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.
Equally interesting is the observation of the writer, that in the
guinea pig the difference in the toxicity between the subcutaneous
and intraperitoneal injections is very slight, while in the cat the
toxicity of caffein is the same whether given by mouth or injected into
the subcutaneous tissues, and is markedly less when injected into the
peritoneal cavity. The experiments on dogs show considerable variation
of effective dose when given by mouth, but the interesting observation
was made that the toxic dose by mouth may be smaller in some cases
than the average dose by subcutaneous injection. If the resistance to
caffein by subcutaneous injection of the different species of animals
experimented upon in the present research be compared, it will be
noticed that the gray rabbit or Belgian hare, which is more resistant
than the other varieties employed, stands more caffein in proportion to
the weight of the body than the other animals.
Although the minimum fatal dose was found to be somewhat larger for
the guinea pig than for the gray rabbit when caffein was injected
intraperitoneally, it was on the contrary smaller by other paths of
introduction, and approximated quite closely the minimum fatal dose for
rabbits of the other varieties. Cats as well as dogs were found to be
distinctly less resistant to caffein than the herbivora.
There are a number of factors far more important than zoological
differences which influence the toxicity of caffein. Some of these are
age, season, and pathologic conditions. As these factors have already
been dwelt upon in their appropriate places, further discussion might
seem unnecessary, but owing to their importance in determining the
action of a drug, emphasis is desirable. Especially is this the case
with pathological conditions in relation to toxicity. While no positive
proof of diminished resistance to caffein in pathological conditions
was obtained by subjecting the suggestion to experimental test, it was
observed in these experiments on rabbits that death occurred in some
individuals after small doses which are usually not even toxic. The
findings at autopsy indicate the presence of pathological conditions.
The same was observed in some experiments on cats and dogs. It is
extremely probable, therefore, that disease modifies the reaction of
the organism to caffein as well as to other drugs.(78)
That the resistance to drugs may vary according to the age of the
subject has been maintained by a number of pharmacologists. According
to Guinard,(30) young dogs, rabbits, and guinea pigs are very
susceptible to morphin, resembling children in this regard.[E] The
minimum fatal dose for these animals is about one-third less than
for the adult. This is not true, however, for the young of other
species. Cats under 15 days of age tolerate twice the toxic dose of
morphin for the adult cat. Young beeves and goats are likewise more
resistant to this alkaloid than adults. On the other hand, according
to Livon,(54) young guinea pigs are more sensitive to alkaloids than
adults. The toxicity of caffein, as shown in the present investigation,
was found to be less in the young than in the adult. In dogs the young
subjects are in some instances almost twice as resistant as adults. The
difference was found to be less in cats and rabbits than in dogs, but
it was quite marked.
[E] A case of accidental poisoning reported recently by Wichura
(Münich. Méd. Woch., 1911, No. 30, p. 1618) throws some doubt on the
accepted view that the susceptibility of young children to morphin is
greater than that of adults. Wichura also found that the therapeutic
doses of codein preparations ordinarily recommended for children in
pleuritic cough are not effective in this condition.
The effect of season on the toxicity of drugs has been discussed in the
section on the experiments on guinea pigs, which were more resistant
to caffein in the fall than in February and March. The effect of
season seems to vary with the animal, but it may also differ with the
substance employed. In Noe's(65) studies on this subject cantharidin
was found to be more toxic for the hedgehog in November than in July.
The effect of season was different for morphin, as it was observed that
the resistance of the hedgehog was greater at the end of the summer
than earlier in the season.
The relation of diet to toxicity of drugs has been studied by
Hunt.(39) His experiments indicate that this is an important factor
in the resistance to acetonitril. The studies here reported on the
effect of diet on toxicity of caffein in rabbits were confined to
experiments with oats and carrots and do not show any modification of
the resistance to caffein. The question of diet in chronic intoxication
in dogs, however, suggests that in these animals diet may affect the
toxicity of caffein, although the data on this subject are far from
satisfactory. There is nevertheless sufficient evidence to suggest that
a high protein diet for the adult dog tends to greater resistance of
the animal to caffein and similarly the growing dog tolerates larger
quantities of caffein on a milk diet than on a diet of meat.
This brings us to a consideration of the behavior of caffein in chronic
intoxication. Although in both rabbits and dogs absence of cumulation
was evident, in other respects decided differences in the resistance
to caffein were observed. 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. The difference in the behavior of
the rabbit and dog toward caffein is interesting as showing complete
reversal of resistance in acute and chronic intoxication. From the
statement in the introduction it is evident that the size of the
single toxic or lethal dose of a substance is in no wise an index of
the active degree of its toxicity. The experiments with caffein here
reported furnish additional evidence that this is true, at least for
the rabbit.