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New generic approach to the treatment of organophosphate poisoning: Adenosine receptor mediated inhibition of ACh-release

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Author: Helden, H.P.M. van · Groen, B. · Moor, E. · Westerink, B.H.C. · Bruijnzeel, P.L.B.
Type:article
Date:1998
Institution: Prins Maurits Laboratorium TNO
Source:Drug and Chemical Toxicology, SUPPL. 1, 21, 171-181
Identifier: 234811
Keywords: Adenosine-5'-(N-ethylcarboxamide) · Animals · Brain Chemistry · Cholinesterase Inhibitors · Dinucleoside Phosphates · Injections, Intramuscular · Injections, Subcutaneous · Poisoning · Rats · Receptors, Purinergic P1 · Soman · Survival Rate · Time Factors

Abstract

Current treatment of acute organophosphate (OP) poisoning includes a combined administration of a cholinesterase reactivator (oxime), a muscarinic receptor antagonist (atropine) and an anticonvulsant (diazepam). This treatment is not adequate since it does not prevent neuronal brain damage and incapacitation. Here, as in a recent review it is stated that other therapeutic approaches may improve protection. Former studies on the 'direct effects' of oximes led to the conclusion that drug-induced inhibition of acetylcholine (ACh)-release shortly (1 min) after the acute OP-intoxication, could prevent and counteract convulsions and improve survival. In general, the accumulation of ACh in the synaptic cleft is considered to be responsible for the symptoms that ultimately lead to death. Therefore, prevention or suppression of this excessive accumulation of ACh could be a generic approach to antagonize OP-poisoning. Preliminary evidence for this concept has been put forward. Evaluation of drugs that would be able to prevent and counteract ACh accumulation, led to the conclusion that adenosine receptor agonists could be promising candidates. Pilot experiments demonstrated that intramuscular administration of the adenosine receptor agonists NECA (5'-N- ethylcarboxamido-adenosine) or CPA (N6-cyclopentyl adenosine) 1 min following a subcutaneous soman poisoning (1.5-2LD50) in rats, resulted in (1) prevention or postponement of chewing, salivation, convulsive activity, and respiratory distress (cholinergic symptoms), (2) improvement of survival rate (24 h), (3) a low level of extracellular brain ACh, as opposed to high levels of extracellular brain ACh in untreated animals. It is concluded that (1) adenosine agonists protect acutely soman-poisoned rats without the need of additional treatment with atropine, oxime or diazepam, (2) prevention of ACh accumulation in this way may be a new generic approach in the treatment of OP-poisoning.