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

Journal Article · Tue Dec 14 23:00:00 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, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 3 Vol. 249; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

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