JOHN A. KOLMER 1117 



TOXICITY AND PHARMACOLOGICAL ACTION OF THE ANILIN DYES 

 IN RELATION TO CHEMOTHERAPY 



Since some of the anilin dyes, and especially gentian violet, rivanol, acriflavin, 

 and proflavin, are sometimes injected intravenously in the treatment of streptococcus 

 staphylococcus, and other bacteremias of human beings, it is important to inquire into 

 the matter of their toxicity and pharmacological action. As would be expected in view 

 of the complicated chemistry and preparation of these substances, toxicity varies con- 

 siderably with the dififerent dyes and, indeed, with different lots of the same dye pre- 

 pared in dififerent laboratories. It is imperative in the interests of safety to select for 

 intravenous injection only those dyes especially prepared for intravenous injection by 

 processes of purification to remove the numerous impurities which may be present 

 and dyes suitable for ordinary bacteriological work may be quite too toxic and un- 

 suitable for intravenous injection. 



In my toxicity tests, employing white rats of 100-200 gm. weight, the following 

 results expressed in terms of the maximum tolerated doses over a period of at least 

 two weeks have been usually observed; the solutions varied from 0.5 to i per cent 

 and were injected at a constant rate of about 2 cc. per minute. 



Gm. per Kg. 



Gentian violet (C and B) o. 125 



Gentian violet (N) 025 



Acriflavin (N) 035 



' Acid fuchsin (C and B) 130 



Basic fuchsin (C and B) 025 



Methylene blue (C and B) 050 



Rivanol 0.015 



Since gentian violet and acriflavin have been injected into the pleural cavities in 

 the treatment of pleuritis, I have determined the toxicity of these in addition to acidic 

 ^nd basic fuchsin and methylene blue by this route of administration. Normal rats 

 and rabbits were employed, and the general results have been that all of these dyes 

 were approximately 0.5 per cent more toxic by this route than by intravenous injec- 

 tion. 



I have also employed some of the dyes in the chemotherapy of experimentally pro- 

 duced streptococcus and staphylococcus meningitis of rabbits; toxicity tests employ- 

 ing normal rabbits injected intracisternally showed that the maximum tolerated dose 

 of gentian violet was from o.ooi to 0.002 gm. per kilogram, being at least ten to 

 twenty times more toxic by this route than by intravenous injection. The maximum 

 tolerated dose of acriflavin was between 0.002 to 0.003 g"^- per kilogram, and methyl- 

 ene blue and acid fuchsin were tolerated in about the same or slightly larger doses. 

 The total amount of fluid injected was about 0.25 cc, per kilogram, as this amount of 

 saline solution does not produce untoward effects by pressure and is a convenient 

 amount to inject by this route. Subdural injections in the lumbar region of rabbits 

 and through trephine openings of the skull over the frontal lobes of the cerebrum 

 yielded approximately the same results. 



The dose of gentian violet commonly administered by intravenous injection to 

 human beings is 0.005 gm- per kilogram, corresponding to 0.3-0.4 gm. for an adult of 



