J. B. Rieger

“ While the rabbit tolerates more than twice the single dose of caffein per kilo for the dog, the result is quite different in repeated dosage of the drug, the rabbit succumbing to continued administration of much smaller doses of the drug than the dog. This is probably due to lesions of the gastro-intestinal canal caused by caffein which occasions loss of appetite much more readily in the rabbit than in the dog. The abundant energy reserve in the dog makes it possible for this animal to stand inanition much longer than the rabbit and other herbivora. ”

“ That the acute effects of a substance can hardly be considered a correct estimate of its toxicity is shown by the evidence obtained in experiments on tolerance and cumulative action of drugs; for the toxicity of a substance may diminish when the substance is given steadily for a long time if the body acquires tolerance for it. Arsenic, morphin, and cannabis indica may be cited as illustrations of drugs, the toxicity of which decreases with repeated doses, while digitalis and lead show a tendency to increased toxicity when similarly administered. ”

“ When the dose was doubled the frequency of the pulse was still more increased, heart action became stronger, and tremors and confusion of thought with excitement of the imagination made their appearance. ”

“ The minimum fatal dose is less by intraperitoneal injections, but greater than by subcutaneous injections, thus differing from the rabbit in this regard. The adult cat is less resistant than the guinea pig or rabbit to caffein. The minimum lethal dose by mouth is the same as by subcutaneous, and is less than by intraperitoneal, injection. The minimum fatal dose for dogs was found to be the same by mouth as by subcutaneous injection and is almost the same as for the cat. The toxicity of caffein varies in the guinea pig according to season of the year. ”

“ The results of the experiments on rabbits show considerable variation in the toxicity of the single dose. Individuals differed so widely in their resistance to this drug that the same experiments had to be repeated many times with each method of administration before satisfactory conclusions could be drawn. This is strikingly illustrated in the experiments by intravenous injection in which a dose of nearly 0.2 gram per kilo was not fatal. Similar instances of exceptional resistance or of sensitiveness to caffein were observed when it was given in other ways. ”

“ Caffein was therefore given by mouth and injected subcutaneously into the peritoneal cavity, into the muscles, and intravenously. As far as could be judged by appearance, healthy animals were selected for the subjects of the experiments, but as it is impossible to diagnose with any degree of accuracy the condition of the animal while it is alive, post mortem examinations were resorted to in many cases in which the issue of the experiment was fatal. Since the age of the animal may modify toxicity full grown, as well as young, animals were employed for these experiments ”

“ Experiments on cats were carried out by subcutaneous, intravenous, and rectal injections. The symptoms observed after the administration of 0.5 to 0.7 gram of caffein were the same as in rabbits except that the cats developed diarrhea when caffein was given and no anatomic lesions were found on autopsy. The effect of caffein on dogs indicated that in subjects of medium weight a dose of 0.5 gram given by mouth might produce restlessness and increased frequency of respiration, while the injection of the same amount intravenously into such animals may cause death. ”

“ It is practically certain, therefore, that this amount of caffein in proportion to the weight of the animal will in the great majority of cases prove fatal, and perhaps in a smaller percentage of individuals it is surely toxic if it does not escape absorption. Smaller doses may cause irritability in some individuals, but symptoms referable to nervous symptoms of muscles were absent, as in experiments Nos. 93 and 100. The minimum fatal dose of caffein for the cat when given by mouth is, therefore, 0.15 gram per kilo. ”

“ White, male, young.
Although he was growing rapidly this dog's weight was constant, but he looked anemic. He received a high protein diet until December 3, when the rations were increased by one-third. This dog was under observation from October 26 to December 6 when the administration of caffein was begun. He then received 50 mg caffein per kilo daily for nine days consecutively without showing any effects, when the dose was increased to 75 mg per kilo, then to 100 mg per kilo. This dose was further increased to 150 mg per kilo without causing symptoms, which was repeated the next day. ”

“ That the rate of absorption from the intramuscular tissues is unequal and varies for different substances appears from the experiments of Meltzer and Auer.58 The difference was very striking between intramuscular and subcutaneous administration of curara or adrenalin; the results were somewhat different with morphin and with fluorescin. As shown in their protocols, the onset of the symptoms after the intramuscular injection of morphin was sooner than after subcutaneous injection, but in time the difference diminishes and disappears altogether. ”

“ Since the motor nerves retained their irritability even after the reflexes disappeared, he concluded that the loss of motion was due to the action of caffein on the nerve centers.
Binz11 (1878) reported experiments on dogs and also made some observations on man with caffein. The subcutaneous injections of 0.2 gram caffein may prove fatal to dogs, although some survive such [Pg 15] a dose. The toxic dose in man varies from 0.5 to 1.5 grams. Disturbance of the circulation, such as palpitation of the heart and fullness of pulse, restlessness, and diarrhea were the symptoms he observed. ”

“ Moreover the acute and chronic effects are sometimes qualitatively different. According to Igersheimer41 the symptoms in acute atoxyl intoxication are nausea, vomiting, and diarrhea. These symptoms are absent in chronic intoxication, in which trophic disturbances of the skin and inflammation of the mucous membranes were the effects produced. That the acute action of atoxyl differs from the chronic effects was likewise shown by experiments on animals. ”

“ According to Kobert45 amygdalin is without effect on dogs, but it is poisonous to rabbits. Lapicque49 found that the toxicity of curara varies in different species of frogs, the dose required to produce paralysis in Rana esculenta being three times greater than in Bufo vulgaris. Weir Mitchell59 pointed out long ago that turtles stand enormous doses of curara. Schmiedeberg's experiments with caffein on Rana temporaria and Rana esculenta (and more recently those of Jacobi and Golowinski42 with caffein, theobromin, and theophyllin) are also of interest in this connection. ”

“ The recognition of the importance of these factors in determining pharmacological action has contributed much to the elucidation of the mechanism by which drugs and other substances produce physiological effects in the body. ”

“ Although the symptoms and organic changes produced by this substance in a variety of animals present no great differences, the resistance of some has been found to vary; according to Köster46 it is more toxic for dogs than for rabbits. A number of other substances have been found by various experimenters to vary in toxicity for different species of animals. ”