AN EXPERIMENTAL STUDY OF CAMPHORIC ACID

GEORGE B. ROTH

From the Pharmacological Laboratory, University of Michigan

Received for publication February 27, 1911

The introduction of camphoric acid by Furbringer (1) as a

means of preventing phthisical sweating led many clinicians to
investigate its properties. Previous to this it was used by
Furbringer and others as an antiseptic against tubercie bacilli.
While engaged in a clinical study of its antiseptic value, Wittkow-
ski, working under the direction of Furbringer, discovered its
efficacy in stopping the night sweats of tuberculosis and further
study by Furbringer led him to believe that camphoric acid was
as efficient as atropine in controlling this symptom of the disease.
Other early workers who have investigated its properties are
Bohiand (2), Leu (3), Niesel (4), Dreesman (5) and Hartleib (6).
Stockman (7) used it in non-tubercular as well as tubercular
cases with equally good results and he concluded that it acted
as efficiently as atropine in phtbisical cases while in obstinate
cases it was inferior to picrotoxin. Wood (8) also found that
in many cases of tubercular sweating only a few doses were re-
quired to give immediate and in some cases lasting relief. More
recently Tyrode (9) reported the results of clinical observations
made by several of his colleagues who concluded that it has no
value in checking the night sweats of phthisis. In some cases
they found that the patients became worse under the camphoric
acid treatment.
From the pharmacological standpoint there is a wide differ-
ence of opinion as to its mode of action; also as to its value in
checking sweating produced experimentally. Stockman (7)
believed that it checks the sweating by paralyzing the nerve
405

Thj On

(!I!!JAIIOhIiIiiI
406 GEORGE B. ROTh

ends in the same way as atropine. Kobert (10) advanced the

theory that the sweating in pulmonary diseases is due to defi-
cient respiration. Hence any drug which stimulates the res-
piratory center would cause a disappearance of this symptom.
He ascribed a camphor-like action to camphoric acid, which
resembling picrotoxin would combat the sweats by stimulation
of the medulla. Schmiedeberg (11) gives it a place among the
nerve stimulants.
The recent work of Fugitani (12) and Tyrode (9) on the phar-
macology of camphoric acid being so widely divergent the neces-
sity of further investigation along experimental lines is made
evident. The first experimental work was done by Wagener (13)
who found in two experiments on cats that camphoric acid injec-
ted as the sodium salt has an action similar to camphor, namely
to produce periodic convulsions of an epileptiform nature and
a rise in blood pressure, while in frogs a curara-like action is
produced. Dreesman (5) tried to check the sweating in cats
produced by 0.010 gram of piocarpine with from 1 to 3 grams
of camphoric acid, but was unsuccessful. Hayashi (14) gave
camphoric acid neutralized with sodium carbonate torabbits
per stomach and obtained a slight fall in temperature. If given
in large doses as an acid the temperature would drop several
degrees in the course of a few hours. However, the death of
the animal followed later. Stockman (7) repeated the work of
Dreesman but obtained opposite results. He succeeded in
stopping the sweating produced in cats by one-eighth grain of
pilocarpine nitrate with 15 grains of sodium camphorate, and
from this he concluded that camphoric acid paralyzed the ter-
minations of the secretory nerves in the sweat glands. Using
2 to 4 grain doses on frogs, only slight depression was obtained
and occasionally an increase of reflexes, while 75 grain doses in
rabbits gave practically the same symptoms. Fugitani (12)
found that in the frog with sodium camphorate in doses lip to
0.1 gram nothing abnormal was obtained except local irritation.
In doses of from 0.15 gram to 0.2 gram there developed in the
course of an hour a gradual depression accompanied by a decrease
in respiration. He obtained neither convulsions nor increased re-
 ACTION OF CAMPHORIC ACID 407

flexes. Larger doses of 0.4 gram or more produced a prompt

central paralysis, the motor end plates not being affected. The
heart rate was diminished and the force lessened. He further
found that it increased the blood pressur em mammals and caused
a marked increase in the depth and frequency of the respiration.
No symptoms were produced in rabbits, cats or dogs even with
2 to 7 gram doses, except that in rabbits an increase in the res-
piration was noticed after an intravenous injection of 0.3 gram
or more and that with doses of 1.5 grams a period of dyspnea
occurred. The drug proved comparatively non-toxic in his hands.
As it failed to check the sweating produced in cats by stimulation
of the sciatics he concluded that it did not paralyze the peripheral
nerves to the sweat glands.
Tyrode (9) using the sodium salt of camphoric acid found that
it had no well marked pharmacologic action. In frogs 0.5 gram
was required to give symptoms. These consisted of lessened
movements followed by a gradual central paralysis, the heart
being stopped in diastole. In a series of experiments on frogs
with the heart exposed he obtained no specific effect even when
solutions as strong as 20 per cent were used. The general effects
were studied in rabbits and cats and no well defined symptoms
were ever noticed even after 5 grams of sodium camphorate.
Upon the respiration and blood pressure it was equally inactive.
He obtained an increase in urinary secretion but attributed it
to salt action. In determining its effects upon the nutrition in
rabbits no marked chauges were noted. The weight remained
constant when it was administered to grown rabbits and increased
normally in young animals.
In this investigation three specimens of camphoric acid were
used. One was obtaiaed from Schuchardt with a melting-point
of 182#{176}
C. A second preparation obtained from Merck and Com-
pany had a melting-point of 187#{176}
C: The other sample obtained
from local sources had a melting point of 182.5#{176}C. All of these
samples conformed to the requirements of the TJ.S.P. VIII. as
to color, odor, solubility, reaction of aqueous solution to litmus,
and absence of nitric acid.
408 GEORGE B. ROTH

Sodium camphorate (or the sodium salt of camphoric acid)

wks used entirely for the animal experiments, being made by
neutralizing the acid with sodium carbonate or sodium hydroxide.
As a further check upon the work sodium camphorate made by
Merck and Company was used to confirm the earlier results.
Every preparation of sodium camphorate was tested as to its
reaction toward litmus and its behavior to zinc and nickel salts,
and all specimens met the requirements as stated by Fehling.
Neues Handw#{246}rterbuch der Chemie 1875, II, 382.

ACTION UPON THE FROG

In the intact animal sodium camphorate injected into the

ventral lymph sac in doses up to 0.010 gram per gram of body
weight does not produce prominent symptoms other than a
noticeable increase in respiration. If doses of 0.010 gram and
up per gram of body weight were given, the animal immediately
showed violent movements, which were no doubt due to the
irritation produced by the solution. This was soon followed
by irregular respiration and general depression. In from 5 to
40 minutes muscular twitchings would begin appearing first
in the toes of the hind limbs and then becoming generalized. In
many of the animals the reflexes were distinctly increased and
convulsions which were usuallyof a tonic type occurred later,
followed by paralysis and death in from one to several hours.
In case smaller doses had been given the animal would live from
eight to ten days.
The following protocol may be taken as typical of the result
usually obtained.

11-9-O9. Frog, Weighi, t4 grams

1:40 Injected 1.8 cc. of a 20 per cent solution of Merck’s sodium

camphorate (0.015 gram per 1 gram body weight) into the
ventral lymph sac.
1:41 Jumps about violently.
1:45 Respiration somewhat irregular.
1:50 Head bent, animal rather quiet.
 SI
ACTION OF CAMPHORIC ACID 409

1:58 Raises hind legs over body. Toes twitch violently, also vio-
lent muscular twitchings in hind extremities.
2:00 Twitchings over entire body, but especially in the extremities.
2:01 Reflexes not increased, violent twitchings throughout.
2:02 Tries to move, breathing slow and irregular.
2:10 Still twitches. Slight increase in reflexes.
2:15 Moves about with difficulty. Head down. Gasps.
2:20 Reflexes diminished. Twitchings continue but are less fre-
quent and violent.
2:24 Breathing better. Sitting up in more natural position.
2:40 Still twitches. Breathing better. Moves about.
3:10 Twitchings less violent.
3:40 Respiration irregular. No increase in reflexes.
4:30 Sitting up. Respiration normal.
5:30 Same.

On the next day the frog was alive but drowsy, and on the third
day death occurred.
Whenever paralysis appeared it was always found to be of
central origin. The twitchings were not due to an action on

the muscles as they never appeared in curarized animals.

In one series of frogs the brain and cord were pithed before
the injection of the drug and in these animals no twitchings
appeared. On the other hand if the pithing was postponed
until after twitchings were present they immediately disappeared
when the central nervous system was destroyed. The twitchings
then were mainly of central origin but in a few animals in which
the sciatics had been cut, very slight movements were noticed
in the toes, indicating that there was in addition to the central
action, also a very feeble peripheral effect. The entire centr.al
nervous system seemed to be stimulated in the frog although in
many cases the twitchings would almost entirely disappear after
the higher parts of the nervous system were destroyed.
The action on the frog’s heart was studied in the intact animal
and upon the isolated heart.

Intact animal. The animal was pithed and the heart exposed. In
general any dose below 0.010 gram per 1 gram of body weight had little
or no effect but with doses as large as 0.024 gram per 1 gram body weight
a slowing of from ten to thirty beats was obtained in the course of
410 GEORGE B. ROTH

an hour. The slowing was not influenced by previous application of

atropine.
Isolated heart. The excised organ was perfused with modified Ringer’s
solution made after the following formula:
NaC1 0.6 per cent; CaC12 0.02 per cent; KCI 0.0125 per cent.
The arterial cannula was held in approximately a perpendicular posi-
tion so as to give the heart from 20-30 mm. of fluid to work against.
The pressure of the perfusion fluid was kept constant at the height of
about 70 mm.
One experiment will suffice to show the effect of both weak and strong
solutions of the drug. (See Table on opposite page.)

The experiment shows us clearly that the drug has little effect
upon the excised heart except when used in strong solutions and
then causes a rapid and marked decrease in rate and a prompt
decline in the efficiency of the organ. We may therefore reach
the conclusion that sodium camphorate in moderate doses has
little effect upon the heart of the frog.
Action upon Mammal& The effect of the drug upon higher
animals was studied upon cats and rabbits.

ACTION ON THE CAT

1-27---1O. Cat, Weight, 1.35 Kg.

1:55 Injected subcutaneously 8.7 cc. of a 20 per cent solution of

sodium camphorate (1.29 0. per Kg.)
1:58 Meows.
2:04 Quiet.
2:10 At ease. Respiration.35 per minute.
2:30 No change.
2:40 Respiration 34 per minutes
3:00 Sitting quietly as usual.
3:20 Respiration 38; more attentive to surroundings.
3:40 Respiration 38; slight movement of ears. Pupils widely dilated.
3:50 Respiration 35; not as attentive to surroundings as before.
4:30 Respiration 35. Pupils still dilated. No increase in reflexes.
5:00 No change.
5:20 Pupils dilated. Animal quiet.
1-29-10, 10 A.M. Animal apparently normal. Pupils of
normal size.
 ACTION OF CAMPHORIC ACID 411

Experiment XXXV. November 10, 1909. Perfusion of Frog’s heart. Heart

atropinized before starting experiment

FLUID PUMPED REMARESS

per mi perimin.
10.00 51 cc.
10.05 45 48 S

10:10 43 48
10:15 41 45
10:20 41 48

10:22 per cent sodium camphorate in

10:23 42 Ringer’s solution.
10:25 42 46
10:30 42 47
10:35 42 49

10:36 Ringer’s solution.

10:40 41 50
10:45 41 46
10:50 41 47

10:52 per cent sodium camphorate in

10:54 41 Ringer’s solution.
10:55 41 49
11:00 40 37
11:05 40 42
11:10 39 37

11:11 Ringer’s solution.

11:15 39 38
11:20 40 39
11:25 40 40

11:26 per cent sodium camphorate in

11:28 38 Ringer’s solution.
11:30 35 16
11:33 27
11:35 25 4
11:37 Ringer’s solution. S

11:40 18 2
11:45 19 2
11:50 21 4
11:55 30 10 Discontinued experiment.
412 GEORGE B. ROTH

ACTION UPON THE RABBIT

The above experiment was duplicated upon the rabbit giving

a large dose of sodium camphorate subcutaneously and the results
were in every way similar to those obtained in the cat. Subcu-
taneous injections of sodium camphorate in the cat and the rabbit
may then be said. to have very little effect except to produce a
slight increase in rate of respiration and dilation of the pupil.
It is possible that the absence of symptoms in these animals
might have been due to a very slow absorption so in order to
avoid this factor I isolated an ear vein in the rabbit and inserted
a cannula, thus injecting the drug directly into the circulation.

3-30-10. Rabbit, Weight .07 Kg.

2:13 Injected intravenously 25 cc. of a 20 per cent solution of sodium

camphorate (2.4 grams per Kg.)
2:17 Animal quiet. Respiration 46. Pupils equal, 9 mm. in di-
ameter.
2:27 Eating. Respiration 52.
2:30 Urinates. Moves about cage. Drinks water.
2:40 Quiet. Respiration 42, but deeper.
3:00 Respiration 42, condition not changed.
3:15 Respiration about same. Urinates.
3:30 Respiration 50; deep and full.
3:45 Respiration 52; drinks water.
3:50 Respiration 70, very deep. Quiet in corner of cage.
3:58 Clonic convulsions. Pupils 5 mm. in diameter.
3:59 Respiration 100, not so deep. Animal depressed. No increase
in reflexes. -

4:03 Respiration 92, labored.

4:30 Pupils not so much contracted. Respiration 74. Animal
not so depressed as before.
4:45 Respiration 80. Animal sitting up. Pupils still somewhat
contracted. On the three following days the animal was
apparently normal, but on the fourth day after the injec-
tion it was found dead in its cage.

To a second rabbit a slightly larger dose (2.7 grams per Kg.)

was given which gave similar results with the exception that
 --

ACTION OF CAMPHORIC ACID 413

death occurred during the convu!sion which came on two and a

half hours after the drug was injected.
The drug is thus shown to be relatively non-toxic when given
subcutaneously, and to possess well marked physiological prop-
erties when it is injected into the blood stream.
Perhaps the most’ striking feature of the poisoning is the late
appearance of the convulsions even when the drug is injected
directly into the circulation. This would seem to indicate clearly
that they are not produced by camphoric acid itself but by some
other substance which is slowly formed from it in the body.

ACTION ON THE SALIVARY GLANDS

Wagener (13) obtained a flow of saliva in cats and to ascertain

whether it had any effect upon the salivary secretion I carried
out one experiment upon the dog, anaesthetizing the animal with
morphine and chioretone. After dissecting out the submaxillary
duct a cannula was inserted into it and in this way the flow of
saliva could be observed. The drug was injected into the femoral
vein. To guard against a possible error in technic the chorda
tympani was also isolated and stimulated to show that the lumen
of the duct was patent. The results were entirely negative even
with large doses of sodium camphorate (total of 5 grams). Chorda
stimulation always Droduced a flow of saliva while injections of
the drug were entirely inactive.

DIURETIC ACTION

In the above experiments it was observed that all the animals

urinated frequently, and accordingly experiments were carried
out to study this action more carefully. An increased flow of
urine was to be expected, being due to the salt action. In order
to eliminate this factor I compared its effect with that of sodium
chloride making both solutions isotonic with the blood.
 S

414 GEORGE B. ROTH

2-7-10. Rabbit, Weight 2.1 Kg. Anaesthetic: paraldehyde (1.7 per Kg.) per stom-
ach. Bladder cannula inserted. Drug injected into external jugular vein

TINS AMOUNT OP UBINS REMARKS

2:10
:15 0.260 G.
:20 .420
:25 .420
:30 .370
110 cc. Sodium Camphorate
:35 .310 t0.58
IRequired some ether to allow of injection.
:44) .340
:45 .450
:50 .320
:55 .230
3:00 .350
.5 .290
:10 .290 10 cc. NaCl. = 0.58
Few whiffs of ether given as before.
:15 .300
:20 .510
:25 .260
:30 .470
:35 .490
:40 .600
:45 .320
:50 .410
:55 .430
400 .260
:05 .400
:10 .540
:15 .430
:20 .260
:25 .460
Discontinued

The above experiment showed that any diuretic effect which

the drug possessed was due directly to salt action.
 ACTION OF CAMPHORIC ACID 415

ACTION UPON THE CIRCULATION

The effect upon the circulation was studied in the cat, rabbit
and dog. The result in a general way was the same in all these
animals, namely to produce a small but constant rise in pressure
with either small or large doses. The extent of rise was greatly
influenced by the depth of anaesthesia. In some cases, especi-
ally with the rabbit, large doses would invariably give a pre-
liminary fall followed by the usual rise. A sustained fall would
also be caused by small or large doses given late in the course of

‘A a

4Jt/Vv-.S I

1u 5.’.

Fio. 1. Effect of sodium camphorate solution, isotonic with the blood, in a

cat of medium size. Upper tracing shows the carotid blood pressure and the lower
respiratory movements.

the experiment when the animal already had had large amounts
of the drug. Both the preliminary fall and the sustained fall
in pressure described above as well as the subsequent rise in
pressure are due to salt action as was shown by the fact that when
isotonic solutions of sodium camphorate and sodium chloride
were injected into the blood, similar circulatory changes were pro-
duced. The heart rate was decreased in every experiment but
one, the slowing being the same after atropine as before.
416 GEORGE B. ROTH

The following protocol shows the effect of small and large

doses of sodium camphorate in a lightly anaesthetized cat while
the curves of Fig. 1 taken from another animal represent the
effect of an isotonic solution of sodium camphorate upon the
blood pressure and respiration.

Blood Pressure. Cat. 1-7-10. Weight 2.6 Kg. Anaesthetic 0.2 G. chioretone per
Kg.andether. Vagi cut

BLOOD EXTENT OF
TIME HEART RATE RESPIRATION PRESSURE RESPIRATION REMARKS

per 10 sec per 10 sec. mm. mm.

3-8’-lO” 64 7 64 30 0.05G.sodium cam-
9’ 63 5 76 55 phorate per Kg.
10’ 65 6 70 40
13’ 65 7 74 27
21’ 61 7 70 34
0.2G. sodium cam-
21’-40” 60 7 70 32 phorate per Kg.
22’ 58 6.5 90 45
-20” 62 6 100 43
23’-20” 63 7 100 38
26’ 61 7 90 30
27’-20” 7 80 29
.4G. sodium cam-
30’-40”... 63 7 86 28 phorate per Kg.
31’ 7 98 40
32’ ? 7 120 60
34’ 7 110 28
37’ ? 7 100 30
Discontinued

ACTION ON SWEAT GLANDS

The sciatics of cats and dogs were exposed and sweating pro-
duced experimentally by stimulating the nerve trunk with the
electric current. Sodium camphorate was then injected but in
no case did it have any effect upon the secretion of sweat. Sweat-
ing was obtained in the dog after 16 grams of sodium camphorate
had been given and in the cat after 5.2 grams. The drug then
has no effect upon peripheral nerve endings.
 * -k

ACTION OF CAMPHORIC ACID 417

ACTION UPON RE3PIRATION

As a respiratory stimulant sodium camphorate has a distinct

effect the higher
upon animals as shown by an increase in the
depth of respirations, and in the volume of air expired. The
extent of respirations was found by using a tambour and piston
recorder, while the respiratory volume was measured by means of
an air-tight water tank according to the method described by
Impens.’ In brief this is simply a measurement of the volume
of expired air by water displacement from an air tight tank.
Volume readings were taken for a period of one minute.

Respiratory Volume. 4-6-10: Cat, Weight 2.35 Kg. Anae8thetic, chloretone 0.3
gram per Kg. (per stomach). Vagi cut

TIME AMOUNT RiO REMARKS

cc.
2:37- :38 450
0.05 gram sodium camphorate per Kg.
:40
:41- :42 500
:44- :45 460
:48 0.2 gram sodium camphorate per Kg.
:49- :50 460
:50- :51 480
:55- :56 450

:59 0.4 gram sodium camphorate per Kg.

3.00-3.01 430
02- .03 510
.06- 07 470
:14- :15 460
:17 5 cc. sodium camphorate. (Isotonic with blood.)
:19- :20 502
:21- :22 470

:24 5 cc. sodium chloride. (Isotonic with blood.)

:25- :26 430
:27- :28 465
:4.5- :46 430

‘Impens:-Arch. f. d. ges. Physiol. 1899, lxxviii, 537.

418 GEORGE B. ROTH

By both methods a distinct increase in respiration was shown.

The curve shown on p. 11 the protocol from the cat used 1-7-10,
and the abOve protocol will illustrate this plainly.

DISCUSSION

A study of the pharmacological action of camphoric acid

shows that most of its effects are due to salt action. The only
well marked physiological action it possesses is its stimulant
action on the central nervous system. The clonic convulsions
and the increase in respiration would seem to point to an action
on the medulla and adjacent areas, resembling in this respect its
parent substance camphor.
Clinically camphoric acid has been used extensively to allay
sweats incident to phthisis. Any value it may possess in this
direction can not be ascribed to a paralyzing action upon the
nerve in the sweat
ends glands such as is produced by atropine,
as camphoric acid is utterly devoid of any such property.
According to Kobert these sweats are asphyxia! in origin,
being due to a depression of the respiratory center. Therefore
the stimulant action of camphoric acid upon the respiratory
center would serve to explain the favorable results reported in
this disease. Similar good results have been reported from the
use of other medullary stimulants such as picrotoxin.

CONCLUSIONS

1. Both on frogs and higher animals, sodium camphorate

acts as a stimulant to the central nervous system, producing in
the frog at times a distinct increase in reflexes.
2. It is devoid of effect upon the secretory nerve endings of
the sweat glands and in addition has no influence on the salivary
secretions.
3. The drug given as the sodium salt is comparatively non-
toxic for frogs, cats or rabbits. It is more toxic when given
intravenously than subcutaneously.
4. Its diuretic effects are comparable to those of an indifferent
salt such as sodium chloride.
 #{149}T**

ACTION OF CAMPHORIC ACID 419

5. It raises the blood pressure in mammals and has some

depressing effect upon the heart muscle. These circulatory
changes like the effects upon the kidney are due to salt action.
6. Camphoric acid given to animals as sodium camphorate
is a true respiratory stimulant.

BIBLIOGRAPHY

(1) FtRBEINGER: Berl. klin. Wchnschr., 1888, XXV, 571.

(2) Boni&xn: Deutsches Arch. f. klin. Med., 1891, XLVII, 289.
(3) LEU: Charit&-Ann., 1889, XIV, 345.
(4) NIESEL: Deutsche med. Wchnschr., 1888, XIV, 818.
(5) DREISMAN: Inaug. Dissert. Bonn. 1889.
(6) HARTLEIB: Inaug. Dissert, Greifswald, 1889.
(7) STocxss: Edin. Med. J., 1897, XLIII, 45.
(8) WooD: Med. News. 1892, LX, 293.
(9) TYR0DE: Arch. internat. de Pharmacod., 1908, XVIII, 393.
(10) KOBERT: Pharmakotherapie, 1897, 304.
(11) SCaMIEDEBEEG: Pharmakologie, 1906, 260.
(12) Fuorw.z: Arch. internat. de Pharmacod., 1906, XVI, 273.
(13) WAGENER: Inaug. Dissert., Marburg, 1889.
(14) HATASHI: Arch. f. exper. Path. u. Pharmacol., 1903, L, 263.