The question whether caffein is cumulative in the rabbit, suggested in
the preceding experiments, was the subject of further investigation
in Series B. Caffein was given by mouth or subcutaneously. Carrots
formed the exclusive diet, a measured amount being given. The rabbits
were kept under observation for two weeks, except Nos. 370 and 373,
records of which were made only for four days before the administration
of caffein was begun. Caffein was given by mouth in experiments of
Groups I and III. Rabbits 292, 293, and 295 received daily 20 cc water
by mouth for four days previous to the administration of caffein,
while in the rabbits of Group II the caffein treatment was preceded
by the injection of 0.8 per cent salt solution subcutaneously. The
object in both cases was to ascertain whether or not the method of
the administration of caffein has any influence on the animal, but
observation made from day to day failed to show any effect of such
treatment. About 1 decigram of caffein per kilo was administered daily,
with occasional intermissions. Later in the course of the experiment
the doses were increased, 0.15 gram per kilo being the maximum dose
given. Rabbit 293 died after the third dose with symptoms of typical
caffein poisoning. The administration of the same dose of caffein was
continued 10 days longer in Nos. 292 and 295. It was omitted on the
seventh, fourteenth, and fifteenth days of the experiment. On the
eighteenth day of the experiment the dose was increased to 150 mg per
kilo and was repeated 2 days later. No. 295 was found dead the next
day. No. 292 survived. Rabbits 313 and 315 may be considered together,
as they were treated alike in every respect. The initial dose of 100
mg caffein per kilo was finally increased to 122 mg. After the twelfth
dose the emaciation was well marked and the rabbits were very weak.
No. 313 was found dead 2 days, and No. 315 3 days, after the last dose
of caffein was given. It should be remarked in this connection that
symptoms of caffein poisoning were never observed in these rabbits.
Death was not due, therefore, primarily to caffein, but the rapid loss
of flesh and strength observed during the last few days suggests that
it was due to malnutrition apparently brought about by caffein.
The results obtained by subcutaneous injection of caffein are given in
the table as Group II. The initial dose of 100 mg per kilo was injected
daily. No. 298 died after the second dose. Nos. 223 and 296 received
this amount daily for 6 days. An intermission of 2 days followed, at
the end of which the same dose was given again. The next day it was
increased to 150 mg per kilo, but no effect was observed; 48 hours
later this dose was repeated. No. 223 was found dead, but its mate
survived. Symptoms of acute caffein intoxication were not observed in
any of these rabbits. It would seem, therefore, that caffein is not
cumulative. This supposition, however, appears somewhat contradictory
in view of the fact that out of the eight rabbits of this series six
died, nor could any cause of death be ascribed other than caffein.
Also the first results of Experiments 293, 370, and 373 might be
considered as indicating that cumulation, though to a moderate extent,
does take place, since in these cases reflexes developed after the
drug was given for some time. But this view is contradicted by the
results of Experiment 371, in which 150 mg per kilo given 5 days after
the daily dosage of caffein was suspended likewise caused increased
reflexes. Cumulation, therefore, does not account for the effects
noted in the other rabbit. It will be observed that rabbit No. 370,
as well as Nos. 371 and 373, had diarrhea for several days. It is
quite possible that the weakened condition rendered the rabbits more
sensitive to the action of the drug. This is made highly probable by
the observations recorded in the experiments on acute intoxication
with caffein in which death occurred after small doses. In such cases
some pathological condition was often disclosed by the autopsy. The
results of this series corroborate, therefore, those of Series A, and
indicate again the absence of cumulative action. The results obtained
are in all probability due to malnutrition and other conditions brought
about by congestion of the viscera and consequent injury to the
gastro-intestinal canal.
TABLE 16.--_Chronic caffein intoxication of rabbits; Series B
on cumulation._
--------------+--------------------+--------------------+-------------
| Group I. | Group II. | Group III.
Data. +------+------+------+------+------+------+------+------
| No. | No. | No. | No. | No. | No. | No. | No.
| 292. | 293. | 295. | 296. | 223. | 298. | 315. | 313.
--------------+------+------+------+------+------+------+------+------
Diet (grams | | | | | | |
carrots in | | | | | | |
2 days) 1,000| 1,000| 975| 930| 905| 880| 355| 300
Caffein | | | | | | |
administered | | | | | | |
(cc) and weight | | | | | | |
(grams): | | | | | | |
| | | | | | |
Mar. 5 { | | | | | | |
{1,410| 1,470| 1,045| 1,040| 1,070| 955| 770| 770
| | | | | | |
Mar. 7 { | | | | | | |
{1,415| 1,360| 1,140| 1,090| 1,095| 1,000| 715| 690
| | | | | | |
Mar. 9 { | | | | | | |
{1,350| 1,270| 1,070| 1,000| 1,055| 1,005| 655| 665
| | | | | | |
Mar. 11 { | | | | | | |
{1,505| 1,465| 1,190| 1,230| 1,285| 1,250| 755| 760
| | | | | | |
Mar. 16 { | | | | | | |
{1,580| 1,460| 1,230| 1,165| 1,170| 1,145| 730| 745
| | | | | | |
Mar. 17 { | | | | | | |
{1,515| 1,415| 1,080| 1,040| 1,115| 1,105| 720| 685
| | | | | | |
Mar. 19 { | | | | | | |
{1,565| 1,570| 1,280| 1,195| 1,235| 1,220| 710| 735
| | | | | | |
Mar. 21 { 7| 7| 6| | | | 4| 4
{1,585| 1,530| 1,265| 1,150| 1,215| 1,260| 755| 700
| | | | | | |
Mar. 22 { 7| 7| 6| (1) | (1) | (1) | 4| 4
{1,440| 1,315| 1,175| 1,100| 1,045| 1,150| 675| 635
| | | | | | |
Mar. 23 { 7| 7| 6| (1) | (1) | (1) | 4| 4
{1,335| 1,140| 1,110| 1,145| 1,190| 1,230| 715| 700
| | | | | | |
Mar. 24 { 7| | 6| (1) | (1) | (1) | 4| 4
{1,310| (2) | 1,090| 1,115| 1,170| 1,250| 680| 650
| | | | | | |
Mar. 25 { 7| | 6| (1) | (1) | (1) | 4| 4
{1,375| | 1,035| 1,125| 1,215| 1,215| 695| 685
| | | | | | |
Mar. 26 { 7| | 6| | | | 4|
{1,255| | 1,095| 1,105| 1,155| 1,150| 675| 695
| | | | | | |
Mar. 27 { | | | | | | |
{ | | | | | | |
| | | | | | |
Mar. 28 { 7| | 6| 5.5| 6| 6| 4| 4
{1,355| | 1,115| 1,120| 1,160| 1,155| 595| 685
| | | | | | |
Mar. 29 { 7| | 6| 6| 6| 5| 4| 4
{1,385| | 1,150| 1,155| 1,165| 955| 695| 675
| | | | | | |
Mar. 30 { 7| | 6| 6| 6| | 4| 4
{1,330| | 1,075| 1,035| 1,095| Dead.| 630| 610
| | | | | | |
Mar. 31 { 7| | 6| 6| 6| | 4| 4
{1,325| | 1,170| 1,110| 1,140| | 690| 605
| | | | | | |
Apr. 1 { 7| | 6| 6| 6| | 4| 4
{1,335| | 1,050| 1,050| 1,120| | 625| 620
| | | | | | |
Apr. 2 { 7| | 6| 6| 6| | 4| 4
{1,390| | 1,125| 1,090| 1,155| | 695| 625
| | | | | | |
Apr. 3 { | | | | | | |
{ | | | | | | 200|
| | | | | | |
Apr. 4 { | | | | | | |
{1,300| | 1,005| 1,105| 1,080| | 585| 580
| | | | | | |
Apr. 5 { 7| | 6| 6| 6| | 4| 4
{1,385| | 1,090| 1,130| 1,090| | 655| 630
| | | | | | |
Apr. 6 { 9| | 7.5| 7.5| 8| | |
{1,260| | 1,010| 1,050| 1,110| | 560| 530
| | | | | | |
Apr. 7 { | | | | | | |
{ | | | | | | | (3)
| | | | | | |
Apr. 8 { 9| | 7.5| 7.5| 8| | |
{1,260| | 1,000| 1.090| 1.965| | Dead.|
| | | | | | |
Apr. 9 Survived.| | Dead.|Surv. | Dead.| | | Dead.
---------------------+------+------+------+------+------+------+------
(1) On these days 5 _cc_ of salt solution was administered
subcutaneously.
(2) Dead Mar. 23.
(3) Found dead 9 a. m.
TABLE 17.--_Chronic intoxication of rabbits, series B, Group
IV, on cumulation._