Acetylcholinesterase inhibition antidotes

Glickman, A. H., Wing, K. D.. and Casida, J. E, (1984). Profenofos insecticide bioaciivaiion in reiatiwi to antidote action and the. slcreo,spcciriciiy of acetylcholinesterase inhibition, reactivation, and aging. Toxicol. Appl. Pharmacol. 73, 16-22. 

Obidoxime is an antidote used to treat poisoning with insecticides of the organophosphate type (p. 102). Phosphorylation of acetylcholinesterase causes an irreversible inhibition of ace-Ltillmann, Color Atlas of Pharmacology 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. 

The first suggestion of a practical form of antidotal therapy came in 1949 from Hestrin, who found that acetylcholinesterase (AChE) catalyzed the formation of acetohydroxamlc acid when incubated with sodium acetate and hydroxylamine. Critical in vitro studies in the next decade led to the development of a practical approach to therapy. The crucial concept in these studies was the recognition that the compound formed when AChE reacted with a phosphorus ester was a covalent phosphoryl-enzyme Intermediate similar to that formed in the hydrolysis of acetylcholine. 3 Wilson and colleagues, beginning in 1951, demonstrated that AChE inhibited by alkyl phosphate esters (tetraethyl pyrophosphate, TEPP) could be reactivated by water, but that free enzyme formed much more rapidly in the presence of hydroxylamine. 0 21 Similar results... 

Worek, F., Reiter, G., Eyer, P., Szinicz, L. (2002). Reactivation kinetics of acetylcholinesterase from different species inhibited by highly toxic organophosphates. Arch. Toxicol. 76 523-9. Yang, G.Y., Yoon, J.H., Seong, C.M., Park, N.S., Jung, Y.S. (2003). Synthesis of bis-pyridinium oxime antidotes using... 

This function is quite unlike the action of the nerve agents, where there is too much acetylcholine due to the inhibition of acetylcholinesterase. What occurs with botulism is a lack of the neurotransmitter in the synapse. Therefore, using atropine as an antidote would not be helpful and could even provoke symptoms. When contaminated food is ingested by adults, the toxin is absorbed from the intestines and attaches to the nerves, causing the signs and symptoms of botulism poisoning. 

Compounds which appear to be somewhat more effective antidotes have now been evolved. They act by releasing the phosphoryl group which has become attached to the serine residue in the inhibited enzyme. For example, DFP reacts with acetylcholinesterase (and certain other enzymes) to produce a phosphoryl-bonded enzyme which becomes inactive or inhibited (12.151). 

Khan MAS, Lo R, Bandyopadhyay TT, Ganguly BB (2011) Probing the reactivation process of sarin-inhibited acetylcholinesterase with a-nucleophiles hydroxylamine anion is predicted to be a better antidote with DFT calculations. J Mol Graph Model 29(8) 1039-1046. doi 10.1016/j.jmgm.2011.04.009... 

The structure-activity requirements for inhibition of acetylcholinesterase and NTE are different this is demonstrated by the fact that many OPs with powerful anticholinesterase properties do not have the capability to produce OPIDP. Thus, the OP chemical warfare nerve agents that are very potent anticholinesterases, have little propensity to cause OPIDP, ° although, at supralethal doses, sarin can cause delayed neuropathy in antidote-protected chickens while tri-o-cresyl phosphate, which has little anticholinesterase activity, is powerfully neuropathic. ... 

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