758 6. ARSENICALS 



Tolerance has also been induced in the higher animals but this will be con- 

 sidered separately, inasmuch as different problems are involved. 



Conditions under Which Resistance May Develop 



An excellent discussion of the techniques used to induce resistance in 

 microorganisms is given by Schnitzer and Grunberg (1957), in which the 

 reader may find a more detailed account than is necessary here. In general, 

 procedures may be classified as to whether exposure is in vitro or in vivo. 

 Before trypanosomes could be grown in cultures, in vitro exposure was 

 carried out during an interval between passages, so that contact with 

 the arsenical was made only during a nonproliferative stage. Several expo- 

 sures of only 1-hr duration each led to a strain at least 500-fold more resis- 

 tant than the original strain to tryparsamide oxide (Yorke et al., 1931 c). 

 Continuous exposure of organisms growing in liquid media to increasing 

 concentrations of arsenicals often leads to quite marked tolerance. Resis- 

 tance can be achieved surprisingly easily in vivo. For example, in a single 

 infected animal a high degree of resistance may be produced by successive 

 arsenical administrations; even a single exposure is occasionally effective, 

 although the resistance is not great. One of the most effective techniques 

 is the "relapse method," in which sufficient arsenical is administered to 

 clear the blood of trypanosomes, and when new ones appear they are trans- 

 ferred to other animals, this procedure continuing as long as necessary. 



Degree, Rate of Onset, and Duration of Resistance 



The resistance factor, the ratio of the arsenical dosage or concentration 

 necessary to immobilize or kill a tolerant strain to that required for the 

 normal strain, may vary from 2 to over 1000, depending on the arsenical 

 used, the organism, and the conditions of the exposure (a few examples 

 are given in Table 6-16). The rate at which resistance develops varies, of 

 course, with many factors but it is interesting that different arsenicals 

 are apparently able to induce resistance at various rates. Results obtained 

 with Trypanosoma rhodesiense are shown in the accompanying tabulation 



Time for maximal ^ . . 



... . , Kesistance tactor 



Arsenical resistance . . . , , 



_. (tryparsamide oxide) 



256 



96 



256 



256 



4 



