Mechanism of action of HI-6 on soman inhibition of acetylcholinesterase in preparations of rat and human skeletal muscle; comparison to SAD-128 and PAM-2.
HI-6 is presently considered the most potent oxime antidote against soman poisoning in mice, rats, dogs and monkeys. However, it is still an open question whether efficiency of HI-6, observed in experimental animals, can be extrapolated to soman intoxicated humans. In this paper efficiency of HI-6 and possible mechanisms of action were compared in rat and human fresh muscle preparations. In rat muscle, about 50% of control AChE activity could be recovered by both therapeutic (5 min after soman) and prophylactic (5 min before soman) application of HI-6. On the other hand, in human muscle therapeutic treatment restored only 5%, while prophylactic application of HI-6 again resulted in about 50% recovery of control AChE activity. As revealed by comparison of the prophylactic effects of HI-6 and the non-oxime bispyridinium compound SAD-128, competitive inhibition of AChE plays a minor role as a protective mechanism. Immediate reactivation of rapidly aging human AChE must therefore be instituted for successful protective treatment by HI-6. Retardation of aging, a direct effect of SAD-128, was roughly estimated to improve reactivation by HI-6 for about 10% of control AChE activity of the human muscle. PAM-2 proved completely inefficient as a therapeutic and as a prophylactic agent on both rat and human muscle preparations.
Grubic
Z
Z
Institute of Pathophysiology, School of Medicine, University of Ljubljana, Yugoslavia.
Tomazic
A
A
D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D000931:Antidotes / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D009132:Muscles / Q000201:enzymology*; D010091:Oximes; D011220:Pralidoxime Compounds / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012999:Soman / Q000494:pharmacology*
D000931:Antidotes; D002800:Cholinesterase Inhibitors; D010091:Oximes; D011220:Pralidoxime Compounds; D011726:Pyridinium Compounds; C016845:SAD-128; D012999:Soman; D000110:Acetylcholinesterase; C022870:asoxime chloride; C028797:pralidoxime