Oximes and Atropine in Sarin Poisoning

Abstract

Three oximes, monoisonitrosoacetone (MINA), pyridine-2-aldoxime methiodide (PAM) and diacetylmonoxime (DAM), have been examined in combination with atropine as antidotes in sarin poisoning. When treatment was administered 15 min. before sarin, atropine enhanced the protective effect of MINA and DAM 2 to 3 times and of PAM 9 to 10 times in mice and rats. In mice, rats, and guinea-pigs, atropine increased by no more than 2 times the protective effect of all three oximes when given 30 sec. after sarin. Atropine given to monkeys 1 min. after sarin raised the LD50 approximately 3 times. When given in conjunction with MINA or DAM, the LD50 of sarin was raised 7 to 14 times.It has been shown previously that two oximes, monoisonitrosoacetone (MINA) and diacetylmonoxime (DAM), exert a marked protective effect in rats poisoned with isopropyl methylphosphonofluoridate (sarin) (Askew, 1956). Although less active in other species, they still appeared sufficiently promising to justify a further examination in conjunction with atropine. A third oxime, pyridine-2-aldoxime methiodide (PAM), the fastest known reactivator in vitro of cholinesterase (ChE) inhibited by sarin , was found ineffective against sarin poisoning in rats (Askew, 1956), although active in mice poisoned with diisopropyl phosphorofluoridate (dyflos, DFP) or diethyl p-nitrophenyl phosphate (paraoxon) (Kewitz, Wilson, and Nachmansohn, 1956). These three oximes have now been examined as adjuvants to atropine in sarin poisoning. METHODSThe animals used were female mice (18 to 22 g.), rats (180 to 200 g.) and guinea-pigs (320 to 380 g.), and male and female monkeys (2.5 to 4.0 kg.).The oximes and atropine were given intraperitoneally in aqueous solution, except where otherwise stated. When atropine was given in conjunction with an oxime, the required amount of atropine was dissolved in the oxime solution immediately before use. Sarin was diluted with 0.85% saline and injected subcutaneously in a standard volume for each species. This was 10 ml./kg. for mice, 1 ml./kg. for rats and guinea-pigs, and 0.2 ml./kg. for monkeys.LD50 values, based on a 24 hr. mortality, were determined both for sarin alone and sarin in the presence of oximes or atropine or both. For each test, the same number of animals was used at each dose, but this number varied in different experiments between four and six animals/ group. The ratio between successive doses was 1.26. Since the supply of monkeys was limited, the number used varied at different dose levels, but it was never less than two; here the ratio between doses was 1.3. LD50 values were normally calculated by the method of moving averages (Thompson, 1947), using the tables constructed by Weil (1952). Where this was not possible the technique of probit analysis (Finney, 1947) was employed. The " relative potency " of an oxime has been expressed as the ratio of the LD50 of sarin in the presence of an oxime to the LD50 of sarin alone. The limits were obtained from the sum of the variances (V) of the individual estimates of the log. LD...

2‐HYDROXYIMINOMETHYL‐N‐METHYLPYRIDINIUM METHANESULPHONATE AND ATROPINE IN THE TREATMENT OF SEVERE ORGANOPHOSPHATE POISONING

“…A similar species variation was noticed as in the therapeutic experiments, especially in the resistance to treatment of rats and mice poisoned with sarin. This anomaly in the behaviour of rats was particularly striking in the light of earlier therapeutic experiments with the oximes hydroxyiminoacetone and diacetyl monoxime (Askew, 1956(Askew, , 1957. These two compounds, especially the latter, were far more effective against sarin poisoning in rats than in any other species.…”

“…of atropine, given intraperitoneally, were effective against diethyl p-nitrophenyl phosphate (E600) or dyflos (di-isopropyl phosphorofluoridate). Askew (1957), using 100 mg./kg. of the iodide with 17.4 mg./kg.…”

Protection Against Lethal Organophosphate Poisoning by Quaternary Pyridine Aldoximes

“…or more) has been repeatedly demonstrated (Kewitz, Wilson, and Nachmansohn, 1956;Askew, 1957;Hobbiger, 1957a). Since mice tolerate weight for weight more than 100 times the amount of atropine fatal to adult man (Gordon and Frye, 1955) experiments with low doses of atropine should be more important than experiments with large doses of atropine.…”

The Effect of Some Oximes in Sarin Poisoning

“…Diacetylmonoxime, at an equimolar dose, produced only a slight increase in enzyme activity, and pyridine-2-aldoxime methiodide, the best reactivator in vitro, reactivated blood but not brain cholinesterase. There is a relationship between protection and reactivation of brain cholinesterase and prevention and alleviation of signs of poisoning.Several oximes, which are known to react with isopropyl methylphosphonofluoridate (sarin) in vitro and to reactivate cholinesterase inhibited by this substance, have recently been found to be effective against sarin poisoning in animals (Green and Saville, 1956;Childs, Davies, Green, and Rutland, 1955;Askew, 1956Askew, , 1957. No clear relationship between their in vitro activity and in vivo potency is obvious, however.…”

“…Several oximes, which are known to react with isopropyl methylphosphonofluoridate (sarin) in vitro and to reactivate cholinesterase inhibited by this substance, have recently been found to be effective against sarin poisoning in animals (Green and Saville, 1956;Childs, Davies, Green, and Rutland, 1955;Askew, 1956Askew, , 1957. No clear relationship between their in vitro activity and in vivo potency is obvious, however.…”