CONTRIBUTIONS TO THE PHARMACOLOGY OF

POSTURE AND OF LABYRINTHINE

REFLEXES

THE NINETEENTH COMMUNICATION: PYRAMIDON,

VERAMON AND VERONAL, WITH SPECIAL REFER-
ENCE TO THE QUANTITATIVE EVALUATION OF
STIMULANT AND DEPRESSIVE ACTIONS UPON THE
CENTRAL NERVOUS SYSTEM OF MAMMALS

R. MAGNUS
Pharmacological Laboratory of the University of Utrecht (Holland)

It was the purpose of the present investigation, to see whether

the statements made by Starkenstein (1) concerning the action
of veramon2 in rabbits as compared with those of veronal on
one side and of pyramidon on the other are correct, how far
pyramidon is antagonized by veronal, whether veramon in
large doses is deprived of the stimulant actions of pyramidon,
and whether on the contrary the hypnotic action of veronal is
antagonized by pyramidon.
Therefore experiments on 36 rabbits have been performed,
arranged in 12 sets of 3 animals each, one of which was given a
certain dose of veramon, the second the amount of veronal
present in it, and the third the amount of pyramidon present in
it. All applications were made per os.
The doses used were the following:
Large dose (1.6 millimol) 4 sets
Medium dose (1.1 millimol) 2 sets
Small dose (0.91 millimol) 3 sets
Smallest dose (0.75 millimol) 3 sets

1 Communications 1 to S were published in Acta oto-laryngologica, vol.4 (1922),

communications 5 to 18 in Pflugers Archiv f.d. ges. Physiologie, vol. 196, 197, 198,
204, 205, 209 (1922-1926).
2 Veramon is said to be a combination of 1 mol acidum diaethylo-barbi-
turicum (veronal) and 2 mol dimethyl-amidoantipyrinum (pyramidon).
35

THE JOUR. OF PHARM. AND EXPER. TRERAP., VOL. XXIX, NO. 1

36 R. MA(NUS

The following can be said about the aim and methods of the
investigation.
In order to get an impression of the mode of action of hyp-
notics and central stimulants on animals, one was formerly con-
fined to observe a few characteristic conditions (such as convul-
sions, sleep, lateral position, complete paralysis) and reflexes
(cornea reflex, knee-jerk, etc.). As a result of investigations on
posture carried out in the pharmacological laboratory at Utrecht
we now are able to divide the development of stimulation or
depression of the central nervous system in a sequence of exactly
defined gradations and, in this way, to make possible a quanti-
tative measurement of the degree of stimulation or paralysis.
Therefore a relatively great number of reflexes and reactions
has been continuously followed in the animals after poisoning
by veramon, veronal and pyramidon. The physiological
basis and all details of the procedure are reviewed elsewhere (2)
as well as the methods for testing the different reflexes (3). De-
tailed tables of all experiments are given in the appendix. Here
only the main results may be summarized.
I. Pyramidon stimulates rabbits. The frequency of the
respiration is increased, after medium and large doses to very
high values. The animals show abnormal sitting posture,
erection of the ears, headjerks, strong muscle-tone in the limbs,
considerable increase of the reactions to progressive movements,
great restlessness, quick and active movements of defense dur-
ing handling. Convulsions appeared-in the Utrecht rabbits-
only once (experiment II). This state of excitement lasted after
doses above 0.9 millimol till the next day. After the smallest
doses no symptoms were present the next morning.
II. Veronal causes according to the dose a progressive para-
lysis of certain centers of the central nervous system. The
frequency of respiration is decreased already after the smallest
dose. After this, the possibility to correct abnormal + positions
of the limbs is diminished and abolished. Then disappears the
orientation of the body by the aid of stimuli, evoked by touching
the ground. This makes the sitting unsteady and impedes and
finally abolishes the function of running. The reactions to
 POSTURE AND LABYRINTHINE REFLEXES 37

progressive movements disappear, and after them the possibility

to orientate the-head in space by means of labyrinthine stimuli.
Then Only the head can be righted by stimuli arising in the body-
wall. This function also disappears finally; in the highest de-
grees of paralysis the reflexes governing the position of the body
according to the head are gone. Relatively resistant are the
reactions of the ammal to rotation, only the nystagmus-move-
ments disappear, those of the head earlier than those of the eyes.
The compensatory positions of the eyes are interfered with only
in the highest degrees of poisoning. The tone of the limb-
muscles decreases early. The sequence, in which after verona!-
poisoning these different reactions become diminished and para-
lyzed, is so constant, that it is possible to measure quantitatively
in every+ moment of the experiment the depth of the narcosis by
stating the presence or absence of certain reflexes.
III. By comparing the picture of symptoms after poisoning
by a certain dose of veramon+ with the stage of the control-
animals, which received the corresponding dose of veronal and
pyramidon, one finds without any exception that the condition
of the veramon-poisoned animal is lying between those of the
pyramidon and veronal-animals, i.e., that the stimulating action
of pyramidon and the paralyzing action of veronal are diminished
or neutralized. + +

The detailsare. as follows:

IV. Experiments with the smallest dose (0.75 millimol). The
pyrarnido#{241}-animn#{225}l shows general marked stimulation and in-
creased frequency of respiration, the verona1.animal--decreased
frequency of respiration, diminished righting reflexes evoked
from the body surface and acting on the body, diminished tone
of the limb-muscles, diminished correction of abnormal position
of the limbs, disturbances of sitting and running. + The vera-
mon-animal, on the contrary, remains quite normal during the
whole period of observation and shows only diminished rate of
respiration. With the exception of the last named symptom
therefore a complete neutralization of stimulating and depress-
ing effects takes place.
V. Experiments with the small dose (0.91 millimol). In
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46 R. MAGNUS

veramon the stimulant action of pyramidon is completely

neutralized, the depressant action of verona! greatly diminished.
As at the end of the experiment the animals completely recover,
it seems advisable to compare the maxima of paralysis reached
in each experiment. In experiment VIII in the veramon-ani-
mal besides slowing of the respiration only a very slight
unsteadiness in running and a slight diminution of muscle-tone
was to be seen. In experiment IX besides minimal disturbances
of sitting and running especially the correction of abnormal posi-
tions of the limbs was interfered with. In experiment VII
the disturbances of sitting and running were slightly more ac-
centuated and the righting reflexes arising in the body-wall and
acting on the trunk and limb-musculature showed a transitory
diminution. In all sets of experiments however the contrast
between the very slight action of veramon and the distinct
paralysis with verona! was apparent. Even after exchanging
the veramon- and veronal-animals of different sets of experi-
ments this difference remains.
VI. Experiments with the medium dose (1.1 millimol). Also
in these sets the veramon-animal always takes a position inter-
mediate to the veronal- and pyramidon-animal. The animals
become normal after sixteen to twenty hours. The compari-
son therefore can be made by watching the maximal depth of
narcosis. The stimulation by pyramidon is-in the veramon-
animals-in all cases completely neutralized, the narcotic action
of verona! is greatly diminished. In experiment VI, e.g. the
veramon-animal only showed slight disturbances of sitting and
running, of the correction of abnormal limb-positions, of the
righting-reflexes arising in the body-wall and acting on the trunk
and limb-muscles and of the vertical rotatory nystagmus of the
eyes, whereas the veronal-animal could neither sit nor run, had
lost all his righting reflexes arising in the body-wall and acting
on head, trunk and limbs, as well as the labyrinthine righting
reflexes, showed no reactions to progressive movements and had
diminished tone of the limb-muscles. The pyramidon-anima!
was, on the other hand, strongly excited.
VII. Experiments with the large dose (1.6 millimol). In these
 4

POSTURE AND LABYRINTHINE REFLEXES 47

sets of experiments veramon causes a progressive poisoning, so

that finally, but much delayed, the veronal-condition is reached.
In this case pyramidon causes a remarkable retardation of
the symptoms of veronal-poisoning. This can be shown by
investigating most of the reactions studied and especially the
respiration.
VIII. In all sets of experiments it comes out clearly, that in
veramon the stimulating action of pyramidon is completely
neutralized by veronal, and that on the other hand, the depress-
ing action of veronal is, according to the dose given, either
strongly delayed, greatly diminished or completely neutralized,
By these experiments therefore, in spite of a different and more
delicate method, the statements of Starkenstein have been in
the main confirmed,
IX. The following point may be of importance: It is known,
that in animals after extirpation of the fore-brain or narcosis by
chlora! or ether peculiar reactions to painful stimuli (pseudo-
effective reflexes of Sherrington) can be observed, especially
strong and long-lasting crying. As the action of the fore-brain
has been eliminated, these reflexes depend on the activity of
certain brainstem-centres.
This pseudo-affective pain-reaction was present in all experi-
ments with large and medium doses of veronal (in one case also
after a small dose of verona!). The pain-reaction on the con-
trary was absent (with one exception-experiment II at 2:15) in
all animals receiving veramon. In the experiments with
large doses the veramon-animals without pain-reaction were more
paralyzed than in experiment VIII (small dose) the veronal-
animal, which showed a strong pain-reaction. This observation
is worth being worked out more in detail, because it shows in an
objective manner the absence of pain-reactions after veramon,
which are present after veronal.
X. In several experiments with veramon slight symptoms of
stimulation appeared within the first thirty minutes, depending
on the pyramidon present in veramon and disappearing in the
further course of the experiment in consequence of the action of
veronal. In one experiment (I, large dose) the stimulation was
48 R. MAGNUS

increased to convulsive contractions, but the animal was not in

a lateral position ; the stimulation passed off after a short time.
XI. Everyone, who has tried to demonstrate e.g. in a lecture-
experiment the mutual compensation of stimulation and depres-
sion of the central nervous system by two drugs, as by para!-
dehyd and picrotoxin, knows how unreliable these antagonisms
are and how often the experiments fail or show the opposite;
on the contrary, the success of the pyramidon-veronal- and
veramon-experiments is of a surprising regularity, so that they
can be recommended for demonstration purposes. Out of all
36 animals there was not a single one which fell out of the ranks.
The conclusions therefore get a higher degree of certainty.

SUMMARY

It is possible by investigating a great number of postural and

labyrinthine reflexes to measure quantitatively the stimulant
and depressing action of drugs upon the central nervous system.
As an example are described experiments on rabbits on the
action of a combination of verona! and pyramidon (= veramon),
which show, that in veramon the stimulating action of pyram-
idon is completely neutralized by verona!, and that on the
other hand by pyramidon the depressing action of verona! is,
according to the dose given, either strongly delayed, or greatly
diminished or completely neutralized.
APPENDIX
Methods and Protocols
The rabbits were deprived of food twenty-four hours before the experiments.
The drugs were given by stomach tube in 45 to 70 cc. of water. The doses in grams
per kilogram of body weight were:

)ULLIMOI VERONAL PYRAMIDON YERAHON

grams grams grams

0.75 0.14 0.35 0.49

0.91 0.17 0.43 0.60
1.1 0.20 0.50 0.70
1.6 0.30 0.75 1.05

The animals were examined every fifteen to thirty minutes, later every hour,
and on the next morning. If necessary also on the next evening.
 POSTURE AND LABYRINTHINE REFLEXES 49

The following functions and reflexes were examined:

1. Rate of respiration:
2. Silting. In the tables means:
* head elevated, ears erected, head-jerks.
+ normal.
staggering, or hindpart in lateral position.
- lateral position; sits, if stimulated, partially up.
0 lateral position; no sitting up after stimulation.
3. Correction of abnormal positions (forelimbs, hindlimbs, lateral position
of hindpart).
+ spontaneously.
- only if stimulated.
0 no correction.
4. Running (spontaneously and after stimulation).
+ normal.
with staggering.
- almost no progression.
0 impossible.
5. Righting reflexes.
a. Righting reflexes artsing in the body-wall and acting on the trunk and
limb musculature (method of testing: Acta oto-laryngologica,
vol.4, p. 39).
+ normal.
- after shaking only.
0 absent.
b. Labyrinthine righting reflexes in lateral and supine positions(p. 38).
+ normal.
diminished.
-

0 absent.
c. Righting reflexes arising in the body-wall and acting on the head
(can only be tested after paralysis of the labyrinthine righting
reflexes) (p. 38).
normal. +
after - stimulation only.
0 absent.
d. Righting reflexes arising in the neck (influenced only after large
doses (p. 39).
+ present.
- present.
6. Reactions to progressive movements (p. 34).
* increased.
+ normal.
- diminished.
0 absent.
7. Reactions to rotation.
a. Reactions of the head (p. 31).
* with nystagmus.
50 R. MAGNUS

+ without nystagmus (the reaction of the head was never para-

lyzed)
b. Reactions of the eyes (p. 32).
+ horizontal and vertical nystagmus present.
vertical nystagmus absent, horizontal ng. present.
- vertical and horizontal nystagmus absent. (The horizontal
and verticalreactions were always present.)
8. Compensatory eye-positions (p. 36).
+ normal.
vertical diminished.
- verticalabsent, rotatory present.
9. Knee-jerks. Homoiateral flexion-reflex of the hindlimb (evoked by pinch-
ing).
* exaggerated.
+ normal.
10. Tone of hindlimbs (examined in supine position).
* exaggerated.
+ normal.
(-) slightly diminished.
- diminished.
11. General condition, 8timuiation or depres8ion.
+ stimulation.
#{149}
normal.
(-) slight depression.
- marked depression.
12. P#{233}eudo-affective crying. In narcotized animals after pinching of the tail:
strong and long-lasting crying.
* strong.
+ present.
- absent.

In the tables the result of examination of every single symptom is put side by
side for
P. =pyramidon
Vn. = veramon
Vi. =veronal
So the course of poisoning can be followed for every animal and for every
symptom in corresponding intervals of time.

Summary of table 1 (smallest dose, 0.76 millimol)

1. Respiration increased by P, equally decreased by Vi and Vn: VI neutral-

izes the stimulant action of P upon the respiratory centre.
2. In all 3 sets the Vn-animal remains (except slowing of respiration) practi-
cally nr,nal, in experiment X only at 5.30 minimal disturbance of correction.
Complete mutual compensation of Py-stimulation and Vi-depression.
P causes marked stimulation: head elevated, ears erected, head-jerks, re-
actions to progression and tone of hindlimbs exaggerated, general excitation.
 POSTURE AND LABYRINTHINE REFLEXES 51

Vi causes depression: staggering in sitting and running, no correction of

abnormal positions of limbs, righting reflexes arising in the body-wall and acting
on trunk and limbs only after shaking, tone of the hindlimbs diminished.
3. All symptoms have disappeared after twenty-four hours.

Summary of table (small dose, 0.91 millimol)

1. Respiration. In experiment VII the increase of frequency by P is not

distinct (only in the afternoon), in contrast to experiments VIII and IX, where
it is very marked. In all cases the reduction of frequency by Vi and Vn is very
distinct. Vi neutralizes the stimulating action of P upon the respiratory centre.
2. All animals are at the end of the experiment normal again.
P causes always marked 8timulation (sitting, reaction to progression, tone of
hindlimbs, general stimulation, respiration).
Vi causes marked depression,, which in the experiments VII and VIII goes as
far as paralysis of reactions to progressive movements, in experiment VII of
labyrinthine righting reflexes, in experiments VII to IX of correction of abnormal
positions. In all cases the animals are lying in lateral position.
In the Vn-animala there is much less depression. In experiment VIII besides
the influence on the respiration only very slight staggering in running and slight
decrease of tone in the hindlimbs was found. In experiment IX, besides a mini-
mal disturbance of sitting and running, especially the correction of abnormal
positions of the limbs was impaired (the righting reflexes arising in the body-wall
and acting on trunk and limbs were disturbed only at 3.30). In experiment VII
the disturbances are somewhat more marked. But even by comparing the Vn-
animal of experiment VII with the VI-animal of experiment IX, the smaller de-
pression after Vn becomes evident (see: sitting, righting reflexes acting on trunk
and limbs, reactions of eyes to rotation, general condition).
3. Important is the appearance of pseudo-affective crying in the Vi-animal
of experiment VIII during relatively light narcosis (at 10:30 reaction to progres-
sive movement is present), whereas after Vn even in deeper narcosis the reaction
to painful stimuli (with one single exception) never was seen.

Summary of table 5 (medium dose, 1.1 millimol).

1. The rate of respiration, greatly increased by P, is (in Vn) by Vi markedly

diminished.
2. In both sets of experiments the animals were normal again after sixteen to
twenty hours. The maximal depth of narcosis after Vi and Vii can therefore
be compared. The narcosis after Vi is always much deeper than after Vn. In
Vn, Vi removes the stimulant effects of P, whereas P makes the narcosis after
Vi less deep.
In experiment VI the Vn-animal shows only slight disturbances of sitting,
running, correction of abnormal positions, righting reflexes arising in the body-
wall and acting on trunk and limbs, eye-nystagmus after rotation, whereas the
Vi-animal is unable to sit and to run, has no righting reflexes arising in the body-
wall and acting on body and head, no labyrinthine righting reflexes, no reactions
to progressive movements and diminished tone of limb-muscles. The P-animal
on the contrary shows strong excitation.
52 R. MAGNUS

In experiment V the Vl-animal shows (in contrast to the Vn-auimal) no cor-

rection of abnormal position, impossibility of running, paralysis of labyrunthine
righting reflexes and of head-nystagmus after rotation.
In both sets of experiments pseudo-affective crying was present in the Vi-
animal, absent in the Vn-animal.

Summary of table 4 (large dose, 1.6 millimol)

1. Respiration. In these experiments with large doses it is evident, that P

accelerates, Vi slows the respiration, whereas the frequency after Vii remains
higher than after Vi alone (this difference disappears in the later hours (see
experiment I at 10:30 p.m.).
2. The stimulation after P was very marked in all experiments. The P-
animal of experiment III died after a few minutes with heavy convulsions.
The poisoning with this great dose of Vu takes a progressive course, but it is
evident that P delays the appearance of the Vl-symptoms. Therefore after syn-
chronous poisoning the Vl-animal is always ahead of the Vn-animal by several
hours, so that in a simultaneous examination the Vn-animal always shows less
severe symptoms.
Immediately after ingestion of Vn the animal may show symptoms of the
stimulating action of P (see e.g., experiment I), but after 4 hour this always is
gone and the P-excitation is completely antagonized by Vi. -
3. In all experiments with Vi the pseudo-affective crying-reflex was found.
After Vn this reflex appeared only once in one animal.

REFERENCES

(1) STARKENSTEIN: Therapeutische Halbmonatshefte, 1921, p. 629.

STARKENarxIN: Klinische Wochenschrift, 1925, i, 114.
(2) MAGNUS, R.: Korperstellung. Berlin, Springer, 1924.
(3) MAGNUS, R.: Acta oto-laryngologica, 1922, iv, 21.