80 THE TOXICITY OF CAFFEIN. 



dog. It was thought, however, that the large initial doses or the quick change to large 

 doses when the amounts used in the beginning were small, might have something to 

 do with failure to induce a marked degree of tolerance. The experiment on dog 21 

 was therefore carried out by giving from 40 to .60 mg per kilo for eight days, and then 

 increasing the dose, but tolerance could not be induced, as is shown in the protocol 

 to the experiment. 



SERIES B. 



According to the studies of Chittenden, 16 low protein diet improves the general 

 metabolism of the body, fatigue is diminished, and bodily vigor, therefore, corre- 

 spondingly increased. The expectation is, therefore, justified that the defense of the 

 organism against deleterious substances introduced into the body is much improved 

 by such a diet, thus increasing its resistance to poisons. Hunt's experiment on this 

 subject, also quoted by Chittenden, lends support to this view. He found that mice 

 fed on carbohydrates chiefly, or on foods containing only a small amount of protein, 

 were more resistant to acetonitril. It was interesting, therefore, to inquire whether 

 the toxicity of caffein-differs under similar conditions of diet. 



A fixed diet of the same calorific value was provided for all dogs of this series, but 

 the protein content for three of the animals was approximately one-third of the amount 

 usually fed to dogs. Caffein was at first administered subcutaneously, but all the dogs 

 on a low protein diet developed abscesses at the site of injection, while none of those 

 on high protein diet showed a local reaction. Feeding by mouth was then begun 

 and continued throughout the experiment in each case. The initial dose was 50 mg 

 per kilo, which was given daily for seven to nine days. It was then increased pro- 

 gressively by 25 mg per kilo; 75 mg per kilo were administered for one to two days, 

 100 mg for two to three days, 125 mg for one to two days, 150 mg for one to two days, 

 and a single dose of 175 mg. It will be remarked that sometimes an interval of one 

 day had to be allowed during which no caffein was fed. 

 Dog 30. Black and tan hound, male. 



The dog was under observation for about eight weeks before the experiment was 

 begun and had received altigh protein diet. He was then given 50 mg caffein for nine 

 consecutive days. On the tenth day the dose was increased to 75 mg per kilo. As no 

 symptoms developed, this dose was increased to 100 mg per kilo, and was fed one day 

 apart. It was then raised to 125 mg per kilo. For the first time since the drug was 

 fed, symptoms appeared; they were noticed a few hours after feeding and persisted 

 during the next day. Although the appetite was good, no caffein was given on this 

 day. On the following day this dose was repeated . As the symptoms were not serious, 

 150 mg per kilo were given daily for the next three days, until 175 mg per kilo was 

 reached. This dose proved fatal within six hours. Record of experiment follows: 



November 3: Weight, 9.10 kilos. 



November 10: Weight, 9 kilos. 



November 20: Weight, 9.55 kilos. 



November 29: Weight, 8.70 kilos. 



December 6, 7, 8, and 9: Received subcutaneously 22 cc 2 per cent caffein. Condi- 

 tion good, site of injection normal. 



December 10, 11, 12, 13, and 14: Received 0.4375 gram caffein by mouth equal to 

 0.050 gram per kilo, no symptoms, appetite and general condition good. 



December 15: 11.30 a. m., received 0.6563 gram caffein by mouth, or 0.75 gram per 

 kilo, no symptoms, appetite good, condition excellent. 



December 16: 11 a. m., received 0.870 gram caffein by mouth, or 0.1 gram per kilo, 

 weight 8.70 kilos, no symptoms. 



December 17: No caffein given. 



December 18: Received 0.870 gram caffein, or 0.1 gram per kilo, no symptoms. 



December 20: 2.45 p. m., received 1.0875 grams caffein, or 0.125 per kilo; 4 p. m., 

 ate food readily, seemed very uncomfortable and sick. 



December 21: 9 a. m., stiffness in muscles, but no other symptoms, appetite good, 

 no caffein given. 



