The experiments of this series formed a preliminary study for the
purpose of testing the effect of moderate doses. One decigram of
caffein per kilo was given daily for several days; when administered
at longer intervals the dose was increased to 150 to 200 mg per kilo.
It was found that the smaller doses did not produce any symptoms; even
the weights of the animals were not influenced. Doses of medium size
given on two successive days were likewise without any noticeable
effect (Nos. 182, 183, 123, 101). When a third dose of this size was
given within 48 or 24 hours it proved fatal (Nos. 123, 182, and 183).
Exceptionally, however, moderately large doses (for rabbits) may be
given for three consecutive days without fatal issue, as in rabbit No.
101. When given at intervals of two to three days, larger doses, as may
be seen from the protocols, can be administered without causing acute
death (Nos. 173, 181, 201).
The results of the tests of this series point to the absence of
any accumulation and to the possible elimination of moderate doses
of caffein and its products of decomposition within 24 hours or
thereabouts. When the doses are larger the time of its elimination is
apparently longer, as shown by the fact that repetitions of the dose
the next day may be fatal, but when a longer interval is allowed it
may be given without causing death. It will be observed that only one
rabbit of this series survived, but it was extremely emaciated. This
condition has been observed in a number of cases after caffein had been
given for several days. Even when the drug was withdrawn the animals
continued to lose weight. This may be explained by the condition of
the gastro-intestinal canal as found at autopsy. The presence of
inflammation of the mucous membrane of the stomach and intestines, with
ulceration of the mucous membrane of the pylorus in one of the rabbits
(No. 173) of the series, in all probability caused diminution or loss
of appetite, which of itself would tend to cause loss of flesh and
strength and finally death. Protocols of the experiments follow.
_Rabbit 173._ _Carrots were fed from October 1 to 18 and oats for the
remainder of the experiment._
---------+---------+---------
Date. | Weight. | Caffein
| |per kilo.
---------+---------+---------
| _Grams._| _Gram._
Oct. 9 | 1,980 | 0.141
Oct. 11 | 1,905 | .190
Oct. 13 | 1,930 | .207
Oct. 16 | 2,005 | 0.220
Oct. 18 | 1,845 |
Oct. 20 | 1,740 | .230
---------+---------+--------
October 21: Paralysis of posterior extremities.
October 22: 9 a. m., found dead.
The urine was examined before and after the administration of caffein.
No symptoms were observed after the administration of caffein (5 doses
in 11 days), nor was albumen or sugar found in the urine after any of
the experiments on this rabbit. _Autopsy_: Pyloric mucosa exhibited
several ulcers; small intestines showed slight inflammation; liver
deeply congested; kidneys showed marked inflammation of cortex; other
organs practically normal.
_Rabbit 181._ _Diet, carrots September 29-October 17, then oats._
---------+---------+----------
Date. | Weight. | Caffein
| |per kilo.
---------+---------+----------
| _Grams._| _Gram._
Oct. 4 | 1,425 | 0.105
Oct. 5 | 1,450 | .100
Oct. 6 | 1,270 | .100
Oct. 7 | 1,210 | .100
Oct. 8 | 1,375 | .130
Oct. 9 | 1,305 | .153
Oct. 11 | 1,370 | 0.175
Oct. 13 | 1,385 | .180
Oct. 16 | 1,345 | .200
Oct. 17 | 1,030 |
Oct. 18 | 1,230 |
Oct. 20 | 1,215 |
---------+---------+----------
Rabbit was markedly emaciated and weak. No albumen or sugar found in
the urine as a result of caffein feeding.
_Rabbit 182._ _Diet of carrots from September 29._
Received caffein subcutaneously as follows:
---------+---------+-----------
Date. | Weight. | Caffein
| |per kilo.
---------+---------+-----------
| _Grams._| _Gram._
Oct. 4 | 1,765 | 0.100
Oct. 5 | 1,880 | .100
Oct. 6 | 1,750 | .100
Oct. 7 | 1,710 | .100
Oct. 8 | 1,685 | .135
Oct. 9 | | .150
Oct. 11 | 1,605 | .174
---------+---------+----------
October 12: 11 a. m., 23 hours after caffein was given, convulsions
with recovery; rabbit died at 1.30 p. m. No sugar was found in the
urine at any time after the administration of caffein. Albumen was
present only in one specimen.
_Rabbit 183._ _Diet of carrots from September 29._
Received caffein subcutaneously as follows:
---------+---------+----------
Date. | Weight. | Caffein
| |per kilo.
---------+---------+----------
|_Grams._ | _Gram._
Oct. 4 | 1,385 | 0.100
Oct. 5 | 1,460 | .100
Oct. 6 | 1,385 | .100
Oct. 7 | 1,240 | .122
Oct. 8 | 1,310 | 0.153
Oct. 9 | 1,390 | .142
Oct. 11 | 1,390 | .187
---------+---------+---------
October 12: 9 a. m., found dead. No albumen was found in the urine.
Only one sample contained sugar.
_Rabbit 123._ _White, female._ _Diet, oats._
Received caffein subcutaneously as follows:
---------+---------+---------
Date. | Weight. | Caffein
| | per
| | kilo.
---------+---------+---------
|_Grams._ |_Grams._
Apr. 14 | 2,350 | 42
Apr. 16 | 2,250 | 90
Apr. 17 | 2,325 | 86
Apr. 20 | 2,126 | 141
Apr. 21 | 1,965 | 152
Apr. 22 | 1,876 | 160
---------+---------+---------
Rabbit died 30 minutes after last injection of caffein. _Autopsy_:
Stomach exhibited marked inflammation of mucosa. Slight enteritis.
Liver and kidneys were deeply congested and dark colored.
_Rabbit No. 101, white male._ _Diet, oats._
Received caffein subcutaneously as follows:
---------+---------+---------
Date. | Weight. | Caffein
| | per
| | kilo.
---------+---------+---------
|_Grams._ |_Grams._
Mar. 18 | 2,025 | 0.100
Mar. 19 | 1,970 | .100
Mar. 20 | 2,009 | .100
Mar. 22 | 1,855 | .100
Mar. 23 | 1,738 | .114
Mar. 24 | 1,815 | .166
Mar. 25 | 1,830 | .185
Mar. 26 | 1,710 | .176
Mar. 29 | 1,734 | .219
Apr. 1 | 1,606 | .224
---------+---------+---------
April 5: Found dead. _Autopsy_: Marked inflammation of gastric mucosa.
Considerable enteritis affecting the whole extent of the intestines;
liver congested and friable; kidneys deeply congested in cortical and
medullary portions; spleen congested, but of normal size; lungs and
heart normal.
Four days, 0.1 per kilo; 10 doses in 14 days.
_Rabbit 201._ _Diet of carrots begun October 1; October 19, oats._
Subcutaneous injections as follows:
---------+---------+---------
Date. | Weight. | Caffein
| | per
| | kilo.
---------+---------+---------
|_Grams._ |_Grams._
Oct. 9 | 1,000 | 0.150
Oct. 11 | 1,015 | .180
Oct. 13 | 1,065 | .187
Oct. 16 | 1,065 | .225
Oct. 18 | 850 |
Oct. 20 | 890 | .111
---------+---------+---------
Under observation six hours October 20; no symptoms.
October 23: Died; was much emaciated but did not show any symptoms;
emaciation set in when caffein was withdrawn; urine never contained
sugar or albumen; symptoms observed after second dose only.