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Therapy of organophosphate poisoning in the rat by direct effects of oximes unrelated to ChE reactivation

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Author: Helden, H.P.M. van · Lange, J. de · Busker, R.W. · Melchers, B.P.C.
Type:article
Date:1991
Institution: Medisch Biologisch Laboratorium TNO
Source:Archives of Toxicology, 7, 65, 586-593
Identifier: 231594
Keywords: Biology · Acetylcholinesterase · Direct effect · HGG-12 · HI-6 · Obidoxime · Organophosphate poisoning · P2S · 1 (4 carbamoylpyridinio) 1' (2 hydroxyiminomethylpyridinio)dimethyl ether · [(3 benzoyl 1 pyridiniomethyl) (2 hydroxyiminomethyl 1 pyridiniomethyl)] ether · Obidoxime · Organophosphate · Oxime · Soman · Animal experiment · Animal tissue · Diaphragm · Enzyme inhibition · Enzyme reactivation · Intravenous drug administration · Male · Nonhuman · Priority journal · Rat · Animal · Antidotes · Blood-Brain Barrier · Cholinesterase Reactivators · Diaphragm · In Vitro · Male · Neuromuscular Junction · Obidoxime Chloride · Organophosphorus Compounds · Oximes · Pralidoxime Compounds · Pyridinium Compounds · Rats · Respiratory Insufficiency · Synaptic Transmission · Animalia

Abstract

Isolated rat diaphragm preparations treated with soman or with the irreversible and oxime resistant cholinesterase (ChE) inhibitor S27 (see Compounds) showed a considerable recovery of neuromuscular transmission (NMT) during incubation with the (bis)pyridinium oximes HI-6, HGG-12, P2S and obidoxime. In the soman-treated preparations this NMT recovery was predominantly caused by reactivation of acetylcholinesterase (AChE) but in the S27-treated preparations it was caused by a direct (pharmacological) effect unrelated to enzyme reactivation. Atropinized rats were artificially ventilated after injection with 3 x LD50 soman for 3 h and then treated with HI-6, i.e. at a time when oxime reactivation of soman inhibited ChE is no longer possible. Nevertheless, these rats started to breathe spontaneously and 50-60% survived more than 24 h, whereas all control animals (saline instead of HI-6) died within 10 min after artificial ventilation was terminated. In such animals no significant reactivation of ChE activity at various time intervals followed HI-6 treatment was found, either in the diaphragms or in the brains. There was a significant amount of NMT (50%) in vitro in diaphragms obtained from these animals. This NMT did not improve in vitro in the presence of HI-6 and was not inhibited by soman administered to the medium. It is concluded that in this case the NMT found was based on synaptic adaptation to the continued inhibition of ChE and that the survival of the animals might be due to a combination of this synaptic adaptation and central direct effects of HI-6. Chemicals/CAS: Antidotes; Cholinesterase Reactivators; HGG 12, 83972-73-0; HI 6, 34433-31-3; Obidoxime Chloride, 114-90-9; Organophosphorus Compounds; Oximes; Pralidoxime Compounds; pralidoxime, 6735-59-7; Pyridinium Compounds