December 15: 11.30 a. m., received 0.8175 gram caffein by mouth; 2 p. m., depressed in spirit, acted as though sick, no other symptoms.
December 16: Weight, 11 kilos; 11 a. m., received 0.100 gram caffein per kilo (1.100 grams) by mouth, no symptoms.
December 17: Rested.
December 18: 2.30 p. m., received 1.100 grams caffein by mouth; 4 p. m., no symptoms.
December 19: 12 noon, received 1.100 grams caffein by mouth; 4.15 p. m., no symptoms.
December 20: 2.45 p. m., given 1.375 grams caffein (0.125 gram per kilo); 3.45 p. m., vomited—one of the capsules being found intact, the other broken open; 4 p. m., given regular diet, containing 1.3757 grams caffein in capsules, ate most of this during the night, whined at intervals, coordination disturbed, appeared very sick, but exhibited no other symptoms.
December 21: 9 a. m., found dead, stiff, and cold.
The total amount of caffein received by dog 24 was between 10.109 and 11.484 grams. As one of the capsules vomited was intact and the other broken open, the amount was probably about 10.75 grams. The fatal dose in this case was undoubtedly less than 185 mg per kilo—somewhere between 125 and 185 mg. Autopsy showed heart in diastole; posterior lobe of right lung deeply congested; liver engorged; gall cyst filled; spleen appeared normal; stomach well filled with semifluid mass; pyloric portion of stomach exhibited a severe inflammation of mucosa; mucosa of duodenum greatly inflamed and showed hemorrhagic areas and catarrhal exudate; remainder of small intestine also exhibited mild inflammation; kidneys deeply engorged, mesentery injected.
A comparison of the fatal doses of caffein in the experiments on high and low protein diet does not show much difference in the resistance to caffein, since 175 mg per kilo proved fatal to Nos. 30 and 32, while No. 29 died after receiving 150 mg per kilo, and No. 24 received 125 to 185 mg per kilo. Moreover, No. 28, which was changed from low to high protein diet, succumbed when given 125 mg per kilo. Observations made during the experimental period indicate, however, greater toxicity of caffein in the subjects on low protein diet. Dog 30 showed the effects of the drug when the dose was increased to 125 mg of caffein per kilo, while in No. 32, 150 mg per kilo were received without any manifestation of symptoms. Dog 31, which was likewise on a high protein diet, is evidently an exception, and its low resistance to caffein may be accounted for by the condition found at autopsy. In other dogs on low protein diet symptoms of intoxication appeared early in the experiment. In Nos. 29 and 24 it was observed as soon as the amount of caffein was increased to 75 mg per kilo. In dog 28 the first dose of caffein 50 mg per kilo was toxic. The symptoms of gastro-intestinal disturbance were especially marked after caffein on low protein diet. This may seem to contradict the results of experiments on dogs 11 and 20, in which larger doses of caffein failed to induce symptoms of intoxication. But it should be observed that the diet, which consisted almost exclusively of carbohydrates, was given only during the administration of caffein, while in the experiments of series B the subjects received a low protein diet for several weeks before the administration of caffein was begun, and it was continued through the entire caffein period. It will be remarked that the absence of cumulative action in the experiments of the preceding series was also observed in dogs on high as well as on low protein diet. The appearance of symptoms after smaller doses of caffein in the latter experiments might suggest cumulative action, but since these symptoms disappeared on continued administration of the substance cumulation is clearly not indicated. The gastrointestinal lesions observed on post-mortem examination were, it will be recalled, also found in rabbits similarly treated. The explanation suggested probably applies also in the case of dogs.
Series C.