Abstract
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.
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References
Clement JG (1981) Toxicology and pharmacology of bispyridinium oximes — insight into the mechanism of action of soman poisoning in vivo. Fundam Appl Toxicol 1: 193–202
De Jong LPA, Wolring GZ (1980) Reactivation of acetylcholinesterase inhibited by 1,2,2-trimethylpropylmethyl phosphonofluoridate (soman) with HI-6 and related oximes. Biochem Pharmacol 29: 2379–2387
De Jong LPA, Wolring GZ (1984) Stereospecific reactivation by some Hagedorn-oximes of acetylcholinesterase from various species including man, inhibited by soman. Biochem Pharmacol 33: 1119–1125
Grubič Z, Sketelj J, Klinar B, Brzin M (1981) Recovery of acetylcholinesterase in the diaphragm, brain and plasma of the rat after irreversible inhibition by soman: a study of cytochemical localization and molecular forms of the enzyme in the motor end plate. J Neurochem 37: 909–916
Harris LW, Heyl WC, Stitcher DL, Broomfield CA (1978) Effects of 1,1′-oxydimethylene bis-(4- tert-butylpyridinium chloride) (SAD-128) and decamethonium on reactivation of soman and sarin-inhibited cholinesterase by oximes. Biochem Pharmacol 27: 757–761
Lewis MK, Eldefrawi ME (1974) A simple, rapid and quantitative radiometric assay of acetylcholinesterase. Anal Biochem 57: 588–592
Maksimović M, Bošković B, Radović L, Tadić V, Deljać V, Binenfeld Z (1980) Antidotal effects of bis-pyridinium-2-mono-oxime carbonyl derivatives in intoxications with highly toxic organophosphorous compounds. Acta Pharm Jugosl 30: 151–160
Puu G, Artursson E, Bucht G (1986) Reactivation of nerve agent inhibited human acetylcholinesterases by HI-6 and obidoxime. Biochem Pharmacol 25: 1505–1510
Schoene K, Steinhanses J, Oldiges H (1976) Protective activity of pyridinium salts against soman poisoning in vivo and in vitro. Biochem Pharmacol 25: 1955–1958
Schoene K, Steinhanses J, Oldiges H (1983) Reactivation of soman inhibited acetylcholinesterase in vitro and protection against soman in vivo by bispyridinium-2 -aldoximes. Biochem Pharmacol 32: 1649–1651
Smith AP, Van der Wiel HJ, Wolthuis OL (1981) Analysis of oxime-induced neuromuscular recovery in guinea pig, rat and man following soman poisoning in vitro. Eur J Pharmacol 70: 371–379
Van Helden HPM, Wolthuis OL (1983) Evidence of intramuscular depot of the cholinesterase inhibitor soman in the rat. Eur J Pharmacol 89: 271–274
Van Helden HPM, Van der Wiel HJ, Wolthuis OL (1983b) Therapy of organophosphate poisoning: the marmoset as a model for man. Br J Pharmacol 78: 579–589
Van Helden HPM, Van der Wiel HJ, Wolthuis OL (1988) Retention of soman in rats, guinea-pigs and marmosets: species-dependent effects of the soman simulator, pinacolyl dimethylphosphinate (PDP). J Pharm Pharmacol 40: 35–41
Wolthuis O, Vanwersch RAP, Van der Wiel HJ (1981) The efficacy of soman bis-pyridinium oximes as antidotes to soman in isolated muscles of several species including man. Eur J Pharmacol 70: 355–369
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Grubič, Z., Tomažič, A. 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. Arch Toxicol 63, 68–71 (1989). https://doi.org/10.1007/BF00334637
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DOI: https://doi.org/10.1007/BF00334637