Part 40

November 17: Weight, 1,325 grams; 22 cc 2 per cent caffein injected at 2.55 p. m. (329 mg per kilo), no symptoms.

November 18: Rabbit in good condition.

Rabbit 224. Belgian hare, female. Diet, carrots.

October 18: Weight, 1,935 grams; 11.20 a. m., 15 cc 2 per cent caffein (155 mg per kilo) injected.

November 1: Weight, 1,780 grams; 20 cc 2 per cent caffein (224 mg per kilo) injected subcutaneously, reflexes increased, muscle tremors present, but no other symptoms.

November 4: Weight, 1,710 grams; 21.5 cc 2 per cent caffein (252 mg per kilo) injected.

November 8: Weight, 1,435 grams; 22.5 cc 2 per cent caffein or 314 mg per kilo injected at 11.40 p. m.; 5 a. m., no symptoms.

November 17: Weight, 1,340 grams; 24 cc 2 per cent caffein (358 mg per kilo) injected subcutaneously.

November 18: 9 a. m., rabbit died.

Rabbit 226. Gray male. Diet, carrots.

October 28: Weight, 1,045 grams; 10 cc 2 per cent caffein injected subcutaneously at 1.50 p. m.; 4.30 p. m., tremors observed, but no other symptoms.

October 29: Rabbit in good condition.

November 1: Weight, 950 grams; 10.55 a. m., 11 cc 2 per cent caffein injected subcutaneously (231 mg per kilo).

November 4: Weight, 930 grams; 2.50 p. m., 12 cc 2 per cent caffein injected subcutaneously (258 mg caffein per kilo).

November 6: Weight, 945 grams; 11.45 a. m., 15 cc 2 per cent caffein (313 mg per kilo) injected subcutaneously.

November 17: Rabbit still alive; weight, 890 grams.

The results of these experiments indicate that when sufficient time is allowed between two successive injections, susceptibility to caffein is not increased. The rabbit, on the contrary, seems to acquire a tolerance for the drug, for the fourth dose was 15 per cent larger than the minimum fatal dose of caffein. This is in all probability due to the better elimination of caffein and its products of decomposition and to recovery from the deleterious effects of each dose, made possible by long intervals between injections.

The results of these experiments may be briefly summed up by stating that subminimum doses of caffein given to the rabbit daily or at intervals (not too long) do not produce any symptoms such as were observed in acute caffein intoxication, namely, increased reflexes and convulsions, or increased rate of respiration, thus showing that it is not cumulative. But evidence of undoubted summation of effect was adduced to show that if the administration of subminimum doses of caffein be continued daily for a period of 11 to 18 days the result is fatal. Tolerance, however, may be acquired, although to a limited extent only, provided sufficiently long intervals between injections are allowed to give time for repair of the injury done by the drug and to develop a mechanism for its better decomposition and elimination. Furthermore, the evidence just given indicates that the elimination of subminimum doses of caffein and its products of decomposition is probably accomplished within 24 hours or thereabouts. That the elimination of larger doses is not accomplished in this interval is made probable by the following experiment:

Gray rabbit 455. Female. Diet, oats.

October 12: Weight, 1,185 grams; 3.30 p. m., 11.5 cc 2 of per cent caffein injected into the lumbar muscles; 3 p. m., reflexes increased.

October 13: 10 a. m., rabbit weighed 1,070 grams; no symptoms of caffein poisoning, reflexes normal; 10.30 a. m., 10 cc 2 per cent caffein injected into the lumbar muscles; 11.30 a. m., rabbit jumped off the table, had convulsions, and died.

EXPERIMENTS ON DOGS.

Having gained some information respecting the effects of repeated doses of caffein on rabbits, it was of interest to find out how carnivora reacted to the drug when similarly administered. A number of dogs were used for the purpose. Considerable variation in the mode of experimentation, as will appear later, was allowed.

Since the condition of the animal, its age, environment, or diet might be factors influencing toxicity, tests were made on full-grown and on young growing dogs whose 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 portion 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. Symptoms 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.