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

Journal Article · Wed Dec 15 00:00:00 EST 2010 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2010.09.021· OSTI ID:21529107

Worek, Franz ^[1]; Wille, Timo; Aurbek, Nadine ^[1]; Eyer, Peter ^[2]; Thiermann, Horst ^[1]

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1. Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstrasse 11, 80937 Munich (Germany)
2. Walther-Straub-Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University, Goethestrasse 33, 80336 Munich (Germany)

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.

• OSTI ID: 21529107
• Journal Information: Toxicology and Applied Pharmacology, Vol. 249, Issue 3; Other Information: DOI: 10.1016/j.taap.2010.09.021; PII: S0041-008X(10)00363-7; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

63 RADIATION, THERMAL, AND OTHER ENVIRONMENTAL POLLUTANT EFFECTS ON LIVING ORGANISMS AND BIOLOGICAL MATERIALS
ATROPINE
BIOCHEMICAL REACTION KINETICS
GUINEA PIGS
HUMAN POPULATIONS
IN VIVO
MONKEYS
NERVOUS SYSTEM
ORGANIC PHOSPHORUS COMPOUNDS
POISONING
SWINE
TOXICITY
ALKALOIDS
ANIMALS
AUTONOMIC NERVOUS SYSTEM AGENTS
DOMESTIC ANIMALS
DRUGS
KINETICS
MAMMALS
ORGANIC COMPOUNDS
PARASYMPATHOLYTICS
POPULATIONS
PRIMATES
REACTION KINETICS
RODENTS
VERTEBRATES