Part 11

September 27: 12 noon, convulsions and death. Autopsy: Congestion of the lungs; no other lesions.

Rabbit 423. White, male. Weight, 1,205 grams. Diet, oats.

September 26: 2 p. m., 18 cc 2 per cent caffein administered by mouth; 4 p. m., reflexes increased, no tetanus; 6 p. m., condition unchanged since 4 p. m.

September 27: 9 a. m., found dead. Autopsy: Lungs, liver, and kidneys congested; other organs normal.

Rabbit 422. White, male. Weight, 1,440 grams. Diet, oats.

September 26: 2 p. m., 21 cc 2 per cent caffein (291 mg per kilo) given by mouth; reflexes increased at 4 p. m.

September 27: 3 p. m., alive, no symptoms; 4 p. m., convulsions with recovery, this was soon followed by a violent attack of tetanus, which lasted about one minute and was succeeded by paralysis; rabbit died at 4.30. Autopsy: Liver slightly congested; a small portion of the intestine showed congestion and edema; other organs normal.

A study of these experiments shows also considerable variation in the toxicity of caffein when given by mouth. In some cases a dose of 300 mg per kilo, and even less, caused death, as in rabbits 423 and 424. In other rabbits, however, approximately the same doses of caffein produced increased reflexes only. The same symptoms were produced in Nos. 248 and 249 after the administration of 325-330 mg of caffein per kilo, while another rabbit (No. 239) survived a dose of 363 mg per kilo. That this is exceptional, however, appears from the result of the following experiments on rabbits Nos. 419, 420, and 421, all of which died after receiving 350 mg of caffein per kilo, and rabbits 267 and 268, to which doses of 363 and 342 mg, respectively, per kilo proved fatal. It will be observed further that the gray rabbits are more resistant to caffein than the white animals, as 350 mg per kilo was the smallest fatal dose for rabbits 419, 420, and 421, all of which were gray rabbits, while a dose of 290 mg per kilo was fatal for some of the white rabbits. Again, it will be noticed that of the two gray rabbits, Nos. 254 and 239, which received the largest doses in these experiments, namely, 369 and 363 mg, respectively, one survived. The largest doses given to the white rabbits were 363 and 342 mg caffein per kilo. Both of these died from the effects of the drug. It may be concluded, therefore, that the minimum toxic dose for the gray rabbit is about 325 mg of caffein per kilo, and the minimum fatal dose is at least 350 mg per kilo. It is to be remarked in this connection that post-mortem examination showed extensive coccidiosis in rabbit 420 and fatty liver in No. 421, while the macroscopical examination of the organs of Nos. 424 and 423 failed to show the presence of such abnormalities. Since, as was observed in the section on subcutaneous injection and elsewhere in this investigation, pathological changes are apt to decrease the resistance to caffein, it is quite possible that 350 mg per kilo is not the minimum fatal dose for the normal rabbit. Indeed, the experiment on rabbit 239 lends support to this view, thus furnishing additional evidence of difference in the resistance to caffein in the two varieties of rabbits.

TABLE 2.--Administration of caffein by mouth.

SERIES A.

------+--------+-------+-----------+--------------+-------+----------- Rabbit| |Caffein| | Duration | | No. | Weight.| per | Symptoms | of life. | Diet. |Remarks. | | kilo. | | | | ------+--------+-------+-----------+--------------+-------+----------- |Grams.| Mg. | | | | 248 | 1,170 | 330 |3 hours |Survived |Oats |Gray. | | | 10 minutes| | | 241 | 1,380 | 290 |2 hours | do. | do. |White male. | | | 15 minutes| | | 249 | 890 | 325 |3 hours | do. | do. |Gray male. ------+--------+-------+-----------+--------------+-------+-----------

SERIES B.

------+--------+-------+-----------+--------------+-------+----------- 239 | 935 | 363 | |Survived |Oats |Gray male. 254 | 975 | 369 | |About 2 days | do. |Gray female. 267 | 1,050 | 342 |50 minutes |1 hour | do. |White. | | | | 4 minutes | | 268 | 1,100 | 363 | |About 3 hours | do. | Do. 419 | 1,600 | 350 |6 hours |Less than | do. |Gray male. | | | | 24 hours | | 420 | 1,250 | 352 |1 hour |2 hours | do. | Do. | | | | 35 minutes | | 421 | 1,485 | 351 |6 hours |Less than | do. | Do. | | | | 24 hours | | 424 | 1,295 | 293 |2 hours |22 hours | do. | White male. 423 | 1,205 | 300 | do. |Less than | do. | Do. | | | | 19 hours | | 422 | 1,440 | 291 | do. |2½ hours | do. | Do. ------+--------+-------+-----------+--------------+-------+------------

INJECTION INTO THE PERITONEAL CAVITY.

In a number of experiments caffein was introduced into the peritoneal cavity. Rabbits of different varieties receiving a diet of oats or carrots were employed for this purpose; food and water were given ad libitum. The minimum doses required to induce symptoms or cause death in these animals were determined; tests with caffein were also made on young rabbits in order to study the influence of age on the resistance to this substance. The results are shown in the following experiments:

SERIES A.

In this series large doses were administered, approximating 0.3 gram per kilo.

Rabbit 71. Gray female. Weight, 1,659 grams.

January 20: 2.20 p. m., 25 cc aqueous solution 2 per cent caffein (300 mg per kilo) were injected into the peritoneal cavity; 3.45 p. m., when doors of cage were opened rabbit had spasm of short duration.

January 21: Rabbit found dead.

Rabbit 72. Gray and white. Weight, 1,402 grams.

January 21: 11.17 a. m., 20.2 cc (aqueous solution) of 2 per cent caffein (300 mg per kilo) injected into peritoneal cavity from burette; 11.25 a. m., paralysis; 11.30 a. m., rabbit had convulsion when picked up from the floor, followed by several spasms later; 11.35 a. m., typical tetanus; 12.30 noon, found dead.

Rabbit 61. Black female. Weight, 2,143 grams.

January 19: 40 cc 2 per cent caffein, aqueous solution (300 mg per kilo), injected into peritoneal cavity from burette; tetanus when about 30 cc were injected; when removed from holder, repeated and violent convulsions, terminating in death.

SERIES B.

The object of these experiments was to determine the minimum lethal dose; 0.2 to 0.15 gram of caffein per kilo was injected into the rabbits of this series.

Rabbit 69. White female. Weight, 1,714 grams.

January 20: 10.15 a. m., 6 cc 2 per cent caffein, aqueous solution, injected into peritoneal cavity. No symptoms, under observation for 45 minutes, rabbit defecated rather copiously; feces were soft; 11 a. m., 6 cc 2 per cent caffein, aqueous solution, injected into peritoneal cavity, no symptoms, under observation for 40 minutes; 11.40, 6 cc 2 per cent caffein injected into peritoneal cavity; 11.45, rabbit is restless, reflexes increased.