
  
  
  METHODS
  N/A.
  
  
  METHODS
  N/A.
  
  
  RESULTS
  The potassium channel blocker AVE0118 administered topically to the UA in doses of 1, 3, and 10 mg per nostril sensitized the NPR, shifting the mechanoreceptor response threshold for the genioglossus muscle to more positive pressures (P < 0.001; n = 6 per group) and dose-dependently inhibited UA collapsibility. Ten mg of AVE0118 prevented UA collapses against negative pressures of -150 mbar (P < 0.01) for > 4 h in all pigs, while in control pigs the UA collapsed at -50 mbar or less negative pressures. The effect of AVE0118 was abolished by UA lidocaine anesthesia. Acute intravenous administration of naloxone or acetazolamide was ineffective; paroxetine and mirtazepine were weakly effective and fluoxetine was moderately effective in line with reported clinical efficacy.
  
  
  CONCLUSIONS
  Topical administration of AVE0118 to the UA is a promising pharmacologic approach for the treatment of OSA.
authors: Sanofi-Aventis Deutschland GmbH, R&D, Frankfurt am Main, Germany. Klaus.Wirth@sanofi.com
authors: Klaus J
authors: KJ
authors: Wirth
authors: Klaus
authors: K
authors: Steinmeyer
authors: Hartmut
authors: H
authors: Ruetten
mesh_terms: D000281:Administration, Intranasal; D000403:Airway Resistance / Q000502:physiology*; D018686:Anesthetics, Intravenous; D000818:Animals; D001713:Biphenyl Compounds / Q000008:administration & dosage*; D002698:Chloralose; D003692:Delayed-Action Preparations; D004195:Disease Models, Animal; D008297:Male; D008465:Mechanoreceptors / Q000187:drug effects / Q000502:physiology*; D026902:Potassium Channel Blockers / Q000008:administration & dosage*; D020181:Sleep Apnea, Obstructive / Q000188:drug therapy* / Q000209:etiology; D013552:Swine
chemical_list: C501729:AVE 0118; D018686:Anesthetics, Intravenous; D001713:Biphenyl Compounds; D003692:Delayed-Action Preparations; D026902:Potassium Channel Blockers; D002698:Chloralose
keywords: AVE0118; Animal model; mechanoreceptors; negative pressure reflex; obstructive sleep apnea
references: Sleep. 2011 Apr 01;34(4):541-8
references: 21461333
references: Expert Opin Investig Drugs. 2009 May;18(5):647-56
references: 19388881
references: Diabetes Care. 2003 Mar;26(3):702-9
references: 12610025
references: Expert Opin Investig Drugs. 2011 Aug;20(8):1033-7
references: 21635196
references: J Physiol. 1991 May;436:31-44
references: 2061834
references: Nat Rev Neurosci. 2001 Mar;2(3):175-84
references: 11256078
references: Respir Physiol Neurobiol. 2008 Jan 1;160(1):1-7
references: 17869188
references: Am J Respir Crit Care Med. 1999 Jan;159(1):149-57
references: 9872833
references: Am J Respir Crit Care Med. 1995 Apr;151(4):1108-12
references: 7697239
references: Sleep. 2009 Mar;32(3):361-8
references: 19294956
references: Thorax. 2010 Sep;65(9):829-32
references: 20805182
references: J Appl Physiol (1985). 2005 Sep;99(3):937-43
references: 15831801
references: Sleep. 2011 Aug 01;34(8):1061-73
references: 21804668
references: Eur Respir J. 2011 Aug;38(2):338-47
references: 21177842
references: Nat Rev Cardiol. 2010 Dec;7(12):677-85
references: 21079639
references: Sleep Med Rev. 2008 Feb;12(1):33-47
references: 18201662
references: J Hum Hypertens. 2009 Jul;23(7):431-43
references: 19129854
references: Respir Physiol. 1989 Jan;75(1):29-38
references: 2497502
references: Am J Respir Crit Care Med. 2002 May 1;165(9):1217-39
references: 11991871
references: J Appl Physiol (1985). 1995 Jun;78(6):2180-6
references: 7665415
references: Curr Opin Pulm Med. 2003 Nov;9(6):459-64
references: 14534395
references: Naunyn Schmiedebergs Arch Pharmacol. 2004 Sep;370(3):183-92
references: 15340774
references: Thorax. 2005 May;60(5):418-26
references: 15860719