22 CAFFEIN IN NEPHRECTOMIZED KABBITS. 



EXPERIMENTS. 

 CUMULATION WITH MODERATELY LARGE DOSES (SERIES I). 



Rabbit 110. Gray; weight, 1,400 grams. 



March 17: 11.30 a. m., both kidneys removed by lumbar route; 2 p. m., 7 cc of 2 per 

 cent aqueous caff em solution injected subcutaneously in tissues of back. 



March 18: 9.30 a. m., 7 cc of 2 per cent aqueous caffein solution injected subcutane- 

 ously in tissues of back; 1.45 p. m., no symptoms; 1.50 p. m., 7 cc of 2 per cent 

 aqueous caffein solution injected subcutaneously in tissues of back; 4.30 p. m., rabbit 

 became paralyzed; this was followed by convulsion, marked opisthotonos, and death. 



At first sight the result obtained in rabbit No. 110 seems to point 

 to the absence of cumulation, as two doses of 100 mg caffein per kilo 

 administered at an interval of about 20 hours may be given without 

 producing symptoms of toxicity. The fate of the first dose, aside 

 from the. portion that found its way into the gastrointestinal canal, 

 which, as was shown above, is about 8 or 10 per cent of the amount 

 injected, admits of two possibilities. Either it was destroyed or it 

 was neutralized partly or entirely in the body by substances formed 

 after removal of the kidney. The effect of the third injection would 

 indicate, however, that some of the first dose was still in the body in 

 an active condition, since, as was observed in this investigation, 0.2 

 gram per kilo is not fatal within three hours. That cumulation, 

 though to a small degree, does apparently take place is further indi- 

 cated in rabbit No. 229. 



The effect of the second injection of caffein in this rabbit makes 

 this evident, since a single dose of this size is w^ell borne by nephrec- 

 tomized rabbits, as is illustrated in rabbit No. 232, which died about 

 18 hours after receiving 150 mg caffein per kilo. Experiments on 

 rabbit No. 229 show the same after a single dose. It may be recalled 

 that such a dose given on two successive days likewise proved fatal 

 to normal rabbits. 



Rabbit 229. Black and white male; weight, 2,140 grams. 



November 1: 3 p. m., both kidneys removed by dorsal route under ether anaesthesia 

 and wound closed; practically no loss of blood, perhaps 1 cc; 3.05 p. m., rabbit recov- 

 ered from operation and was running around in the room; 3.30 p. m., 15 cc of 2 per cent 

 caffein (140 mg per kilo) injected subcutaneously; under observation until 5 p. m. 



November 2: 9 a. m., condition of rabbit excellent; feces in cage hard; no evidence 

 of diarrhea; 9.30 a. m., 15 cc of 2 per cent caffein injected subcutaneously; 12 m., 

 rabbit restless; this continued until 1.30 p. m., when paralysis was observed ; 1.45 p. m., 

 convulsion and death. 



Rabbit 232. Gray male; weight, 2,010 grams. 



November 2: 11 a. m., double nephrectomy; 1.45 p. m., 15 cc of 2 per cent caffein 

 injected subcutaneously in the back; operation uneventful; loss of blood slight. 



November 3: 9 a. m., found dead; body still quite warm. 



CUMULATION WITH SMALLER DOSES (SERIES II). 



The questions of cumulation and neutralization were tested again 

 in experiments in which smaller doses were repeated at proper 

 intervals, but only one dose of medium size was administered. By 



