_Guinea pig 66. Yellow and dark brown male. Weight, 510 grams.
Diet, oats._
October 4: 5 cc 2 per cent caffein (0.2 gram per kilo) injected
subcutaneously in the back at 3 p. m.; 5 p. m., no symptoms.
October 5: 9 a. m., alive; condition good.
October 9: Found dead. _Autopsy_: Congestion of liver, kidney, and
small intestine.
_Guinea pig 65. White and black male. Weight, 510 grams. Diet, oats._
October 4: 5 cc 2 per cent caffein (0.2 gram per kilo) injected
subcutaneously in the back at 3 p. m.; 5 p. m., no symptoms.
October 5: 9 a. m., condition good.
_Guinea pig 60. White and gray female. Weight, 320 grams. Diet, oats._
October 3: 2.25 p. m., 3.5 cc 2 per cent caffein (0.219 gram per kilo)
injected subcutaneously in the back; 3.40 p. m., convulsion with
recovery; 3.50 p. m., frequent spasms with paralysis, especially of
anterior extremities; 5.30 p. m., tetanus when removed from cage and
put on floor.
October 4: 8.50 a. m., found dead. _Autopsy_: Congestion of small
intestines, lungs, liver.
_Guinea pig 57. White and gray female. Weight, 350 grams. Diet, oats._
October 3: 2.15 p. m., 3.5 cc 2 per cent caffein injected
subcutaneously in the back (0.2 gram per kilo); 3.40 p. m., convulsions
with recovery; 5.30 p. m., no marked symptoms.
October 4: 8.50 a. m., alive, active.
October 6: Found dead at 9 a. m. _Autopsy_: Congestion of lungs and
liver; kidneys petechiated; severe gastro-enteritis.
_Guinea pig 68. Yellow male. Weight, 785 grams. Diet, oats._
October 6: 11.35 a. m., 7.8 cc 2 per cent caffein (0.2 gram per kilo)
injected subcutaneously; 12 noon, reflexes increased markedly;
4.20 p. m., reflexes the same as at 12 noon.
October 7: 9 a. m., dead. _Autopsy_: Lungs congested; liver congested
and fatty; spleen congested, kidney showed hemorrhagic spots; gastric
mucosa necrotic; small portion of small intestine inflamed.
_Guinea pig 69. White male. Weight, 585 grams. Diet, oats._
October 6: 11.40 a. m., 5.8 cc 2 per cent caffein injected
subcutaneously; 12 noon, reflexes increased, but not as much as in No.
68; 4.20 p. m., guinea pig hypersensitive, reflexes increased more than
at 12 noon.
October 7: 9 a. m., alive.
October 15: 9 a. m., found dead.
_Guinea pig 61. Brown and black female. Weight, 330 grams. Diet, oats._
October 3: 4 p. m., 4 cc 2 per cent caffein (240 mg per kilo) injected
subcutaneously; 5.30 p. m., reflexes increased; runs, but drags
posterior extremities.
October 4: 8.50 a. m., found dead.
_Guinea pig 62. White, yellow, and black female. Weight, 335 grams.
Diet, oats._
October 3: 4.05 p. m., 4 cc 2 per cent caffein (238 mg per kilo)
injected subcutaneously in the back; 5 p. m., convulsions; 5.20 p. m.,
convulsions, alternating with paralysis of anterior and posterior
extremities.
October 4: 8.50 a. m., found dead.
_Guinea pig 70. White and brown male. Weight, 545 grams. Diet, oats._
October 7: 3 p. m., 6.5 cc 2 per cent caffein (238 mg per kilo) aqueous
solution injected subcutaneously; 3.50 p. m., reflexes increased.
October 9: 9 a. m., found dead.
_Guinea pig 71. Brown and white male. Weight, 540 grams. Diet, oats._
October 7: 3 p. m., 6.5 cc 2 per cent caffein solution (0.24 gram per
kilo) injected subcutaneously; 3.45 p. m., reflexes increased, tetanus.
October 9: 9 a. m., found dead.
_Guinea pig 72. Brown and white male. Weight, 560 grams. Diet, oats._
October 7: 3 p. m., 6.5 cc 2 per cent caffein (0.232 gram per kilo)
aqueous solution administered by subcutaneous injection; 3.35 p. m.,
reflexes increased.
October 10: found dead. _Autopsy_: Nos. 70, 71, 72 showed congestion of
organs.
The reaction to caffein in the experiments of this series (C) showed
considerable variation. The appearance of symptoms, as well as the
final outcome of the experiments, differed markedly in a number of
cases, notwithstanding the fact that the conditions were the same;
thus the administration of 0.2 gram per kilo to guinea pigs, all of
which received the same diet, induced no symptoms in two of the animals
(Nos. 66 and 65), while marked symptoms were observed in the other
four; in two of these the symptoms appeared in one hour and a quarter
after injection, and in two others (Nos. 68 and 69), mild symptoms only
appeared in 20 or 25 minutes. The last two were under observation for
4 hours longer, but there was no visible change in their condition.
The duration of life in all of these guinea pigs, as indicated in the
table, likewise varied. Two (Nos. 60 and 68) died during the night
after they received caffein, one survived (No. 65), and three others
(Nos. 57, 66, and 69) lived 2½, 5, and 9 days, respectively.
Experiments with larger doses likewise showed differences in the
behavior of these animals toward caffein, but they were not quite so
marked. As shown in the table, symptoms appeared in from 35 minutes to
1.5 hours after injection. The duration of life was less than 1 day in
two pigs, about twice as long in two others, and in one case between 2
and 3 days.
A comparison made with results obtained in the preceding series shows
a striking difference in the resistance to caffein. As 2 decigrams per
kilo proved more rapidly fatal to the guinea pig than the larger doses
employed in the later experiments, this difference in the resistance
to caffein may be due to several factors. As pointed out in the
experiments on rabbits, age might be an important factor influencing
the toxicity of caffein. Unfortunately, no accurate data were available
on the age of the guinea pigs, but they were all apparently full grown,
although they differed in weight considerably. The difference in their
ages was in all probability not very great. Moreover, it will be
observed that the resistance in series B and C differed in animals of
approximately the same weight. This is evident on comparing experiments
Nos. 20, 38, and 13 of series B with Nos. 65, 66, and 69 of the next
series. Again, further inspection and analysis of these tables show
no difference in the toxicity, although there may be considerable
difference in the weight, from which it may be concluded that the
animals were of about the same age or that this plays no part in the
resistance to caffein in the guinea pig.
Diet is another factor which should be taken into consideration in
this connection. The recent work of Hunt(39) indicates that this may
influence the resistance of animals to some poisons. Our experiments,
however, fail to show any difference in the toxicity of the caffein
in guinea pigs, whether fed oats, carrots, or both, for different
results were obtained on the same diet, and there seemed to be
little or no difference in the toxicity of caffein when the diet was
different. Other explanations suggest themselves to account for the
results obtained. Seasonal changes have been assigned by a number of
investigators as a cause of variation in the resistance to drugs.
According to Focke,(24) frogs are more susceptible to digitalis in the
spring than in the summer, while Moschkowitsch(61) and Edmunds(21)
reported the very opposite results. Schmiedeberg's(80) observations
on strophantin in frogs were in harmony with those of Edmunds(21) and
Moschkowitsch.(61) Similar results were reported with guinea pigs.
Harrington's(34) experiments indicate that stimulation of the vagus is
less effective from October to January than from February to April,
when they are also much more susceptible to operative procedure. Hunt
found that the resistance of guinea pigs to aceto nitril is about twice
as great in the summer months as it is in January and February.
Race might also be thought of as an important factor in this
connection. Since the guinea pigs used at different seasons of the year
were of several varieties, there is no reason to suppose, however,
that the varieties experimented upon in the summer were more resistant
than those used in the winter and spring. It is highly probable,
therefore, that the greater resistance to caffein of the guinea pigs of
series C than those of series B was due to seasonal variation.
Doses of 0.20 to 0.24 gram caffein per kilo weight, therefore, may
be regarded as the minimum fatal dose for the guinea pig, depending
upon the season. Since 0.2 gram per kilo proved to be rapidly fatal
in series B, this quantity was perhaps not the minimum fatal dose for
the guinea pig at the season during which the experiments were made.
Additional tests with smaller doses were therefore carried out during
February and March. The results are shown in series D.