Reactivation of organophosphate-inhibited human AChE by combinations of obidoxime and HI 6 in vitro.
Highly toxic organophosphorus-type (OP) chemical warfare agents (nerve agents) and OP pesticides may be used by terrorists and during military conflicts emphasizing the necessity for the development of effective medical countermeasures. The standard treatment with atropine and acetylcholinesterase (AChE) reactivators (oximes) is considered to be ineffective with certain nerve agents due to low oxime efficacy. Despite research over decades none of the oximes has turned out to be a broad spectrum reactivator to cover the whole range of potential threat agents. The prospective oxime HI 6 is a weak reactivator of tabun- and pesticide-inhibited AChE, while the established oxime obidoxime mainly lacks efficacy with cyclosarin-inhibited enzyme. In order to investigate the feasibility of combining obidoxime and HI 6, human AChE inhibited by sarin, cyclosarin, VX, tabun and paraoxon was reactivated by these oximes either alone or in combination. Two major findings of this study were that a combination of HI 6 and obidoxime did not impair reactivation, compared with HI 6 or obidoxime alone, but broadened the spectrum compared with the individual oximes. By using different oxime concentrations a combination of oxime doses may be suggested which could be an alternative to individual obidoxime or HI 6 autoinjectors.
Worek
F
F
Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstrasse 11, 80937 Munich, Germany. FranzWorek@Bundeswehr.org
Aurbek
N
N
Thiermann
H
H
D000110:Acetylcholinesterase / Q000378:metabolism*; D000931:Antidotes / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D002801:Cholinesterase Reactivators / Q000494:pharmacology*; D004910:Erythrocyte Membrane / Q000187:drug effects* / Q000201:enzymology; D005240:Feasibility Studies; D006801:Humans; D009768:Obidoxime Chloride / Q000494:pharmacology*; D010755:Organophosphates / Q000633:toxicity; D009943:Organophosphorus Compounds / Q000633:toxicity; D009946:Organothiophosphorus Compounds / Q000633:toxicity; D010091:Oximes; D010261:Paraoxon / Q000633:toxicity; D011726:Pyridinium Compounds / Q000494:pharmacology*; D012524:Sarin / Q000633:toxicity; D013997:Time Factors
D000110:Acetylcholinesterase; D000931:Antidotes; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D009768:Obidoxime Chloride; D010755:Organophosphates; D009943:Organophosphorus Compounds; D009946:Organothiophosphorus Compounds; D010091:Oximes; D010261:Paraoxon; D011726:Pyridinium Compounds; D012524:Sarin; C009680:VX-agent; C022870:asoxime chloride; C009374:tabun; C053914:cyclohexyl methylphosphonofluoridate