XII. DETOXICATIOX OF AHSKNlf" ALS 03 



tration of PAHA in conjunction with lethal doses of the pentavalent ar- 

 .sonicals lrvi)aisami(le, acctarsonc, arsaniHc acid, and benzenearsonic acid 

 was reported l)y Santlground'- - to be attended by simihir protective ac- 

 tion, and this was found to be true regardless of the route of administration 

 of either the arsenical or the PABA. The protection is evident within 24 

 hours, and the usual symptoms of arsenic poisoning, such as tremor, di- 

 arrhea, paralj'^sis, and emaciation, are minimized. Histologically, the most 

 significant manifestation of the beneficial action of PABA is in the con- 

 siderable reduction, both in extent and in severity, of the renal lesions pro- 

 duced by the arsenicals.' 



It had long been known that the toxicity of trivalent arsenicals could ])e 

 substantially reduced by means of various agents. The injection of sulf- 

 hydryl-containing compounds (e.g., reduced glutathione) simultaneously 

 with, or prior to, the administration of the arsenical was used with success 

 by Voegtlin et al} to offset to a large degree the toxic effects in the rat of 

 mapharside (3-amino-4-hydroxyphenylarsenoxide). Similarly, the sup- 

 pression of the toxic manifestations of neoarsphenamine was accomplished 

 by Durel^ and by McChesney and his associates,^ by means of ascorbic 

 acid. In contrast to these results with the trivalent arsenicals, no effective 

 means of counteracting the ill effects of the pentavalent compounds had 

 been demonstrated, and the elucidation by Sandground of tliis particular 

 function of PABA was attractive in its implication of potential clinical 

 significance. 



In a series of papers devoted to a more detailed study of this detoxication 

 effect, Sandground and his associates reported that essentially all rats are 

 protected against a LD90 of carbarsone (1000 mg. per kilogram) or of 

 arsanilic acid (400 mg. per kilogram) by the prior administration of 500 

 mg. per kilogram for the latter. The use of 750 mg. per kilogram of the 

 vitamin protects all animals against a dose of carbarsone of 1500 mg. per 

 kilogram, a dose which is not tolerated by a single unprotected rat. As 

 little as 15 mg. of PABA per kilogram protects 50 % of animals subjected 

 to a LD90 of arsanilic acid.^ 



In addition to estabhshing the amount of the vitamin required for a 

 specific measure of protection, Sandground demonstrated^- ^ the vital 



2 J. H. Sandground and C. R. Hamilton, /. Pharmacol. Expll. Therap. 78, 109 (1943). 



3 P. N. Harris, J. Pharmacol. Exptl. Therap. 82, 254 (1944). 



-•C. Voegtlin, H. A. Dyer, and C. S. Leonard, /. Pharmacol. Exptl. Therap. 25, 



297 (1925). 

 5 P. Durel, Bull, soc.franq. dermatol. syphilig. 44, 1077 (1937) [C. A. 32, 3816 (1938)]. 

 6E. W. McChesney, O. W. Barlow, and G. H. Klinck, Jr., ./. Pharmacol. Expll. 



Therap. 80, 81 (1944). 

 ' J. H. Sandground and C. R. Hamilton, /. Pharmacol. Exptl. Therap. 78, 203 (1943). 



8 J. H. Sandground, /. Pharmacol. Exptl. Therap. 78, 209 (1943). 



9 J. H. Sandground and C. R. Hamilton, J. Lab. Clin. Med. 28, 1821 (1943). 



