The subjects used in these experiments were rabbits of medium size and
were apparently young or at any rate were not very old. The series
was planned for the study of the possible effect of diet on the
toxicity of caffein when given for some time, and therefore oats were
substituted for carrots, which had been fed in the previous work, as
already stated. Caffein was given by mouth in the usual way, in 1 per
cent solution, 100 mg. per kilo daily. Fourteen rabbits were used for
these tests. Their weights were recorded daily and observations made at
frequent intervals during the day.
The only change noticed in all of the experiments of this series was
progressive loss of weight which set in from 3 to 8 days after the
administration of the drug was begun. The duration of life varied
considerably. No. 382 died after the first dose. No. 389 lived 2
days, No. 386, 3 days, and No. 385, 5 days; No. 390 lived 7 days and
No. 404 lived 20 days after the administration of caffein was begun.
The duration of life in all the others was from 11 to 16 days. The
findings at autopsy are interesting and suggestive as regards the
possible explanation of the effects of repeated dosage of caffein.
In eight of the rabbits there was involvement of the mucous membrane
of the stomach or intestines or of both. Since the same condition of
the gastro-intestinal canal was observed in previous experiments with
caffein when injected subcutaneously, the mere passing of the tube
into the stomach is obviously not the cause of this condition. The
fatal outcome due is therefore, as was suggested above, to inanition
brought about by the condition of the gastro-intestinal canal. Moreover
parallel experiments carried out on rabbits in the same way with
alcohol survived this treatment much longer. Obviously then the passing
of the soft rubber catheter is not the cause of this condition of the
gastro-intestinal canal nor the diet. Rabbits were fed oats exclusively
for several months in this laboratory and thrived. The presence of
pneumonia in the other rabbits of this series may be regarded as
accidental, as it is inconceivable that one or two doses of caffein,
as was the case in Nos. 382 and 389, could predispose the lungs to
infection. The results of these experiments therefore are in harmony
with those of the preceding two series, indicating that caffein does
not accumulate in the body, and that the toxicity of caffein, whether
of the single dose or of repeated doses is the same, on a diet of
carrots or of oats. These results also show that caffein is much more
toxic with repeated dosage. As stated in the historical part of this
bulletin the same view was held by Gourewitch.(28)
_Rabbit 386._ _Belgian female._
Given 1 cc of 1 per cent caffein for each 100 grams, through stomach
tube.
--------+--------+----------
Date. | Weight.|Treatment.
--------+--------+----------
|_Grams._| _cc._
Aug. 17| 1,300 | 13.0
Aug. 18| 1,215 | 12.0
Aug. 19| (?) | (?)
--------+--------+----------
August 20: Found dead 9 a. m. _Autopsy_: Lungs slightly congested;
liver engorged and friable; gall cyst well filled.
_Rabbit 389._ _Black male._
Given 1 cc of 1 per cent caffein for each 100 grams, through stomach
tube.
--------+--------+----------
Date. | Weight.|Treatment.
--------+--------+----------
|_Grams._| _cc._
Aug. 17| 1,070 | 10.0
Aug. 18| 1,025 | 10.0
--------+--------+----------
August 19: Found dead 9 a. m. _Autopsy_: Lungs severely congested and
partially hepatized; liver was engorged; other organs appeared normal.
_Rabbit 382._ _Belgian female._
On August 17 weighed 1,035 grams; received 1 cc of 1 per cent caffein
for each 100 grams; 10 cc of 1 per cent caffein given in all.
August 18: Found dead 9 a. m. _Autopsy_: Lungs congested and hepatized;
liver engorged; stomach showed numerous petechial hemorrhages on
mucosa; kidneys slightly congested; intestines appeared normal.
_Rabbit 385._ _Belgian female._
Given 1 cc of 1 per cent caffein for each 100 grams, through stomach
tube.
--------+--------+----------
Date. | Weight.|Treatment.
--------+--------+----------
|_Grams._| _cc._
Aug. 17| 780 | 8.0
Aug. 18| 760 | 7.5
Aug. 19| 755 | 7.5
Aug. 20| 715 | 7.0
Aug. 21| 700 | 7.0
--------+--------+----------
August 22: Found dead 9 a. m. _Autopsy_: Lungs exhibited pneumonic
lesions, with inflammation of adjacent pleura; a fibro-plastic exudate
present around lung; liver showed a coccidial infestation; stomach
distended with ingesta; mucous membrane characterized by a catarrhal
inflammation; contents of small intestine liquid in nature and bile
stained; large intestine somewhat impacted; liver and kidneys seemingly
normal.
_Rabbit 404._ _White male._
Given 1 cc 1 per cent caffein for each 100 grams.
------------+---------+------------
Date. | Weight. | Treatment.
------------+---------+------------
|_Grams._ | _cc._
Aug. 20 | 1,465 | 14.5
Aug. 21 | 1,475 | 14.5
Aug. 22(1) | |
Aug. 23 | 1,475 | 14.5
Aug. 24 | 1,400 | 14.0
Aug. 25(2) | 1,405 | 14.0
Aug. 26 | 1,415 | 14.0
Aug. 27 | 1,400 | 14.0
Aug. 28(1) | |
Aug. 29 | 1,310 | 13.0
Aug. 30 | 1,320 | 13.0
Aug. 31 | 1,330 | 13.5
Sept. 1 | 1,335 | 13.5
Sept. 2 | 1,315 | 13.0
Sept. 3 | 1,350 | 13.5
Sept. 4 | 1,335 | 13.5
Sept. 5 | 1,350 | 13.5
Sept. 6 | 1,380 | 14.0
Sept. 7 | 1,375 | 14.0
Sept. 8 | 1,325 | 13.0
------------+---------+------------
(1) Not fed.
(2) Reflexes.
September 9: Found dead 9 a. m. _Autopsy_: Both lungs showed extensive
pneumonia, with adhesions to pleura; pleuritis and pericarditis very
marked; large amount of fibrous exudate in pleural cavity; pyloric end
of stomach slightly congested; liver congested; other organs normal.
_Rabbit 393._ _Belgian._
Given 1 cc of 1 per cent caffein to each 100 grams, through stomach
tube.
------------+---------+------------
Date. | Weight. | Treatment.
------------+---------+------------
| _Grams._| _cc._
Aug. 17 | 950 | 9.5
Aug. 18 | 910 | 9.0
Aug. 19 | 895 | 9.0
Aug. 20 | 910 | 9.0
Aug. 21 | 905 | 9.0
Aug. 22(1) | |
Aug. 23 | 825 | 8.0
Aug. 24 | 870 | 8.5
Aug. 25 | 835 | 8.5
Aug. 26 | 780 | 8.0
Aug. 27 | 765 | 7.5
Aug. 28(1) | |
Aug. 29 | 710 |
Aug. 30(2) | |
Aug. 31(1) | |
------------+---------+------------
(1) Not fed.
(2) Condition very poor; not fed.
September 1: Found dead. _Autopsy_: Lungs congested and adhering to the
pleura; extensive inflammation of pleura; liver slightly enlarged and
congested; mucosa of stomach and small intestines slightly congested;
other organs normal.
_Rabbit 390._ _Belgian, male._
Given 1 cc of 1 per cent caffein to each 100 grams through stomach tube.
------------+---------+------------
Date. | Weight. | Treatment.
------------+---------+------------
| _Grams._| _cc._
Aug. 17 | 1,490 | 15.0
Aug. 18 | 1,370 | 14.0
Aug. 19 | 1,365 | 13.5
Aug. 20 | 1,340 | 13.5
Aug. 21 | 1,265 | 12.5
Aug. 22(1) | |
Aug. 23 | 1,120 | 11.0
------------+---------+------------
(1) Not fed.
August 24: Found dead 9 a. m. _Autopsy_: Heart and lungs appeared
normal; abdominal viscera showed no apparent pathologic change other
than coccidial infection of the liver and fullness of the blood
vessels.
_Rabbit 392._ _Maltese, female._
Given 1 cc of 1 per cent caffein to each 100 grams through stomach tube.
------------+---------+-----------
Date. | Weight. | Treatment.
------------+---------+-----------
| _Grams._| _cc._
Aug. 17 | 1,265 | 12.5
Aug. 18 | 1,275 | 12.5
Aug. 19 | 1,240 | 12.5
Aug. 20 | 1,220 | 12.0
Aug. 21 | 1,245 | 12.5
Aug. 22(1) | |
Aug. 23 | 1,180 | 12.0
Aug. 24 | 1,190 | 12.0
Aug. 25 | 1,155 | 11.5
Aug. 26 | 1,140 | 11.5
Aug. 27 | 1,140 | 11.5
Aug. 28(1) | |
Aug. 29 | 1,115 | 11.0
Aug. 30 | 1,080 | 11.0
Aug. 31 | 1,020 | 10.0
Sept. 1 | 995 | 10.0
Sept. 2 | 930 | 9.0
------------+---------+-----------
(1) Not fed.
Died at 3 p. m. September 2. _Autopsy_: The stomach and small
intestines showed numerous small hemorrhagic spots; a thick coating of
mucus surrounded the contents of the stomach; the other organs were
apparently normal.
_Rabbit 403._ _Black._
Given 1 cc of 1 per cent caffein for each 100 grams.
------------+---------+-----------
Date. | Weight. | Treatment.
------------+---------+-----------
| _Grams._| _cc._
Aug. 20 | 1,640 | 16.5
Aug. 21 | 1,640 | 16.5
Aug. 22(1) | |
Aug. 23 | 1,490 | 15.0
Aug. 24 | 1,515 | 15.0
Aug. 25 | 1,475 | 15.0
Aug. 26 | 1,390 | 14.0
Aug. 27 | 1,330 | 13.5
Aug. 28(1) | |
Aug. 29 | 1,130 | 11.5
Aug. 30 | 1,055 | 10.5
------------+---------+-----------
(1) Not fed.
August 31: Found dead at 3 p. m. _Autopsy_: Extensive gastroenteritis;
liver enlarged and congested; spleen slightly congested; peritoneum
thickened and congested; other organs normal.
_Rabbit 884._ _Black, female._
Given 1 cc of 1 per cent caffein for each 100 grams through stomach
tube.
------------+---------+-----------
Date. | Weight. | Treatment.
------------+---------+-----------
| _Grams._| _cc._
Aug. 16 | 1,195 | 12.0
Aug. 17 | 1,205 | 12.0
Aug. 18 | 1,140 | 11.5
Aug. 19 | 1,180 | 12.0
Aug. 20 | 1,145 | 11.5
Aug. 21 | 1,145 | 11.5
Aug. 22(1) | |
Aug. 23 | 1,005 | 10.0
Aug. 24 | 1,035 | 10.5
Aug. 25 | 990 | 10.0
Aug. 26 | 960 | 9.5
Aug. 27 | 955 | 9.5
Aug. 28(1) | |
Aug. 29 | 870 | 9.0
Aug. 30(2) | 850 | 8.5
Aug. 31 | 810 | 8.0
Sept. 1 | 740 | 7.5
------------+---------+-----------
(1) Not fed.
(2) Poor condition, mucus from rectum.
September 2: Found dead at 9 a. m. _Autopsy_: The mucosa of stomach
showed numerous hemorrhagic spots; the first portion of the small
intestines was slightly congested; the other organs were apparently
normal in appearance.
_Rabbit 383._ _Belgian, female._
Given 1 cc of 1 per cent caffein for each 100 grams through stomach
tube.
-----------+---------+------------
Date. | Weight. | Treatment.
-----------+---------+------------
| _Grams._| _cc._
Aug. 16 | 995 | 10.0
Aug. 17 | 1,005 | 10.0
Aug. 18 | 990 | 10.0
Aug. 19 | 895 | 9.0
Aug. 20 | 945 | 9.5
Aug. 21 | 965 | 9.5
Aug. 22(1) | |
Aug. 23 | 875 | 9.0
Aug. 24 | 855 | 8.5
Aug. 25 | 850 | 8.5
Aug. 26 | 785 | 8.0
Aug. 27 | 710 | 7.0
-----------+---------+------------
(1) Not fed.
August 28: Found dead at 9 a. m. _Autopsy_: Lungs, heart, and spleen
apparently normal; liver infected with coccidia; stomach apparently
normal; walls of small intestines injected; colon marked congestion and
hemorrhagic; kidneys hemorrhagic.
_Rabbit 387._ _Belgian male._
Given 1 cc of 1 per cent caffein for each 100 grams through stomach
tube.
-----------+---------+------------
Date. | Weight. | Treatment.
-----------+---------+------------
| _Grams._| _cc._
Aug. 17 | 1,260 | 12.5
Aug. 18 | 1,340 | 13.0
Aug. 19 | 1,335 | 13.0
Aug. 20 | 1,300 | 13.0
Aug. 21 | 1,325 | 13.0
Aug. 22(1) | |
Aug. 23 | 1,205 | 12.0
Aug. 24 | 1,200 | 12.0
Aug. 25 | 1,285 | 12.5
Aug. 26 | 1,185 | 12.0
Aug. 27 | 1,255 | 12.5
Aug. 28(1) | |
Aug. 29 | 1,115 | 11.0
Aug. 30 | 1,135 | 11.5
Aug. 31 | 1,175 | 12.0
Sept. 1 | 1,050 | 10.5
Sept. 2 | 900 | 9.0
-----------+---------+------------
(1) Not fed.
September 3, found dead. _Autopsy_: Stomach and small intestines showed
numerous hemorrhagic spots; thick coating of mucus surrounded the
contents of the stomach; bladder was greatly distended with urine; the
other organs were apparently normal.
_Rabbit 388._ _Belgian male._
Given 1 cc of 1 per cent caffein for each 100 grams, through stomach
tube.
-----------+---------+------------
Date. | Weight. | Treatment.
-----------+---------+------------
| _Grams._| _cc._
Aug. 17 | 1,080 | 10.0
Aug. 18 | 1,115 | 11.0
Aug. 19 | 1,150 | 11.5
Aug. 20 | 1,130 | 11.5
Aug. 21 | 1,120 | 11.0
Aug. 22(1) | |
Aug. 23 | 1,020 | 10.0
Aug. 24 | 985 | 10.0
Aug. 25 | 960 | 9.5
Aug. 26 | 900 | 9.0
Aug. 27 | 875 | 9.0
Aug. 28(1) | |
-----------+---------+------------
(1) Not fed.
August 29, found dead 9 a. m. _Autopsy_: Heart and lungs normal; liver
and kidneys engorged; stomach normal; intestines showed a catarrhal
inflammation, though not severe; spleen normal; walls of colon somewhat
injected.
_Rabbit 391._ _Belgian._
Given 1 cc of 1 per cent caffein to each 100 grams through stomach tube.
-----------+--------+-----------
Date. | Weight.|Treatment.
-----------+--------+-----------
|_Grams._| _cc._
Aug. 17 | 940 | 9.5
Aug. 18 | 950 | 9.5
Aug. 19 | 955 | 9.5
Aug. 20 | 935 | 9.5
Aug. 21 | 945 | 9.5
Aug. 22(1)| |
Aug. 23 | 835 | 8.5
Aug. 24 | 805 | 8.0
Aug. 25 | 800 | 8.0
Aug. 26 | 765 | 7.5
Aug. 27(2)| 690 | 7.0
Aug. 28(1)| |
Aug. 29 | 565 | 5.5
-----------+--------+-----------
(1) Not fed.
(2) Poor condition.
August 30, found dead 9 a. m. _Autopsy_: Heart injected; lungs normal;
liver affected slightly with coccidiidea; stomach normal in appearance;
small intestines normal, but colon considerably inflamed; kidneys
slightly engorged; other organs normal.
_Rabbit 402._ _Black female._
Given 1 cc of 1 per cent caffein to each 100 grams.
-----------+--------+-----------
Date. | Weight.|Treatment.
-----------+--------+-----------
|_Grams._| _cc._
Aug. 20 | 2,030 | 20.0
Aug. 21 | 1,950 | 19.5
Aug. 22(1)| |
Aug. 23 | 1,955 | 19.5
Aug. 24 | 1,905 | 19.0
Aug. 25 | 1,890 | 19.0
Aug. 26 | 1,780 | 18.0
Aug. 27 | 1,765 | 17.5
Aug. 28(1)| |
Aug. 29 | 1,630 | 16.5
Aug. 30 | 1,540 | 15.5
Aug. 31 | 1,510 | 15.0
Sept. 1 | 1,425 | 14.0
-----------+--------+-----------
(1) Not fed.
September 2, found dead 9 a. m. _Autopsy_: The lungs were badly
congested, the posterior lobe of the right lung showing hepatization;
the liver was considerably enlarged and congested; the mucous membrane
of the stomach and small intestines was congested and showed numerous
hemorrhagic spots; the kidneys showed slight congestion; all other
organs normal.