242 CHEMOTHERAPY 



destroy the trypanosomes in the blood of infected mice; but at the same 

 time it acted as a severe general poison. Atoxyl was then 

 Atoxyl. introduced by Ferd. Blumenthal and was found to be less 

 poisonous and just as efficient. Extensive experiments 

 were undertaken with this drug and its effects both in infected mice 

 and human beings (sleeping sickness) carefully studied. Most of this 

 work was carried out in the infected districts of Africa by Robert Koch 

 and his co-workers. While the trypanocidal action of atoxyl was distinct, 

 its effect was not permanent and relapses occurred. Uhlenhuth tried 

 this arsenic compound in animal syphilis, basing his application upon 

 the apparently close relationship existing between the spirochete and 

 trypanosome as pointed out by Schaudinn. The results were very 

 encouraging, so that for a time atoxyl was employed in the treatment of 

 human syphilis with beneficial effect upon its clinical manifestations. Its 

 use had to be abandoned, however, on account of its very severe asso- 

 ciated toxic actions, of which optic atrophy was the most important. 



Up to that time the chemical compositioji of atoxyl had been repre- 

 sented as meta-amino-phenylarsenic acid. Ehrlich and Bertheim found 

 that this was incorrect and that in reality it was p-amino-phenylarsenic 

 acid, called by Ehrlich arsanilic acid. It was thus made possible by 

 systematic substitution to attain specifically active but less poisonous 

 products. 



For a long time too it was unexplained why the trypanocidal action 

 of atoxyl was so very marked in vivo and yet no effect could be noticed in 

 vitro. Ehrlich presumed that when atoxyl enters the system it undergoes 

 the chemical change of reduction; from a quinquivalent arsenic combina- 

 tion a trivalent one resulted; and it is this reduction product to which 

 atoxyl owed its activity. He proved this hypothesis by reducing atoxyl 

 in the test-tube; he thus obtained the phenylarsenious acid which even in 

 the dilution of i to i ,000,000 was capable of destroying the trypanosomes, 

 whereas atoxyl in the dilution of i to 100 was inactive. " The arsenoceptor 

 cannot unite with quinquivalent arsenic products, but requires ones 

 with trivalent arsenic; this lack of saturation of the arsenic molecule 

 is essential for the chemical union with the arsenic receptor" (Ehrlich). 

 The numerous trivalent arsenic combinations are by no 

 Arseno- means equally potent. Many are entirely unable to destroy 

 phenyl- the protozoa, others are slightly active, while only few show 

 glycm. a distinct specific action. Belonging to the last class is arseno- 

 phenylglycin which contains an acetic-acid radical. This com- 

 pound is peculiar in that it can attack trypanosomes which have become 

 resistant to atoxyl. If, however, these " atoxyl-f ast " trypanosomes are 

 treated for a long time with arsenophenylglycin, they became resistant 

 also to the latter compound. According to Ehrlich's explanation for this 



