Journal
TOXICOLOGY AND APPLIED PHARMACOLOGY
Volume 249, Issue 3, Pages 231-237Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.taap.2010.09.021
Keywords
MMB 4; Nerve agents; Acetylcholinesterase; Reactivation; Kinetics; Species differences
Categories
Funding
- German Ministry of Defence
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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 (C) 2010 Elsevier Inc All rights reserved
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