title: Non-cholinergic intervention of sarin nerve agent poisoning.
abstract: The protective effects of selected anesthetic regimens on sarin (GB) were investigated in domestic swine. At 30% oxygen, the toxicity of this agent in isoflurane anesthetized animals (LD(50)=10.1μg/kg) was similar to literature sited values in awake swine (LD(50)=11.8μg/kg) and slightly higher than that of both ketamine (LD(50)=15.6μg/kg) and propofol (LD(50)=15.3μg/kg) anesthetized swine. Use of 100% oxygen in ketamine anesthetized animals resulted in three-fold protective effects compared to 30% oxygen. Use of 100% oxygen in both isoflurane and propofol anesthetized animals, compared to 30% resulted in profound protection against GB poisoning (>33×). There were no differences in the severity of the poisoning or recovery time in animals treated over dose ranges of 10-350μg/kg (isoflurane) or 15-500μg/kg GB (propofol). Survivors of high GB challenges that were revived from propofol anesthetic exhibited no signs of cognitive impairment seven days later. Protective treatments did not attenuate cholinesterase (ChE) inhibition; survivors of otherwise supralethal GB concentrations exhibited very low blood ChE activities. This work indicates that propofol has protective effects against GB, and that oxygen tension may have an important role in treating nerve agent casualties. More importantly, it demonstrates that non-cholinergic protective mechanisms exist that may be exploited in the future development of medical countermeasures against organophosphorous nerve agents.
authors.affiliation: Defence Research & Development Canada-Suffield, Box 4000, Medicine Hat, Alberta, Canada T1A 8K6. Thomas.Sawyer@drdc-rddc.gc.ca
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Sawyer
authors.forename: John
authors.initials: J
authors.lastname: Mikler
authors.forename: Catherine
authors.initials: C
authors.lastname: Tenn
authors.forename: Stephen
authors.initials: S
authors.lastname: Bjarnason
authors.forename: Robert
authors.initials: R
authors.lastname: Frew
mesh_terms: D000778:Anesthetics, Dissociative / Q000008:administration & dosage / Q000494:pharmacology; D018685:Anesthetics, Inhalation / Q000008:administration & dosage / Q000494:pharmacology; D018686:Anesthetics, Intravenous / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D002619:Chemical Warfare Agents / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D007530:Isoflurane / Q000494:pharmacology*; D007649:Ketamine / Q000008:administration & dosage / Q000494:pharmacology*; D007928:Lethal Dose 50; D008297:Male; D010100:Oxygen / Q000008:administration & dosage; D015742:Propofol / Q000008:administration & dosage / Q000494:pharmacology*; D012524:Sarin / Q000008:administration & dosage / Q000633:toxicity*; D012720:Severity of Illness Index; D013552:Swine; D013997:Time Factors
chemical_list: D000778:Anesthetics, Dissociative; D018685:Anesthetics, Inhalation; D018686:Anesthetics, Intravenous; D002619:Chemical Warfare Agents; D007649:Ketamine; D012524:Sarin; D007530:Isoflurane; D010100:Oxygen; D015742:Propofol