Administration by mouth 60         Subcutaneous injection 60         Experiments on puppies 61         Summary 62 Chronic caffein intoxication 63     Experiments on rabbits 63     Experiments on dogs 75 Discussion of results 91 General summary and conclusions 95 Bibliography 97

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THE TOXICITY OF CAFFEIN.

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INTRODUCTION.

Comparative physiology has established the fundamental fact that some properties are common to all forms of living matter. But the same method of inquiry has also led to the recognition of marked differences in the physiological processes of various species of animals. Among the most important investigations which contributed to the knowledge of such variation of function are the studies in comparative metabolism. It is now recognized that metabolism is in some respects quite different in herbivora and in carnivora. Some forms of oxidation are much greater in the rabbit than in cats and dogs. Nuclein metabolism presents important differences in the rabbit and in man, while the mode of neutralizing acid in the body may be cited as another variation in the metabolism of these forms. Perhaps the most striking examples of differences in the metabolism of different organisms is furnished by the results of studies on the fate of certain poisons introduced into the body.

The classical experiments of Bunge and Schmiedeberg¹⁵[A] on the synthesis of hippuric acid are of interest in this regard. It will be recalled that in the dog the synthesis takes place in the kidney; the rabbit is able to form hippuric acid in the liver as well as in the kidney, while frogs can synthesize hippuric acid even when both of these organs have been removed or excluded from the circulation. Observations on the fate of some of the alcohols of the fatty acid series have likewise shown that these substances may be combined with glycuronic acid in some animals but not in others. According to Thierfelder and Von Mering,⁸⁴ tertiary alcohols are combined in this manner in the rabbit but not in the dog. According to Neubauer,⁶⁴ the primary and secondary alcohols are so combined in the dog as well as in the rabbit, but to a greater degree in the latter.

Pohl⁷³ found that amyl alcohol is largely eliminated by the lungs in the cat and in the dog. The protocols of his experiments show that 65 per cent of the alcohol given these animals was thus recovered, while he recovered only 22 per cent of this substance in the expired air of the rabbit. Examination of the urine showed the presence of glycuronic acid. Hofmeister's³⁷ work with tellurium in the dog is of interest in this connection. He made the important discovery that some animals possess the power of methylation as well as of demethylation. Abderhalden and Brahm's¹ experiments with pyridin show that the same is true of young dogs when on a meat diet. His experiments on rabbits with this substance were negative.

The metabolism of caffein and theobromin furnish another illustration of differences in the physiological mechanism of animals. Although the substances found in the urine of man, dog, and rabbit after the administration of caffein and theobromin were the same, the quantities varied considerably. According to Krüger and Schmidt,⁴⁷ over 14 per cent of the theobromin introduced into the rabbit is eliminated as 7-methyl xanthin in the urine. The dog eliminates only about 0.67 per cent. On the other hand, the amount of tri-methyl xanthin eliminated was only 3 per cent in the dog and not quite 1 per cent in the rabbit.

It appears, therefore, from studies in comparative metabolism, whether endogenous or exogenous, that well-marked physiologic and chemical differences exist in various species of animals. That pharmacological action may likewise vary in different species of animals is shown by the following investigations. According to Guinard,³¹ who made an exhaustive study of morphin, the reaction to this alkaloid varies in different forms of life, both qualitatively and quantitatively. He established its narcotic effect in the