Oral Prophylaxis for Anticholinesterase Poisoning

Abstract

A method of protection against poisoning by cholinesterase inhibitors involving the use of N-methyl pyridinium-2-aldoxime methanesulphonate (P-2-S) orally, prior to exposure to the anticholinesterase agent, in combination with intramuscularly administered atropine sulphate after exposure, has been examined. In rats poisoned with O,O-diethyl S-2-diethylaminoethyl phosphorothiolate (DSDP), the treatment permitted survival from a dose of 28 times the LD50 in untreated animals. The protection given by oral P-2-S lasts for an extended period of time decreasing to one half the maximum value in about 4 hours. Mice, guinea pigs, and rabbits so treated demonstrated a high tolerance to DSDP but of lower order than the rat. Treatment with oxime and atropine afforded protection to mice and rats exposed to paraoxon, vinylphosphate, isosystox, DFP, TEPP, and eserine, but was relatively impotent against sarin, tabun, and schradan. The possible application of this mode of treatment to human exposures to anticholinesterase agents is discussed.

Plasma concentrations of the oxime Pralidoxime Mesylate (P2S) after repeated oral and intramuscular administration.

“…It is important therefore to know that liberal use of P2S itself carries no unacceptable risks. If used as a prophylaxis (Sundwall, 1960;Quinby, 1968;Taylor et al, 1965;Coleman et al, 1961) P2S cannot be expected to prevent the symptoms of cholinesterase inhibition occurring and it is logical to assume that in many instances the drug will still have to be given intramuscularly with atropine. It has been shown that up to three intramuscular doses of 500 mg P2S can be tolerated by humans despite earlier oral P2S administration but ocular disturbances may occur.…”

“…Holland, Parkes, and Shakespeare (1972) have shown that administration of absolute intramuscular doses of 500 mg P2S per man is needed to achieve plasma P2S levels of 3-0 ,ug/ml to 4-0 ug/ml recommended as necessary for adequate therapy of O-P anticholinesterase poisoning (Crook et al, 1962;Sundwall, 1961). It has also been suggested that P2S might be of benefit if given orally as prophylactic in situations where the more potent O-P anticholinesterases are handled and used continuously (Quinby, 1968;Taylor, Llewellyn-Thomas, and Sellers, 1965;Coleman, Little, and Grant, 1961). Doses of greater than 1 0 g per man (Sundwall, 1960) and 2-0 g to 4-0 g per man (Sidell, Groff, and Kaminskis, 1972) have been shown to be necessary for adequate prophylactic therapy.…”

Toxogonin: Oral Administration to Man

“…Oral oximes also might be given prophylactically (10,11) to men with a high risk of exposure to anticholinesterases, such as crop dusters. Finally, oral administration of oximes might be considered for a poisoned individual whose signs and symptoms are very mild, not requiring urgent treatment.…”

“…One report indicated the possibility of a relationship between viscosity and molecular weight of acacia (10). An earlier investigation indicated that acacia with a molecular weight of 280,000 may be split into fragments with molecular weights of less than 10,000 after autohydrolysis for 1 day (11).…”