CHRONIC INTOXICATION DOGS. 75 



Rabbit 24. Belgian hare, female. Diet, carrots. 



October 18: Weight, 1,935 grams; 11.20 a. m., 15 cc 2 per cent caffein (155 mg per 

 kilo) injected. 



November 1: Weight, 1,780 grams; 20 cc 2 per cent caffein (224 mg per kilo) injected 

 eubcutaneously, reflexes increased, muscle tremors present, but no other symptoms. 



November 4: Weight, 1,710 grams; 21.5 cc 2 per cent caffein (252 mg per kilo) 

 injected. 



November 8: Weight, 1,435 grams; 22.5 cc 2 per cent caffein or 314 mg per kilo 

 injected at 11.40 p. m.; 5 a. m., no symptoms. 



November 17: Weight, 1,340 grams; 24 cc 2 per cent caffein (358 mg per kilo) 

 injected subcutaneously. . 



November 18: 9 a. m., rabbit died. 

 Rabbit 226. Gray male. Diet, carrots. 



October 28: Weight, 1,045 grams; 10 cc 2 per cent caffein injected subcutaneously 

 at 1.50 p. m.; 4.30 p. m., tremors observed, but no other symptoms. 



October 29: Rabbit in good condition. 



November 1: Weight, 950 grama; 10.55 a. m., 11 cc 2 per cent caffein injected sub- 

 cutaneously (231 mg per kilo). 



November 4: Weight, 930 grams; 2.50 p. m., 12 cc 2 per cent caffein injected sub- 

 cutaneously (258 mg caffein per kilo). 



November 6: Weight, 945 grams; 11.45 a. m., 15 cc 2 per cent caffein (313 mg per 

 kilo) injected subcutaneously. 



November 17: Rabbit still alive; weight, 890 grams. 



The results of these experiments indicate that when sufficient time is allowed 

 between two successive injections, susceptibility to caffein is not increased. The 

 rabbit, on the contrary, seems to acquire a tolerance for the drug, for the fourth dose 

 was 15 per cent larger than the minimum fatal dose of caffein. This is in all proba- 

 bility due to the better elimination of caffein and its products of decomposition and 

 to recovery from the dfleteriqus effects of each dose, made possible by long intervals 

 between injections. 



The- results of these experiments may be briefly summed up by stating that sub- 

 minimum doses of caffein given to the rabbit dai]y or at intervals (not too long) do 

 not produce any symptoms such as were observed in acute caffein intoxication, 

 namely, increased reflexes and convulsions, or increased rate of respiration, thus 

 showing that it is not cumulative. But evidence of undoubted summation of effect 

 was adduced to show that if the administration of subminimum doses of caffein 

 be continued daily for a period of 11 to 18 days the result is fatal. Tolerance, 

 however, may be acquired, although to a limited extent only, provided sufficiently 

 long intervals between injections are allowed to give time for repair of the injury 

 done by the drug and to develop a mechanism for its better decomposition and elimi- 

 nation. Furthermore, the evidence just given indicates that the elimination of sub- 

 minimum doses of caffein and its products of decomposition is probably accomplished 

 within 24 hours or thereabouts. That the elimination of larger doses is not accom- 

 plished in this interval is made probable by the following experiment: 



Gray rabbit 455. Female. Diet, oats. 



October 12: Weight, 1,185 grams; 3.30 p. m., 11.5 cc 2 of per cent caffein injected 

 into the lumbar muscles; 3 p. m., reflexes increased. 



October 13: 10 a. m., rabbit weighed 1,070 grams; no symptoms of caffein poisoning, 

 reflexes normal; 10.30 a. m., 10 cc 2 per cent caffein injected into the lumbar muscles; 

 11.30 a. m., rabbit jumped off the table, had convulsions, and died. 



EXPERIMENTS ON DOGS. 



Having gained some information respecting the effects of repeated doses of caffein 

 on rabbits, it was of interest to find out how carnivora reacted to the drug when simi- 

 larly administered. A number of dogs were used for the purpose. Considerable 

 variation in the mode of experimentation, as will appear later, was allowed. 



Since the condition of the animal, its age, environment, or diet might be factors 

 influencing toxicity, tests were made on full-grown and on young growing dogs whose 



