THIOARSENITES 789 



tance, but the behavior in contact with biological material cannot neces- 

 sarily be predicted from the simple rates of hydrolysis (see page 610), inas- 

 much as the equilibrium may be shifted in the presence of substances 

 which bind the arsenical more tightly than does the thiol to which it was 

 united initially. In biological systems it is presumably the reaction: 



S— R' S— C 



/ / 



R — As +2 C— SH ^ R — As +2 R'— SH 



\ \ 



S— R' S— C 



where C-SH represents cellular SH groups (which may or may not be vicinal 

 for ring formation), 'that is the most important with respect to both the 

 rate and degree of effect. Certain thioarsenites are trypanocidal, spirochaeti- 

 cidal, or amebicidal, and are therapeutically active (Anderson et al., 1949; 

 Barber, 1929; Cohen et al, 1931; Strangeways, 1937; Yorke et al, 1931 a). 

 The apparent paradox between the activity of these thioarsenites and the 

 ability of thiols to prevent or reverse the effects of the arsenicals is explained 

 on the basis of the amount of thiol present; in the cases of antagonism, it 

 generally requires an excess of the thiol, so that the equilibrium is shifted 

 to the left, whereas in using a thioarsenite the ratio is equimolar. The 

 toxicity of a thioarsenite may well be less than that of the corresponding 

 arsenical, as Labes (1929 b) found with conjugates of arsenite and cysteine, 

 since, first, there is the time factor so that the arsenical may be released 

 slowly and, second, a good deal may be excreted as thioarsenite. 



Several investigations of the therapeutic efficacy of various thioarsen- 

 ites have been made (see review by Eagle and Doak, 1951), and it has been 

 shown that the therapeutic index may be somewhat greater than for the 

 corresponding arsenical. The therapeutic potency is certainly much greater 

 than for the oxidized forms of the corresponding arsenicals (Yorke et al., 

 1931 a); for example, the effective trypanocidal dose of tryparsamide in 

 mice is 300 mg/kg whereas that for reduced tryparsamide-thioglycolate 

 is only 1.74 mg/kg. The fact that the activity of these thioarsenites can be 

 antagonized by excess thiol indicates that the activity is indeed due to a 

 splitting of the complex. It is not necessary, of course, that the thioarsenites 

 act in exactly the same manner as the corresponding arsenical. The thio- 

 arsenites are generally either more or less lipid-soluble than the arsenicals 

 and may be distributed in the body or cells in a different way. The clinical 

 value of dimercaprol lies mainly in its ability to form soluble thioarsenites 

 which diffuse readily from the cells and are readily excreted. Thus the action 

 of a thioarsenite may be greater on a particular tissue if the combination 

 of the arsenical with the thiol allows it to penetrate better, assuming this 

 to be followed by hydrolysis. This may possibly explain the observations 

 of Koppanyi and Sperling (1947) that rabbits receiving certain doses of 



