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 Schmiedeberg(15)[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.
[A] The small figures refer to the bibliography at the end of this
bulletin.
Pohl(73) 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's(37) 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's(1) 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 dog, rabbit, guinea pig, white
mice, and rats, while for the cat, horse, ox, sheep, hog, and goat
it is, on the contrary, a stimulant. Moreover, there is no evidence
of cerebral effect. The stimulating effect of morphin on the nervous
system in some animals was also observed by Noe(65) in experiments with
this substance on the hedgehog.
Guinard(29), (30) has also shown that morphin has no narcotic effect
in the marmot, although this animal is very sensitive to the drug.
Two milligrams per kilo were found to be a surely fatal dose for this
animal. His experiments on the comparative toxicity of morphin(30), (31)
show a considerable range of variation in different species. Thus the
fatal dose for the dog was found to be 0.65 per kilo, while 7 mg per
kilo is the fatal dose for the horse. About twice the amount is fatal
for the ox and 0.2 mg per kilo kills the pig. Experiments with other
drugs has shown that a considerable range of variation in resistance
exists in animals of different species.
Noe's(65) studies on the comparative toxicity of chloral brought out
the interesting fact that the rabbit is more resistant to it than the
hedgehog and the latter more resistant than the guinea pig. Perhaps the
most striking example of a difference in reaction of the same substance
in widely different species is that furnished by apocodein, quinin,
and yohimbin. According to Gunn(32) these substances have been found
to cause vasodilation in warm-blooded animals, but they constrict the
blood vessels of the frog.
Experiments with apomorphin likewise show that the reaction to this
substance varies in different species of animals. The resistance of the
cat to this drug is, according to Guinard(31), ten times greater than
that of the dog, and the latter is more sensitive than the rabbit to
the crystalline form of apomorphin when given intravenously. According
to Kobert(45) amygdalin is without effect on dogs, but it is poisonous
to rabbits. Lapicque(49) 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 Mitchell(59) 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
Golowinski(42) with caffein, theobromin, and theophyllin) are also of
interest in this connection. These experimenters observed well-marked
differences of reaction to methyl-xanthins in these closely allied
forms.
Experiments with quinin have shown that the action of this substance
differs in some animals. It causes a fall of temperature immediately
after its administration in the guinea pig, but frequently produces,
at first, a rise of temperature, followed by an unimportant fall, in
rabbits, dogs, and man.
The numerous investigations which have been carried out on the effect
of atoxyl within recent years have contributed much to the comparative
pharmacology of this substance. 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 Köster(46) 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. Cantharadin, phenol,
atropin, and strychnin may be mentioned as illustrations.
Pharmacological studies on lower forms of life have also revealed
marked variations in the effect of some poisons. Observations made by
Danilewski(18) with hydrochinone indicate that solutions of 1 to 100
or 200 are toxic to Celentrates, causing paralysis in these organisms.
Echinoderms are killed within one or two hours in 1 to 1,000 or 2,000
solution, while in Vermes even weaker solutions cause tetanus and
finally paralysis. The experiments of Drzewina(19) with potassium
cyanid are also interesting in this connection. Teleosts placed in 100
cc of sea water containing twentieth-normal potassium cyanid showed
signs of asphyxia and died in 10 to 20 minutes. Actinia placed in a
solution of sea water containing five times as much potassium cyanid
were active on the thirteenth day of the experiment. Similar results
were obtained with other marine organisms.
From these data it is evident that the toxicity of a substance may vary
considerably in different forms of life. It has been shown also by some
investigations cited by Salant(78) that the action of drugs may be
modified by different conditions in the environment as well as in the
subject of the experiment. 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. Moreover, such knowledge has
often enhanced the therapeutic value of pharmaco-dynamic agents and has
frequently served to avert effects of an undesirable character in man
and domestic animals. The results obtained in one species of animals
under a particular condition do not admit, therefore, of universal
application. Furthermore, the nature of the action of a drug can only
be partly learned from the manifestation of its acute effects. Equally
important, therefore, especially in studies on toxicity, are the
changes produced in chronic intoxication.
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. Moreover the acute and chronic effects are sometimes
qualitatively different. According to Igersheimer(41) 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.
The studies of von Anrep(5) on chronic atropin intoxication are of
interest in this connection, as he found that after 10 to 15 injections
of atropin there is no manifestation of symptoms such as is observed
in acute intoxication, while the effects on the circulation are also
less marked, the acceleration of the pulse being less than after the
same dose in a normal subject not accustomed to its use. When the
administration of atropin is continued for a longer time its usual
effects on the pulse disappear altogether; there is, on the contrary a
decreased frequency of the pulse. If atropin has been administered for
from two to three weeks, respiration is likewise affected.