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. 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 toxicity 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 cent 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 administered by the
subcutaneous and intraperitoneal routes, and is about half that
injected intravenously. Meltzer and Auer,(58) 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 experiments of
Sollman and Brown(81) with ergot, the effect was quite different from
those obtained by Meltzer and Auer(58) 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 absorption. 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. The absorption
of fluorescin is much faster when the intramuscular path is used than
when given subcutaneously, 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(55) 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(56) experiments show
that various substances behave differently in this regard. Thus the
toxicity of strychnin, he states, is three times as great when given
subcutaneously 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 introducing the substance was used. Differences in the
toxicity of substances have also been observed between subcutaneous and
intravenous modes of administration, but here, too, the differences for
various substances were unequal.