138 OXIDATION-REDUCTION POTENTIALS 



specifically lethal to the invasive agent ; absolutely non-toxic to the host cells or 

 beneficial symbiotic organisms ; it should rapidly proceed to the focus of infection 

 and should remain there. As this is not in sight it is necessary to discuss what agents 

 we have, how they appear to function and hence to attempt to plan improvements 

 since, despite all theorising most of our advances to date have arisen empirically, by 

 trial and error and ex improviso. 



ORGANIC ARSENICALS 



Outside the body chlorine is one of the commonest disinfectants in use and the 

 problem of our water supplies would be difficult to solve without chlorine. In the 

 body, however, the oxidising properties of chlorine cannot be utilised for the destruc- 

 tion of micro-organisms, since the cells of the host are damaged first. The phenolic 

 anti-septics also are restricted to use in vitro. In the case of arsenic compounds, on 

 the other hand, not only does arsenite poison the enzymic activities of micro-organisms- 

 in the test-tube but organic compounds of arsenic are used in the body to eliminate 

 trypanosomes in sleeping sickness and spirochaetes in syphilis. 



Ehrlich and subsequent workers have concluded that when organic arsenicals- 

 are used for the treatment of protozoal infections the active agents are tervalent 

 arseneoxides. If quinquevalent arsonic acids (I) are injected they are reduced 

 in vivo to the oxide (II) and if III or IV are injected they are oxidised in the body 

 to the oxide : — 



RAsOgH -> RAsO ^ RAs : AsR <- RAsHg 

 I II III IV 



To be active therapeutically, therefore, organic arsenicals should be capable of 

 reduction or oxidation to the tervalent oxide, but the arsene oxide is also the toxic 

 agent to the host. The possibility arises that the toxicity of arsonic acids is dependent 

 upon the ease with which they are reduced to the arsene oxide. This is not an easy 

 matter to determine since the arsonic acid : arsene oxide system appears not to be a 

 reversible oxidation-reduction reaction which could be measured by the use of 

 indicator dyes, since the arsonic acids do not oxidise the reduced dyes. In order 

 to obtain a measure of the ease of reduction of the arsonic acids Cohen, King and 

 Strangeways (19-32) adopted an ingenious method. They first concluded that the 

 ease of reduction of the arsonic acids would be inversely proportional to the ease 

 of oxidation of the arsene oxide, and this was measured by adding optically active 

 cystine. The cystine oxidised the arsene oxide and was itself reduced to cysteine 

 which has a much lower optical rotation so that, by following the fall in rotation, 

 the rate of reduction of the cystine and hence the rate of oxidation of the arsene 

 oxide was measured. It was not possible to obtain, however, any correlation between 

 the rate of oxidation of the arsene oxide and the toxicity of the corresponding 

 arsonic acid to the host, nor was there any relation to the curative effect of the 

 arsonic acids in injections. The curative action is naturally dependent upon other 

 factors such as the rate of excretion. (See also Crawford and Levvy, 1947.) 



The toxicity and chemotherapeutic action of organic arsenicals have been 

 investigated in a different way. The toxic effect has been traced to combination 

 with sulphydryl groups whereby enzyme systems such as tlie pyruvic oxidase of 



