TOXICITY OF CAFFEIN IN NEPHRECTOMIZED RABBITS. 21 



cation in these experiments soon after its injection precludes such a 

 possibility. The toxicity of caffein may be expected to be greater 

 in the rabbit after the removal of both kidneys, since the kidney is 

 the chief organ for the elimination of cafFein. Increased excretion 

 into the gastrointestinal canal is probably of not much importance, 

 however, in modifying the toxicity of caffein, for it has been shown 

 that reabsorption takes place. 



Moreover, there is reason to believe, from previous studies by vari- 

 ous investigators, that the action of a substance on a normal animal 

 furnishes no guide to its toxicity when the renal function is impaired 

 or altogether abolished. It may be recalled in this connection that 

 similar results were obtained in experiments with strychnin on rab- 

 bits by Meltzer and Salant 18 and by Meltzer and Langmann, 16 who 

 corroborated these findings on guinea pigs. The reaction of animals 

 after removal of the kidney is not the same, however, toward all 

 substances. Claude Bernard 4 showed long ago that curare becomes 

 poisonous when given by mouth to dogs in which the ureters are 

 tied or the kidneys removed. Since it has been established that this 

 substance may ordinarily be taken by mouth without injurious 

 effects, the findings of Claude Bernard, corroborated by Herrman, 

 are of interest as showing undoubted accumulation in the body of a 

 poison which is normally eliminated by the kidney. This is shown 

 even more strikingly by the experiments of Meltzer and Lucas, 17 who 

 brought forward evidence of diminished resistance to magnesium sul- 

 phate in rabbits deprived of both kidneys. These investigators have 

 also found that cumulation of this substance takes place after removal 

 of the kidneys, which is not the case in the normal subject. On the 

 contrary, the experimental data obtained in the first part of this 

 investigation strongly suggest decreased toxicity of caffein after the 

 removal of the kidney. Additional evidence, however, was consid- 

 ered necessary to determine accurately the resistance of the rabbit 

 to caffein in this condition. For this purpose several methods of 

 inquiry were employed, the following being particularly valuable and 

 suggestive : 



The effect of repeated nontoxic doses administered at long intervals 

 was tried to test whether or not the action of caffein is cumulative 

 after the removal of both kidneys. Since it was found that 200 mg per 

 kilo are surely toxic, the injection of several subminimum doses, the 

 total of which is equal to the toxic dose, should produce symptoms if 

 cumulation takes place. If, on the other hand, there is some mechan- 

 ism by which caffein is destroyed more easily or neutralized in 

 nephrectomized rabbits, the administration of several doses of this 

 size, if given at proper intervals, may be expected to be without any 

 effect. Moderate amounts of caffein were given at fairly long intervals 

 in the series following to test whether cumulation takes place. 



