Hpm. Van Helden et al., New generic approach to the treatment of organophosphate poisoning: Adenosine receptor mediated inhibition of ACh-release, DRUG CHEM T, 21, 1998, pp. 171-181
Current treatment of acute organophosphate (OP) poisoning includes a combin
ed administration of a cholinesterase reactivator (oxime), a muscarinic rec
eptor antagonist (atropine) and an anticonvulsant (diazepam). This treatmen
t is not adequate since it does not prevent neuronal brain damage and incap
acitation. Here, as in a recent review(1) it is stated that other therapeut
ic 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) aft
er the acute OF-intoxication, could prevent and counteract convulsions and
improve survival(1). In general, the accumulation of ACh in the synaptic cl
eft is considered to be responsible for the symptoms that ultimately lead t
o death. Therefore, prevention or suppression of this excessive accumulatio
n of ACh could be a generic approach to antagonize OF-poisoning. Preliminar
y evidence for this concept has been put forward(1,2).
Evaluation of drugs that would be able to prevent and counteract ACh accumu
lation, led to the conclusion that adenosine receptor agonists could be pro
mising candidates.
Pilot experiments demonstrated that intramuscular administration of the ade
nosine receptor agonists NECA (5'-N-ethylcarboxamido-adenosine) or CPA (N-6
-cyclopentyl adenosine) 1 min following a subcutaneous soman poisoning (1.5
- 2LD50) in rats, resulted in (1) prevention or postponement of chewing, s
alivation, convulsive activity, and respiratory distress (cholinergic sympt
oms), (2) improvement of survival rate (24 h), (3) a low level of extracell
ular brain ACh, as opposed to high levels of extracellular brain ACh in unt
reated animals.
It is concluded that (1) adenosine agonists protect acutely soman-poisoned
rats without the need of additional treatment with atropine, oxime or diaze
pam, (2) prevention of ACh accumulation in this way may be a new generic ap
proach in the treatment of OP-poisoning.