66 THE TOXICITY OF CAFFEIN. 



day failed to show any effect of such treatment. About 1 decigram of caffein per 

 kilo was administered daily, with occasional intermissions. Later in the course of 

 the experiment the doses were increased, 0.15 gram per kilo being the maximum dose 

 given. Rabbit 293 died after the third dose with symptoms of typical caffein poison- 

 ing. The administration of the same dose of caffein was continued 10 days longer in 

 Nos. 292 and 295. It was omitted on the seventh, fourteenth, and fifteenth days of 

 the experiment. On the eighteenth day of the experiment the dose was increased to 

 150 mg per kilo and was repeated 2 days later. No. 295 was found dead the next 

 day. No. 292 survived. Rabbits 313 and 315 may be considered together, as they 

 were treated alike in every respect. The initial dose of 100 mg caffein per kilo was 

 finally increased to 122 mg. After the twelfth dose the emaciation was well marked 

 and the rabbits were very weak. No. 313 was found dead 2 days, and No. 315 

 3 days, after the last dose of caffein was given. It should be remarked in this con- 

 nection that symptoms of caffein poisoning were never observed in these rabbits. 

 Death was not due, therefore, primarily to caffein, but the rapid loss of flesh and 

 strength observed during the last few days suggests that it was due to malnutrition 

 apparently brought about by caffein. 



The results obtained by subcutaneous injection of caffein are given in the table 

 as Group II. The initial dose of 100 mg per kilo was injected daily. No. 298 died 

 after the second dose. Nos. 223 and 296 received this amount daily for 6 days. 

 An intermission of 2 days followed, at the end of which the same dose was given 

 again. The next day it was increased to 150 mg per kilo, but no effect was observed; 

 48 hours later this dose was repeated. No. 223 was found dead, but its mate survived. 

 Symptoms of acute caffein intoxication were not observed in any of these rabbits. 

 It would seem, therefore, that caffein is not cumulative. This supposition, however, 

 appears somewhat contradictory in view of the fact that out of the eight rabbits of 

 this series six died, nor could any cause of death be ascribed other than caffein. Also 

 the first results of Experiments 293, 370, and 373 might be considered as indicat- 

 ing that cumulation, though to a moderate extent, does take place, since in these 

 cases reflexes developed after the drug was given for some time. But this view is 

 contradicted by the results of Experiment 371, in which 150 mg per kilo given 5 

 days after the daily dosage of caffein was suspended likewise caused increased reflexes. 

 Cumulation, therefore, does not account for the effects noted in the other rabbit. It 

 will be observed that rabbit No. 370, as well as Nos. 371 and 373, had diarrhea for 

 several days. It is quite possible that the weakened condition rendered the rabbits 

 more sensitive to the action of the drug. This is made highly probable by the obser- 

 vations recorded in the experiments on acute intoxication with caffein in which 

 death occurred after small doses. In such cases some pathological condition was 

 often disclosed by the autopsy. The results of this series corroborate, therefore, those 

 -of Series A, and indicate again the absence of cumulative action. The results ob- 

 tained are in all probability due to malnutrition and other conditions brought about 

 by congestion of the viscera and consequent injury to the gastro-intestinal canal. 



