title: Reactivation of nerve agent-inhibited human acetylcholinesterase by obidoxime, HI-6 and obidoxime+HI-6: Kinetic in vitro study with simulated nerve agent toxicokinetics and oxime pharmacokinetics.
abstract: Despite extensive research for decades no effective broad-spectrum oxime for the treatment of poisoning by a broad range of nerve agents is available. Previous in vitro and in vivo data indicate that the combination of in service oximes could be beneficial. To investigate the ability of obidoxime, HI-6 and the combination of both oximes to reactivate inhibited human AChE in the presence of sarin, cyclosarin or tabun we adopted a dynamic in vitro model with real-time and continuous determination of AChE activity to simulate inhalation nerve agent exposure and intramuscular oxime administration. The major findings of this kinetic study are that the extent and velocity of reactivation is dependent on the nerve agent and the oxime-specific reactivating potency. The oxime-induced reactivation of inhibited human AChE in the presence of nerve agents is markedly impaired and the combination of obidoxime and HI-6 had no additive effect but could broaden the spectrum. In conclusion, these data indicate that a combination of obidoxime and HI-6 would be beneficial for the treatment of poisoning by a broad spectrum of nerve agents and could present an interim solution until more effective and broad-spectrum reactivators are available.
authors.affiliation: Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany. Electronic address: franzworek@bundeswehr.org.
authors.forename: Franz
authors.initials: F
authors.lastname: Worek
authors.affiliation: Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany.
authors.forename: Marianne
authors.initials: M
authors.lastname: Koller
authors.affiliation: Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany.
authors.forename: Horst
authors.initials: H
authors.lastname: Thiermann
authors.affiliation: Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Wille
mesh_terms: D000110:Acetylcholinesterase / Q000187:drug effects / Q000378:metabolism; D002801:Cholinesterase Reactivators / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D006801:Humans; D019570:Inhalation Exposure; D007273:Injections, Intramuscular; D008954:Models, Biological; D000067397:Nerve Agents / Q000633:toxicity*; D009768:Obidoxime Chloride / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D010755:Organophosphates / Q000633:toxicity; D009943:Organophosphorus Compounds / Q000633:toxicity; D010091:Oximes / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011726:Pyridinium Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D012524:Sarin / Q000633:toxicity; D066007:Toxicokinetics
chemical_list: D002801:Cholinesterase Reactivators; D000067397:Nerve Agents; D010755:Organophosphates; D009943:Organophosphorus Compounds; D010091:Oximes; D011726:Pyridinium Compounds; D009768:Obidoxime Chloride; D012524:Sarin; D000110:Acetylcholinesterase; C022870:asoxime chloride; C009374:tabun; C053914:cyclohexyl methylphosphonofluoridate
keywords: Acetylcholinesterase; Kinetics; Nerve agents; Oximes; Pharmacokinetics; Reactivation; Toxicokinetics