76 THE TOXICITY OF CAFFEIN. 



food was varied. The subjects of the experiment were kept under observation for 

 a few days to several weeks before the administration of caffein was begun, in order 

 to determine whether or not any morbid condition existed, as well as to ascertain 

 whether the new environment had any effect on these animals. Caffein was given 

 chiefly by mouth, but the subcutaneous method was also employed during a por- 

 tion of the experimental period in some dogs. The initial dose, which varied for 

 different individuals, was maintained for a variable length of time. It was then 

 progressively increased, in most cases until the death of the animal. With larger 

 doses the intervals between successive injections were also increased. 



SERIES A. 



Six dogs were used in this series. Caffein was administered by mouth for periods 

 of six days to five weeks. It was given daily or at intervals of two, and sometimes of 

 three, days. In a few instances the drug was withheld for four or even for seven 

 days, and its administration was resumed at the end of this time. The initial dose 

 in these experiments varied approximately between 40 and 140 mg per kilo. The- 

 doses were then increased gradually, and thus the maximum resistance of the subject 

 to caffein was tested. The diet consisted either exclusively of meat or largely of 

 carbohydrates with a minimum amount of meat to give flavor to the food. 



Dog 11. Female. 



Diet consisted of rice, 250 grams; cane sugar, 250 grams; meat, 50 grams; cracker 

 meal, about 100 grams. Caffein was given by mouth daily or at intervals of one day, 

 when the dose did not exceed 1.5 grams. Before the dose was increased to 2 grams, or 

 approximately 0.213 gram caffein per kilo, an interval of two days was allowed. Symp- 

 toms were noticed the next day. An interval of two days was therefore allowed again 

 at the end of which the same dose was repeated. It will be remarked that there were 

 no symptoms this time, and the general condition of the dog seemed to be good. Two 

 grams of caffein were, therefore, given daily during the next two days without any 

 untoward effects; the dose was then increased to 2.5 grams. Even after this enormous 

 quantity no symptoms were observed except slight tremors. When this dose was 

 repeated 26 hours later, it proved fatal. No albumin or sugar was found in the urine, 

 although the dog was fed on a very liberal carbohydrate diet. The following is a 

 complete record of the experiment. 



April 20: Urine acid, no albumin, no sugar. 



April 21: Urine free from sugar. 



April 22: Urine free from sugar. 1 gram caffein given in the afternoon. 



April 23: 9 a. m., dog was very thirsty, drank a large quantity of water, urine did 

 not reduce Fehling's solution. 



April 24: 2.30 p. m., 1 gram caffein, no sugar in urine. 



April 25: 1 gram caffein administered. 



April 26: Weight, 10.6 kilos, urine collected in the morning, no sugar; 4.10 p. m., 

 1.5 grams caffein. 



April 27: 1.5 grams caffein; 1.30 p. m., diet as before, no sugar in urine. 



April 28: Weight, 10.2 kilos, no caffein, no sugar in urine. 



April 30: Weight, 10.4 kilos, no sugar in urine; 4.20 p. m., 2 grams caffein. 



May 1: Urine examined, sugar absent, weight 10 kilos, vomited, sick, tremors 

 observed, drank 500 cc water at one time, appetite poor. 



May 2: No caffein, drank 150 cc water. 



May 3: Urine, no sugar, moderate quantity of albumen present; 12 noon, 2 grams 

 caffein given by mouth, weight 10.3 kilos; 2 p. m., urine, sugar negative, condition 

 of dog good, no symptoms of caffein intoxication. 



May 4: 10 a. m., about 10 cc thick, dark-colored mucilaginous urine found in col- 

 lecting bottle; albumin a little more than a trace, decidedly less than on May 3, 

 no sugar, condition of dog pretty good except for slight muscular tremors j-- 4 p. m., 

 2 grams caffein by mouth (as usual). 



May 5: Urine not examined, no symptoms; 4 p. m., 2 grams caffein. 



May 6: Urine not examined; 2.30 p. m., 2.5 grams caffein given by mouth; 4 p. m., 

 slight tremor, no other symptoms. 



May 7: No examination of urine, no symptoms observed; 4 p. m., 2.5 grams 

 caffein. 



May 8: 9 a. m., found dead, urine collected since last dose of caffein was given 

 did not contain any sugar or albumin, the amount of caffein fed to this dog was 18 



