Reactivation of organophosphate-inhibited human, Cynomolgus monkey, swine and guinea pig acetylcholinesterase by MMB-4: a modified kinetic approach.

Abstract

Treatment of poisoning by highly toxic organophosphorus compounds (OP, nerve agents) is a continuous challenge. Standard treatment with atropine and a clinically used oxime, obidoxime or pralidoxime is inadequate against various nerve agents. For ethical reasons testing of oxime efficacy has to be performed in animals. Now, it was tempting to investigate the reactivation kinetics of MMB-4, a candidate oxime to replace pralidoxime, with nerve agent-inhibited acetylcholinesterase (AChE) from human and animal origin in order to provide a kinetic basis for the proper assessment of in vivo data. By applying a modified kinetic approach, allowing the use of necessary high MMB-4 concentrations, it was possible to determine the reactivation constants with sarin-, cyclosarin-, VX-, VR- and tabun-inhibited AChE. MMB-4 exhibited a high reactivity and low affinity towards OP-inhibited AChE, except of tabun-inhibited enzyme where MMB-4 had an extremely low reactivity. Species differences between human and animal AChE were low (Cynomolgus) to moderate (swine, guinea pig). Due to the high reactivity of MMB-4 a rapid reactivation of inhibited AChE can be anticipated at adequate oxime concentrations which are substantially higher compared to HI-6. Additional studies are necessary to determine the in vivo toxicity, tolerability and pharmacokinetics of MMB-4 in humans in order to enable a proper assessment of the value of this oxime as an antidote against nerve agent poisoning.

• Authors: Franz Worek, Timo Wille, Nadine Aurbek, Peter Eyer, Horst Thiermann
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 249 Issue 3 Pg. 231-7 (Dec 15 2010) ISSN: 1096-0333 [Electronic] United States
• PMID: 20888357 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Elsevier Inc. All rights reserved.

Chemical References

• Chemical Warfare Agents
• Cholinesterase Inhibitors
• Cholinesterase Reactivators
• Organophosphorus Compounds
• Oximes
• N,N'-monomethylenebis(pyridiniumaldoxime)
• Acetylcholinesterase

Topics

• Acetylcholinesterase
• Animals
• Chemical Warfare Agents (toxicity)
• Cholinesterase Inhibitors (toxicity)
• Cholinesterase Reactivators (pharmacology)
• Guinea Pigs
• Humans
• Macaca fascicularis
• Organophosphorus Compounds (toxicity)
• Oximes (pharmacology)
• Swine