Six dogs were used in this series. Caffein was administered by mouth
for periods of six days to five weeks. It was given daily or at
intervals of two, and sometimes of three, days. In a few instances
the drug was withheld for four or even for seven days, and its
administration was resumed at the end of this time. The initial dose
in these experiments varied approximately between 40 and 140 mg per
kilo. The doses were then increased gradually, and thus the maximum
resistance of the subject to caffein was tested. The diet consisted
either exclusively of meat or largely of carbohydrates with a minimum
amount of meat to give flavor to the food.
_Dog 11. Female._
Diet consisted of rice, 250 grams; cane sugar, 250 grams; meat, 50
grams; cracker meal, about 100 grams. Caffein was given by mouth daily
or at intervals of one day, when the dose did not exceed 1.5 grams.
Before the dose was increased to 2 grams, or approximately 0.213
gram caffein per kilo, an interval of two days was allowed. Symptoms
were noticed the next day. An interval of two days was therefore
allowed again at the end of which the same dose was repeated. It will
be remarked that there were no symptoms this time, and the general
condition of the dog seemed to be good. Two grams of caffein were,
therefore, given daily during the next two days without any untoward
effects; the dose was then increased to 2.5 grams. Even after this
enormous quantity no symptoms were observed except slight tremors. When
this dose was repeated 26 hours later, it proved fatal. No albumin
or sugar was found in the urine, although the dog was fed on a very
liberal carbohydrate diet. The following is a complete record of the
experiment.
April 20: Urine acid, no albumin, no sugar.
April 21: Urine free from sugar.
April 22: Urine free from sugar. 1 gram caffein given in the afternoon.
April 23: 9 a. m., dog was very thirsty, drank a large quantity of
water, urine did not reduce Fehling's solution.
April 24: 2.30 p. m., 1 gram caffein, no sugar in urine.
April 25: 1 gram caffein administered.
April 26: Weight, 10.6 kilos, urine collected in the morning, no sugar;
4.10 p. m., 1.5 grams caffein.
April 27: 1.5 grams caffein; 1.30 p. m., diet as before, no sugar in
urine.
April 28: Weight, 10.2 kilos, no caffein, no sugar in urine.
April 30: Weight, 10.4 kilos, no sugar in urine; 4.20 p. m., 2 grams
caffein.
May 1: Urine examined, sugar absent, weight 10 kilos, vomited, sick,
tremors observed, drank 500 cc water at one time, appetite poor.
May 2: No caffein, drank 150 cc water.
May 3: Urine, no sugar, moderate quantity of albumen present; 12
noon, 2 grams caffein given by mouth, weight 10.3 kilos; 2 p. m.,
urine, sugar negative, condition of dog good, no symptoms of caffein
intoxication.
May 4: 10 a. m., about 10 cc thick, dark-colored mucilaginous urine
found in collecting bottle; albumin a little more than a trace,
decidedly less than on May 3, no sugar, condition of dog pretty good
except for slight muscular tremors; 4 p. m., 2 grams caffein by mouth
(as usual).
May 5: Urine not examined, no symptoms; 4 p. m., 2 grams caffein.
May 6: Urine not examined; 2.30 p. m., 2.5 grams caffein given by
mouth; 4 p. m., slight tremor, no other symptoms.
May 7: No examination of urine, no symptoms observed; 4 p. m., 2.5
grams caffein.
May 8: 9 a. m., found dead, urine collected since last dose of caffein
was given did not contain any sugar or albumin, the amount of caffein
fed to this dog was 18 grams in 18 days. _Autopsy_: Post-mortem
examination showed marked enteritis with hemorrhagic spots on the
mucosa; liver and kidneys congested and dark colored; lungs congested;
thyroid gland was greatly enlarged and congested.
_Dog 28_.
April 30: Weight, 6.8 kilos; the diet consisted of 250 grams rice,
250 grams sugar, 100 grams cracker meal, and 100 grams of meat. On
May 3 his weight was 7 kilos. He received 1 gram of caffein by mouth
at 12 noon. At 2 p. m. he vomited and tremors were observed. The
next day, May 4, tremors were still present though less pronounced.
Examination of the urine for sugar and albumin was negative; on May 4,
1 gram caffein was given again and repeated on May 5. On this date his
general condition was not good--dog had no appetite and refused to take
caffein. As the dog lost 10 per cent of his weight he was put on a meat
diet exclusively and the dose of caffein was reduced to 0.5 gram. He
became sick after the second dose, and the administration of caffein
was therefore discontinued. It was resumed after five days and the
caffein was administered in increasing amounts, i. e., on May 18, 0.5
gram; May 19, 0.5; May 20, 1; May 21, 1 gram in two doses of 0.5 each,
given at intervals of one hour; May 22, 1 gram. Dog became irritable,
but no other symptoms were observed. The administration of caffein
was omitted the next day. On the following day when the same dose of
caffein was given there was again marked irritability and tremors. The
experiment was therefore discontinued.
_Dog 22. Male bulldog._
June 24: Dog weighed 13.7 kilos. Diet consisted of meat exclusively;
1 gram caffein was given by mouth; diarrhea developed; no caffein was
given for three days.
June 28: Dog weighed 13.6 kilos, 1.5 grams caffein given at 10 a. m.
June 30: 1.75 grams caffein administered.
July 2: Dog weighed 13.5 kilos; 2 grams caffein or 0.15 gram per kilo,
caused well-marked thirst, but did not produce any other symptoms.
_Dog 20. Female_.
May 12: Weight, 7.7 kilos. Fed liberal carbohydrate diet, consisting of
rice, 100 grams; sugar 100 grams; meat and cracker meal, a sufficient
quantity to flavor the food.
May 14: Weight, 7.7 kilos. Examination of urine for albumin and sugar
gave negative results. Urine was acid to litmus.
May 17: Weight, 7.4 kilos. Three hours after it was fed the dog
received 0.5 gram caffein by mouth. The test of the urine the next day
for sugar was negative, but a trace of albumin was present. It will
be noticed that the doses were increased gradually and that symptoms
were observed only after the fourth dose of 0.1 gram per kilo. Later
meat was substituted for the carbohydrate diet and the administration
of caffein was stopped for four days. At the end of this period 100
mg caffein per kilo was fed daily for five days, and the dose was
then very gradually increased. Diarrhea occurred twice, but no other
symptoms, the second attack having lasted a few days. The following is
a complete record of the experiment:
May 19: 0.5 gram caffein 11.45 a. m.
May 20: 0.75 gram caffein 12.45 a. m.
May 21: 0.75 gram caffein 12 noon; no sugar, no albumin in urine.
May 22: 0.75 gram caffein; urine, same condition found; no symptoms.
May 23: Weight, 7.5 kilos; no caffein.
May 24: 0.75 gram caffein; tremors very marked.
May 25: No caffein.
May 26: 0.75 gram caffein.
May 27: 0.75 gram caffein.
May 28: 0.75 gram caffein.
May 29: 1 gram caffein in two doses of 0.75 and 0.25 gram.
May 30: No caffein.
May 31: No caffein; meat diet exclusively.
June 1: No caffein; meat diet exclusively.
June 2: No caffein; no sugar, no albumin in urine.
June 3: Weight, 7.6 kilos; 0.75 gram caffein; no sugar in urine.
June 4: Weight, 7.3 kilos; 0.75 gram caffein; no sugar in urine.
June 5: Weight, 7.5 kilos; 0.8 gram caffein; drank 500 cc water; ate
200 grams meat.
June 6: Weight, 7.4 kilos; 0.8 gram caffein; 500 cc urine; drank 500 cc
water; ate 200 grams meat; no symptoms.
June 7: Weight, 7.7 kilos; 0.8 gram caffein 10 a. m.; 400 cc urine, 500
cc water, 200 grams meat.
June 8: Weight, 7.5 kilos; 0.9 gram caffein, 450 cc urine, 1 p. m.; 200
grams meat, 500 cc water.
June 9: Weight, 7.6 kilos; 0.9 gram caffein, 1 p. m.; 500 cc water, 200
grams meat and bone dust; diarrhea and restlessness all afternoon.
June 10: Weight, 7.6 kilos; 1 gram caffein, 500 cc water, 200 grams
meat, 480 cc urine.
June 11: Weight, 8 kilos; 1 gram caffein, 470 cc urine, 500 cc water,
200 grams meat.
June 12: Weight, 7.8 kilos; 1 gram caffein, 710 cc urine, 500 cc water,
200 grams meat.
June 13: 450 cc urine, 500 cc water, 300 grams meat.
June 14: Weight, 7.9 kilos; 1.2 grams caffein, 500 cc water, 300 grams
meat, 490 cc urine.
June 15: Weight 7.8 kilos, 500 cc water, 300 grams meat, 550 cc urine.
June 16: Weight 8.0 kilos, 1.2 gram caffein, 500 cc water, 300 grams
meat, bone dust added to check diarrhea.
June 17: 500 cc water, 300 grams meat, 450 cc urine, diarrhea
continues, bone dust added.
June 18. Weight 7.8 kilos, 1.3 gram caffein, 300 grams meat, 500 cc
water, 300 cc urine.
June 19: Dog very thirsty, drank 1 liter of water and ate 350 grams of
meat; 960 cc urine passed during the past 24 hour.
June 21: Weight 7.5 kilos, 1.5 grams caffein given at 10 a. m. At 2
p. m. convulsions and death. This dog received a total of 21.15 grams
caffein in 25 doses during a period of 35 days, which amounts to an
average of 85 mg per kilo daily.
_Dog 19._ _Female fox terrier._
May 13: Weight 6.4 kilos. Diet consisted of rice, 100 grams; sugar,
100 grams; and a sufficient quantity of meat and cracker meal to give
flavor to the food. Examination of the urine showed a trace of albumin
but no sugar. The urine was acid to litmus. Two days later the urine
was alkaline to litmus. There was still a small amount of albumin but
no sugar.
May 17: 0.5 gram caffein was given by mouth. Examination of the urine
collected the next day still showed the presence of albumin and the
absence of reducing substances. The dog had tremors. Caffein was,
therefore, not administered.
May 19: 0.5 gram caffein was given by mouth.
May 20: 0.75 gram caffein was fed at 12.45 p. m. The dog vomited
during the night and tremors were observed the next morning. The urine
collected was examined for albumin and sugar, but neither was found.
May 21: 12 noon, 0.75 gram caffein was fed. The dog weighed 6 kilos,
which therefore represented a loss of 0.4 kilo. Grew abnormally thirsty
and lost appetite, but no other symptoms of caffein poisoning were
observed.
May 22: The dog was again given 0.75 gram caffein at 12 noon. The
examination of the urine for albumin and sugar gave negative results.
The dog died at 4.15 p. m. The fatal dose for this dog was therefore
0.125 gram caffein per kilo, and the total amount of caffein ingested
in six days amounted to 3.25 grams, or 0.54 gram per day, which makes
90 mg per kilo.
_Dog 21._ _White female bull._
This dog was kept on a diet exclusively of meat, and was given water
ab libitum. From 0.5 to 0.6 gram of caffein was administered daily for
seven days; the doses were then increased and were given at longer
intervals. No symptoms of the effects of caffein were observed until a
dose of 1.5 gram was fed, when diarrhea was noticed on the next day. In
the following record the details of the experiment are given:
----------+---------+----------
Date. | Weight. | Caffein.
----------+---------+----------
| _Kilos._| _Grams._
June 7 | 12.5 | 0.5
June 8 | 12.5 | .5
June 9 | 12.5 | .5
June 10 | 12.3 | .6
June 11 | 12.3 | .6
June 12 | 12.3 | .6
June 13 | 12.3 | .6
June 14 | 12.3 | .8
June 16 | 12.7 | 0.8
June 18 | 12.9 | 1.0
June 21 | 13.4 | 1.2
June 24 | 13.3 | 1.5
June 25 | (1) | .0
June 27 | 13.5 | 1.5
June 30 | 13.5 | 1.75
----------+---------+----------
(1) Diarrhea.
July 2: 11.30 a. m., 2.0 gram caffein fed by mouth; 1.30 p. m.,
tetanus, dog died. The total amount of caffein fed to dog No. 21 out
of the 25 days of the experiment was 14.45 grams, or an average of 578
mg per day, which amounts to about 42 to 43 mg per kilo of body weight.
Notwithstanding the diversity in the method of experimentation,
there was a striking uniformity in some of the results obtained. All
the experiments of the series showed absence of cumulative action
of caffein. The experimental evidence presented indicates that
moderately large doses may be given at intervals of about 24 hours
without inducing any symptoms of nervous or any other disturbance.
This is illustrated in the tests on dog 11, which were preliminary
in character. In this subject 100 to 150 mg of caffein per kilo were
ingested daily for several days without showing any changes. Later
in the course of the experiment, after larger doses were given, mild
symptoms only, such as tremors, were observed. Additional evidence
of the absence of cumulative action of caffein was furnished by the
results of the following experiments:
Dog 23 received 142 mg of caffein per kilo on three successive days.
His general condition indicated that these amounts of caffein were
toxic, but he survived. In another series of tests, made after he was
allowed to rest a few days, he again failed to show any cumulation of
the drug, as he survived this time a series of tests of longer duration
than the first.
A much better illustration of the absence of cumulative action of the
drug is furnished by the experiments on dog No. 20. In this case 100 to
125 mg of caffein per kilo, given on 10 consecutive days, did not cause
any marked effects. Diarrhea and restlessness were the only symptoms
observed. These experiments therefore show that the elimination and
decomposition of caffein are apparently effected by the body within
twenty-four hours or thereabouts.
Experiments on dog 19, however, form an exception--the third dose of
125 mg caffein per kilo having proved fatal. The very low protein
content of the diet of this dog suggests itself as a possible cause of
the lower resistance to caffein of this subject. But it may be observed
that the same diet was furnished to dog 20, which stood such amounts of
caffein much longer. The presence of a trace of albumin in the urine
of dog 19 is likewise inadmissible as a cause of the difference in
the toxicity of caffein in this dog, for the urine of dog 20 likewise
contained a trace of albumin. The alkaline reaction of the urine,
together with the fact that the first dose of only 60 mg of caffein per
kilo induced symptoms of toxicity, suggests the presence of an abnormal
condition which in all probability was the cause of the death of this
subject under the conditions indicated.
In a large number of experiments on caffein performed in this
laboratory it has been observed that symptoms due to caffein often
disappeared when the administration of the same dose of the drug
was continued. Thus dog 19 vomited when the amount of caffein was
increased to 125 mg per kilo. When this amount was repeated the next
day there was no vomiting. Similar observations were made on dogs
11 and 23, also on other dogs. No. 22 developed diarrhea at first;
when the administration of caffein was resumed several days later,
however, there was no diarrhea. In other experiments performed in
this laboratory, symptoms of nervous irritability induced by caffein
disappeared on continued treatment.
It was interesting, therefore, to inquire whether resistance to caffein
would be increased by the continued administration of progressively
larger amounts of the drug. When doses of 150 and over were fed, the
intervals allowed were usually longer than 24 hours. Two and sometimes
three days were permitted to elapse between two successive doses. This
was done in order to allow time for recovery from possible changes
induced by larger doses of caffein, and thus prevent the summation of
effect. In the experiments considered, therefore, Nos. 11, 23, 20, and
19, the toxicity of caffein does not seem to be greater than in the
experiments on acute caffein intoxication in the dog. It was thought,
however, that the large initial doses or the quick change to large
doses when the amounts used in the beginning were small, might have
something to do with failure to induce a marked degree of tolerance.
The experiment on dog 21 was therefore carried out by giving from 40
to 60 mg per kilo for eight days, and then increasing the dose, but
tolerance could not be induced, as is shown in the protocol to the
experiment.