CHRONIC INTOXICATION DOGS. 79 



July 2: 11.30 a. m., 2.0 gram caffein fed by mouth; 1.30.p. m., tetanus, dog died. 

 The total amount of caffoin iV<l to dog No. 21 out of the 25 days of the experiment was 

 14.45 grams, or an average of 578 mg per day, which amounts to about 42 to 43 mg per 

 kilo or body weight. 



Notwithstanding the diversity in the method of experimentation, there was a 

 striking uniformity in some of the results obtained. All the experiments of the series 

 showed absence of cumulative action of caffein. The experimental evidence pre- 

 sented indicates that moderately large doses may be given at intervals of about 24 

 hours without inducing any symptoms of nervous or any other disturbance. This is 

 illustrated in the tests on dog 11, which were preliminary in character. In this sub- 

 ject 100 to 150 mg of caffein per kilo were ingested daily for several days without 

 showing any changes. Later in the course of the experiment, after larger doses were 

 given, mild symptoms only, such as tremors, were observed. Additional evidence of 

 the absence of cumulative action of caffein was furnished by the results of the following 

 experiments: 



Dog 23 received 142 mg of caffein per kilo on three successive days. His general 

 condition indicated that these amounts of caffein were toxic, but he survived. In 

 another series of tests, made after he was allowed to rest a few days, he again failed to 

 show any cumulation of the drug, as he survived this time a series of tests of longer 

 duration than the first. 



A much better illustration of the absence of cumulative action of the drug is fur- 

 nished by the experiments on dog No. 20. In this case 100 to 125 mg of caffein per 

 kilo, given on 10 consecutive days, did not cause any marked effects. Diarrhea and 

 restlessness were the only symptoms observed. These experiments therefore show 

 that the elimination and decomposition of caffein are apparently effected by the body 

 within twenty-four hours or thereabouts. 



Experiments on dog 19, however, form an exception the third dose of 125 mg caf- 

 r fein per kilo having proved fatal. The very low protein content of the diet of this 

 dog suggests itself as a possible cause of the lower resistance to caffein of this subject. 

 But it may be observed that the same diet was furnished to dog 20, which stood such 

 amounts of caffein much longer. The presence of a trace of albumin in the urine of 

 dog 19 is likewise inadmissible as a cause of the difference in the toxicity of caffein 

 in this dog, for the urine of dog 20 likewise contained a trace of albumin. The alkaline 

 reaction of the urine, together with the fact that the first dose of only 60 nig of caffein 

 per kilo induced symptoms of toxicity, suggests the presence of an abnormal condition 

 which in all probability was the cause of the death of this subject under the conditions 

 indicated. 



In a large number of experiments on caffein performed in this laboratory it has been 

 observed that symptoms due to caffein often disappeared when the administration of 

 the same dose of the drug was continued. Thus dog 19 vomited when the amount of 

 caffein was increased to 125 mg per kilo. When this amount was repeated the next 

 day there was no vomiting. Similar observations were made on dogs 11 and 23, also 

 on other dogs. No. 22 developed diarrhea at first; when the administration of caffein 

 was resumed several days later, however, there was no diarrhea. In other experi- 

 ments performed -in this laboratory, symptoms of nervous irritability induced by 

 caffein disappeared on continued treatment. 



It was interesting, therefore, to inquire whether resistance to caffein would be 

 increased by the continued administration of progressively larger amounts of the drug. 

 When doses of 150 and over were fed, the intervals allowed were usually longer than 

 24 hours. Two and sometimes three days were permitted to elapse between two suc- 

 cessive doses. This was done in order to allow time for recovery from possible changes 

 induced by larger doses of caffein, and thus prevent the summation of effect. In the 

 experiments considered, therefore, Nos. 11, 23, 20, and 19, the toxicity of caffein does 

 not seem to be greater than in the experiments on acute caffein intoxication in the 



