596 6. ARSENICALS 



was the discovery by Thomas and Breinl in 1905 of the value of atoxyl 

 (sodium arsanilate) in murine trypanosomiasis; in the same year Koch 

 showed it to be effective in human trypanosomiasis. Atoxyl had been 

 known chemically since 1863 and had been shown to be inactive in vitro 

 by Ehrlich in 1903. These observations initiated the impressive series of 

 organic arsenicals used for the treatment of syphilis (arsphenamine in 

 1910 and oxophenarsine in 1932), trypanosomiasis (tryparsamide in 1919), 

 and amebiasis (acetarsone in 1924 and carbarsone in 1931), not to mention 

 many of the more recent derivatives. These compounds are often more 

 interesting metabolic and enzyme inhibitors than the inorganic arsenicals. 

 The importance of the trypanosome work can scarcely be overestimated, 

 since it and the concepts formulated by Ehrlich and his collaborators 

 have formed the basis for all the specific chemotherapy since that time, 

 and were the first attempts to visualize the lethal actions of chemicals 

 in terms of specific receptor groups within the cell. Ehrlich (1909) demon- 

 strated that the pentavalent arsenicals must be reduced to the trivalent 

 forms to be active, that they do not act by release of inorganic arsenite, 

 and that the actions can best be explained by assuming vital arsenore- 

 ceptors.* 



The early work was much concerned with the comparison of the effects 

 of arsenite and arsenate, and the possibility that the tri- and pentavalent 

 forms are interconverted in the tissues. Although earlier attempts to settle 

 these problems were made, the preparations were often impure, and so 

 we must attribute to Ringer and Murrell (1878) the first clear demon- 

 stration that arsenite is more toxic than arsenate when injected into frogs, 

 and that arsenite acts more rapidly. Loew (1887) in general confirmed 

 these results in plants and the lower animals, but claimed that some of 

 the fungi and higher animals are equally sensitive or insensitive to arsen- 

 ite and arsenate. Kionka (1911) felt that the issvie was not yet settled 

 and performed various experiments with opalinids, frogs, and rabbits 

 which purported to show the greater activity of arsenite, but Joachimoglu 

 (1915) criticized these results on the basis that data from whole animals 

 are not able to establish the relative toxicities, and proceeded to show 

 that isolated tissues are more sensitive to arsenite than to arsenate. It 

 was soon realized that the pentavalent organic arsenicals are not directly 

 inhibitory and are reduced in the body to the active forms. All recent 

 work has fully established that arsenite and arsenate act very differently, 

 but the possibility of their interconversion in the systems studied must 

 always be borne in mind. We shall not discuss the actions of arsenate in 



* "/cA bin, uni es vorweg zu nehmen zu der Anschauung gelangt, dass in Protoplasma 

 der Trijpanosomen-Zellen gewisse Gruppierungen vorhanden sind, die imstande sind, 

 sich mit dem dreiwertigen Arsenrest zu verbinden, und die ich deshalb in Anlehnung 

 an die Terminologie der Immunitdtslehre als ' Arsenoceptoren' bezeichne'" (Ehrlich, 1909). 



