The synergism of atropine and the cholinesterase reactivator HI-6 in counteracting lethality by organophosphate intoxication in the rat.
Rats were intoxicated with two different S-aminoalkyl-phosphonothioate cholinesterase inhibitors, viz. I-1 (S-diethylaminoethyl-O-cyclohexyl-methyl-phosphonothioate), which has a mixed central/peripheral mode of action, and I-2, the methiodide derivative of I-1, which acts almost solely peripherally. It was found that atropine did not have any beneficial effect on lethality in the case of an I-2 intoxication but did so, although only slightly, in the case of I-1. Therefore, the effect of atropine against I-1 intoxications must be mediated through central mechanisms, the peripheral parasympatholytic effect being negligible in counteracting lethality. Furthermore atropine antagonized the convulsions caused by intoxication with I-1. The oxime used as a reactivator of inhibited acetylcholinesterase, HI-6, was more effective than atropine against either organophosphate. In the case of an I-2 intoxication HI-6 proved extremely active. It is, therefore, concluded that HI-6 acts mainly peripherally. It was also found that HI-6 has a slight anticonvulsive action. The combination of HI-6 and atropine had a large synergistic effect in the case of I-1, but in the case of I-2 hardly any synergism was observed. Obviously, the combination of the oxime and atropine is particularly effective when the toxicant has a mixed central/peripheral action. In such intoxications the acetylcholinesterase reactivation in the respiratory neuromuscular synapse by the oxime is supplemented by the central action of atropine, which improves respiratory control at the level of the central nervous system.
Ligtenstein
D A
DA
Prins Maurits Laboratory TNO, AA Rijswijk, The Netherlands.
Moes
G W
GW
D000818:Animals; D001285:Atropine / Q000008:administration & dosage / Q000494:pharmacology*; D002801:Cholinesterase Reactivators / Q000008:administration & dosage / Q000494:pharmacology*; D004357:Drug Synergism; D007928:Lethal Dose 50; D008297:Male; D009943:Organophosphorus Compounds / Q000633:toxicity*; D063086:Organothiophosphates / Q000633:toxicity; D010091:Oximes; D011726:Pyridinium Compounds / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012640:Seizures / Q000517:prevention & control
D002801:Cholinesterase Reactivators; D009943:Organophosphorus Compounds; D063086:Organothiophosphates; D010091:Oximes; D011726:Pyridinium Compounds; D001285:Atropine; C022870:asoxime chloride