EFFECTS ON PROTOZOA 733 



changes. One may here, perhaps, call upon other actions of the arsenicals. 

 It is probably not justifiable to conclude in acute poisoning, or with respect 

 to the effects of relatively high arsenical concentrations on isolated tissue 

 functions, that the mechanism is entirely a blockade of keto acid oxidation. 

 It is really very difficult to prove that the inhibition of keto acid oxidation 

 is the direct cause of any effect. However, all in all, the theory holds up 

 well and is an important approach to arsenical toxicity. In the case of arsine, 

 some of the pentavalent arsenicals, or the disubstituted arsenoxides, other 

 mechanisms are generally more important. Sandground and Hamilton 

 (1943) found that p-aminobenzoate protects rats against atoxyl and 

 carbarsone, relatively small doses of the protector being necessary; this 

 has not been explained. It seems very questionable, however, whether 

 this theory can be extended to other metals and vitamin deficiencies, as 

 has been attempted by W. Hughes (1950). 



EFFECTS ON PROTOZOA 



Arsenicals are used clinically chiefly in the therapy of protozoan infec- 

 tions and much work has been done to elucidate the mechanisms of this 

 inhibitory action. An excellent review of the historical aspects of the field 

 may be found in the book by Work and Work (1948). A short time before 

 1900, Lingaard found that arsenite is of some value in surra, a trypanosomal 

 disease of horses in India, and Bruce discovered that it causes a temporary 

 remission of the tsetse fly disease in Africa. Ehrlich began work on human 

 trypanosomiasis, for which no cure was known, around 1902, using dyes 

 and then arsenicals. In 1903 he tested atoxyl against trypanosomes in vitro 

 and found it to be inactive. However, Thomas and Breinl observed that 

 atoxyl cures trypanosomiasis in mice, and Koch reported that preliminary 

 work in Africa had demonstrated some efficacy in the human form of the 

 disease. This revived Ehrlich's interest and, upon finding its correct struc- 

 ture, he proceeded to synthesize numerous derivatives, this work leading 

 to essentially all the known arsenicals and drugs of use in other infections. 

 Most of the work aimed at discovering the mechanisms of action has been 

 done on trypanosomes, rather than spirochaetes. It should be mentioned, 

 however, that many types of protozoa have been found to be susceptible 

 to the arsenicals: spirochaetes, such as Treponema pallidum (syphilis) 

 and Treponema pertenue (yaws); trypanosomes of many species, including 

 Trypanosoma gambiense and Trypanosoma rhodesiense (human sleeping 

 sickness), and Trypanosoma equiperdum (equine trypanosomiasis); ciliates, 

 such as Paramecium, Colpidium, and Tetrahymena; flagellates, such as 

 Trichomonas and Strigomonas; and various species of Entamoeba, Leish- 

 tnania, and Balantidium. Different arsenicals are commonly used to treat 

 infections by these agents; e. g., oxophenarsine for syphilis, tryparsamide 



