42 THE TOXICITY OF CAFFEIN. 



STJMMAKY. 



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 ad- 

 ministration 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 sensi- 

 tiveness to caffein were observed when it was given in other ways. A comparison 

 of the toxicity of caffein administered by different methods in this investigation 

 shows well-marked differences in its activity, although they are not quite so striking 

 as similar experiments with other alkaloids reported by several observers. The tox- 

 icity of caffein in these experiments on the rabbit indicates that it is greatest when 

 given by vein and least when given by mouth. The ratio of the minimum toxic 

 doses by these two methods of introduction of caffein was about 7.1; the relation of 

 the minimum fatal dose was about 3.1. The toxicity when given subcutaneously is 

 about 15 to 20 per cant greater than when given by mouth. The difference between 

 the intramuscular and subcutaneous injection is even more marked. The toxicity 

 of caffein when injected into the muscles is about midway between that adminis- 

 tered by the subcutaneous and intraperitoneal routes, and is about half that injected 

 intravenously. Meltzer and Auer, 68 who experimented with a number of drugs 

 found that the intramuscular method of administration is as effective as the intravenous, 

 fluorescin forming the only exception according to their observations. In the experi- 

 ments of Sollman and Brown 81 with ergot, the effect was quite different from those 

 obtained by Meltzer and Auer 68 with the drugs they used. It is quite possible that 

 the result obtained with ergot is merely illustrative of a difference in the behavior of 

 various substances in this regard. This appears probable on account of the difference 

 in the rate of absorption for various substances. Thus, according to Achard, Gaillard, 

 and Ribot (Compt. rend. Soc. biol., 1907, 62: 90), absorption from the peritoneal 

 cavity varies with the concentration of the solution and the size of the molecule. The 

 smaller the molecule and the greater the concentration the more rapid the absorp- 

 tion. That the rate of absorption from the intramuscular tissues is unequal and 

 varies for different substances appears from the experiments of Meltzer and Auer. 68 

 The difference was very striking between intramuscular and subcutaneous adminis- 

 tration of curara or adrenalin; the results were somewhat different with morphia 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. The absorption of 

 fluorescin is much faster when the intramuscular path is used than when given sub- 

 cutaneously, but the writers state that the rate falls far behind that of the intravenous 

 administration. The difference in toxicity we observed between feeding by mouth 

 and subcutaneous injection, although distinct, was not very great. It was much 

 less than Maurel 65 obtained with the hydrobromid of caffein in the rabbit. Whether 

 this difference between his results and ours is due to the use of the pure alkaloid in 

 our experiments and the hydrobromid employed by Maurel can not be stated at 

 present with any degree of accuracy. It is hoped that the work in progress in the 

 laboratory will throw some light on the subject in the near future. But Maurel's 66 

 experiments show that various substances behave differently in this regard. Thus 

 the toxicity of strychnin, he states, is three times as great when given subcutane- 

 ously as when given by mouth and six times that of the minimum fatal dose by vein. 

 It may be remarked, however, that examination of his data shows that his doses are 

 much too large for the rabbit. In experiments with other drugs little or no difference 

 between the two modes of administration was noticed. Thus, digitalin was but 

 slightly more active when given subcutaneously than by mouth, while the toxicity 

 of emetin hydrochlorid was just the same, whichever one of these methods of intro- 



