PUP NO. 6.
Date. Weight. Food.Treatment (2 per cent caffein). Symptoms.
Grams. Milk cc. cc.
Apr. 28 300
Apr. 29 1,280 300
Apr. 30 1,290 300
May 1 1,315 300
May 2 1,330 300
May 3 300
May 4 1,360 300
May 5 1,365 300
Meat
(grams).
May 6 1,395 60
May 7 1,365 80
May 8 1,340 180
May 9 1,380 180
May 10 1,400 180
May 11 1,425 180 14.5No symptoms.
May 12 1,470 180 None.
May 13 1,485 180 None.
May 14 1,510 115 14.5 Do,
May 15 1,500 115 14.5 Do,
May 16 1,485 115 14.5Passed worms.
May 17 1,480 115 14.5
May 18 1,485 115 19.5Feces soft and black; almost diarrhea.
May 19 1,495 115 19.5
May 20 1,500 115 19.5Scratches her eyes and chases her tail.
May 21 1,500 115 17.0
May 22 115 17.0
May 23 1,470 115 17.0
May 24 1,465 115 20.0
May 25 1,450 115 20.0Feces soft and black.
May 26 1,450 115 23.0Diarrhea and worms.
May 27 1,355 115 23.0Refused to eat all food.
May 28 1,270 115 23.0Threw up worms, stiff, and has skin over both eyes.
May 29Found dead.

Highest amount of caffein given, 362 mg per kilo. No autopsy.

Examination of the results obtained in the experiments of series C shows that young and growing dogs tolerate large amounts of caffein. In four subjects of this series, Nos. 1, 2, 3, and 6, no effect was observed when moderately large amounts (160 to 200 mg per kilo of caffein) were fed. Symptoms were noticed only when these amounts of caffein were increased from 50 to 60 per cent. The other two dogs, Nos. 4 and 5, of this series were less resistant, however, to caffein, as 0.16 gram of the drug per kilo induced well-marked symptoms. Since these were fed meat, while Nos. 1, 2, and 3 received milk, the difference in toxicity may be due to the diet employed, but No. 6, which likewise received a meat diet, failed to show the effects of caffein when 200 mg per kilo were fed. On the other hand, it should be noticed that No. 1 died after receiving 360 mg per kilo, No. 2 survived a dose of 334 mg, while No. 3 died after a dose of 322 mg per kilo of caffein. The fatal doses for Nos. 4, 5, and 6 were 287, 335, and 300 mg per kilo, respectively. Although the differences are too small to justify any definite conclusion regarding the effect of a milk diet or of a meat diet on the toxicity of caffein, the results nevertheless suggest a reasonable possibility that caffein is more toxic to young dogs when on an exclusively meat diet than when fed milk. It is perfectly evident, however, that the resistance to caffein in either case is very great, almost twice that of adult subjects. As shown in series A and B, 125 to 175 mg per kilo proved fatal to all but two animals in these experiments, while symptoms of toxicity appeared after much smaller doses. In other respects the behavior of young dogs toward caffein was the same as that of the adult. In neither case was cumulation nor tolerance observed under the conditions of these experiments. The findings at autopsy were likewise similar, as gastro-enteritis was the chief lesion observed on macroscopic examination. It might be mentioned, however, in this connection, that the symptoms of caffein intoxication in young dogs often presented marked differences from those observed in those of more advanced age. The resemblance of the effects of caffein in young puppies and in rabbits was very striking. In both, the tonic with clonic convulsions were observed after a sufficient quantity of caffein was administered. In the dogs which were fully grown a large dose of caffein was usually followed by tonic convulsions and almost instantaneous death.

Moderately large amounts of caffein fed daily to puppies for several days—in some cases as long as 10 days—induced mild symptoms only. No cumulative effect was observed in any of the experiments of series C. There seems to be tolerance of certain functions toward caffein, but no general tolerance of the body could be obtained in these experiments. Caffein is apparently less toxic for adult dogs on high than on low protein diet. In young and growing dogs caffein is somewhat less toxic when milk, rather than meat, forms the exclusive diet. Some pathological conditions apparently increase the toxicity of caffein also in dogs. The symptoms of caffein intoxication observed in young dogs are in some respects different from those in full grown and older animals, and resemble those noticed in rabbits.

[DISCUSSION OF RESULTS.]

It was pointed out at some length in the introduction that the toxicity of some drugs may not be the same for all forms of life. This observation was also made by some investigators who experimented with caffein on different species of animals. Thus Maurel[55] stated that caffein is twice as toxic for the frog as for the rabbit when administered by mouth. Fröhner's[26] experiments, on the other hand, made on domestic animals, failed to show great differences in the toxicity of caffein. According to this observer, horses seem to be more susceptible than cattle, goats, and swine, the minimum toxic dose being the same for all of these, while the resistance of the dog to caffein is about midway between that of the horse and the other animals mentioned. It may be remarked, however, that Fröhner made only 13 experiments. That these data are inadequate for the formation of any conclusions as to the toxicity of caffein is evident since the most striking effect of caffein observed in the work herein reported was the comparatively wide range of variation in the resistance of individuals of the same species to this drug. This was found to be the case even when the conditions of experimentation were approximately uniform, and was observed whatever the mode of administration of the drug employed. The toxicity for different individuals also varied in acute as well as in chronic intoxication. It is for this reason that the number of tests employed were often quite large, for no conclusions of any value could be drawn without averaging the results of a sufficiently large number of experiments. Furthermore, it is to be borne in mind that the action of a drug may differ according to the mode of its introduction into the body and that different species of animals may vary in this regard. This is especially true of some substances when given by mouth, the range in toxicity for certain species of animals being much greater when thus administered than when injected subcutaneously or intravenously.

Maurel's[56] investigations are of interest in this connection, as his work embraces a systematic study of the toxicity of a large number of substances in the rabbit, pigeon, and frog when given by mouth, subcutaneously, intravenously, or when injected into the muscles. According to this investigator the range of variation of the toxicity of a substance is widest when given by mouth. Potassium sulphocyanid, for example, is about 2.5 times as toxic for the frog as for the rabbit when given by mouth. Quinin hydrobromid is three times as toxic for the frog as for the pigeon, while for the rabbit it is twice as toxic as for the pigeon. When given by hypodermic injection the toxic dose per kilo weight is practically the same for all three species. The difference of resistance according to the mode of administration is even more marked for spartein sulphate. When given by mouth the toxicity for the rabbit is six times as great as for the frog, but when injected subcutaneously the toxic dose is about the same for the rabbit and for the frog. The relation of the mode of administration to toxicity is further shown in the following substances: For the rabbit the minimum fatal dose per kilo of quinin hydrobromid is 1.5 grams administered by mouth, 0.5 gram when injected subcutaneously, and 0.07 gram by the intravenous path, while strychnin sulphate is twice as toxic administered intravenously as subcutaneously, and six times as toxic as when administered by mouth. The mode of introduction, however, does not always affect the toxicity of a substance. This is made evident by the action of strychnin on frogs in which, according to Maurel[56], the toxic dose is the same whether given by mouth or injected into the subcutaneous tissues. This appears to hold true also for other animals as demonstrated by the experiments of Hatcher[35] on the cat, in which he observed that strychnin is as readily absorbed from a full stomach as from the subcutaneous tissues. These findings are extremely interesting, especially in view of Maurel's[57] work on the subject, according to which he finds that a substance is much less toxic when given by mouth than when administered by hypodermic injection or intravenously. That this generalization does not admit, however, of universal application is made evident by the work of various experimenters. Claude Bernard[10] observed that curara is as poisonous for the pigeon when given by mouth as when injected subcutaneously, while Zalesky[86] found that samandarin is more toxic for frogs when introduced into the stomach than by injection into the lymph sacs. Our experiments with caffein likewise show that Maurel's generalization does not always hold good, since it was found in experiments with gray rabbits that the minimum fatal dose is but moderately greater by mouth than by the subcutaneous path.