_Guinea pig 49. Male. Weight, 510 grams. Diet, oats for 1 month
previous to experiment._
March 17: 3 p. m., 4 cc 2 per cent caffein (0.16 gram per kilo) were
injected subcutaneously; 4.40 p. m., reflexes increased; 5.40 p. m., no
symptoms.
March 18: 9 a. m., found dead, died in less than 18 hours. _Autopsy_:
Hemorrhage into abdominal cavity; liver and spleen unduly congested;
intestines injected; hemorrhagic area at point of injection.
_Guinea pig 40. Male. Weight, 630 grams. Diet, oats and carrots one
week previous to injection._
February 12: 11 a. m., 5 cc 2 per cent caffein (0.158 gram per kilo)
injected subcutaneously into back.
February 13: 1 p. m., still alive.
February 14: 9 a. m., found dead.
_Guinea pig 45. Female. Weight, 435 grams. Diet, oats for about one
month previous to injection._
March 17: 3 p. m., 3.5 cc of 2 per cent caffein injected subcutaneously
in the back (0.160 gram per kilo); 4.35 p. m., no symptoms; 5.40 p. m.,
no symptoms.
_Guinea pig 39. Male. Weight, 820 grams. Diet, oats and carrots._
February 12: 11 a. m., 6 cc (0.15 gram per kilo) 2 per cent caffein
injected subcutaneously in back.
February 14: 9 a. m., alive; seemed to be in good condition; found dead
at 1 p. m.
_Guinea pig 41. Weight, 660 grams. Diet, oats and carrots one week
previous to injection._
February 12: 11 a. m., 5 cc (0.15 gram per kilo) 2 per cent caffein
injected subcutaneously.
February 14: 2 p. m., pig alive; apparently normal.
February 18: Guinea pig still alive and apparently in good condition.
_Guinea pig 46. Female. Weight, 470 grams. Diet, oats about one month
previous to experiment._
March 17: 3.15 p. m., 4 cc (0.170 gram per kilo) 2 per cent caffein
injected into back subcutaneously; 4.35 p. m., reflexes increased,
tremors on handling marked; 5.40 p. m., no change, symptoms about as
before.
March 18: 2.30 p. m., no symptoms.
The experiments of this series (D) likewise showed a considerable
difference in the resistance of the individual guinea pigs. Nos. 41,
45, and 46 survived; the rest of the pigs died within 18 hours to 2
days after the administration of caffein. Since an autopsy was held on
one only, it is impossible to assign a cause for the variation in the
toxicity of caffein in these guinea gigs, as the diet and the other
conditions under which the experiments were conducted were the same.
It was found in the experiments on cats and rabbits that the presence
of morbid processes tends to increase the toxicity of caffein. The
observations of Ophüls(66) are of interest in this connection. He found
spontaneous lesions of the kidney and liver in a large proportion of
guinea pigs examined. The greater susceptibility to caffein of guinea
pigs Nos. 39, 40, 49, is probably due therefore to some pathological
change which increased its toxicity. About 0.2 to 0.24 gram per kilo
may therefore be regarded as the minimum lethal dose for the normal
guinea pig when caffein is introduced subcutaneously, the minimum toxic
dose being about 150-160 mg per kilo.
Experiments were also conducted to determine the largest dose which
does not produce any visible effects. In a number of tests with from
100 to 120 mg caffein per kilo (series E, see Table 6, p. 51) no
manifestation of nervous or muscular disturbance nor any departure
from the normal in respiratory activity was observed. Such quantities
may be regarded as the largest doses which are surely safe for these
animals. It is quite possible, therefore, that the greater variation in
the toxicity of caffein observed in these experiments is due to morbid
conditions. Moreover, there is some evidence that caffein increases
the toxicity of certain poisons, as shown by Hale(33) for acetanilid.
Is it not possible that caffein may similarly be affected by poisons
circulating within the body? Indeed the recent work of Loeb(23) makes
this supposition highly probable. This investigator found that caffein
and adrenalin injected together produce myocarditis in the rabbit. It
is conceivable that the combined action of caffein and some preexisting
poison may cause changes which terminate in the death of the animal.
The delayed death of guinea pigs after the administration of caffein
observed in this and other series may probably be accounted for in this
way.
Experiment 57 lends some support to this view. The condition of the
kidneys and the presence of a severe gastro-enteritis are sufficient to
account for the death of this case. Again the frequent association of
gastro-enteritis and congestion of the organs in caffein intoxication
found in different animals makes it highly probable that these lesions
were caused by caffein.