The Antidotal Activity of Some Dithiols and Acetyldithiols in Mice Poisoned with Oxophenarsine

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Abstract
Summary: The toxicity in mice has been studied of oxophenarsine, the oxophenarsine-dimercaprol compound, 15 dithiols and 10 acetyl dithiols. The LD50 of oxophenarsine given intramuscularly was about 0ṁ14 mM/kg. Significant differences in mortality were not observed when oxophenarsine was given intraperitoneally. Death occurred more rapidly after large than after small doses of oxophenarsine. The lungs of mice dying of oxophenarsine poisoning were heavier than normal, particularly when the doses were small and the time of survival long. The LD50 of the oxophenarsine-dimercaprol compound given intramuscularly was about 0ṁ06 mM/kg. and given intraperitoneally was about 0ṁ30 mM/kg. Death occurred more rapidly than in oxophenarsine poisoning and the lungs were much heavier than either normally or in oxophenarsine poisoning. The LD50 of dimercaprol glucoside was found to depend on the iodine titre of the solution used. Estimated on this basis, the least toxic samples examined had an LD50 of about 4ṁ5 mM/kg. Dimercaprol glucoside was effective against larger doses of oxophenarsine than was dimercaprol when the thiols were given immediately after oxophenarsine. The glucoside was less effective than dimercaprol when the thiols were given more than about 20 minutes after oxophenarsine. Approximately equimolar mixtures of oxophenarsine and dimercaprol glucoside were not more toxic than oxophenarsine alone. No other dithiols examined had as good a combination of low toxicity and high activity against oxophenarsine as dimercaprol glucoside. The nearest approach was made by other dimercaprol sugar ethers. Acetylated dithiols of low molecular weight had quite good anti-arsenical activity, but were not more active relative to their toxicity than free dithiols. Acetylated dithiols with a molecular weight greater than about 300 had very low toxicity and little or no activity against oxophenarsine. Three substances (diacetyl dimercaprol, 1:4-dithioerythritol and particularly 1:4-dithiothreitol) accelerated death and increased the mortality in mice poisoned with oxophenarsine. The dimercaprol used in these experiments was a sample of water-purified BAL kindly presented by Professor R. A. Peters. Some of the dimercaprol glucoside was prepared by Dr. L. N. Owen, some was provided by the Ministry of Supply, and one sample was provided by Boots Pure Drug Co., Ltd. The other dithiols and all the acetylated dithiols were prepared by Dr. L. N. Owen and his associates. Oxophenarsine (mapharside, not diluted with sucrose as in commercial preparations) was generously presented by Dr. J. S. White, of Parke Davis and Co., Ltd. The oxophenarsine-dimercaprol compound was synthesised and kindly presented by Dr. L. A. Stocken. I am most grateful for all these gifts. I am much indebted also to Dr. L. N. Owen for numerous helpful discussions, to Mr. Leslie Angus, Miss Jean Tulloch and Miss Irene Munro for technical assistance, to Mrs. J. A. C. Weatherall for performing certain of the toxicity tests, and particularly to Professor J. H. Gaddum for his advice and criticism. The work was initiated during the tenure of a personal grant from the Medical Research Council and was supported by a grant for expenses from the Council.