30m PHvs'xOLOGt-CAL RESPONSES .
OF DOGS TO ARECOLINE ‘

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SOLE PHYSIOLOGICAL RESPONSES 0F mGS V
TO ARECOLINE

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SOME PHYSIOLOGICAL RESPONSES OF DOGS TO ARECOLINE

by
HUMBERTO 33912 URBINA

A THESIS
Submitted to the Graduate School of Michigan
State College of Agriculture and Applied

Science in partial fulfilment of the
requirements for the degree of

MASTER OF SCIENCE

Department of Surgery and Medicine

191+6

THES‘s

7/zc/qg

ACKN'WLEDGMENT

The writer wishes to express his sincere appreciation
to Dr. Bernard V. Alfredson, Professor of Physiology and
Pharmacology, for the able guidance and helpful suggestions
offered during the course of this work.

The author also wishes to express his indebtedness to
Dr. Claude S. Bryan, Professor and Head of the Department
of Surgery and Medicine, for the extensive use of facili—
ties, to Dr. Benjamin B. Roseboom, Professor and Head of
the Department of Physiology and Pharmacology, for his help-
ful advice and to Dr. Edward K. Sales, Professor of Surgery
and Medicine, for his valuable assistance in surgery.

Thanks are due to the Institute of International Edu-
cation cf New York for making available one of the Latin—

American scholarships at Michigan State College.

FOREWORD

In the course of his investigations concerning the action
of a drug on the living organism, the initial efforts of the
pharmacologist is usually confined to qualitative observa-
tions. It is only when the drug shows promise of becoming a
pharmacodynamic tool of clinical or experimental value that
the emphasis is extended further to include the much more dif—
ficult studies on quantitative effects. Oftentimes, such data
become conclusive only when supplemented by results from data
accumulated through clinical usage over extended periods of
time.

Veterinary pharmacodynamic research has never been able
to compete with allied activities in the human field. As a
consequence it has become customary to borrow basic data when
applicable. Furthermore, the decentralized nature of applied
veterinary medicine makes it difficult to conduct adequate
and proper clinical trials with drugs both new and old. As a
consequence of these conditions, the status of drugs of purely
veterinary interest continues to remain obscure. The alka—
loid arecoline is a typical example of such an agent. A re—
view of the literature indicates a disproportionately meager
knowledge concerning the pharmacology of this drug particu—
larly as it applies to the use of the compound in veterinary
medicine. The drug is employed by veterinarians to accomplish
the single objective of rapidly emptying the lower digestive
tract, serving as a so~called rapid purgative principally in

horses and for the mechanical removal of tapeworms in small

animals. That it fails of its purpose in many instances is
common knowledge to every clinician that has ever used this
drug. It was, therefore, not surprising that the appearance
of arecoline in the form of nemural (Winthrop) was eagerly
greeted by many practitioners and subjected to clinical trial
with the variable results not unusual in this method of in-
vestigation. No results from organized investigation con-
cerning nemural hareever come to the attention of the veteri-
nary profession. The purpose of this effort is an attempt to
shed further light on the action of arecoline in dogs and to

compare this action with that of nemural.

TABLE OF CONTENTS

I REVIEW OF LITERATURE '

II EXPERIMENTAL PROCEDURE
A. Selection of Subjects
B. Selection of Dosage
C. General Plan of the Experiment
D. Procedure for Clinical Observation
E. Procedure for Studies on Gut Motility

1. Ordinary Fistulae
2. Thiry Fistulae
a. Thiry—Vella Fistulae
. Respiratory and Pulse Rates

III EXPERIMENTAL RESULTS
A. Clinical Observations

1. Arecoline Hydrobromide
a. Dosage Rate of 3.2 mgm.
per kgm. Body Weight
b. Dosage Rate of #.8 mgm.
per kgm. Body Weight
0. Comparison of Results with
Arecoline on the Same Animals
at the Two Levels of Dosage:
3.2 and “.8 mgm. per kgm.
Body Weight
2. Nemural ~
a. Dosage Equivalent to Arecoline
Hydrobromide at the Rate of
-3.2 mgm. per kgm. Body Weight
b. Dosage Equivalent to Arecoline
Hydrobromide at the Rate of
#.8 mgm. per kgm. Body Weight

B. Results of Kymographic Studies from In—
testinal Balloons in Degs under Arecoline
and Nemural at Two Levels of Dosage

1. Preliminary Trials in Anesthetized
Animals
2. Ordinary Fistulae of the Ileum
and Colon
E. Thiry Loop
. Thiry—Vella Loop

IV DISCUSSION
A. Effects with Arecoline
1. Pulse Rate
2. Purgative Action

33
3s

38

42

TABLE OF CONTENTS (cont'd.)

Page

3. Nauseant and Emetic Effects 115

. Urinary Effects 117

5. Effects on Gut Motility 117

B. Comparative Effects with Nemural 119

1. Pulse Rate 120

2. Purgative Action 120

&. Nauseant and Emetic Effects 12

. Effects on Gut Motility ' 12

V SUMMARY 127

REFERENCES ' 129

APPENDIX

Protocols of Clinical Experiments with
Arecoline Hydrobromide at a Dosage Rate

of 3.2 mgm. per kgm. 134
Protocols of Clinical Experiments with
Arecoline Hydrobromide at a Dosage Rate

of 4.8 mgm. per kgm. 192
Protocols of Clinical Experiments with
Nemural at a Dosage Rate EQuivalent to

Arecoline Hydrobromide 3.2 mgm. per kgm. 213

Protocols of Clinical Experiments with
Nemural at a Dosage Rate Equivalent to
Arecoline Hydrobromide 4.8 mgm. per kgm. 259

I REVIEW OF LITERATURE

Arecoline is a liquid alkaloid present in the fruit of
Areca catechu, a tree that belongs to the family of palm in-
digenous to the tropical countries of the far East. Betel I
nut, the fruit of the Areca plant, was known to the Chinese
for its properties as a tasnicide as early as the sixth cen-
tury (18). It has been also used by people of the Malaya
area for many ages; the natives used to chew the powdered
nut because it was thought to sweeten the breath and improve
digestion.

In 1888, Jahns (23) succeeded in isolating several a1-
kaloids from the fruit of the Areca palm. These alkaloids
are: arecoline, 0.07 to 0.1 percent, along with traces of
arecaidine, arecaine, choline and guvacine. Fluckinger (16)
found that Areca seeds also contain about 15 percent of a
vegetable tannin and about 14 percent fat.

Immediately after the isolation of arecoline, Marne
1690 (32) investigated the actions of the pure alkaloid. He
experimented with it in human subjects and in such animals
as dogs, cats, rabbits, chickens, pigeons, etc. He compared
the action of arecoline in these animals and also made a
comparison with the action of pelletierine, which has a simi-
lar chemical constitution, as well as with the action of nus-
carine and pilocarpine.

Marni'showed that solutions as weak as 0.04 percent

causes a burning sensation with hyperemia when applied to the

tongue, and if one drop of such a solution be placed in the
eye, it causes miosis reducing the pupil after a few min—
utes to 1/3 of the normal size. This miosis persists for
about one hour and disappears completely after one to one
and a half hours. With strong concentration (one percent)
in the eyes of rabbits, he found that after one to two min-
utes, there occurred ptyalism, temporary slowing of the
heart and emptying of the bowels.

Working with frogs and using arecoline by subcutaneous
injection, he observed changes in the heart beat and res—
piration. Doses of 3 to 5 mgm. injected subcutaneously in
male frogs caused a gradual decrease in heart rate until the
heart stepped in diastole. Respirations were irregular and
dyspnoeic.

Moderate doses given by stomach tube caused in dogs and
cats repeated emesis, then foamy stools followed by feces of
soft consistency and finally liquid. In small doses, the
results were continuous defecations only..

Working with arecoline intravenously on dogs, cats and
rabbits, he found that the effect on vague endings was simi—
lar to those of muscarine. With large doses in the same
species under artificial respiration and with the heart ex-
posed, he observed an initial transient steppage of both
ventricles. This was succeeded by weak contractions of the
right ventricle while the left one remained in systolic ar-
_rest. As a result of these observations, Marme/states that
the action of arecoline upon the musculature of the left

ventricle is similar to that described by Kobert (26) after

-3...

large doses of muscarine.

Marme’alsc noted that arecoline like pelletierine de-
velops paralytic effects upon the brain and causes, like
pelletierine and also pilocarpine, an increase in spinal re-
flexes up to the degree of develOping tetanus. He also
states that arecoline after absorption acts similarly to
muscarine and pilocarpine upon the glands. It increases the
secretion of the salivary glands and spastic contractions of
the gut, while it influences the sweat secretion much less
than does pilocarpine.

Leepin 1891 (28) conducted experiments in dogs and cats
and concludes that fairly large doses of arecoline when
given to these animals causes an increase in the relative
hemoglobin content of the blood due to the loss of water by
way of the salivary glands and the gut. He also describes
an increase in the movements of the gut after the oral ad-
ministration of arecoline.

rrohnsr 1894 (17) reported clinical results from the
use of arecoline on one cow and four horses. He concludes
that arecoline produces effects upon the muscular and glandu-
lar structures of the gut as well as vague and respiratory
effects similar to pilocarpine and eserine. The respiratory
effects were evident only with large doses. He compares the
action of this alkaloid with that of others and concludes
that arecoline hydrobromide is an excellent sialagogue much
better than pilocarpine. It causes salivation after 5 min-
utes following subcutaneous injection which reaches a maxi-

mum in 1/2 hour and lasts for one hour. is a laxative, he

_ 4 -

states it is superior to eserine and pilocarpine either
alone or in combination but causes great dehydration.

Graefe 1894 (19) gives some clinical reports on the
use of arecoline hydrobromide in intestinal disturbances of
large domestic animals. When given subcutaneously (0.08 gm.
in 10 cc. of distilled water) to horses, the symptoms were
increased salivary secretion and increased expulsion of in—
testinal contents. The animals became restless and showed
increased barborygmus and peristaltic movements of the gut;
sweating was profuse. The surface of the body became warm,
respiration increased, and pulse decreased. After one and
one half hours, most of the symptoms observed were abating.

Lavagna 1895'(27) investigated the miotic action of
arecoline hydrobromide by instillation into the normal hu-
man eye. One drOp of one percent solution placed into the
lower conjunctival sac causes a feeling of warmth locally
followed by lacrimation and spasm of the eye lids. The
local irritation lasts only one minute. It causes hyperemia
and after two minutes is followed by diminution of the pupil
size. He concluded that arecoline has a more marked effect
on the pupil than pilocarpine, but somewhat less than physo—
stigmine.

Plesch in 1895 (45) conducted experiments concerning
the action of arecoline on dogs, white mice, and pigeons, in
an attempt to show that this alkaloid beleags in the class
with B—piperidin. He gave special attention to the saliva

inciting action, the action on the respiratory nerves and

-5...

its narcotic and cramping actions.

Coenders 1904 (8) using arecoline hydrobromide in ex-
periments on mice showed that the alkaloid salt has a defi-
nite stimulant action upon intestinal peristalsis and does
not seem to have any cumulative effect. He also concludes
that arecoline results in a temporary stimulation of the
respiratory center with death usually being caused by paraly-
sis of the heart.

Milks 1906 (36) experimented on several dogs to ascer-
tain the effects of arecoline hydrobromide in different
doses. On a fox terrier of 18 pounds, 1/2 gr. of arecoline
hydrobromide injected subcutaneously resulted in the follow—
ing symptoms: in three minutes, the dog was dull and weak.
He was thrown into convulsions at each attempt to move. In
a short time, he was quiet, lying upon his side; his breath-
ing was irregular; the pupils were dilated; the bowels moved
in fifteen minutes and again in one and.a half hours.

Another dog weighing about 25 pounds received subcu-
taneously on four successive days doses of l/20, 1/5, l/10
and 1 grain. The dog was, apparently, as well as ever the
day following the injection of the 1 grain dose. Three days
later, 2 gr. were injected and were followed by toxic sympu
toms with blood appearing in the feces. After 6 days, the
dog, apparently, recovered. Two weeks from the beginning of
the experiments, 3 gr. were injected during the afternoon
and the dog died the following forenoon.

He also experimented on several kittens and found that

doses of 1/8 to 1/2 grain were toxic with the following

-5...

symptoms: passage of feces in about three minutes; signs of
illusions; running about the cage with tail bristled and
spitting at imaginary objects; pupils were dilated; lay upon
its side in eight to ten minutes. Soon the respiration
ceased but the heart did not stop until one or two minutes
later.

To further study the cardiac effects, he performed ex-
periments upon the horse and the frog. In the case of the
former, intravenous injections were used and a blood pres-
sure tracing made. In each case, a very rapid fall in blood
pressure occurred. In the case of the frog, a minim of the
solution was dropped upon the heart. It was found that a
1 percent solution would stop the heart within one heat and
more permanently than stimulation of the vague. Solutions
of 0.1 percent acted nearly as strongly as the 1 percent.

He concluded that arecoline is a rapid intestinal
evacuant, increasing both peristalsis and the secretion and
that its action is accompanied by colic symptoms and profuse
salivation. Also, its action upon the eye is twofold; lo-
oally being miotic and internally a mydriatic. The chief
dangersin its use are its action upon the heart and res-
piration.

Fish 1907 (15) conducted experiments on five horses
testing the action of arecoline hydrobromide upon the cir-
culatory system. He obtained blood pressure tracings from
horses under chloroform anesthesia following the intrap

venous and hypodermic injection of the drug. The doses used

"to 0.]. “8.. 0005 “go, 0019 figs, 001 I8. 811d. 0.]- mg.

a
0..

 

I

 
 

_7..

respectively per kgm. of body weight. He concluded that in
all five cases, there was a uniform lowering of blood pres-
sure and slowing of the heart rate. Other symptoms seen
were profuse salivation, increased sweating and in some
cases increased venosity of the blood. Atropine sulfate in
the same dose and administered in the same manner as areco-
line hydrobromide counteracted its actions upon the circu-
latory system as shown by the more rapid beat of the heart
and an increase in blood pressure.

Meier 1907 (33) working with frogs, turtles and rab-
bits reported the action of arecoline upon the heart, blood
pressure and respiration. He concludes that when given in
large doses this alkaloid causes paralysis preceded by con-
vulsions, decreased heart rate and a fall in blood pressure.
The drug may kill by stepping the heart but appears to be
without influence upon respiration. He adds that atropine,
to a certain degree, counteracts the action of arecoline,
and that nicotine, pilocarpine and arecoline have the same
type of action; nicotine acting more upon the central ner-
vous system; pilocarpine upon the peripheral, with areco-
line occupying a midway position.

Pats 1910 (43) using Magnus method (31) worked on iso-
1ated intestine of cats in order to study the action of
arecoline on the automatic movements of the gut. He found
that in the isolated gut, arecoline (l to 80,000,000) in-
creases rhythmic movements of the smooth muscle. This con—
centration caused little or no increase in tonus, but a di-

lution of l to 20,000,000 produces a maximum tonus increase.

_ g _

Jackson 1914 (22) studied the action of certain drugs
on the bronchioles and he states that if about one~eighth
of a milligram of arecoline hydrobromide is injected intra—
venously into a cat or medium sized dog, a most profound
bronchoconstriction is produced immediately. He also
states that the action is very much more marked than that
of pilocarpine and death might easily follow from the abso~
lute failure of air to enter the lungs. Injection of epi-
nephrine will promptly cause dilatation of the bronchioles
when constricted by arecoline. Also a minute dose of atro—
pine or hyoscine hydrobromide will cause relaxation and
will prevent a later injection of arecoline in any sized
dose from causing constriction. In comparing the action of
arecoline and pilocarpine on the bronchioles, he concludes
that with arecoline the constriction comes on quickly but
tends to disappear early while with pilocarpine, the con~
striction comes on more slowly but tends to persist for a
considerable time.

Hall and Shillinger 1923 (21) tested arecoline hydro-
bromide as an anthelmintic in dogs and birds. They gave
the drug in tablets per os and hypodermically. The authors
concluded that arecoline hydrobromide in therapeutic doses
is an efficient anthelmintic and purgative. It will some-
times remove all the tapeworms from dogs and will do this
in the majority of cases (4 out of 7 cases in experiments).
In therapeutic doses, it will sometimes fail to remove any

tapeworms from dogs, but this will happen, probably, in a

- 9 -

minority of cases (3 out of 7 cases in their experiments).
In excessive doses (1.5 to 2 gr.), it may remove all the
tapeworms present or as little as 37.5 percent; conceivably,
it might fail to remove any under certain conditions. They
also state that arecoline hydrobromide may sometimes fail

in practice as well as in experiments. It causes depression,
emesis and catharsis, but animals recover rather promptly
from its effects.

Ross 1924 (47) conducted clinical experiments on dogs
in an effort to demonstrate the possible value of arecoline
hydrobromide as an anthelmintic. He observed the effect of
arecoline given in watery solutions per as and states that
arecoline administered by mouth in aqueous solution is ef-
fective in bringing about purgation in from twenty minutes
to one hour, and does not appear to cause any untoward after
effects. A dosage rate ranging from a minimum of 1/16 gr.,
in the case of dogs from 5 to 10 pounds in weight, up to a
maximum of 1/2 gr. for dogs over 30 pounds appears to be
quite safe. It was also found that in some cases, dogs
showed a tendency to vomit soon after administration, but
this was not general. He also states that due to the ra—
pidity of the action of the drug and the cessation of this
action after the passage of the stool, it would appear that
little, if any, is absorbed, its action being due to direct
stimulation of the nerve endings in the gut wall. This be-
ing the case, it was probable that the dilution in which
arecoline is given might have a marked effect, apart from

any variation in the dose, in causing more or less marked

- 10 _

increase of peristalsis, and so increasing or lessening the
time taken to induce purgation. It is possible that beyond
a certain dilution, no manifest reaction might be observed.
Experiments on seven dogs showed the following results: di-
lution of l to 2000 does not appear to be effective in bring-
ing about purgation rapidly; dilution 1 to 1000 produced pur-
gation in from twenty to forty-five minutes. The production
of vomition is not very definitely shown to depend on the di-
lution at which the drug is given, though it probably has
some relation to it. One dog vomited in seven minutes when
given a dilution of l to 2000, another dog after five minutes
with a dilution of l to 1000; another dog vomited after nine
minutes with a dilution of l to 1000 and after three minutes
with dilution of l to 500 while another dog did not vomit
even when given a dilution of l to 120.

Dale 1930 (9) performed some experiments on the rabbit
heart before and after section of the A-v (atria-ventricular)
bundle. With the A-V bundle intact, injection of 0.001 mg.
of arecoline is followed by a slowing of heart rate, accom-
panied by a diminution in the amplitude of the auricular and
the ventricular contractions. After section of the A-V bun-
dle, a dose of 0.01 mg. will inhibit the auricular contrac-
tions almost completely, while the ventricular rate is
slightly diminished.

In experiments on cows, Amadon 1930 (3) observed that
half-grain doses of arecoline used in the initial experi-
ments caused complete depression of rumino-reticular move—

ments for intervals ranging from forty to fifty minutes, with

- 11 -

no apparent improvement in motility succeeding this action.
In further experiments with reduced doses of the drug, it
was discovered that no depression appeared with administrap
tion of less than l/h gr. and that very pronounced stimu—
lant action resulted from doses as small as 1/16 gr. and
1/8 gr. The improvement in the strength of the rumen and
reticular contractions appeared in five to twelve minutes
and persisted for one and one half hours. The reticulum
was more strongly affected than the rumen.

Schwarte and Dukes 1931 (#8) in a series of studies
on the effect of drugs on the cardiovascular system of the
pig showed that arecoline hydrobromide, in doses ranging
from 1 to 5 mg. in four different animals produced in each
instance a decided fall in blood pressure. This was ac-
companied by cardiac depression as shown by membrane mano-
meter rscords. The fall in blood pressure varied from ap-
proximately 20 to 50 percent of normal. There was, however,
only a slight correlation between the size of the dose and
the magnitude of the fall in blood pressure. The action of
arecoline on the pig is similar to its action on other ani-
mals. In doses of 4 to 5 mg. increased salivation and pro-
nounced muscular tremors were observed.

Epstein 1932 (12) conducted experiments on the responses
of the batrachian alimentary canal (XenOpus 1aevis, the
South African clawed toad) to autonomic drug and showed that
arecoline causes contraction of every portion of the alimen-
tary canal of x. 1aevis, and that atropine can antagonize

this effect. It was shown also that pilocarpine fails to

- 12 -

produce a definite measurable rise in tone of the ileum, but
arecoline on the other hand was usually able to cause con-
traction of this structure. Arecoline thus appears to have
a more powerful effect on motor parasympathetic nerve endp
ings.

In a dissertation of Tierarztliche Hochschule in Berlin
1933 (51) concerning the action of arecoline base and of the
hydrobromide on the isolated small intestine of dogs, chan-
gee in tone, pendulum motion, and volume are described. The
drug shows prompt effects including an increased tone,
greater amplitude of contractions and greater variations in
intestinal volume with rhythm remaining practically un—
changed. These effects were the results of pure local dif-
fusion of the drug from the intestinal lumen and could be
checked with atropine.

Kristinn Stefanson 1937 (50) studied the action of aren
coline on the intestine of guinea pigs and concluded that
arecoline increases peristalsis and tone of the small and
large intestines, and restores to normal the decreased ac—
tivity after morphine.

Kadonaga 1938 (2h) reported that arecoline hydrochloride
injected into the dorsal lymph sac of the frog caused paraly-
sis sometimes preceded by convulsive attacks; the H.L.D. was
0.005 gm. per 10 gm. body weight. The drug inhibited the
isolated frog's heart, decreased blood pressure in rabbits
chiefly by slowing the heart, while large doses accelerated

respiration.
Richter 1939 (#6) concludes from his work on isolated

- 13 _

intestine of the guinea pig, that arecoline lowers irri-
tability of the intestinal musculature resembling nicotine.
Atropine counteracts the muscular action of arecoline.

lentova 19u0 (3a) in a series of studies on the effects
of parasympathetic drugs upon the coronary vessels reports
that arecoline has a vaso-constrictor effect when given in
large doses although it acts as a vaso—dilator in small
doses. These experiments were performed on isolated rabbit
hearts. The author concludes that the dilator effect is
parasympathetic, as evidenced by its absence in the atro—
pinised heart.

Oppenheimer and Mann l9ul (#0) reported experiments .
studying the influence of cathartics on the activity of the
small intestine. By means of balloons in thiry-vella loops
they tested arecoline hydrobromide, administered by stomach
tube to eight dogs in doses of 1/10 to 1/2 gr. (0.006 to
0.032 gm.). In all cases, tonus curves were marked and am-
plitude of segmenting contractions was increased. Although}
the increase in amplitude was sometimes more than threefold,
the rate remained fixed (1:1 per minute) when compared with
the control period. They comment that none of the agents
studied changed the rate of contraction of the small intes-
tine and also give other references concluding that in the
intact small intestine, with nerve and blood supply intact,

this rate is not easily altered.

- 1h -

lemursl', marketed by the Winthrop Chemical Company in
tablet of 18 mg. appeared in 1939*' as a substitute for are—
coline as a vermicidal agent against tapeworm in small ani-
mals. According to the laboratory data on this new compound
obtained from the manufacturer, nemural tablets contain two
ingredients, 1. e., a double salt of spirocide (paroxyl) and
arecoline in molecular pr0portions. Thus, the tablet con-
tains 3.13 mg. of arsenic as spirocide and 6 mg. of areco-
line. Fanslau (1N) conducted clinical experiments on two
different groups of cats using arecoline and nemural. He
concluded that arecoline alone is a more drastic purgative
than nemural. The alkaloid in a dosage of 6 mg. produced
stools within 15 to 25 minutes after medication, but nemural
(one tablet containing 12 mg. of parcxyl and 6 mg. of are-
coline) produced purgative action somewhat later, 20 to 60
minutes, and was less severe than the reaction to arecoline
alone.

Davidson (10) reports the use of nemural for a period
of over one year in the treatment of tapeworms and as a pur~
gative in small animals (cats and dogs) and gives some com—
ments on indications for its use as well as some results of
his clinical observations. He observed that best results
are obtained when nemural is administered in a small gelap

tine capsule. Occasionally, vomiting occurs a short time

‘ Nemural is stated by Winthrop Chemical Company (New‘York)
to be: 4-oxy-3-acetyl-amino—phenyl-arsonic acid N—diethyl-
tetrahydro~piridine~B~carbonic acid methyl ester.

‘* There is evidence that this compound was marketed by a
German firm for some time prior to this date (#1) in certain

South American countries.

- 15 -

after the drug has been given. However, this symptom does
not appear to disturb the patient, nor does it interfere
with the action of the drug. The passage of mucus from the
intestinal tract appears to be a good guide for indicating
satisfactory action of the drug. He also observed that it
is necessary to vary the dosage of nemural for use as a
teniacide in dogs and cats (In his work he has used the
drug in tablet form, each tablet containing 18 mg.). He
adds that there is reason to believe that in some patients
one tablet (18 mg.) would have been as efficacious as two.
He has used a little as 1/8 tablet (2.25 mg.) and as much
as 12 tablets (216 mg.) in other cases with good results
and, apparently, no ill effects. He also noted that dogs
seem to be inclined to drink more water than usual after
nemural medication and recommends that it would be wise to
regulate this intake, in order to avoid emesis caused by
drinking too much water at one time. He finally concludes
that nemural is not infallible in the treatment of teniasis
or when used as a purgative in small animals; however, he

believes that the drug has definite merit in small animal

practice.

- 15 _

II EXPERIMENTAL PROCEDURE

A. Selection of Subjectg. All dogs used in the experi-

 

ments were purchased from a city dog pound. Every effort was
made to control the incidence of distemper commonly affecting
dogs from such a source. As soon as the animals arrived, the
temperature was checked and those showing rise of temperature
were given subcutaneously injection of anti—canine distemper
serum at the rate of 1 cc. per pound body weight and repeated
every eight days for at least three doses. In some instances,
especially after experimental surgery, anti-canine distemper
anti-bronchiosepticus—streptococcus-typhimurium serum (Homo-
logous) was used. These animals were kept in cages and fed
with commercial dog food.

B. Selection of Dosage. Table I gives the various
therapeutic dosages of arecoline hydrobromide and nemural*
as reported in the literature. It also includes the fatal
dose of arecoline hydrobromide by different authors and prac-
titioners. Partly on the basis of the dosages reported in
Table I and partly on the basis of the amount of arecoline
present in the recommended dose of nemural, it was decided to
use arecoline hydrobromide at the rate of 3.2 mg. and.u.8 mg.
per kgm. of body weight given as a solution by stomach tube.

In order to have a comparison of both drugs under the same

* Nemural in fine powder was obtained through the courtesy
of linthrop Chemical Company (New York). The same drug in
tablets was purchased from the same company. Arecoline hy-
drobromide in powder was supplied in part by courtesy of

Merck Company (Rahway, New Jersey).

- 17 -

dosage rate, the dose of nemural was calculated on the basis
of its arecoline content. According to the manufacturer,
each gram of nemural powder contains 0.360 gm. of arecoline
and 0.640 gm. of paroxyl. Each tablet of nemural containing
18 mg. of the above powder contains in each tablet arecoline
base 6.48 mg. and paroxyl 11.52 mg. To calculate the quan-
tity of arecoline as the hydrobromide represented in nemural,

the following procedure was used:

Holecular weight of arecoline‘ 155.11
Molecular weight of arecoline hydrobromiden 236.12

236.12 ‘+ 155.11 : 1.52 (Factor)
One gram of nemural powder contains 0.360 gm. of
arecoline base, therefore its equivalent to arecoline
hydrobromide wquld be:

0.360 4X 1.52 = 0.547 gm.
thus:
One gram of nemural powder is equivalent to 0.547 gm.
of arecoline hydrobromide.

0n the other hand, one tablet of nemural contains

6.48 mg. of arecoline base, therefore its equivalent to
hydrobromide would be:

6.48 X 1.52 z 9.85 mg.
thus:
One tablet of nemural is equivalent to 9.85 mg. of

‘TEQEFIESZ

" National Formulary VII.

- 18 -

TABLE I

The Dosage of Arecoline and Nemural in Dogs

as Reported by Various Investigators

Drug: Arecoline Hydrobromide

 

Therapeut ic Dosage

 

 

 

 

 

Author Metric Apothecaries' Administration
H.F. VII (38) 1.5 mgm./kgm. 1/80 gr./lb. per os
Parker (42) 6-12 mgm. 1/20-1/10 gr. per os
nilks (35) 1.5 mgm./kgm. 1/12—1 gr. per os
Hall (20) 1/8—1/4 gr. per os
Lents (29) _ 1/8~1/4 gr. per os
Author Fatal Dosage Admini strati on
Solis-Cohen (49) 8-10 mgm./kgm. subcut.
larme’ (32) 100~120 mgm. per os
Bocquillon-Limousin (5) 75 mgm. 1 1/6 gr. subcut.
Drug: Hemura

Therapeutic Dosage Equiv. to

Author (Oral)

Arecoline HBr

 

Hilks (38)- 1 tablet per 8 lbs. body weight 2.7 mgm./kgm.

Davidson (10) 1 tablet per 15 lbs. body weight 1.4 mgm./kgm.

 

- 19 -

arecoline hydrobromide. When nemural in tablets was
used, solutions were made containing 1 mg. per cc.
of arecoline hydrobromide equivalent.
C. General Plan of the Experiment. The experimental
work was divided into two main parts as follows:
1. Clinical Observations
a. Arecoline hydrobromide
(1) Rate of 3.2 mg. per kgm. body weight
(2) Rate of 4.8 mg. per kgm. body weight
b. Nemural
(1) Equivalent to arecoline hydrobromide
at the rate of 3.2 mg. per kgm. body
weight
(2) Equivalent to arecoline hydrobromide
at the rate of 4.8 mg. per kgm. body
weight
2. Experiments on Gut Activity
a. Ordinary fistulas
(1) Arecoline hydrobromide
(a) Rate of 3.2 mg. per kgm. body
weight
(b) Rate of 4.8 mg. per kgm. body
weight
(2) Nemural
(a) Equivalent to arecoline hydro-
bromide at the rate of 3.2 mg.
per kgm. body weight

- 20 -

(b) Equivalent to arecoline hydro-

bromide at the rate of 4.8 mg.
per kgm. body weight

b. Thiry 100p

(1) Arecoline hydrobromide

(a)

(b)

Rate of 3.2 mg. per kgm. body
weight
Rate of 4.8 mg. per kgm. body
weight

(2) Nemural

(a)

(‘0)

Equivalent to arecoline hydro-
bromide at the rate of 3.2 mg.
per kgm. body weight

Equivalent to arecoline hydro-
bromide at the rate of 4.8 mg.

per kgm. body weight

0. Thiry-Vella fistulas

(1) Arecoline hydrobromide

(a)

(‘0)

Rate of 3.2 mg. per kgm. body
weight
Rate of 4.8 mg. per kgm. body
weight

( 2) Nemural

(a)

(10)

Equivalent to arecoline hydro—
bromide at the rate of 3.2 mg.
per kgm. body weight
Equivalent to arecoline hydro-
bromide at the rate of 4.8 mg.
per kgs. body weight ‘

- 21 —

D. Procedure for Clinical Observations. Before the
drug was administered, each animal was weighed and the body
temperature checked. When the subject was quiet, the pulse
rate was taken by means of palpation of the femoral artery
or by counting the heart beats by placing the hand on the
left thorax in the region of the heart. The total dose was
accurately weighed in milligrams and dissolved in from 30
to 50 cc. of tap water. Administration in all cases was
made by passing the stomach tube and using a 50 00. glass
syringe to introduce the solution directly into the stomach.
After the administration of the drug, the animal was main-
tained under constant observation. The pulse rate was taken
at intervals of about ten minutes and special attention was
paid to such symptoms as nausea, emesis, defecation, mucus
from anus, micturition, etc. All observations were accurate-
1y timed as is shown in the data of the appendix. A total of
66 dogs were used in the experiments. In some dogs, one of
the two drugs was given at the lower level only; in others,
both drugs were given at the two levels and the alternation
was as follows: arecoline hydrobromide at the lower level;
nemural at the lower level; arecoline at the higher level and,
finally, nemural at the higher level. The time elapsing be-
tween clinical experiments on the same animal with one or both
drugs at different levels was from four to six days.

E. Procedure for Studies on Gut Motility. Selected fe-
male dogs were used for the observation on gut activity. These

dogs were previously subjected to the clinical studies with

‘-

a 22 -

both arecoline hydrobromide and nemural at the two dosage
levels previously described.

Experimental surgery was performed under general anes-
thesia using pentobarbital sodium at the rate of 30 to 40 mg.
per kgm. of body weight injected intravenously. Anti-canine
distemper anti-bronchiosepticusastreptococcus-typhimurium
serum (Homologous) was given to the animal at the rate of one
cubic centimeter per pound body weight after completion of
the surgery. Animals were given sulfathalidine at the rate
of 1 gr. per pound of body weight daily divided in two doses
for at least six days after surgery.

Three different types of technical procedures were used
in preparing the animals for experimental study:

An ordinary fistulas was made by bringing out a loop of
lower ileum through the median line of the abdominal wall.
After eight days, the loop of intestine was cut, using co-
caine in crystals applied to the loop as the local anesthetic.
These animals were ready for use one week after sectioning of
the loop.

Thiry fistulas were performed in two adult female dogs.
The lower ileum was chosen for this purpose and the length of
the 100ps in each instance was about 10 inches. These ani-
mals were not used until ten days after the operation.

Thiry-Vella fistulas of the lower ileum were also pre-
pared in three subjects. The ends of the 100ps were brought
out through the median line. The length of the 100ps was

about 12 inches. These animals were not used until two

a23-

weeks after the operation.

Records of the intestinal movements were obtained by
means of the apparatus diagramed in Figure I. The balloon
made of special thin rubber was passed into the isolated
100p of the intestine. Then it was distended with air under
a pressure of about 8 cm. of chloroform at the manometer ar-
ranged to record the rise and fall of the chloroform column
representing the movements of the intestine at the level of
the balloon. The advantages of the method used are: a di-
rect graphic record of muscular contractions and tone of the
viscus, the absence of anesthesia as a complicating factor
during the experiment. In the Thiry and Thiry-Vella fistu-
lae the effects of the drug on muscular activity are not
modified by the presence of food, products of digestion or
digestive juices, for although the 100p has its normal blood
and nerve supply, its lumen is not connected with the ali—
mentary canal. The method also makes possible repeated ob-
servations on the same animal over a long period of time
making possible comparative studies on the two drugs.

The records of intestinal movements, as reported by
Plant (44) and others, show that there is a gradual relax-
ation of the intestinal musculature for a period of 30 to
120 minutes or more after insertion of the balloon. For
this reason, 30 minutes were allowed to elapse following in-
sertion of the balloon before bringing the manometer pres~
sure to the 10 cm. level. A normal tracing of from 30 to

60 minutes was taken before administration of the drug. The

- an .

Recording
needle
__Le__ng_th_l_3__0.cm1

H ' """" ' - ;

: Part introduced ,
: into the loop
—-_20_CI_.______'

‘(

  

 

..Rubber

 
 
   

 

\
--l9.99- |

----

 

 

 

 

Qlass :
I

I
Rubber
C2E:::::::::::<::;E:::l<::>
Chloroform ' 1‘
Balloon made of
special thin rubber

Figure 1. Diagram of apparatus and hook-up used to
record intestinal movements in the seg-
ments of isolated intestine.

 

 

 

_ 25 -

effect of the drug was recorded continuously for periods
ranging from 60 to 90 minutes.

Respiratory rate was recorded by means of an elastic
stethograph placed on the thorax of the animal and arranged
to record by means of a rubber tambour. Pulse rats was de-
tected by slight pressure on the femoral artery about every
five minutes, and these values were written on the base line
of the record. An electric timer was used arranged to re-
cord at five seconds intervals. Any particular observations
as to defecation, emssis, administration of the drug, etc.,
were written upon the base line of the record.

In the interpretation of the kymographic records, there
will be considered the following kinds of intestinal move-
ments: rhythmic contractions, peristaltic waves and tonus.

Rhythmic contractions (Segmenting and pendular). These
are myogenic in nature (1) that is, they are dependent solely
upon the rhythmical property of the intestinal muscle itself.
This type of movement has been carefully studied by Cannon (7).
It has also been reported (25) that there is a definite gradi~
ent of rhythmicity in the intact intestine of the dog, "The
frequency of the rhythmic contraction varies inversely as the
distance from the pylorus" (l).

The peristaltic contractions. These are probably de~
pendent upon the intrinsic nerve plexuses (7). But though
carried out through local reflexes in the bowel well, they are
readily influenced through the extrinsic nervesu-the vague and
the sympathetic. The vague, whose terminals connect with

-25..

ganglion cells in Ausrbach's plexus, augments the movements.
The sympathetic is inhibitory (4).

22223. Dukes (11) describes two types of tonus, "Tonus
waves, which are slow changes in the length of the muscle
fibers of the intestinal wall. They may exist alone or may
show superimposed rhythmic contractions. Both muscular coats
of the bowel may be involved”. 'Tonue rings, these are
strong local contractions of the circular musculature of the
intestine". The tone may be influenced by the extrinsic
nerves, the vague increasing,ths sympathetic diminishing
this property. In the present work the tone level would be
the distance from the base line on the kymographic record
to the lowest point reached by the ileumwballoon tracing.

- 27 -

III EXPERIMENTAL RESULTS

A. Clinical Observations
l. Arecoline Hydrobromide
a. Dosage Rate of 3.2 mgm. per kgm. Body

Weight. Arecoline hydrobromide at the rate of 3.2 mgm. per
kgm. of body weight was administered to 47 dogs ranging from
5 to 24 kgm. body weight. Protocols of each experiment with
data and other observations are inserted in the appendix
(see appendix pages 134 to 191).

The results of the more significant observations on
45 dogs according to the time of occurrence are summarized
in Table II. Analysis of these data and of the correspond!
ing protocols in the appendix shows that, with the exception
of one dog, arecoline hydrobromide at the level of 3.2 mgm.
per kgm. body weight caused slowing of the pulse rate. In.
some cases the number of beats decreased gradually and re-
covery to normal occurred by the end of the period of obser-
vation (see appendix, degs No. ll-l3-l4el7-18-4l-57-59-61).
In some animals the slowing of the pulse was pronounced and
lasted longer than the period of observation (see appendix,
dogs Ho. 6-7-12-15-16-26-30-32-39-43-51-54). Other animals
showed a decrease in pulse rate followed by an increase
(see appendix, dogs Ho. 29-38—43~45-49-50—63). All of these
dogs had one late emesis which may hays some influence on
the pulse rate.

Defecaticn occurred once or twice in more than fifty

percent of the cases; a third defecation occurred in more

- 25 _

 

 

 

 

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. 3o -

than one-third of the cases and four defecations occurred in
a few cases (3 of 47 animals). As a rule, the first defeca-
tion appeared of soft consistency and those following were
scanty, semi-fluid or liquid and repeated at frequent inter»
vals. The first defecation occurred in from 3 to 20 minutes
in 73 percent of the animals. A breakdown of these data
shows that 29 percent defecated in from 3 to 10 minutes;

20 percent in from 11 to 15 minutes and 24 percent in from
16 to 20 minutes. The rest of the animals (27 percent) defe-
cated in from 21 to 127 minutes. In general, mucus was ex-
pelled after the second defecation and in some cases, this
was copious.

Emesis occurred in 64 percent of the dogs, but was re-
peated in only a few cases. In the majority of them (63 per—
cent), it occurred in from 5 to 20 minutes. In all the ani-
male in which emssis occurred later than 20 minutes, there
was observed a prolonged period of nausea, the animal was
somewhat depressed and the pulse rate was very irregular. Of
the cases in which early emesis occurred, some expelled rela-
tively large quantity of food material while only a few cases
expelled a liquid, often foamy, material. In all cases where
smesis occurred after 20 minutes the vomited material was
liquid and often foamy. Vomition was also quite prone to oc—
cur following the ingestion of water.

Micturition occurred in less than 50 percent of the shin

male and with a few exceptions, it was more prone to occur in

overweight dogs.

_ 31 -

Small dogs weighing from 5 to 7.5 Kiloe (see appendix
dogs No. 5—ll-l3~38~43~45-55~56-57—61-66) showed almost no
general depression; the decreased pulse rate was not marked
and recovery was rapid. Bowels moved soon after administra»
tion of the drug (with the exception of dogs No. 38-45-55)
and emesis occurred in less than 50 percent of them.

Dogs weighing from 8.5 to 9.5 Kilos (see appendix dogs
No. 6-7-9-10-12~16~30-36~58) showed a marked increase in all
symptoms of drug effect. Cardiac slowing was definite and
psrsistant. Defecaticn occurred twice and three times in
some of them. Emssis was present in the majority (early eme—
sis).

In heavy dogs (from 11 Kilos up) symptoms were even more
marked (see appendix dogs No. l4—l5-l7-l8~28-29-32-37—39-40~
41-46—47-63). Defecaticn occurred two and three times (dogs
No. 14-17—28-32-46). Emssis was present and in some animals
repeated twice (see dogs No. l4—29—32~40—63). Micturition
occurred in most of them.

1. Arecoline Hydrobromide (cont'd.)
b. Dosage Rate of 4.8 mgm. per kgm. Body
Weight. Arecoline hydrobromide at the rate of 4.8 mgm. per
kgm. body weight was administered to 21 dogs which had been
previously subjected to the dosage rats of 3.2 mgm. per kgm.
body weight.

The most significant symptoms are summarized in Table III.

Protocols of each experiment with data and other observations

are inserted in the appendix (see appendix pages 192 to 212).

- 32 -

 

 

 

 

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-33...

Analysis of the data in Table III and of the corresponding
protocoles in the appendix show that in most of the sub-
jects arecoline hydrobromide at the level of 4.8 mgm. per
kgm. body weight caused a marked and persisting slowing of
the pulse rate. In a few cases (see dogs No. 32-40—43-45)
the slowing of the pulse rate was of short duration and an
increased pulse rate occurred instead. These cases showed
a nauseant stage followed by emesis.

In all cases, defecation occurred once in from 5 to
39 minutes. Of these, 84 percent defecated in from 5 to
15 minutes and the rest of them (16 percent) in from 16 to
39 minutes. It was repeated twice in 80 percent and three
times in 39 percent of the cases. Only two cases had a
fourth defecation. Fecal material was of soft consistency
the first time and semi-liquid, scanty when more than one
occurred.r Mucus was expelled in most of the cases, being
copious and continuous.

Emssis occurred in 11 of the 21 dogs used and it was
repeated in four cases. In some cases (see dogs No. 30—32-
45-57-59-66) emesie was late, cecurring in from 31 to 59
minutes and when early emesis occurred (see dogs No. 40-
58-62) in from 2 to 29 minutes it was repeated twice.

Micturition occurred in less than 50 percent of the
experimental animals.

0. Comparison of Results with Arecoline on
the Same Animals at the Two Levels of Dosage: 3.2 and
4.8 mgm. per kgm. Body Weight. The data of Table IV 11—

lustrate the results of arecoline hydrobromide at the two

— 34 -

 

 

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m. n mm... .m m
II} t. mun S a“
m m m .m ..
mucosa emoupmoenon seem cease
«swabs moon .mwm nocI.awe New. ”scam

spoonncm Hm demand seem opp so
an as: moon . a non .mws w.: use m.n
«o nausea new no ecasouponoam omsaoooud nude
mwon ma epoouua ebupsnmmsoo on» no mmcmmcm

>H aqmda

-35...

 

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nausea mmoapmoomon seem spasm

 

assuage. Hm deeas< seem one so

on as: soon .

a sea Isms m.: can m.m
no nausea on» on oessosnosoam ossaoooua some

mwoo ma upoouuu epdpmnmaaoo on» no asesssm

A.e.oeoov >H amm<a

acwaow Noon .mwu Hom1.aws m.: we comm

_ 36 -

levels used expressed by percentage of occurrence of the vari-
ous drug effects in the experimental subjects.

Forty-eight percent of the animals showed a lower pulse
rate on the 3.2 mgm. level than on the 4.8 mgm. level of do-
sage.» In only 38 percent of the cases the reverse occurred.
The remainder (14 percent) showed no difference in heart rate
with the two different levels of the drug. It was also cb~
served that when the lower level of the drug was administered
the decrease in pulse rate persisted for a longer period than
when the higher dose was used. However, these data give no
comparison of value since the pulse rate is susceptible to
variation (rise and fall) due to other manifestations (defe-
cation, emesis, restlessness).

Attempts to defecats seem to be more numerous at the
higher level. It was also more prompt as is shown in Table V.
Repeated defecations were more frequent at the higher level
and caused restlessness and each attempt was followed by
scanty and continuous expulsion of feces of liquid consistency.
Mucus was more copious at the higher level.

The summary of the data shows that emesis was more common
at the lower level (76 percent) and it was also repeated twice
and three times in a.majority of the cases. When the lower
level of the drug was administered, the subjects were more in-
clined to early smesis (from 7 to 30 minutes after administra-
tion of the drug). It also shows that in most of the cases

when emesis occurred in less than 20 minutes it was repeated

twice soon afterwards.

-37..

 

 

 

. Hme II .mmIHH .mmIm .asImm .szmH .mmIm .mnIm .sms m.s
.moHIm .an .mmIm .mmIa .wm .omIom .maIm .mmIm .sms m.m
depends ma pommcncme coconncooo no case
em: as ems mum am mam mom mood awn .sms s.s
am as *3 sea. a: men a: mom as: .8... man
u x. w. n MI x. w u nmm w...“ m.
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w
nausea escaumoonon n.

Announces Hmv ewmpcoomom an commoncmu one flooded seem on» o» cowac
pmmaoh muom .mwu non .sms m.: use N.n no nausea on» we
seasoncoHUhm emdaooond no opossum on» no comamsnaoo

b wands

-33..

Micturition occurred in more cases at the lower (57 per—
cent) than at the higher level (49 percent). When micturi-
tion occurred at the lower level it was more common in over~
weight animals (more than 10 kgm. body weight) appearing in
7 of 12 cases. 0ne~ha1f of the 10 cases showing micturition
at the higher level of dosage were overweight animals.

2. Nemural
a. Dosage Equivalent to Arecoline Hydrobromide
at the Rate of 3.2 mgm. per kgm. Body Weight. Nemural was
given to 38 dogs' ranging from 5 to 17 kgm. body weight. The
dosage used was equivalent to arecoline hydrobromide at the
rate of 3.2 mgm. per kgm. of body weight and the total dose
was obtained according to the procedure already discussed.

Table VI summarizes the results of the more important
observations arranged in the chronolOgical order of their oo-
currence from the time of administration of the drug.

Nemural caused slowing of the pulse rate in 35 of the
38 experimental subjects. The slowing of the pulse rate was
very definite and it lasted longer than the period of obser-
vation. Most of the animals receiving this drug appeared
quite depressed. In a few subjects, this was the most evi—
dent symptom (see dogs No. 20-24—28-29-30-32—35-55-56-66).

Defecaticn occurred in 92 percent of the cases and the
majority of them (83 percent) defecated in from 3 to 25 min-
utes. A breakdown of these data shows that 36 percent

* Twenty-sight of these dogs were previously subjected to
arecoline hydrobromide at the rate of 3.2 mgm. per kgm. of
body weight.

 

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II “I.I

‘l‘l...

‘III II

IIII I II

- ho -

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mamoafl QGOHadomwon ovum onddm anon dance

emu cmaaooeud no unmask moon .mwu non .mws m.m o» pcoaopdsom ovum
owmmon c as amazes: no moapmupmdmam64 ammo on» wmawoaaoh
mwoo ca acoapmbsemco Hmoacaao cadence Ho humsscm

AIe.odoov H> names

- A1 _

defecated in from 3 to 10 minutes; 25 percent in from 11 to
15 minutes; 1“ percent in from 16 to 20 minutes; 8 percent

in from 21 to 25 minutes and the rest of the cases (17 per-
cent) in more than 25 minutes. Two-thirds of the cases defe-
cated twice; cne~half, three times and one-sixth a fourth
time. When defecation was repeated three and four times, it
was sometimes tinged with blood (see dogs No. 23-37-38-57-63)
and accompanied by scanty mucus.

Emssis occurred in 73 percent of the cases and the time
of occurrence was 36 percent in from 2 to 10 minutes; 36 per-
cent in from 11 to 20 minutes and the rest (28 percent) in
more than 20 minutes. Emesis occurred twice in 39 percent of
the number showing this symptom and only a few animals
(3 cases) had a fourth emesis.

micturition occurred in less than one—third of the cases
(12 of 38 dogs).

Dog No. 60 (see appendix), an eight kgm. animal, did
not show any of the common effects such as defecation, emesis
or micturition following the administration of the equivalent
of 2.59 tablets of nemural in solution. Pulse rate decreased
for but a short period from 126 to 120 after 39 minutes from
the time of administration of the drug and most of the time
the pulse rate was increased above the normal counted before
administration of the drug. The observation period lasted
for one hour and twenty—nine minutes. Other dogs (see appen-
dix, dogs No. 2‘1—1I3~55—60) from 5 to 8.5 kgm. body weight

showed but one attempt to defecate and other manifestations

- M2 -

were not observed during the time of observation. In some
other cases, however, (see dogs No. l9-22—3ln33—36u38-45-
M6~63) pronounced effects were observed as evidenced by re~
peated defecation and emesis and the state of restlessness
manifested by these animals. Shivering was observed in
some animals (see dogs No. 36-38-fl1~45~h7) about one hour
following administration of the drug and persisted for the
remainder of the period of observation.

b. Dosage Equivalent to Arecoline Hydrobro~
mide at the'Rate of 4.8 mgm. per kgm. of Body Weight. Ne—
mural was given to 18 dogs'. The dosage used was equiva~
lent to arecoline hydrobromide at the rate of 4.8 mgm. per
kgm. of body weight and the total dose was obtained accord~
ing to the procedure previously discussed.

Table VII summarizes in a more concise form the most
important observations according to the time of occurrence.
Analysis of these data and of the corresponding protocoles
in the appendix shows that nemural at the dosage used caused
slowing of the pulse rate in all of the experimental sub-
jects. There were, however, some variations in the various
responses. In some dogs, the slowing of the pulse rate was
definite and it lasted longer than the period of observation
(see dogs No. 32-u3—55-57~58-63-66). In some others there

‘ These animals were previously subjected to arecoline hy-
drobromide at the two levels of 3.2 and h.8 mgm. per kgm. body
weight and also to nemural in a dosage of an equivalent to
arecoline hydrobromide at the level of 3.2 mgm. per kgm. of
body weight.

— M3 -

 

.oa.efl .1: II .w: .m: II .HH .m .: .om ma mus II a.mm 0.0m m.~ mm
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.miena .NM II II II II II .Nm .mH .Om NN mm omen II N.Hm m.w Hm
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0d N E I h. i I m and? H LN dfi omfl 18 G

me u m m e e w m u I use“ m «m we wee em a

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u
nausea scoaumoonen ovum ended omen Hosea

saws-b boom .swu non .sms w.: we seem on» as seasonnoHUhm ocaaooond op acoambasoa

comm owmeon o as amassmz no coapmHu-aaaau< ammo on» meatoaaoh

omen ca ecodpmbsomno Heodcaao cadence no humaadm

HHb qu<a

_ 4Q -

was a decrease followed by an increase in pulse rate which
attained a rate, in some instances, above the previous nor-
mal (see dogs No. 36-3?-38-h0—60~6l~6#—65).

Defecaticn failed to occur in one case (see dog No. 36)
during the period of observation (lh.#5'). Other experi—
mental subjects defecated once in from n to 18 minutes.
Analysis of the data shows that one—half of the animals
(9 of 18 dogs) defecated in from h to 10 minutes and the
other one-half defecated in from 11 to 18 minutes. A second
defecation occurred in 15 cases of the 18 subjected to the
drug and the time of occurrence ranged from 6 to 5“ minutes.
One-third of the experimental subjects defecated three times
in from 11 to 51 minutes after the administration of the
drug and one-sixth (3 cases) of the cases defecated four
times. As a rule the first defecation was of soft consis-
tency and others were of liquid consistency, scanty but re-
peated at short intervals. With a few exceptions these ani-
mals expelled considerable amount of mucus and some cases
showed defecations tinged.with blood (see dogs No. 40-58).

More than one-half of the experimental subjects (11 of
18 cases) showed emesis and the time of occurrence was as
follows: early emesis from 6 to 20 minutes occurred in only
A cases; the rest of the cases (7 animals) vomited in from
23 to 46 minutes. Emssis was repeated twice in three cases
only. No more emesis was recorded during the period of
observation.

Hicturition occurred in 10 of 18 subjects in from 7 to

flu minutes. With the exception of two cases, micturition

- 45 _

occurred in less than 22 minutes after the drug was given
to the animal.

Dog No. 36 failed to defecate and had one emesis in
25 minutes. Dog No. #3 defecated once. This occurred in
11 minutes and was the only response to the drug shown by
this animal. Some other animals (see dogs No. 37-38) showed
considerable purging effect of the drug (four times), mic-
turition was also present but emesis did not occur.

B. Results of Kymographic Studies from Intestinal

Balloons in Dogs under Arecoline and Nemural at

Two Levels of Dosage

1. Preliminary Trials in Anesthetized Animals.
Because of the greater amount of data obtainable in criti-
cal experiments under anesthesia using a larger number of
dogs the feasibility of this method was first investigated.
Eight dogs under pentobarbital or ether anesthesia arranged
to record blood pressure, per minute volume and rate of
respiration, and intestinal motility from balloon placed at
various levels of the gut were used in these experiments.
The results of these trials are enumerated below.

Dog Nos. 1 and 2 were anesthetized with pentobarbital
sodium at the rate of 50 and 40 mgm./kgm. respectively and
arecoline hydrobromideat the rate of 1.6 mgm./kgm. was
given by stomach tube. No appreciable results were ob-
tained. The same dose of arecoline hydrobromide was injected
subcutaneously toward the end of the experiment and there was

a slight decrease in blood pressure and heart rate.

_ 46 _

Dog Nos. 3 and H were anesthetized with pentobarbital
sodium at the rate of 35 mgm./kgm. After a short normal
tracing arecoline hydrobromide at the rate of 1.6 mgm./kgm.
was given by stomach tube and no results were obtained
after 60 minutes. The same rate was injected directly into
the duodenum and accompanied with lgm of sodium bicarbonate
dissolved in 20 cc. water. No appreciable results were ob-
tained.

Dog No. 7 was anesthetized with ether. Arecoline hydro~
bromide at the rate of 1.6 mgm./kgm. was given by stomach
tube. No appreciable changes were obtained. One hour later,
arecoline hydrobromide at the rate of 3.2 mgm./kgm. was in-
jected directly into the duodenum. It caused a fall in blood
pressure and slowing of the heart rate.

Dog No. 8 was anesthetized with ether and after a short
normal tracing, arecoline hydrobromide at the rate of
3.2 mgm./kgm. was given by stomach tube. No appreciable
changes were seen in after 75 minutes following administration
of the drug. At this time arecoline hydrobromide at the rate
of 3.2 mgm./kgm. was administered directly into the duodenum.
A slight fall in blood pressure and decrease in heart rate
occurred.

Dog lo. 9 was anesthetized with ether. Arecoline hydro-
bromide at the rate of 3.2 mgm./kgm. was administered directly
into the duodenum. No appreciable changes were observed.
After 50 minutes, the dose was repeated with no appreciable

1'esults. After 32 more minutes, arecoline hydrobromide at the

~47-

rate of 1.6 mgm./kgm. was injected subcutaneously. A fall
in blood pressure and a decrease in heart rate occurred.

Dog No. 11 was anesthetized with ether. Arecoline hy—
drobromide at the rate of 3.2 mgm./kgm. was injected twice
directly into the duodenum at an interval of one hour did
not show any appreciable results.

The forgoing results indicate that anesthesia produces
too great a depression of the gut to warrant the use of
this method in evaluating the action of arecoline and ne~
mural. This finding is in agreement with that observed by
other investigators (Mu-hS).

2. Ordinary Fistulae of the Ileum and Colon. The
data derived from an analysis of the various kymographic
records and other observations in this series are set forth
in tables as follows:

Dongo. g5

Table VIII. Arecoline hydrobromide at the rate of

3.2 mgm. per kgm. body weight.
Dog No. 26

Table IX. Arecoline hydrobromide at the rate of
3.2 mgm. per kgm. body weight.

Table x. Arecoline hydrobromide at the rate of
h.8 mgm. per kgm. body weight.

Table II. Nemural in a dose equivalent to arecoline
hydrobromide at the rate of 3.2 mgm. per
kgm. body weight.

Table XII. Nemural in a dose equivalent to arecoline

hydrobromide at the rate of #.8 mgm. per

Dongo. 28
Table XIII.

Table XIV.

Table IV.

Table XVI.

Dog No. 22

Table XVII.

Dog No. 30

Table XVIII.

Dog N0. M8
Table XIX.

-IIII-

kgm. body weight.

Arecoline hydrobromide at the rate of

3.2 mgm. per kgm.

body weight.

Arecoline hydrobromide at the rate of

“.8 mgm. per kgm.
Nemural in a dose
line hydrobromide
3.2 mgm. per kgm.
Nemural in a dose
line hydrobromide

“.8 mgm. per kgm.

body weight.
equivalent to areco-
at the rate of

body weight.
equivalent to areco~
at the rate of

body weight.

Arecoline hydrobromide at the rate of

3.2 mgm. per kgm.

Nemural in a dose

line hydrobromide

3.2 mgm. per kgm.

body weight.

equivalent to areco~
at the rate of
body weight.

Arecoline hydrobromide at the rate of

3.2 mgm. per kgm. body weight.

Dog No. 25

— 49 -

TABLE VIII

Tabulated Data from an Ordinary Fistula

of the Ileum in One Dog

10 kgm. body weight

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight

April 21, 19u5

Total dose: 32 mgm. given in a piece of canned meat

Analysis of the kymographic record:

Ileum Balloon

Colon Balloon

 

Waves Waves
I3 E '3 b. O s '3 >1 0 a
a: a: IE g E; §I§ 3 g E; i3
0 e S .I Ian '4 §., :3 9
O D DI o 0' r4 +1» 0 r4 0
a H I: e 2. °- :8 s a a {3
s« E: a: E. a. «5 Inc) ea a. .5 <3
5 s 05 1 20 1 6 ““ “‘0 -'- -- a- —-.-. ......
5.10 liquid material expelled from ileum
5-15 11“ 15 75 4 34~R - 1H5 7 10—50
5.25 108 17 70 u 30- o - its 8 16-30
5.26 administration of arecoline hydrobromide
s 6 "'2 22 6 m “ -~ 1 .. -—
3.35 8h 18 63 1 37 _— 1§3 -_ _-
5.56 84 16 75 3 32 -— -- ._ _-
6.03 liquid material expelled from ileum
6.06 an in as 3 32-37 __ -- -- ..
6.16 90 1 7o 2 35—37 .— -- _- _-
6.26 90 1 67 3 33-35 —. -- -- --
6.33 liquid material expelled from ileum
6. 6 9o 1% 65 2 32-37 —- -- -- -_
5. 6 9o 13 75 2 25~28 ~- -- -- --
5-56 96 16 73 2 25-27 ~- -- ~- --
7.<36 9c in 83 3 12-17 —— —— —« ——

- 5o -

Analysis of the record and of the corresponding data
presented in Table VIII shows that pulse rate decreased from
108 to to per minute after in minutes following the adminis~
tration of the drug, than increased to 84 in 6 minutes. It
remained below normal for the duration of the experiment
(80 more minutes). Respiratory rate did not show any visible
change.

The ileum tracing showed increase in the tone level
especially a few minutes before liquid material was expelled
from the opening of the fistula. Peristaltic waves decreased
in number and amplitude. Rhythmic contractions could not be
recorded due to the presence of peristaltic waves. Data on
the colon tracing could not be obtained due to an enormous
increase in tonus immediately after the administration of
the drug which necessitated the release of air from the

balloon to avoid overflow of the chloroform from the manometer.

_ 51 -

TABLE IX

Tabulated Data from an Ordinary Fistula
of the Ileum in One Dog

Dog No. 26 April 20, 19u5
9 kgm. body weight

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight

Total dose: 28.8 mgm. given in a piece of canned meat
Analysis of the kymographic record:

 

 

 

Ileum Balloon Oolon Balloon
Waves Waves
-3 -3 '3 >. o '4 °
2 2 I 2 2 .2: E I? § 5
0 0 .4 g I: gig .4 3 i: H
o a D. o 0' .4 +242 ID 0‘ I-I m
3 H 3 5 ° °‘ 88 6 a 2 2
LE... 3 a: [-0 I: 5 (1:0 E4 I52. 4: O
2.00 1&6 15 I6 1 ll 15 70 9 20-45
2.10 132 1 n6 2 7— 9 16 65 10 23~30
2.11 administration of arecoline hydrobromide
2.15 lu2 -~ 60 —~ - -- 70 - ~—
2.21 132 13 37 -1 -- 18 65 9 15~ 0
2.31 138 11 28 1 27 16 62 6 20» 0
2.39 liquid material expelled from ileum
2.41 its 12 33 2 1 -22 14 60 7 20-50
2.51 150 12 26 2 1 21 in 78 10 20-30
3.01 150 12 28 2 7 15 76 9 23-65
3.11 152 11 35 - -— -~ 71 8 25-30
3.19 158 12 35 2 15-33 -- 70 8 23—50
3. 25 2nd. paper
3.35 14% ll #2 - - 14 74 8 25~u0
3. 5 152 13 35 2 7—17 16 69 9 25~u0

- 52 _

This subject showed an increase in pulse rate after
arecoline. This increase was from a normal of 132 to 158
per minute. No visible change was noted in the respiratory
rate except when liquid material was expelled from ileum
which was accompanied by restlessness and an increase in
the respiratory rate. When the animal was not excited
respiration remained slightly below normal (a decrease of
2 or 3 per minute). Ileum tracing shows an increase in
tons level somewhat above normal immediately after adminis-
tration of the drug, lasting only a few minutes (6 minutes),
then it fell below normal. Peristaltic waves were invari-
ably present after expulsion of liquid material from ileum.
After 30 minutes following administration of the drug the
frequency of peristaltic waves was 2 per 10 minutes. While
the height of the contraction was not marked, the duration
was more prolonged. No appreciable change was recorded in
rhythmic contractions. The departure from normal was not
more than 2:2. The colon tracing shows an increase in tone
level immediately after administration of the drug (5 mm.)
and also when liquid material was expelled from ileum (10 mm.).
while there was a decrease in rhythmic waves of l to 2 waves

per 10 minutes the duration was increased.

.L'3

lsII

u.1

OIq
O.‘

‘s

‘
|_w
“‘

I.‘

“
...

‘53...

Dog No. 26 April 15. 1945

Another experiment was conducted on the same animal
using arecoline hydrobromide at the same rate as previously.
Analysis of the tracing shows an increase in pulse rate
(120 to 156) instead of a decrease following the adminis-
tration of the drug. The rate remained above normal for the
entire period of the experiment. Tracing of the ileum bal—
loon showed an increase in tone level terminating in a spas-
tic contraction after expulsion of liquid material from the
ileum. The spastic contraction lasted from 3 to'5 minutes,
but 30 minutes following arecoline the record shows perisu
taltic waves accompanied by frequent expulsions of liquid
material from the ileum. The colon tracing showed a relaxa-
tion 20 minutes following drug administration. This lasted
for about 25 minutes, then rhythmic waves were recorded at
the rate of 12 per minute as compared to a rate of 10 per

minute in the normal tracing.

- 54 _
TABLE 1

Tabulated Data from an Ordinary Fistula
of the Ileum in One Dog

Dog No. 26 May 19. 1945
9 kgm. body weight

Drug: arecoline hydrobromide

Dose: N.8 mgm. per kgm. per body weight

Total dose: ’+3.2 mgm. given in a piece of canned meat

 

 

 

 

Ilesults:
Ileum Balloon Colon Balloon
Waves 33133
0 0 H H s
+2 P o b. o . o b. a: m
d «I I> o '6 0+: I» o 'd .0
III a: o c: :I .I-I o o c: :1 o
. . e v :3 s I: .. ° 8 I.
2 :9. t- 2 8 a 22 a I? 2. ,2
_2".. a 2 2 2. a 28 .2 t 2 8 .
3-20 72 l 68 -- -- 15 102 8 l2~2
3- c an 13 56 2 16 - 98 9 12-23
3- 0 72 13 66 l 7 14 95 9 20—29
3-41 administration of arecoline hydrobromide
3. 1&6 so .. 77 -- -- -- 118 -- --
3-50 60 ll 72 -- -- -— 115 5 10-17
2-57 90 12 83 -- -- -— -- -- --
oOO 90 ll 83 l 11 -- 93 8 8-12
1"-09 liquid material expelled from ileum

h$.10 72 11 85 - -- .— 9lI .— --
l“. 13 66 --- liquid material expelled from ileum
4- 20 72 13 78 3 50-95 - 92 --- ~—

Is '1
u H

w...
I

 

I]
O.‘

-I'.!

I

 

—55-

In general only a slight decrease in pulse rate occurred
in this subject following the administration of arecoline
hydrobromide. This decrease was not marked and the rate was
above normal in two occasions. Respiration showed slight
variation in rate. From the normal of 13 to 14 to 11 to 13
respirations per minute.

The ileum balloon record shows an increase in tone
Ilevel following arecoline administration. This increase was
especially evident immediately after the drug was given and

aLlso when liquid material was expelled from the Opening of
‘tlae ileum. At the 16th minute following arecoline admini~
atration the record shows a spastic contraction which lasted
:tr>r about 13 minutes. During this period an increase in
tone level occurred which was terminated with an expulsion
70f liquid material from the ileum. The colon balloon record
8hows slight activity during the first 19 minutes following
a—1‘eooline. During this period the tone level was somewhat
aflbcrve normal. Rhythmic waves decreased in frequency as well
a3 in amplitude. It was followed by a period of quiescence
‘hich persisted for the rest of the recording time.

Two more records were taken on this subject using are-
°Oline hydrobromide at the rate of 4.8 mgm. per kgm. body
weight.

Mus of the record obtained on May 5, 1945:

Pulse rats showed a gradual increase from the normal of
8"" to 114. It remained above normal for the entire experi-
ment. Liquid material was expelled from the ileum several

- 56 -

times, accompanied in each instance by a spastic contraction

of very short duration (3 minutes) and an increase in tone

level. The colon balloon record showed an increase in tone

during the first 60 minutes following arecoline.

Results of the record obtained on May 25,1945:
Pulse rate decreased from 120 to 54 in 4 minutes follow~

ing the administration of the drug, then gradually increased

areaching 120 beats per minute in 16 more minutes. An increase

sibove the normal was recorded toward the end of the experiment.

The ileum record showed a spastic contraction lasting for

sibout 22 minutes after arecoline. The colon record showed a

spastic contraction which lasted for the entire period of the
At the end of this period there occurred scanty
This was ac»

OXperiment.
and repeated expulsion of material from ileum.

companied by an increase in tone level.

Dog No. 26

-57..
TABLE XI

of the Ileum in One Dog

9 kgm. body weight

Drug: nemural

Dose: equivalent to arecoline hydrobromide at the rate of

3.2 mgm. per kgm. body weight

Total dose: 52.6 mgm. of nemural given in a piece of

canned meat

Tabulated Data from an Ordinary Fistula

April 24, 1945

 

 

Results:
Ileum Colon Balloon
Balloon Waves
0 0 H H
4.) +2 0) e 0) >3 0
a - . t .28 t 2 8
a: ‘n .4 E3“ .4 o I:
O s H :3 «4
O In OI ID PP a: U‘ H
3 r4 m c >.c c 0 I1
«4 O) O .C: O O H
___ 5. I3 I: E« Inc: a. a. .3
1.55 124 13 48 -— 70 10 12-17
11.55 administration of nemural
1.59 -—- -- 53 -- 68 -- ~-
2. O5 116 14 35 —--- 6O . 4 9-13
2.07 liquid material eXpelled from ileum
2.10 129 15 42 -— 70 9 11-15
2.19 liquid material expelled from ileum
2.20 129 12 35 - 60 10 5—15
2.26 liquid material expelled from ileum
2.30 135 -- 57 -- 55 6 5‘21

- 5g -

In this subject, the pulse rate decreased for about

15 minutes following nemural, then increased slightly above

normal for the remainder of the experiment.
The ileum balloon record

Respiratory

rate did not show any variation.

ehowed in general an increase in tone. This was especially

evident immediately after the administration of the drug

and.also toward the end of the experiment. Data on rhythmic

Icontractions could not be obtained due to interference by
The colon balloon showed a rather marked de-

respirat ion.

crease in the tone level. It also showed a decrease in

frequency of rhythmic waves.

_59-

TABLE XII

Tabulated Data from an Ordinary Fistula
of the Ileum in One Dog

Dog N0. 26

9 kgm. body weight

Drug: nemural

Dose:

June 20, 1945

equivalent to arecoline hydrobromide at the rate of

4.8 mgm. per kgm. body weight

‘Total dose: 78.9 mgm. of nemural given in a piece of

canned meat

ltnalysis of the kymographic record:

Ileum Balloon

Colon Balloon

 

 

Waves Waves
3 3 "I? I. II '6' e. I I5
I2 I2 6 .22: :3 E! 8 2 '3 :8
O o .4 E 2 g fl A 0 of;

s s t 2 t1: 8 2. 2 I? a E
_e".. 2 2 .9. 28 t: 8 .2 I: 8 8
3- 7 60 12 45 9 -- 77 9 10—20
3 . 13.7 50 11 47 8 .. -- 75 8 8-20
3-“8 administration of nemural
3- 51 24 ~— -— --- -- -- - -- -- Emcsis
3-53 2 -- 90 -- -- -- 125 -- --

. 03 36 20 70 9 —- -- 105 -- --
’4‘- O6 liquid material expelled from ileum
1'--:1.3 60 15 60 ll -- - 105 10 ll~l8
“-16 liquid material expelled from ileum
1*. 23 56 13 95 9 --— -- 83 -- --
1L. 27 liquid material expelled from ileum
It“ 39 48 11 72 10 - -- 77 -- ~—
-'559 72 10 57 ~- ~— —— 67 -- ~-

-60...

Slowing of the pulse rate was evident after nemural
was given. From the normal of 60 beats per minute, it de—
creased to 36 in about 15 minutes following the administra-
tion of the drug, then the rate increased reaching 72 at
the end of the experiment. Respirations increased somewhat
above normal after one early emesis had occurred and then
it remained close to the previous normal rate.

The ileum balloon shows an increase in tone level. This
increase was evident immediately after nemural was given.
From the normal of 47 mm. it increased to 90 mm. in 5 minutes.
The increased tone was especially obvious when liquid material
was expelled from the cpening of the ileum. Rhythmic con-
tractions were increased by l to 2 contractions per minute.
The amplitude was also increased when liquid material was ex-I

Spelled from the ileum. However, the amplitude was decreased
from the normal in the periods between expulsions of liquid
material. The colon balloon shows an increase in tonus for
the entire experiment. This was greater following the ad--
ministration of nemural. No rhythmic waves appeared during
the first 10 minutes following nemural. The record shows a
long period of quiescence of the colon. It started on the
30th minute following nemural and lasted for the remainder
or the experiment. During this period of quiescence, no

l‘hythmic waves were recorded.

_ 61 _

TABLE XIII

Tabulated Data from an Ordinary Fistula
of the Ileum in One Dog

Dog No. 28

9 kgm. body weight
Drug:
Dose:

Total

arecoline hydrobromide

3.2 mgm. per kgm. body weight

dose: 28.8 mgm. given in a piece

.Amalysis of the kymographic record:

Ileum Ballqgg

 

May 12, 1945

of canned meat

Colon Balloon

 

 

Waves Waves
0 D H H e
'P +9 O h 0 0 b. O In
“ ‘° 6 2 '3 3 J 6 8 "’ '8
a: “.1 e-J d.) P B 03 I—il 0 3
o s :3 w-I H g. '0" H
O I D. G 0" 1"! «PP O H 0)
.5. H 3 8 3 °‘ 3'8 8 3 °‘ :3
___EH E: a: E! a. .3 Inc: 2. a. «5 c3
3. 55 96 19 93 .. -- 14 147 ..- -—
3- 59 liquid material expelled from ileum
4.05 102 25 83 3 17 -~ 147 -~ --
4.08 liquid materiel expelled from ileum
4- 15 102 25 85 2 17-18 -- 151 -- --
“*- 15 administration of arecoline hydrobromide
1*. 21 -- -- 100 - -- -- 157 -- —-
"a 22 liquid material expelled from ileum
it. 25 78 20 93 -- -- -- 150 -- --
g- 30 -- 21 95 -— -- —- —- -- -~
~35 7s 23 93 -- -- 13 145 -~ -~
it. 111 .. ..-. 104 -- -- -- 146 liquid material
expelled
- 45 102 26 103 -»- -- 12 148 - -
g‘ ‘ S5 108 25 90 l 14 12 145 —- --
-05 114 19 102 -- -- 12 145 -- --

-52..

A decrease in pulse rate from the normal of 102 to
60 per minute occurred in 6 minutes following administration

of the drug. This lasted for about 20 minutes, then started

to increase and 40 minutes later the rate was above the pre~

vioue normal. Respiratory rate did not show any significant

The recording of the ileum balloon shows an in»
This remained above normal for about

Peristaltic waves were

change.
crease in tone level.

tone hour after the drug was given.

riot well marked in this case. Rhythmic contractions re-

mained almost constant and in some instances they were so
jJEregular in character due largely to interference by ree~

griration that accurate determinations of rate could not be
This was especially evident immediately following

made.
The colon record shows a slight

abdhninistration of the drug.
increase in tone level immediately after administration of

the drug. Rhythmic waves were not present in the normal,
311: hough after the drug was administer ed some rhythmic waves
a-I>I:>eared. When liquid material was expelled from the ileum
the record showed an increase in tone level and also the

Presence of a peristaltic wave.

- 53 -

TABLE XIV

Tabulated Data from an Ordinary Fistula
of the Ileum in One Dog

D08 NO- 28 May 22, 1945
8.5 kgm. body weight

Drug: arecoline hydrobromide

Dose: 4.8 mgm. per kgm. body weight

Total dose: 40.8 mgm. given in a piece of canned meat

 

 

 

Results:
Ileum Balloon Colon Balloon
Waves Waves
° ° H 7:. . .5
'5 '3 2 5' '3 043 e 3’ to .o
a: a: o C. :3 «~48 to $3 :5 O
A o +3 E .4 o +2
o e a «H H :5 q-c s...
o In D. D H +14: 0 0' H 0)
a .. 2 2 a 2 .22 e a 9- :3
'3: £3 a: so a. '5 cut) 54 a. ‘3 c:
1.25 96 16 56 -« —- 11 116 9 7-21
1. 5 82 la 58 2 12-32 10 120 11 15-42
1. 5 96 l 72 - —— 11 111 9 18—37
1.45 administration of arecoline
1.50 48 —- 85 -~ ~- 12 170 ~—

1. 6 27 73 -- ~-
55 as 18 70 1 27 11 158 7

2.10 2nd paper

2.20 72 0 12 69 2 7—9 - 138 8 22-25
2.33 84 14 63 -— ~~ 11 135 9 24—28
2. 90 13 65 1 31 12 135 9‘ 20-40
2.50 84 12 65 - -- 11 133 9 30-60
3.00 66 14 60 1 18 12 130 .4 ..

- 64 -

In this subject there was a definite slowing of the
pulse rate in 7 minutes following the administration of the
drug. The rate decreased from 96 to 36 and remained at this
level for about 5 minutes, then increased gradually reaching
a rate of 90 in 65 minutes following the drug. At this time
the pulse rate started decreasing again. Respiratory rate
was somewhat increased shortly after the administration of
the drug. This may have been due to excitement since the
data show no appreciable change afterward. The record ob—
tained from the ileum balloon showed an increase in tone
level of 13 mm. following the administration of the drug.
The level then remained above normal for the remainder of
the record and was especially evident before and during the
recording of a peristaltic wave. Peristaltic waves were
somewhat indistinct, of low amplitude and resembling tone
waves. The presence of these waves, however, is not ac-
companied by any increase in the tone level of the colon.
Rhythmic contractions did not vary in frequency from the
normal. A deviation of one contraction above normal was
sometimes noted. The record obtained from the colon balloon
shows an increase in tone immediately after the administran
tion of arecoline hydrobromide, which persisted for the re~
mainder of the experiment. In general, the amplitude of the
rhythmic waves was increased. The highest value was recorded

in 12 minutes following administration of the drug.

\

a 65 2

TABLE XV
Tabulated Data from an Ordinary Fistula

of the Ileum in One Dog

Dog No. 28

9 kgm. body weight

Drug: nemural

may 17. 1945

Dose: equivalent to arecoline hydrobromide at the rate of

3.2 mgm. per kgm. body weight

Total dose: 52.6 mgm. of nemural given in a piece of

canned meat

Analysis of the kymographic record:

Ileum Balloon

Colon Balloon

 

wee—m

 

Waves
0 0 H H e
.p .p o b. o o p. c: m
a 2 t 2.; 2 8 t 2 '3 8
II: D: A Ed 0 +3 .4 0 p
o e H :1 «4 :3 H :4
0 In D- 0 43+, 0‘ H o 0' H o
2 ... 3 8‘ .28 a °~ 8 :3 2- £3
E4 E a: E-0 D30 [:4 5 E4 [2. E O
2.04 96' 12 42 10 l 28 107 10 12—31
2.14 108 ll 55 10 -- -~ 106 8 21-29
2.24 114 12 51 10 «- —- 94 -_ _-
2.25 administration of nemural
2.31 78 17 87 10 -- -- 120 -— --
2.41 90 11 46 10 - -— 95 8 12-23
2.43 liquid material expelled from ileum
2.53 102 11 64 9 -- -- 117 9 10-32
3.00 108 11 51 10 —- -- 95 .. —.

_ 66 _

This subject showed a decrease in pulse rate after drug
administration. From the previous normal of 114 the rate
fell to 78 beats per minute in about 6 minutes following ne-
mural, then started to increase and finally reached a rate
of 108 in 29 more minutes. Respiration did not show any
variation in rate during the entire experimental period.

The ileum balloon tracing showed an increase in tone
from a normal of 51 mm. to 87 mm. immediately after nemural
was given. This increase lasted for about 6 minutes. The
general tone level was increased above normal; this was es-
pecially evident when liquid material was expelled from the
ileum. Rhythmic contractions did not vary in frequency from
the previous normal. The colon balloon showed also an in-
crease in tone level. This was particularly evident immedi—
ately after the administration of the drug and also when liu
quid material was expelled from the ileum. Two periods of
partial quiescence occurred: the first one occurred 12 minn
utes after nemural and lasted for about 6 minutes, while the
second occurring 29 minutes following nemural also lasted for

about 6 minutes.

a 57 _

TABLE XVI

Tabulated Data from an Ordinary Fistula
of the Ileum in One Dog

Dog No. 28 May 29, 1945

8 kgm. body weight

Drug: nemural

Dose: equivalent to arecoline hydrobromide at the rate of
4.8 mgm. per kgm. body weight

Total dose: 70.2 mgm. of nemural given in a piece of

canned meat

 

 

 

Results:
Ileum Balloon Colon Balloon
Waves Waves
0 0 H H

P +3 0 0 >3 0 0) >-. 0

d m > 0+: (3 'o > o 'o

a: a: 0 H o t: :3 0 c: :3

.3 E36 0 P .4 0: ‘P

0 e H :3 H :3 H

o m p. o 194: o‘ .4 o 0* .4

a :4 m : >.c c Q. a o {L

«H a 0 0 £3 0 H E o y E
5' fl: 24 cut) ha Ei &. #“M

10.01 administration of nemural
10.08 liquid material expelled from ileum

10.10 66 19 75 10 a. -- 95 ._ _.
8 8‘ $2 9 - -- a 7 12:;
10. -_ _- __

10.30 a 15 a .. -- ..... it ._ -_

10-50 72 17 59 9 -- —-
11. 03 2nd paper

11.13 96 17 78 10 —- -- 92
11.23 78 12 67 9 -- ~- 88
11. 3 90 13 70 —- -- -- 89
11. 3 90 11 75 —- -- -— 90

i I! i

_ 53 a

In this subject a decrease in pulse rate occurred im-
mediately after the nemural was given, from the normal of
96 to 66 in 9 minutes following the administration of the
drug. Then the rate increased in a progressive manner re»
turning to the normal of 96 beats per minute in 72 minutes
from the time of the drug administration. Respiration did
not show a marked variation from the normal contrary to ob»
servations in other experimental subjects.

The ileum balloon record shows an increase in tone
level following nemural. There were alternate increases and
decreases of a few millimeters but the tone level was always
above the normal for the entire experiment. Rhythmic con-
tractions increased by one contraction per minute on two 00»
casions. The colon balloon record showed a transient in~
crease in tone immediately after the drug was given. It re-
mained slightly below normal coincident with the occurrence
of several periods of quiescence during which no rhythmic

waves appeared on the record.

_ £9 -

TABLE XVII

Tabulated Data from an Ordinary Fistula
of the Ileum in One Dog

Dog No. 29 May 15, 1945
10 kgm. body weight

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight

Total dose: 32 mgm. given in a piece of canned meat

Analysis of the kymographic record:

 

 

Ileum Balloon Colon Balloon
Waves Waves
0 0 H H
+3 +3 o g. o o 0 >5 0
9 . t e 2 .2” t 2 2
“ ‘n .4 o 1. Egg .4 o +a
0 o :1 H H 5 -H
0 II 9. o 0‘ H +24: 0 0' H
a «a n c o a. >.: a o :1
.a ‘E o o H ‘5 £30 0 H ‘3
ea c: s. a. (ms) 5* e.

Other Obs.

 

120 - ~-
127 10 12—18
-— 125 5 20-28

3

8
l

313% 33 13 :2
85.

23
2.54 90 11 21

Ft tare

2.55 administration 0 arecoline hydrobromide

3.05 78 17 105 -- -- --. 155 8 12—18
3.10 78 14 liquid material expelled from ileum
3.15 96 14 86 - -_ -- 144 7 20—24
3.23 liquid material from ileum

3.25 102 16 86 - -- -- 140 9 10-21

3-35 2nd paper

3.45 90 14 106 —— -4 -_ 130 .. a-
.55 78 13 100 -- —- -— 130 -- _-
~05 90 13 85 -— - -~ 128 -— --
4.15 78 12 91 —- -- - 133 9 15-18

4.25 90 13 93 —- ~- 130 5 12~20

-70..

An initial decrease in pulse rate of short duration was
seen in this subject following which considerable variations
in rate occurred. Occasionally the rate was above the pre-
vious normal. Respiratory rate was slightly increased above
normal. Immediately after the drug was given the tone level
of the ileum was increased from 85 to 105 mm. on the record
and remained in spastic contraction for about 9 minutes, then
liquid material was expelled from ileum and the recording
showed a succession of increases and decreases in tone level.
Rise of the tone level was especially evident following the
expulsion of liquid material from the ileum and the record
resembled that which might be produced by a long peristaltic
wave. After 90 minutes the ileum record showed a spastic ‘
contraction which lasted for about 5 minutes. The entire
record failed to show the presence of any peristaltic waves,
although following the expulsion-of liquid material from
ileum the record showed long waves which could be classified
as peristaltic waves. Rhythmic contractions were not suf~
ficiently distinct to be considered in this experiment. If
present, they were so small as to be obscuredby respiratory
interference on the record. The colon record showed an in«
crease in tone level immediately after the administration of
the drug. The tone level remained increased for the duration
of the experiment. Twenty minutes after administration of
the drug, the record showed a relaxation of the colon lasting

for about 25 minutes; during this time, the rhythmic waves

were not present.

_ 71 -

TABLE XVIII

Tabulated Data from an Ordinary Fistula
of the Ileum in One Dog

Dog No. 30 May 18, 1945

5.5 kgm. body weight

Drug: nemural

Dose: equivalent to arecoline hydrobromide at the rate of
3.2 mgm. per kgm. body weight

Total dose: 32.3 mgm. of nemural given in a piece of

canned meat

 

 

 

Results:
Ileum Balloon Colon Balloon
Waves Waves
0 .3 t; e d) '3 >3 0
*3 a3 5 OP 0;" 'd g g '5
C: m t—J g3 0 a A 0 «P
0 0 H :3 H :3 H
0 III 9. 0 PP O‘ H 0 0‘ H
a .4 m s >5G o o. c o :1
H a 0 O .510 H B O 5
e. p: 24 gut) Ba ‘4 Ea &.
2.10 120 12 58 12 -— -- 103 10 10—20
2.20 126 12 90 11 _- -- 105 12 23-28
2.21 administration of nemural
2.27 84 18 119 -— -- —- 162 -- --
2. 7 84 12 88 10 -- -- 110 11 15~51

2. 7 102 ll 90
2.57 108 10 86 11 —- -. 93 9 16—34
3.07 114 -11 87 10 1 31 89 -- .-

3.25 2nd paper

3. 5 102 12 87 11 1 25 91 11 15-29
3. 5 102 10 93 11 2 --
3.55 102 10 90 10 1 36 97 11 9~38
.05 114 11 95 —- 2 32-35 84 —- ~—
4.15 108 12 100 11 - - 98 9 11~41

A decrease in pulse rate occurred after nemural was given.
It was especially evident immediately after drug administration.
From the last normal of 126 beats per minute it fell to 84 in
5 minutes following the drug and remained at this rate for
about 10 minutes, then pulse rate increased to 102 to 108 for
the remainder of the experiment. Data on respiration show an
increase in rate immediately after the nemural was given, but
after this transient increase the rate fell somewhat below
normal. This decrease was not more than 1 to 2 respirations
per minute.

The ileum balloon record shows an increase in tone level
from the normal of 90 mm. to 119 mm. during the first 6 min-
utes following nemural. Then the tone remained at a level
varying from 85 to 100 for the rest of the record. Rhythmic
contractions decreased occasionally by one contraction per
minute. From the previous normal of 11 to 12 it fell to
10 to 11. Peristaltic waves were present in this subject.

They appeared 45 minutes after administration of the drug.

The frequency varied from 1 to 2 waves per 10 minutes inter~
vals and the amplitude ranged from 25 to 36 mm. on the record.
The colon balloon record also showed a definite increase in
tone following nemural administration. From the last normal

of 105 mm. it increased to 162 mm. and lasted until the 6th
minute. In 10 more minutes the tone level decreased to 110 mm.
and for the remainder of the experiment, it alternated between
84 to 98 mm. The frequency of the rhythmic waves showed some

variations. From the normal of 10 to 12 waves in a period of

..73...

10 minutes there was a decrease to 9 to 11. However, ampli-
tude was increased in some of the rhythmic waves. Periods
of partial quiescence of the colon appeared on the record.
During these periods rhythmic waves were small and few in

numb er s

_ 74 -

TABLE XIX

Tabulated Data from an Ordinary Fistula
of the Ileum in One Dog

Dog No. 48 July 18, 1945
10 kgm. body weight

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight

Total dose: 32 mgm. given in a piece of canned meat

Results:
Ileum
Waves

0 o .4 m
«P P O o be 0 0
d m p 0+: (2 'u a
a: a: 0 «'0 a 3 o
.2 E?“ o +3 o
O 0 H :5 H m
0 0 O. a: 9+9 0‘ H o
a .4 m a has 0 o. -H
«4 a I: o no H 3 3'

so a: 20 an: I:

 

3.01 administration of arecoline hydrobromide

3.08 24 44 65 10 -- -— --
3.18 30 a; 36 9 3 35-45 35'

3e 28 96 26 "" ""

3. 8 104 31 2 ~- —- —- ~-

3. 8 108 36 2 -~ -— -- --
.53 96 36 27 -- -- -- ~-
.05 120 35 28 10 -- -- --

4.15 2nd paper

4.22 114 40 27 9 - -- --

4.27 120 35 34 10 -- -~ 19'

4. 7 132 32 25 -- -« ~~ --

4. 7 1 4 38 25 -- -— -- -—

-75..

From the previous normal of 126 the pulse rate fell to
24 beats per minute in 7 minutes following arecoline hydro-
bromide. Then the rate increased progressively to reach
108 in about 40 minutes. After this time, the pulse rate
was irregular but increased above normal toward the end of
the experiment. The respiratory rate was above normal during
the whole experiment and especially increased immediately
after arecoline hydrobromide was given.

The ileum balloon record showed a great activity during
the first 15 minutes following the administration of the drug.
During this time, the tone level increased from the normal of
36 mm. to 65 mm. Rhythmic contractions increased in frequency
from 9 to 10 contractions per minute; they also increased in
amplitude. Three peristaltic waves appeared on the record
ranging in amplitude from 35 to 45 mm. This period of gut
activity was followed by one of quiescence lasting for about
35 minutes. During this time no rhythmic contractions ap~
peared on the record and tone decreased reaching a low of
24 mm. Another period of quiescence of the ileum lasting
about 19 minutes occurred in 86 minutes following arecoline

hYdr Ob: 0m1d° e

3o

Thiry Loop.

- 75 a

The data derived from an analysis

of the various kymographic records and other observations

in this series are set forth in tables as follows:

Dongo. 51
Table XX.

Table XXI.

Table XXII.

Table XXIII.

Dongo. 61
Table XXIV.

Table XXVe

Table XXVI.

Table XXVII.

Arecoline hydrobromide
3.2 mgm. per kgm. body
Arecoline hydrobromide
4.8 mgm. per kgm. body

Nemural in a dose equivalent to

coline hydrobromide at

3.2 mgm. per kgm. body

Nemural in a dose equivalent to

coline hydrobromide at

4.8 mgm. per kgm. body

Arecoline hydrobromide
3.2 mgm. per kgm. body
Arecoline hydrobromide
4.8 mgm. per kgm. body

at the rate of
weight.

at the rate of
weight.

are-

the rate of
weight.

of

the rate

weight.

at the rate of
weight.
at the rate of

weight.

Nemural in a dose equivalent to are~

coline hydrobromide at
3.2 mgm. per kgm. body

the rate of

weight.

Nemural in a dose equivalent to are-

ooline hydrobromide at
4.8 mgm. per kgm. body

the rate of

weight.

-77..

TABLE XX

Tabulated Data from a Thiry Loop
of the Ileum in One Dog

Dog No. 57 October 15, 1945
8 kgm. body weight

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight

Total dose: 25.6 mgm. given in a piece of canned meat

Analysis of the record:

 

 

Ileum
Waves
0 O H 0 e
P 'p ' ° >~ O o m
d d o P b o "d c: .0
a: a: *‘O O a d o (3
.std A: o +3 o
O O H 3 fl m H
s .. 8 as 8 2: e 2 a
9' '3 tn inc: E. a. «3 (y (3
5.00 108 19 11 69 -- _- _-
5.10 108 19 11 70 -- -- _-

5.25 administration of arecoline hydrobromide

5. 5 s4 30 11 6o - —- —-
5. s4 27 11 60 1 16 ~-
5,50 90 33 -— - 13' borborygmue

5.59 102 27 ::
6.13 114 24 9

-o. —. “—

48
23 —~ -- -- defecation
51

_ 73 -

Analysis of the record and of the corresponding data
contained in Table XX shows a decrease in pulse rate im—
mediately following the administration of the drug. From a
previous normal of 102 beats per minute it fell to 84 in
6 minutes following drug administration. This rate per-
sisted for approximately 10 minutes then it began to increase
and reached the previous normal in about 10 more minutes.
This rate was maintained for the remainder of the experiment.
The respiratory rate was increased after drug administration.
From a previous normal of 17 respirations per minute in-
creased to 33 in 20 minutes, then decreased toward the end of
the experiment to 24 respirations per minute.

The recording of the gut activity shows a decrease in
tone which was especially evident during a period when no
rhythmic contractions appeared on the record. For a period
lasting from the 25th to the 38th minute following arecoline
no contractions of any type were recorded. This phenomenon
was preceded by considerable borborygmus with defecation oc—

curring toward the end of this period of evident quiescence.

Dog No. 57

- 79

TABLE XXI

Tabulated Data from a Thiry Loop
of the Ileum in One Dog

9 kgm. body weight

Drug: arecoline hydrobromide

Dose: 4.8 mgm. per kgm. body weight

October 27, 1945

Total dose: 43.2 mgm. dissolved in water and given by

stomach tube

Analysis of the record:

H
H
g .

 

 

Waves
0 O H 0 e
+3 +3 0 0 >5 0 0 D
d d b 0+3 0 '6 a .0
a: a: 0 -Hc> n s 0 <3
.4 210 a) +3 o
o . H s .H m a
0 In D. 0 43+, U‘ H 0 a)
s H 2 s as 2 9 2 f.
e. a. e 2. mo e. 2 0’ 0
10.50 108 13 73 12 —- -~ ~-
11.00 96 ll 73 12 ~~ -- ~-
11.10 96 14 7O 12 -- —— ~-
11.15 administration of arecoline hydrobromide
11.20 96 16 70 12 -~ -- 19'
11.25 138 -- 61 -« —~ —- —- defecation
11.28 102 -— 6 -~ -~ -- -— defecation
11.32 -- -- 6 -- -- —- -- defecation
11.35 96 26 64 -- -— -- -— defecation
11. 9 90 - 63 -- —— -— -
11. 2 ~— 17 62 -- -— - —- defecation and
mucus
11.52 84 14 62 11 ~- -- ~—
12.00 54 15 6o 11 ~- -- -—
12.07 -- ~- —~ -~ -— -- -— 2nd paper
12.17 96 15 57 11 -- —- —- Rhythmic contraCn
tions increased in
amplitude
12.27 84 11 6o 11 -- 1- __
11.37 90 14 55 -« -— -- -~

‘80..

In this subject the administration of arecoline was
followed by a decrease in pulse rate from the normal of
96 to 84 to 90 per minute. There was, however, an increase
in rate to 138 per minute shortly after drug administration.
Respiratory rate was in general slightly increased. This
was especially evident when scanty and repeated defecations
occurred. The ileum balloon tracing shows a progressive
but irregular decrease in tone level. In 5 minutes followa
ing administration of the drug, the record shows a period
of complete quiescence lasting for about 19 minutes. How—
ever, four defecations occurred during this period. The
frequency of the rhythmic contractions decreased from 12 to
11 per minute. In one hour following arecoline hydrobromide
rhythmic contractions increased in amplitude. No other

waves appeared on the record in this subject.

Dog N00 57

TABLE XXII

Tabulated Data from a Thiry Loop

9.5 kgm. body weight

Drug: nemural

of the Ileum in One Dog

November 28, 1945

Dose: equivalent to arecoline hydrobromide at the rate of

3.2 mgm. per kgm. body weight

Total dose: 55.5 mgm. of nemural dissolved in water and

given by stomach tube

 

Results:
Ileum
Waves
3 O H O a;
m '5 043 2 3' '3 2 23
a: m 0H o 0 c: :3 a)
8:0 #3 m -p o H
o o .c: H 8‘ H In a)
o In D. +3 +3 o H 0 £1
a .. ' as 3 -2 a s s
5* 3: 82 0:0» so &. <2 5%
3.09 72 13 8 73 _. _- -_
3.19 84 1 7 75 -- _- _-
3.29 90 16 9 73 -- -- --
3.30 administration of nemural
3.40 90 18 9 75 .. .. _-
3.48 -- -- -- -— —- —- -— defecation preceded
by borborygmus
3.49 -- -- -~ -- -- -- -
3.50 96 22 8 7O -- ~- 17'
3°53 “ “ ‘v -- ~- -- -- emssis
.00 78 25 "" 69 “"' “’ ——
4.09 -— -~ - -- -- -~ -— defecation, bor-
borygmue
4.10 54 31 -— 73 -- -— --
4.16 -- -- - -- -- -- -— defecation
4.20 90 33 10 71 -— —- ~-
4.30 90 2O 12 72 -— -— --
4.32 2nd paper
4. 2 9O 15 11 73 —— _- -_
4.52 90 13 12 74 —- -_ -_
5.02 96 12 10 74 —— _- -_

- 52 _

This subject did not show any appreciable changes in
pulse rate after nemural was given at the level mentioned
above. The respiratory rats showed an increase above nor-
mal during the first 16 minutes following the administra—
tion of the drug. From the previous normal of 16 respira~
tions per minute, the rate increased to a maximum of 33.
Toward the end of the experiment the respiratory rate was
below the last normal counted.

The ileum balloon record shows a slight variation in
tone from the normal. There were small decreases and in~
creases ranging from 2 to 4 mm. Rhythmic contractions
showed some increase in frequency, from the normal of 9
contractions per minute to 10 to 12 after 50 minutes followb
ing the drug. This rate persisted for the remainder of the
experiment.

Other observations recorded were a period of quiescence
at the 20th minute following nemural which lasted for about
17 minutes. During this period no rhythmic contractions
occurred. Defecaticn occurred three times, one in one minute
before and two during the period of quiescence of the iso~
lated loop. Emssis occurred once during this period. Defe~

cations were always preceded by borborygmus.

Dog No. 57

- g3 _

TABLE XXIII

Tabulated Data from a Thiry LOOp
of the Ileum in One Dog

6 kgm. body weight

Drug:

Dose:

Total

nemural

equivalent to arecoline hydrobromide at the rate of

4.8 mgm. per kgm. body weight

August 30, 1945

dose: 52.6 mgm. of nemural given in a piece of

canned meat

Results of the kymographic record:

Ileum Balloon

 

 

Waves
0 0 H 0 e
+3 P e a) p, a) O m
, ,, .2: t e 2 s s
a: m Ed .4 0 +3 0
0 e H 8‘ «'1 (D H
0 no 9: PP 0 H d) 0)
e H : as s a 9 5 .5
la IE um gut) s. a. ‘5 or C)
3.04 78 27 11 5o -- -- _-
3.14 84 29 11 5o -_ ‘_ -_
3.15 administration of nemural
3.18 36 -- 12 60 -- -— 10'
3.23 66 65 -_ 46 -- _- _-
3030 73 v‘ v“ “3 -* -- -« defecation
3.34 -- -* -- 43 -- -- -- defecation
3. 7 72 -~ - 46 -- ~- —- defecation
3.37 72 28 ll 41 -— -- ~—
.50 54 12 10 39 —- -- -— defecation
3.00 72 1 11 8 1 8 -
4.03 34 13 10 s -— -— --

-511...

In this subject the pulse rate fell, frcm the last normal
of 84, to 36 beats per minute in 3 minutes following nemural
administration. This was followed by an increase reaching a
rate of 72 in 12 more minutes. This last rate was maintained
for about 17 minutes, then dropped again to 54. In 8 more
.minutes, the pulse rate returned to 84. Data on respiratory
rate show some variations. Immediately after nemural was
given, respiration increased considerably reaching a rate of
65 per minute from the last normal of 29. For about 32 min»
utes, the respiratory rate remained above normal in which
time defecation occurred three times. Toward the end of the
experiment, respiratory rate fell below normal.

The ileum balloon tracing shows in general a decrease
in tone; however, an increase of 10 mm. on the record is ob—
served immediately after nemural was given. This increase in
tone lasted for about 3 minutes in which time rhythmic con-
tractionswere seldom seen. It was followed by a period of
quiescence of the isolated loop lasting for about 10 minutes.
No rhythmic contracton appeared during this time. Following
the period of quiescence, three defecations occurred at very
short intervals. During this period rhythmic contractions
were somewhat irregular. In the final 20 minutes of the ex~
periment a fourth defecation occurred. One peristaltic wave
8 mm. in amplitude appeared in this subject. The rate of the

rhythmic contractions varied between 10 and 11 per minute.

- g5 -

TABLE XXIV

Tabulated Data from a Thiry Loop
of the Ileum in One Dog

Dog No. 61 October 22, 1945
8 kgm. body weight

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight
Total dose: 25.6 mgm. dissolved in water and given by

stomach tube

Analysis of the record:

 

Ileum
Waves
m 0' H O o
P +3 e 0 >5 0 O (D
d d O ‘P > 0 'd c: p
“3 “3 *‘0 .3 g a o c)
T ‘ ,EES : 12 8 n
0 m a. +3 +3 0 C‘ H 0 Q;
3 H :3 ,2 8 8 2 9 '9 a
3-50 96 47 11 81 -_ _- --
.00 96 38 10 7s _- -- --
4.10 96 31 11 73 __ _- --
4.20 78 28 10 71 _- -- --
4.20 administration of arecoline hydrobromide
4.26 90 31 11 83 ~- __ --
4.30 " ”‘ ‘7 “‘ “ " -* defecation
4.31 '90 34 -- 7O —- -— 6'
4.37 90 3 -- 75 -- -* -~
4. 0 90 3 10 79 -* ~- -~ defecation
4.50 84 28 11 75 _- -- --
5.10 90 3O 10 67 —— __ _-
5°12 “ “ “v v“ *- ~~ -- 2nd paper
5.22 96 38 10 6 -- _- _-
5.132 84 39 10 6 .—.. _- --
5. 2 96 21 10 64 -- -- --
5.52 96 29 10 65 -- _- --

-35-

In this subject the pulse rate remained essentially the
same as the previous normal. Respiration did not show any
changes except when defecation occurred at which time an in—
crease in the rate was observed.

The ileum balloon record shows a definite increase in
tone level and also rhythmic contractions were sharply de-
fined and of equal amplitude following administration of the
drug. This latter effect lasted for about 5 minutes. In
7 minutes following arecoline a period of a quiescence of the
gut lasting for about 6 minutes occurred. During this time,
no rhythmic contractions were recorded and tone level de—
creased somewhat. Toward the end of the experiment, the tone
decrease again and rhythmic contractions showed alternating
period of increased and decreased amplitude. Frequency of
rhythmic contractions, when present, did not show any dif~

ference from the previous normal.

Dog No. 61

Tabulated Data from a Thiry LOOp

TABLE XXV

- 57 -

of the Ileum in One Dog

8 kgm. body weight

Drug: arecoline hydrobromide

Dose: 4.8 mgm. per kgm. body weight

October 29, 1945

Total dose: 38.4 mgm. dissolved in water and given by

stomach tube

Analysis of the record:

 

Ileum
Waves
0 O H 0 e
:3 *3 2 0+; 8’ 3 2 .3
In In 0 rig c s o C)
. '4 a. 0 a :2. H
0 8 c. 0 «94: 3' .4 m m
f. H : s as :3 a '3 s
e. d: a: as cut: 1h .5 0? C)
2.4 96 32 8O 11 —— -- .-
2.5g 84 26 78 11 -- -_ _-
3.05 84 34 77 11 -- -_ __
3.15 84 24 75 12 -- -- --
3.15 administration of arecoline hydrobromide
3.2 72 44 74 11 -- _- --
3.3 “a ‘* ;3 II -~ -- I7' defecation
3:3; I3 22 63 “r -- -- - defecation
3. 9 66 -- 68 -- -- —- —~ defecation
3. 7 72 —~ 66 ~- -- -- —- defecation
with mucus
. 2 -- 6 -- -- -- —- Emssis
3.3: 1.. .2 .. .. .. .n. p...
4.12 66 33 67 11 -- -_ --
4.22 60 17 66 11 -- _- --
4.32 84 26 70 11 -- —- ——

-88..

Arecoline hydrobromide in this subject caused a definite
and sustained decrease in the pulse rate. From a previous
normal of 84 it decreased to 66 in 24 minutes following ad-
ministration of the drug. In 43 more minutes the pulse rate
decreased further to 60 per minute. Then it increased to
normal at the end of the experiment. Respiratory rats showed
an increase immediately after the drug was given. From a
previous normal of 24 it reached 44 in 10 minutes. It re-
mained above normal for about 47 minutes in which time defeca~
tion occurred four times and emesis once. Toward the end of
the experiment, the respiratory rate returned to normal.

The record of the ileum balloon shows a rather slight
decrease in tone level. This was not marked and the values
in the table show some rhythmic variability. A period of
quiescence occurred after 20 minutes following administration
of the drug. This lasted for about 17 minutes and no contrac—
tions or waves were recorded during this time. Rhythmic con-
tractions did not vary in frequency; however, the amplitude
increased somewhat for short periods toward the end of the

experiment.

- 39 -

TABLE XXVI

Tabulated Data from a Thiry Loop
of the Ileum in One Dog

Dog No. 61 July 23, 1945

7 kgm. body weight

Drug: nemural

Dose: equivalent to arecoline hydrobromide at the rate of
3.2 mgm. per kgm. body weight

Total dose: 40.9 mgm. of nemural dissolved in water and
given by stomach tube

Analysis of the record:

Ileum Balloon

 

 

Waves
0 0 H 0 e
d d b 04: 0 'd m I)
a: a: a) "-1 0 £1 :3 0 O
.4 E m a) +2 o
O o H a. «H m H
0 m D. o .94: p. o m
B H m I: in $2 0 O. H .1:
.d ‘g o 0 £30 H E d «P
E-o a: E-4 a: O In 4 O’ O
2.00 administration of nemural
2'16 ”‘ “ “ " “ -* -- defecation
2.30 72 —~ 42 -- -- -- —- gut partially
‘ relaxed

72
2.50 84 - 56 10 -- -- -- rhythmic contrac-
tions increased

3 00 78 4 10 amplitude
3:10 78 - E6 10 ~- ~~ __ fl w n
3.20 -- £3 IO -- -- -- 2nd paper

3.30 72
3. 0 78 -— 46 10 ~— -- -~ rhythmic contrac-
tions increased

amplitude

_ 90 -

From a previous normal of 90 the pulse rate decreased to
66 per minute in 20 minutes following nemural. Data on the
respiratory rate was not obtainable due to continuous panting
of the animal. The ileum balloon record shows a decrease in
tone level during the first 40 minutes. This was from a nor-
mal of 50 mm. to 39 mm. It was followed by an increase above
normal reaching 56 mm. in 10 more minutes, then decreased
progressively to a level of 46 mm. at the end of the observa~
tion period. Rhythmic contractions did not vary in frequency,
although there were periodic increases in amplitude similar

to those seen in previous records. Defecaticn occurred twice.

Tabulated Data from a Thiry Loop
of the Ileum in One Dog

Dog No. 61

7.5 kgm. body weight

Drug:

Dose:

Total

nemural

_ 91 _

TABLE XXVII

July 31, 1945

equivalent to arecoline hydrobromide at the rate

of 4.8 mgm. per kgm. body weight

dose: 65.8 mgm. of nemural given in a piece of

canned meat

Results of the kymographic record:

Ileum Balloon

 

Waves
0 0 H O o
'P ‘P 0 0 b. o o n
m m 04: > 0 vs a .o
m m 2 a: .3 e a 3 °
0 0 .2 H :S H In H
0 In D. P P 0) U‘ H 0 o
s ,.. z 2 s a a a 2 a
54 lg ¢n cnc> 5+ lh ‘5 C? <3
20 0 8n "'" 10 1|! C" -- .04
2. 0 84 "" 9 3 4°- -- --
2.41 administration of nemural
2.44 72 ~~ -- 60 ~- —- --
g.u5 90 -- —— -- ~— - ~~ emssis
2.55 66 —- 10 49 —— —- -—
2.58 72 ~- -- -- -- —— - defecation
3.08 84 -- 10 35 —- -— ——
3.11 -- -- _- 35 -— -- -- defecation
3.14 66 ~- —- 33 -- -- -- defecation
3.24 66 —— 10 37 —— ~- -~
. -- 10 —- —- —— rhythmic contrac—
3 34 72 37 tions increased
in amplitude
3.44 2nd paper
fl
.5u an —- 10 41 -— -— -- n n
a. 0"" 78 ""“ 10 , 37 —~ -u- an n N N
n.1u an -- 10 37 —_ -- --
n.2u 72 -- 10 37 —- -- -_

-92..

In general a decrease in the pulse rate was observed in
this subiect, although alternated decreases and increases
occurred. From the normal of 84 it increased to 90 beats per
minute in about 5 minutes following nemural. Emssis occurred
at this time. then pulse rate decreased to 66 in 10 more min~
utes. It increased again reaching 84 in 13 more minutes.
Defecaticn occurred twice during this time. It was followed
again by a decrease to 66 in 6 more minutes. From this time
to the end of the experiment. pulse rate was 72 to 84 in al-
ternative manner. Respiratory rate could not be recorded
due to continuous panting of the animal.

The ileum balloon record shows a transient increase in
tone immediately after the drug was given. This increase
was from the normal of 43 mm. to 60 mm. and lasted for about
3 minutes. Rhythmic contractions during this period were of
very low amplitude. Alternated periods of increases and de~
creases in the tone level occurred for the remainder of the
experiment but in general there was a mean decrease in tone.
Rhythmic contractions remained consistently at 10 per minute
counted at 10 minute intervahaduring the whole time of the
experiment. An increase in amplitude of the rhythmic con-
tractions was observed after 53 minutes following nemural.

Defecaticn occurred three times and the animal vomited once.

-93...

4. Thiry—Vella Loop. The data derived from an

analysis of the various kymographic records and other ob-

servations in this
follows:

Dog No. 60

 

Table XXVIII.

Table XXIX.

Table XXX.

Table XXXI.

Dog No. 66

Table XXXII.

Table XXXIII.

Table XXXIV.

Table XXXV.

series are set forth in tables as

Arecoline hydrobromide at the rate
of 3.2 mgm. per kgm. body weight.
Arecoline hydrobromide at the rate
of 4.8 mgm. per kgm. body weight.
Nemural in a dose equivalent to are-
coline hydrobromide at the rate of
3.2 mgm. per kgm. body weight.
Nemural in a dose equivalent to are—
coline hydrobromide at the rate of
4.8 mgm. per kgm. body weight.

Arecoline hydrobromide at the rate of
3.2 mgm. per kgm. body weight.
Arecoline hydrobromide at the rate of
4.8 mgm. per kgm. body weight.
Nemural in a dose equivalent to are—
coline hydrobromide at the rate of
3.2 mgm. per kgm. body weight.
Nemural in a dose equivalent to are»
coline hydrobromide at the rate of

4.8 mgm. per kgm. body weight.

The salient features of the data are summarized after

each table.

D08 N0 0 60

TABLE XXVIII

— 94 _

Tabulated Data from a Thiry-Vella Loop
of the Ileum in One Dog

8 kgm. body weight

Drug: arecoline hydrobromide

Doss: 3.2 mgm. per kgm. body weight
Total dose: 25.6 mgm. dissolved in water and given by

stomach tube

Analysis of the record:

 

October 23, 1945

 

2nd paper

Ileum
Waves
0 0 H 0 e
p 43 (D o >. 0 O m
2 :2 t 2 +" 2 '3 5 s
.4 5 8 m p o
0 e H S H (D H
0 02 Q. 0 PP O" H 0 (1‘
a H 3 a 2’8 2. e 2: i:
54 33 a: Ea mun he ‘3 <7 (3
3.00 132 -— 70 12 —— -- —-
3.10 120 —- 66 ll 1 l6 -—
3.20 120 -- 65 ll -- - -
3'38 126 -— 5s 12 3 7-19 --
3. 126 -- 56 12 1 19 ~-
3.43 administration of arecoline hydrobromide
3.48 150 -- 52 10 -—- --- ---
3.5 132 -- 61 10 -— -— --
3.5 114 —— 48 -~ -— - 9'
.03 114 - 3 12 —— -- ~—
4.05 108 -— 7 -- —— —~ 6'
4.11 108 _- 47 ~- —— —- ~—
4.21 120 -- 54 12 —- -~ --
4.22 ~— -- - -- -~ —- ~-
4. 2 120 —— 49 12 ~— -— -
4.52 96 -- 50 12 2 15 -1

-05..

The following summarizes the results from the analysis
of the kymographic record obtained in this subject. A transi~
ent increase in pulse rate from the previous normal of 126 to
a rate of 150 beats per minute was reached in 5 minutes followa
ing administration of the drug. This was followed by a pro-
gressive decrease reaching a low of 96 toward the end of the
experiment. It was not possible to obtain data on respiratory
rate due to a continuous panting of the subject.

The ileum balloon tracing shows an increase in tone from
56 mm. to 61 mm. in 10 minutes following arecoline. Rhythmic
contractions during this period decreased in frequency from
12 to 10 contractions per minute following which there was a
period of quiescence of the gut lasting for about 9 minutes.
This quiescence of the ileum was accompanied by a decrease in
tone from 61 mm. to 48 mm. on the record and no rhythmic con—
tractions were evident. At the end of this period of in-
activity tone level was restored to 53 mm. and frequency of
rhythmic contractions appeared. These were similar to those
seen in the previous normal. After 2 minutes of activity a
second quiescent period is recorded lasting for about 6 minutes.
Tone level decreased again from 53 mm. to 47 mm. and no waves
of any type were recorded during this period of time. When gut
activity was restored. tone increased from 47 mm. to 54 mm. and
rhythmic contractions returned to normal. Toward the end of the
experiment (in about 1h. and 10') the record shows a very slight

decrease in tone level. Rhythmic contractions are to normal

frequency but amplitude is increased for very short periods.

- 96 _

TABLE XXIX

Tabulated Data from a Thiry-Vella Loop
of the Ileum in One Dog

Dog No. 60 November 12, 1945
8.5 kgm. body weight

Drug: arecoline hydrobromide

Dose: 4.8 mgm. per kgm. body weight
Total dose: 40.8 mgm. given by stomach tubs
Analysis of the kymographic record:

Ileum Balloon

 

Waves
0 0 H 0 e
+3 +3 o 0) b. 0 O m
. . “a z a 2 e s
03 u: g (d .4 OJ 3 o
O o H g. H ‘0 H
O Q 0. P +3 a) H C d)
s ... 3 25; e 0 e :3 :3
so 3: a: can) 54 IE ‘5 C? <3
3.29 150 ._ 13 66 -- -- ~—
3.39 180 -— 12 63 -- -— —~
3. 9 -— «- -- 60 -— -- ~-
3.50 administration of arecoline
3.58 144 - -— 54 -~ -- -— defecation
.03 -- «- 12 60 —~ -~ —— defecation
4.06 -— -~ 12 58 -- —— -- defecation
4.09 -- -- -- 6o -— —- ~—
4.19 -— -- 12 60 -- —- -
4.29 -- -- 12 59 —— —- ~-
4.22 -‘ -- —- ~~ -— —- 10'
4. 2 ~- —— 12 53 -- -- ~-
l". 50 """' ""“ ""' ' 53 2 8 “'"

It was impossible to obtain pulse and respiratory rates
due to the extremely excited and the nervous condition of
this animal. The ileum balloon record showed in general a
decrease in tone. There were alternated decreases and in»
creases but the main value was always below normal. Rhythmic
contractions remained normal in frequency. A period of
10 minute quiescence of the ileum was recorded after 42 min—
utes following arecoline. During this period of quiescence
no rhythmic contractions were recorded. Toward the end of
the experiment 2 peristaltic waves of 8 mm. amplitude were
recorded. Other manifestations in this subject were defeca~

tion three times.

_ 93 -

TABLE XXX

Tabulated Data from a Thiry—Vella Loop
of the Ileum in One Dog

Dog No. 60 November 1, 1945

9 kgm. body weight

Drug: nemural

Dose: equivalent to arecoline hydrobromide at the rate of
3.2 mgm. per kgm. body weight

Total dose: 52.6 mgm. of nemural dissolved in water and
given by stomach tube

Analysis of the record:

Ileum Balloon

 

Waves
0 o .4 ' o .
S :3 0.: 2 i? 3 2 S
a: a: «40 0 c: 3 C 0
Ed .4 o «p o
o . H e .H m H
3 .3 8' it; 8 3 2:. .33 E
a a 2 28 a a: 2 a z;
4.02 1 6 -- 10 7o -— _- _-
4.12 1 -- 12 7O -- -—- ~—
".22 150 "'"' 10 66 ...- -— ..
4.23 administration of nemural
4.33 180 -- - 61 -- -- _.
4.3 - ~- -- -- -— —~ ~— defecation
v.3 is. .. 12 66 .. .. ..
4.4 - -- -- -- ~- -~ -- defecation
4.47 -— —- -- -— -- -- -- defecation
4.53 132 -- 12 59 -- -- -

-99...

In this case there was observed a transient increase in
pulse rate immediately after nemural. From a previous normal
of 150 per minute, the rate increased to 180 in 11 minutes.

It was followed by a decrease reaching 132 in 20 more minutes.
Data on respiratory rate were unobtainable due to continuous
panting of the animal. The ileum balloon record shows al~
ternate increases and decreases in tone level. Rhythmic con-
tractions increased in frequency from a normal of 10 to 12

contractions per minute. Defecaticn occurred three times.

— 100 -

TABLE XXXI

Tabulated Data from a Thiry-Vella Loop
of the Ileum in One Dog

Dog No. 60 November 29, 1945

9 kgm. body weight

Drug: nemural

Dose: equivalent to arecoline hydrobromide at the rate of
4.8 mgm. per kgm. body weight

Total dose: 78.9 mgm. of nemural dissolved in water and

given by stomach tube

 

Results:
Ileum
Waves
0 0 H O o
+1 +3 e 0 >5 0 0 (D
52 8% .38 t 8 ‘3 5 '8
Ed A o +3 0
0 o H I3 'H 0) H
o m 0. «94¢ m U' .4 m m
E .4 m bad C m 9. od .fi
H a o no 0 H E :1 +2
E! t: can) E4 h. C? C)

 

2'53 152 -- i;
.0 1 "'"‘
3 124

O\O\O\
WW F
I
I
I
I
I
I

3.15 administration of nemural

3.2 144 ~- 11 66 -- —— -—
3,2 —— —- -— —- -— ~- -~ defecation,
borborygmus
3.31 -- -- —- -— -- -- «—- defecation
3.35 180 ~- 11 66 a~ —— ~-
3. 6 -— —- -- —- -— -- —- defecation
3. 133 —- 11 66 —— - -
3.55 1 -- 11 66 -— ~- ~-
.0 144 —- 12 63 -— -- -
u. -- .. -- -- —— -- -— micturition

~ 101 -

Due to nervousness of this subject representative data
on pulse and respiratory rates could not be obtained. The
ileum balloon tracing showed an increase in tone level im«
mediately after nemural was given. From the normal of 63 mm.
it increased to 66 mm. lasting for about 45 minutes. During
this time rhythmic contractions decreased in frequency by
one contraction per minute. At the 53rd minute following
the drug, tone level and rhythmic contractions returned to
the previous normal. During the experiment, three defeca~
tions occurred, preceded by borborygmus. Micturition oc-

curred at the end of the experiment.

DOg N0. 66

Tabulated Data from a Thiry—Vella LOOp
of the Ileum in One Dog

6 kgm. body weight

Drug:

Dose:

- 102 -

TABLE XXXII

arecoline hydrobromide

3.2 mgm. per kgm. body weight

Total dose: 19.2 mgm. dissolved. in water and given by

stomach tube

Analysis of the record:

 

 

Ileum
Waves
° ” F‘ e .
P +3 0 ' >1 0 o m
:1 a i; .22: 2. '2 g g
o - *‘ 2:3 91’ 1: g 11
a) to Q. m +949 6‘ 1—1 a) a)
a H z s as :2 a t; :3
3.45 120 20 81 9 .m- -- -1
3-55 120 1? 75 9 —-—« -—. ..
.05 1111 16 65 9 1 20 ..
H.15 11H 14 57 9 .«. _- ,_
”~16 administration of arecoline hydrobromide
I-I-. 26 102 15 65 9 2 25-28 .1...
4.36 90 15 58 9 1 32 ..
1+. 6 9o 15 6o 10 2 20-.23 -1.
11.56 96 15 62 10 2 20—25 -—
1+. 56 "'"' "" ““ "“ "" ‘r --—- emesi 3
1,59 -- —- -—~ -- -- -~ .. 1.1.1.
5.05 an 1“- 66 10 5 12-126 ....
5'07 '“' "" "‘ "“ ‘“ """ “W 2nd paper
5.1} -‘ -* "r “r -- -- _- emesis
5.17 96 18 59 -- it H.311 ....
5. 27 9O 13 60 ~- 2 30132 ____
5- 7 102 13 55 9 1 3s -1
5.37 102 12 52 -—- 2 20—23 -
5.57 8’4 12 52 —--- 2 13~28 -1

_ 103 _

Analysis of the kymographic record and of the corres~
pending data inserted in Table XXXII show that arecoline
hydrobromide at the level used in this case caused a de—
crease in pulse rate from the previous normal of 11“ to a
frequency of 84 beats per minute in about #9 minutes
following administration of the drug. A progressive in"
crease is shown toward the end of the experiment. Data on
respiratory rate shows no appreciable changes from the
previous normal during 60 minutes following the drug, then
a slight decrease occurred.

The ileum balloon record shows an increase in tone
following administration of arecoline. This increase was
from 57 mm. to 65 mm. in about 10 minutes. Following the
initial increase there was a progressive but irregular de—
crease in tone for the remainder of the experiment. Rhyth-
mic contractions increased in frequency from 9 to 10 per
10 minute interval. Waves other than rhythmic contractions
were recorded in this subject. These varied in frequency
from 1 to 5 per 10 minute period. They also varied in amp-
litude from 12 to 38 mm. Other manifestations recorded in

this case were emesis which occurred three times.

— 104 -

TABLE XXXIII

Tabulated Data from a Thiry-Vella L00p
of the Ileum in One Dog

Dog No. 66

6 kgm. body weight

Drug: arecoline hydrobromide

Dose: 4.8 mgm. per kgm. body weight

October 30, 1945

Total dose: 28.8 mgm. dissolved in water and given by

stomach tube

Analysis of the record:

 

Ilegm
Waves
0 0 ,4 0 .
P +3 O a) >b a, U m
d C“ 0+9 > C) 'd ‘3 '0
a: a: *‘0 m G 3 o C)
'5‘3 #3 m -P o
0 ° 7" :3 H m 34
O m 9‘ ‘P‘F’ Q3 0‘ H O a)
.3 H g 5.8 g g: D. 3 fi
5'. a (I: “10 £4 13:. a O’ ‘ O
2.3% 90 19 9 63 -- -- -«
2. 96 19 10 60 -- -_ _-
2.55 90 18 10 62 —— -— ..
3.05 90 17 10 60 -~ -— an

3.05 administration of arecoline hydrobromide

3.15 76 18 10 61 -1 _-

2 2 15 11 6o -- _.
g 3% $2 16 10 5s .. ..
3.39 ‘ve-I- “ nu- an— -- “-
3 o u -- “- ----0 one-— a—
3 50

s4 15 12 54 _- --

4.00 66 14 10 5s _- .1
4.10 78 11 11 50 .. __
4.20 78 12 12 52 —- --

rhythmic contrac-
tions increased
amplitude

emesis

2nd paper
rhythmic c0ntra0~
tions increased
amplitude

_ 105 -

This subject showed a marked decrease in pulse rate
following arecoline. From a previous normal of 90 it fell
to 66 in 55 minutes following administration of the drug.
Respiratory rate decreased in pr0gressive manner from a nor-
mal of 17 to 12 respirations per minute at the end of the
experiment.

The ileum balloon record showed alternating periods of
increased and decreased tone but the level was in general de—
creased somewhat from the previous normal. The record also
shows two short periods of partial relaxation of the gut can
curring toward the end of the experiment. Rhythmic contrac—
tions increased in frequency from 10 to 12 per 10 minute
intervals and they also increased in amplitude. This animal

vomited once, 34 minutes following the drug.

~ 106 -

TABLE XXXIV

Tabulated Data from a Thiry—Valle Loop
0f the Ileum in One Dog

Dog N0. 66 November 8, 1945

7.5 kgm. body weight

Drug: nemural

Dose: equivalent to arecoline hydrobromide at the rate of
3.2 mgm. per kgm. body weight

Total dose: 28.8 mgm. 0f nemural dissolved in water and
given by stomach tube

Analysis of the record:

Ileum Balloon

 

 

Waves
'3 ‘3 '3 >1 0 m '
‘ o a:
2 2 2 t; a; 8 ”S g g
0 E33 '4 ”’ *’ "
. :3 0 -rl m H
0 0 o. .94: o ova r4 0 m
3 H 8 E 8 8 1'; 1. 9 g g
E“ ‘a In use) a. find .3 (y (3
3.14 78 25 10 7O -- —- -_
3.24 78 23 11 69 —— .. _-
3.34 66 23 11 67 -- -- ._
3.35 administration of nemural
3.45 60 20 11 64 _- -_ _.
.55 6O 16 12 62 -- _- 3c
0 " “ " ”r - -- - emesis
. 54 31 --- 60 —« -« 26'
0 6o 22 "'"" 60 "" -- —.
e 72 20 11 58 -— —— 6'
‘ “‘ “ “ -~ ~- ~~ 2nd paper

84 30 12 5s —- -- —~
84 17 11 55 —— -- ~-
84 17 11 56 1 19 ~-
78 14 11 55 1 15 3'
66 13 - 55 1 18 7'

\mmgrffrrruw
H OUTU‘I N M I-‘ OU'I
U'IU'IKflUUWU'IU'IU'IW

O

_ 107 _

While the pulse rate in this subject showed some vari~
ation, it was decreased for the first #0 minutes following
nemural. This decrease varied from 6 to 12 beats per minute
below the lowest normal reading. Then an increase in rate
occurred which lasted for 50 minutes. The rates observed
during this period were from 6 to 18 beats per minute faster
than the lowest normal. The rate was normal at the end of
the period of observation. Respiratory rats showed no sig-
nificant changes other than a decrease in rate toward the
end of the experiment. The ileum balloon record shows a
progressive but slight decrease in tone. Periods of partial
relaxation of the gut were observed and during these periods
rhythmic contractions were seldom seen. The frequency of
rhythmic contractions was in general the same as the previ-
ous normal; however, an increase from 11 to 12 was observed
on two occasions. Peristaltic waves at the frequency of one
every 10 minutes followed by partial quiescence of the gut
were seen after 80 minutes following the administration of

the drug. Emssis occurred once.

— 108 —

TABLE XXXV

Tabulated Data from a Thiry-Vella L00p
of the Ileum in One Dog

Dog N0. 66 November 15, 1945

6.5 kgm. body weight

Drug: nemural

Dose: equivalent to arecoline hydrobromide at the rate of
4.8 mgm. per kgm. body weight

Total dose: 57 mgm. of nemural dissolved in water and
given by stomach tube

Results.of the kymographic record:

Ileum Ballomg

 

Waves
3 3 '8 >1 0 C) .
° 0 m
1'2 :9. .2 :3 *1: 8 '8 a «g
0 ,3 ‘3 Q Q) +3 0
0 m :5 +1: 0 g‘ 1: 3 g *
S H 3 28 g a Q. «4 ,q
5‘ E: n: an: Es &. 13 é; E;
4. 3 s4 20 10 63 -_ -- ._
4.33 72 15 11 63 ~- —- ~-
4.53 72 16 10 6O -- -~ . -~ -
4.54 administration of nemural
.04 9O 15 12 61 -— ._ --
5.14 60 20 ll 57 -- -- __
5.24 72 17 12 57 —— _- _-
5.34 72 17 14 5s __ -_ a-
5.26 73 _- m- n- -‘ —- ~~ emesis
5.44 72 14 18 56 —— .. __
5.52 2nd paper

6.32 78 12 10 55 r‘ “‘

_ 109 -

Data on pulse rats showed a transient increase in the
rate during the first 10 minutes following nemural. From a
previous normal of 72 it increased to 90 beats per minute.
A slight decrease from normal was recorded for the remainder
time of the experiment. Respiratory rate was in general
below the last normal counted. A very transient increase of
4 respirations per minute above normal occurred in about
20 minutes following the drug.

The ileum balloon record shows a slight decrease in
tone level. Alternated periods of decreases and increases
in tone were recorded but these were always below normal.
Rhythmic contractions varied in frequency. From the previ—
ous normal of 10 contractions per minute it increased to
11 to 12. However, a frequency of 14 and 18 contractions

per minute was recorded before and after emesis occurred.

~ 110 -

IV DISCUSSION

A. Effects with Arecoline. In general, arecoline hy—

 

drobromide caused the same kind of physiological responses
in the 47 dogs used. However, differences in degree were
shown by groups of these experimental subjects.

1. Pulse Rate. Arecoline hydrobromide at the two
levels used in dogs caused a decrease in pulse rate. One
case, however, Dog No. 46, showed an increase from the
previous normal. Variations in degree of responses were
observed. Some of the experimental subjects"I showed a
gradual decrease in heart rate with recovery to normal by
the end of the experiment. Other subjects“ showed a pro—
.nounced slowing of the pulse lasting for the complete ob-
servation time (This period varied from 60 to 145 minutes).
A third group of subjects’** showed a transient decrease in
pulse rate followed by an increase above previous normal.
This latter occurred toward the end of the experiment.

It was also observed that when arecoline hydrobromide

powder was given in meat to the experimental subjects, a

* .Dogs No. 11~13~14—17-l8~4l-57~59—61 given arecoline
hydrobromide at the rate of 3.2 mgm. per kgm. body weight.

*- Dogs No. 6—7-12415-16~28-30—32-39-48-5lu54 given areco~
line hydrobromide at the rate of 3.2 mgm. per kgm. Also the
majority of the subjects at the rate of 4.8 mgm. per kgm.

see page No. 29—38u43-45—49~50—63 at the rate of 3.2 mgm.
per kgm. and Dogs N0. 32—40~43-45 at the rate of 4.8 mgm. per

kgm.

- 111 -

sudden but transient decrease in pulse rate occurred. This
decrease was in some cases very marked and always occurred
in from 6 to 10 minutes following the administration of the
drug.

TABLE XXXVI

Effects on Heart Rate When Arecoline Powder
Was Given in a Piece of Meat

Dose: 3.2 mgm./kgm.

 

 

Dog_!o. Pulse Rate
LowestfiReached' Time IE
Last Normal from Normal Minutes
25 108 42 10'
26 123 increased
28 102 60 6'
29 9O 78 10'
46 126 24 7 '

 

D089: ”’08 mgm./kgm.

 

26 72 60 5:
28 96 36 10'

 

Table XXXVI contains a group of subjects in which are~
coline hydrobromide powder was given in meat. It shows the
differences in response immediately after drug administran
tion. Dog No. 26 at the lower level of arecoline showed an
increase in pulse rate instead of a decrease. Dog No. 29
showed a very slight decrease in pulse rate. Dogs No. 25,
48 and 28, on the other hand, showed a great fall in pulse

r3159.

- 112 ~

The literature shows that arecoline in its systemic ac~
tion causes cardiac slowing mainly by stimulation of the
parasympathetic nerve endings. In the very early study of
its actions Marme (32) reported a temporary slowing of the
heart when concentrated solutions (1%) were dr0pped into the
eyes of rabbits. The temporary cardiac slowing previously
described was seen to occur in some dogs when the powdered
drug was given orally in meat or when small quantities of
the pure drug was placed in the mouth. When meat alone was
given or when the drug was administered by stomach tube this
phenomenon was absent. Placing in the mouth of these same
animals bitter or irritant agent such as gentian, quinine
and alcohol likewise produced no cardiac slowing. These re~
sults indicate a possible similarity of reflex effect from
the local action of arecoline on the buccal mucosa to those
observed by Marme'with concentrated solution in the eyes of
rabbits. This paradox is difficult to explain in the light
of the usual results from irritation of sensory nerve endings
by such agents as for example dilute ammonia vapor.

It is evident that the slowing of the pulse rate is
caused by the systemic action of arecoline hydrobromide and
also by a reflex stimulation upon the cardio inhibitor mecha—
nism when in direct contact with mucous membrane, at least
in certain areas. However, some animals may respond differ-
ently and an increase in pulse rate instead of a decrease
may occur. Dog No. 26 was given arecoline hydrobromide three
times at the level of 4.8 mgm. per kgm. body weight. Pulse

rats showed varying results. An increase cocurred the first

_ 113 _

time. The second time only a slight decrease in pulse rate
occurred and the third time there resulted a very marked de—
crease.

A possible explanation for the increased rate seen in
some subjects may be that it is part of the reflex effects
accompanying nausea, as described by Traube (52), Brooks
and Luckhardt (6) and others (Miller (37)).

2. Purgative Action. The literature contains
several reports which show that arecoline causes a rather
quick evacuation of the bowels (21, 32, 36, 47). Feces are
described to be of soft consistency at first, followed by
foamy and liquid stools. Presence of mucus after several
defecations has also been reported (32). The results in
this study are in confirmation with those reported in the
references cited.

TABLE XXXVII

Summary of the Incidence of Defecaticn
with Arecoline at Two Levels of Dosage

 

 

No. of Level of Total Number of Defecations Time of

Cases Arecoline HBr _____ Observ.
None 1 '2 3 4

21 4.8 mgm./kgm. — 4 9 6 2 60~138

 

Table XXXVII shows the variation in total number of de-
fecations after arecoline hydrobromide was given orally by
stomach tube. Of 47 dogs treated with arecoline hydrobromide
at the level of 3.2 mgm. per kgm. body weight, 6 cases failed

to defecate; 14 cases showed but one defecation; 15 defecated

— 114 ~

twice; 9 defecated three times and only 3 cases defecated
four times during periods of observation ranging from 52 to
155 minutes. In 21 of these dogs arecoline hydrobromide at
a rate of 4.8 mgm. per kgm. body weight was given by stomach
tube and the results as to number of defecations is inserted
in the same table. In this group of animals, the majority
of them defecated twice and almost one—third defecated three
times during periods of observation ranging from 60 to 138
minutes.

As a rule the first defecation was of soft consistency,
then scanty and repeated liquid or semi~liquid feces followed.
It has been already reported (28) that arecoline causes de-
hydration of the tissues. It was observed that these animals
were thirsty when returned to their cages at the termination
of the experiment.

TABLE XXXVIII
The Time at Which First Defecaticn Occurred and

Number of the Experimental Subjects EXpressed
by Percentage, with Arecoline at Two Levels of Dosage

 

 

Time 47 Do 8 21 Do 3
3.2 mgm.?kgm. 4.8 mgm.?kgm.
-- 10' 29.0% 47.6%
11—15' 20.0% 33.3%
16~20' 24.0% . 9.5%
21~25' 6.4% 4-7%
26-301 2.1% 0.0%
31~up‘ 18.5% 4.9%

Table XXXVIII shows the time and percentage of

occurrence of the first defecation. According to these data

_ 115 _

defecation occurred in the majority of the cases during the
first 20 minutes following administration of arecoline hydro~
bromide at the level of 3.2 mgm. per kgm. body weight and
during the first 15 minutes when 4.8 mgm. per kgm. body weight
was given. However, in some cases no defecation had occurred
60 minutes following the drug and one case (Dog No. 10) defe-
cated after 127 minutes.

3. Nauseant and Emetic Effects. Another relatively
frequent symptom observed after arecoline hydrobromide was
the presence of nausea accompanied by one or more emeses.
Table XXXIX contains the occurrence of emeses expressed in
percentage. Emesis occurred once in more than one~half of
the cases.

TABLE XXXIX

Number of Emeses Occurring in Experimental Animals
after Arecoline Hydrobromide at Two Levels of Dosage

No. of ' Number of Emeses
Cases Dose None 1 2 3

47 3.2 mgm./kgm. 36.2% 63.8% 21.2% 4.2%
21 “‘08 mgm./kgm. 2308% 76.2% 33.3% “07%

 

 

Table XXXX gives the time in which the first emesis
occurred. It may be observed that emesis occurred early
(within 20 minutes) in the majority of the cases treated with

arecoline at the level of 3.2 mgm. per kgm. body weight.

— 116 -

TABLE XXXX

Time of Occurrence of the First Emssis with Arecoline
at Two Levels of Dosage

 

um ,Jmaai. iéefism.
—- 10' 16.6% 18.1%
11—20' u}.3% 27.2%
21-30' 6.6% 0.0%
31-up' 33-5% 5“-T%

 

It is well known that emesis may occur by drugs that
stimulate the vomiting center located in the medulla ob~
longata (Weiss and Hatchet). Mechanical and chemical ir—
ritants of various kinds acting upon vagal or sympathetic
afferent terminations in the gastric mucosa may initiate
vomiting reflexly (4). Harms (32) states that solutions of
arecoline as weak as .0“ percent causes a burning sensation
with hyperemia when applied to the tongue. The presence of
emesis after arecoline hydrobromide administration may be
due to its irritant effects upon the gastric mucosa.

It was also observed that when early emesis occurred
(within.20 minutes) the animal recovered soon from the drug
effects. This is possibly by reason of loss of unabsorbed
drug from the stomach. When emesis occurred later than
30 minutes following drug administration the animal exhibited
a prolonged nauseant stage. A characteristic standing posi-
tion was observed. The animal remained standing with his

head down, his eyes fixed on one point and paying no attention

to his surroundings. This state of depression was observed

_ 117 _

especially in some overweight dogs to which, for this reason,
relatively large total doses of arecoline hydrobromide was
given. It also occurred in a few animals of normal weight
when the higher level of the drug was administered.

M. Urinary Effects. Micturition did not occur
as a constant effect of arecoline hydrobromide. However, it
occurred in 19 of M7 cases when arecoline hydrobromide was
used at the level of 3.2 mgm. per kgm. body weight. It was
particularly observed in overweight dogs and the time of
occurrence ranged from 1 to 105 minutes. It was repeated
once in three cases. Micturition occurred in 10 of 21 dogs
under the same drug at the level of 4.8 mgm. per kgm. body
weight in from 8 to 48 minutes.

5. Effects on Gut Motility. Table XXXXI contains
in a more concise form the comparative results from the
analysis of the kymographic records taken on four dogs in
two of which Thiry fistulas (Dogs No. 57 and 61) and the
other two (DOgs No. 61 and 66) Thiry—Vella fistulas were
prepared. These experimental subjects received arecoline hy—

drobromide at the levels of 3.2 mgm. and H.8 mgm. per kgm. body

weight.

 

 

 

 

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_ 119 a

The effects of arecoline on the motility of the gut can
be studied somewhat satisfactorily with respect to the fre—
quency of rhythmic contractions and to the number of peri~
staltic waves because both of these can be evaluated quanti~
tatively. However, the method used was not suitable for re—
cording peristaltic waves which are supposed to be increased
in number after arecoline (8.31, #0, 50, 51). Rhythmic con—
tractions seem to decrease in frequency by 1—2 contractions
per minute from the previous normal. However, in two cases
(Dogs No. 61 and 66), the amplitude definitely increased.

This was especially evident after 60 minutes following drug
administration. Alvarez (2) has studied the influence of
drugs on intestinal rhythmicity and concludes that drugs
which increase or decrease the tone and amplitude of the con~
tractions do not necessarily affect the rate.

The tone level varied somewhat after drug administration.
An increase above previous normal was observed in the majority
of the cases, but this increase lasted for short periods and
alternated with decreases below the normal.

Periods of quiescence of the gut appeared on the record
in all the cases, with the exception of Dog No. 66 at the
3.2 mgm./kgm. level of arecoline. During these periods of
quiescence, no rhythmic contractions were recorded, the tone
level decreased somewhat and several defecations of semi liquid
feces occurred.

B. Discussion of Results with Nemural as Compared to

Arecoline Hydrobromide on the Same Animals. While

these two related drugs cause the same type of physiological

~ 120 -

responses, they differ somewhat in degree and in the time of
onset of action in the 18 experimental subjects used.

1. Pulse Rate. Both drugs cause slowing of the heart
rate. This decrease rate was very definite and it lasted
longer than the period of observation when nemural was used.
Most of the animals receiving this drug appeared quite depressed.
Under arecoline, these experimental subjects showed less de—
pression or it was absent and heart rate recovered to normal to—
ward the end of the observation period. An increase in heart
rate instead of the expected decrease may occur with either one
of these drugs. Also, a decrease followed by an increase above
the normal was observed with both drugs.

2. Purgative Action. Table No. XXXXII illustrates
the results in 18 experimental subjects in which both drugs
were given at two different levels. At least one defecation
occurred in each of the C see. Two defecations occurred in
about three—fourth of the animals under both drugs. A third and
fourth defecation were more prone to occur when nemural was
given. 'Two cases under arecoline and two under nemural failed
to defecate during the observation time.

There were some differences in the time of occurrence of
the first defecation. With arecoline hydrobromide, 43.7% of the
cases at the lower level and 50.0% of the cases at the higher
level of dosage defecated once during the first 10 minutes fol~
lowing administration of the drug. The values for nemural were
28.2% and 47.0% at the lower and higher levels respectively.
However, at the 20th minute, the incidence of occurrence of the

first defecation was somewhat greater with nemural than with

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-- em.mm ew.ma ea.am em.m ea.am e~.ma em.ms eH.HH .aes\.ama m.m
osaaooone

sum use pun ocoz a»: can use pea ocoz omsmon

monosm escapeoomon use mean

 

omepcoonom ea vommonnwm mamosm use

.ewoa ma ca
Hendsoz use oufiaonponuam seaflooonq mo madam o>apenea800

scapeoomoo mo ooeounsooo

Hanna“ mamas

TABLE XXXXIII

The Time of Occurrence of First Defecaticn
with Arecoline and Nemural

 

 

 

 

 

Arecoline Hydrobromide Nemural
Time 3.2 mgm./kgm. 4.8 mgm./kgm. * **
-- 10' “3.7% 50.0% 28.2% “7.0%
11~15' 12.5% 27.7% 35.2% 35.2%
16-20' 12.5% 11.1% 5.3% 17.8%
21-25 ' 6. 2% 5. 5% 11. 7% 0. 0%
26—30' 0.0% 0.0% 0.0% 0.0%
3l~up' 25.1% 5.7% 19.1% 0.0%
TABLE XXXXIV
The Time of Occurrence of First Emssis
with Arecoline and Nemural
Arecoline Hydrobromide Nemural
Time 3.2 mgm./kgm. ”.8 mgm./kgm. t a.
- 10' 38.4% 11.1% 50.0% 18.1%
11~15' 23.0% 22.2% 30.0% 18.1%
16—20' 0.0% 11.2% 10.0% 0.0%
21-25' 0.0% 0.0% 0.0% 15.1%
26-30' 7. 6% 0. 0% 0. 0% is. 1%
new 31.0% 55.5% 10.0% 26.6%

 

*' Equivalent to arecoline hydrobromide at the rate
of 3.2 mgm./kgm.

** Equivalent to arecoline hydrobromide at the rate
of 4.6 mgm./kgm.

- 123 _

arecoline. With nemural at this time 69.2% at the lower and
100% at the higher level had shown a first defecation. The
values for arecoline at a comparable period were 68.7% and
88.8% at the lower and higher levels respectively. The re~
mainder of the first defecation with arecoline at both levels
and nemural at the lower level were irregularly scattered
throughout the balance of the period of observation. These
periods ranged from 8“ to 140 minutes.

3. Nauseant and Emetio Effect. Table XXXXII shows
that the occurrence of emesis was of about equal frequency
with both drugs. The incidence of occurrence of emesis,
however, was not as great as that of defecation. The time of
occurrence of the first emesis seems to vary with the dose
used. With both drugs emesis was more delayed at the higher
level of dosage. During the first 10 minutes following ad—
ministration of the drug, emesis occurred in 38.4% at the
lower and 11.1% at the higher level of dosage of arecoline.
The values for nemural were 50.0%.and 18.1% at the lower and
higher levels respectively. At the 15th minute following ad-
ministration of the drug, the incidence of occurrence of the
first emesis was 61.u%1and 33.3% with arecoline at the lower
and higher level of dosage respectively and the values for
nemural were 80.0% and 36.2%. Late emesis (in more than
31 minutes) was more prone to occur with arecoline than with
nemural. The influence which the organic arsenic present in
the nemural may have had on the differences in emetic effects
would be difficult to evaluate. The somewhat earlier occur-

rence of emesis with nemural as compared to arecoline may

~12u_

indicate some differences in these two compounds.

u. Effects on Gut Motility. Tables No. XXXXI and
XXXXV give the results from the analysis of the kymographic
records taken on four dogs prepared with Thiry fistulas
(Nos. 57 and 61) and Thiry—Vella 100ps (Nos. 60 and 66) after
arecoline hydrobromide and nemural respectively. Rhythmic
contractions seem to decrease in frequency in 1-2 contrac-
tions per minute when arecoline was given. An increase in
1-3 contractions per minute occurred under nemural. Tone
level increases someWhat with both drugs and it was especially
evident when the drug was given in a piece of canned meat.
Periods of quiescence of the gut appeared on the record almost
always when arecoline was used and it appeared less frequent
under nemural.

Five dogs (Nos. 25, 26, 28, 29 and 48) were prepared with
ordinary fistulas on which kymographic records were taken after
arecoline and nemural in powder were given in a piece of canned
meat. Analysis of these records show an immediate and marked
decrease in pulse rate after arecoline as it is shown in
Table No. XXXVI. This decrease in heart rate was not observed
when nemural was given. The ileum balloon record showed also
an increase in tone level immediately after either one of the
drugs was given. This increase seems to be more marked under
nemural than with arecoline. There was a tendency for rhythmic

contractions to be decreased in frequency under arecoline and

to be increased under nemural.

-125-

Besides the 18 dOgs treated with arecoline and nemural
at the two levels already discussed, 20 more dogs were given
nemural at a dosage equivalent to arecoline hydrobromide at
the rate of 3.2 mgm./kgm. In these subjects one defecation
occurred in 95% of the cases; a second defecation occurred in
60%; a third in I+0% and a fourth defecation in 20% of the
cases. The time of occurrence of the first defecation was as
follows: During the first 10 minutes following nemural, 112.1%
of the cases had shown the first defecation. At the 25th min-
ute, 8M.l% had defecated once and the rest (15.9%) defecated
in more than 26 minutes following nemural. These results in--
dicate some differences in time of onset and number of defeca~
tions as compared with the results obtained with ’47 dogs under
arecoline hydrobromide at the level of 3.2 mgm./kgm. It would
aPPBEur that nemural has a more marked purgative effect causing
more defecations in short time than arecoline.

One emesis occurred in 80% of the cases and it was repeated
once in 53.8%. The first emesis occurred in 15 minutes in about

62.5% of the cases. At the 25th minute following nemural, the

firBt emesis had occurred in 87.5% of the cases. The remainder

(12.5%) vomited once after the 25th minute. These data show
that early emesis is more frequent with nemural. All emetic

efffacts occurred during the first 31 minutes following the ad»-

min 1 stration of nemural.

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neon

1. Both drugs caused slowing of the heart rate. How—
ever, this slowing was more persistent with nemural than with
arecoline hydrobromide when given by stomach tube. When the
powdered drug was given in a piece of meat, arecoline caused
an immediate and definite slowing of the heart rate which did
not occur with nemural.

2. Purgative effect was more rapid in onset, and re~
peated defecations resulted in many subjects when either one
of the drugs was given at the higher level of dosage. In
general, the purgative action of arecoline hydrobromide ap—
peared to be more rapid in onset than nemural, although the
latter drug produced a more complete emptying of the bowels.

3. Early emesis occurred more often under nemural than
with arecoline. Emssis was delayed with both drugs when the
higher level was used. A prolonged state of nausea was ob-
served under nemural similar to that observed with an in~
creased dosage of arecoline. The animals exhibited greater
and more prolonged depression with nemural than with arecoline.

M. The kymOgraphic records showed that arecoline causes
a decrease in rhythmic contractions by l to 2 contractions
per minute and an increase in the tone level followed by a den
crease. They also showed periods of quiescence of the iso»
lated loop of intestine. Nemural caused an increase in the
rate of the rhythmic contractions by l to 3 contractions per
minute. The tone level is also increased followed by a de~

crease. Complete quiescence of the gut was less frequently

— 123 -

seen with nemural.

5. Micturition may be present following arecoline hydro~
bromide and less frequent following nemural.

6. There exists considerable variation in individual
responses. The expected results may fail to occur with either
one of these two drugs.

7. Both drugs caused the animal to be thirsty after medi~
cation. The ingestion of large amounts of water may aggravate

the emetic effects.

1.

2.

3.

5.

6.

7.

9.

10.

- 129 -
REFERENCES

Alvarez, W. C. "The metabolic Gradient Underlying In~
testinal Peristalsis“, Amer. Jour. of
Physiol., A6:186, 1918.

Alvarez, W. C. “The Influence of Drugs on Intestinal
Rhythmicity", Amer. Jour. of Physiol.,

#6:55n, 1918.

Amadon, R. S. "Arecoline Hydrobromide", Jour. Amer.
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Best, C. H. and N. B. Taylor "The Physiological Basis
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Wilkins 00., 1943, Baltimore.

Best, 0. H. and N. B. Taylor Ibid., p. 823.

Bocquillon—Limousin, Cited by Fish, P. A. "Arecoline
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of Vet. Physiol. and Pharm., Cornell Univ.,
No. A, 1907.

Brooks, 0. and A. B. Luckhardt, Cited by Torald Sollman
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Cannon, W. B. "Peristalsis, Segmentation, and the My-
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Coenders, "Vergleich zwischen Arekolin und Physo-
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Dale, A. S. “The Relation between Amplitude of Contrac-

tion and Rate of Rhythm in the Mammalian

11.

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_ 13o _

Ventricle", Jour. Physiol., 70(u):u55_473, 1930.

Davidson, W. G. "A Teniacide for Dogs", The North Amer.
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Dukes, H. H. "The Physiology of Domestic Animals",
p. 332, Comstock Publishing 00., Inc., 1943,
New‘York.

Epstein, D. "The Responses of the Batrachian Alimen~
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(the South African Clawed toad)—Arecoline",
Quart. Jour. Exptl. Physiol., 22:1-5, 1932.

Fanslau, C. E. "Laboratory Data-Nemural", Obtained from
the Biologic and Research Laboratories of
Winthrop Chemical Company, New York, 9 pages,
August 18, 1939.

Fish, P. A. "Arecoline Hydrobromide", Abstr. of Work
Done in the Laboratory of Vet. Physiol. and
Pharm., Cornell Univ., N0. 4:37Hu1, 1907.

Fluckinger, Cited by Patz (43).

Frohner, E. "Untersuchungen uber das Arekolin ein Er—
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f. prakt. Thierh., 5:336, 1894.

Goodman, L. and A. Gilman "The Pharmacological Basis of
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Graefe, Cited by Patz (“3).

Hall, M. C. Cited by Greig, J. and G. Boddie "Hoare's
Veterinary Materia Medica and Therapeutics",

Alexander Eger 00., 1942, Chicago.

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22.

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27.

28.

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Hall, M. C. and Shillinger, J. "Critical Tests of M13.
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Jackson, D. E. ”The Action of Certain Drugs on the
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Jahns, E. "Ueber die Alkaloide der Arecanuss", Berichte
d. d. Chem., 21:3404, 1888.

Kadonaga, C. "Beitrage uber die Pharmakologischen
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Kenneth, B. C. "An Experimental Study of the Movements
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Kobert, Arch. f. exp. Path. u. Pharm., Cited by
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Lavagna, G. "Experimentelle Notizen uber die physio—
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Leepin, "Quantitative Hamoglobinbestimmung nach Fleischl
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Vet. Med. Assoc., 13:396. 1921—22.

_ 133 _

30. Lieb, C. C. and M. G. Mulinos "Some Further Observations
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39. Olmsted, J. and Giragossintz, G. "Barbitals", Proc. Soc.
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- 133a -

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Philadelphia.

\

APPENDIX

PROTOCOLS OF CLINICAL EXPERIMENTS
WITH ARECOLINE HYDROBROMIDE AT A
DOSAGE RATE OF 3.2 MGM. PER KGM.

_ 13h _

DOS N00 5 February 17, 1945

Male

7 kgm. body weight

Temperature: 101.0 F

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight

Total dose: 22.4 mgm. dissolved in water and given by
stomach tube

Results:

TIME PULSE OBSERVATIONS
1057 POM. 90

2.05 Administration of arecoline
hydrobromide.

2.10 84

2.17 84

2.28 84

2.38 78 Animal is very quiet. He rests on

the floor and seems to be depressed.

2.52 72

2.58 72

3.08 78 Animal is restless. Attempt to
defecation.

3.26 84

3.47 84

4. 27 78

H.135...

DOS NO- 6 February 17, 1945
Female
8.5 kgm. body weight
Temperature: 101.8 F
Drug: arecoline hydrobromide
Dose: 3.2 mgm. per kgm. body weight
Total dose: 27.2 mgm. dissolved in water and given by
stomach tube‘

Results:

TIME PULSE OBSERVATIONS
3.25 P.M. 114

3.30 Administration of arecoline
hydrobromide.

3.38 114

3.40 Defecaticn of soft consistency.

3.45 96

3.47 Defecaticn; feces of semi—liquid

consistency in fairly large amount.

3.50 84

4.00 78 Animal shows restlessness. Res~
piration seems to be increased.

4.15 60 Animal seems somewhat depressed.
Salivation is present.

4.30 60

4.45 60

4.46 Defecaticn; feces of liquid

consistency.

H 136 -

Dog No. 6 (cont'd.)

TIME PULSE OBSERVATIONS
5.00 54
5.25 66
5.50 72

6.00 66

_ 137 -

Dog No. 7 February 19, 1945
Male
8.5 kgm. body weight
Temperature: 102.0 F
Drug: arecoline hydrobromide
Dose: 3.2 mgm. per kgm. body weight
Total dose: 27.2 mgm. dissolved in water and given by
stomach tube

Results:

TIME PULSE OBSERVATIONS
3.00 P.M. 168

3.10 Administration of arecoline
hydrobromide.

3.25 132

3.26 Emssis.

3.37 132 _

3.40 Defecaticn; feces of soft
consistency.

3.50 132

4.05 120

4.15 120 . Animal is quiet.

4.30 108

4.45 114

5.00 120

5.15 120

5.45 132

- 13g _

DOS N00 8 February 21, 1945
Male
9.5 kgm. body weight
Temperature: 101.4 F
Drug: arecoline hydrobromide
Dose: 3.2 mgm. per kgm. body weight
Total dose: 30.4 mgm. dissolved in water and given by
stomach tube

Results:

TIME PULSE OBSERVATIONS
2.20 P.M. 108

2.35 Administration of arecoline
hydrobromide.

2.49 Defecation; feces of soft
consistency.

2.55 120

3.02 96

3.10 78

3.15 75

3.25 78

3.35 72

3.45 66

3.55 72

5.10 120

-139-

Dos N0. 9 February 23, 1945
Male
8.5 kgm. body weight
Temperature: 101.2 F
Drug: arecoline hydrobromide
Dose: 3.2 mgm. per kgm. body weight
Total dose: 27.2 mgm. dissolved in water and given by
stomach tube

Results:

TIME PULSE OBSERVATIONS
2.05 P.M. 120

2.17 Administration of arecoline
. hydrobromide.

2.30 114

2.40 Defecaticn; feces of soft
consistency.

2.45 114

2.55 Nausea followed by emesis.

3.00 108

3.10 Defecaticn; feces of liquid
consistency.

3.20 108 Respiration seems to be increased.

3.30 102 Mucus material is expelled from anus.

3.45 96

H 140 -

Dog N0. 10

Female

8.5 kgm. body weight

Temperature: 100.8 F

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight

Total dose: 27.2 mgm. dissolved in water and given by
stomach tube

Results:

TIME PULSE OBSERVATIONS
1.35 P.M. 108

1.45 Administration of arecoline
hydrobromide.

1.55 108

2.05 96

2.15 96 Animal is very quiet.

2.25 90

2.35 90

2.45 84

2.55 84

3.05 84

3.15 90

3.25 90

3-35 3”

3.50 84

3.52 Defecation; feces of solid cone

sistency followed by liquid material.

4.00 90

— 141 «

Dog No. 11

Male

7 kgm. body weight

Temperature: 102.0 F

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight

Total dose: 22.4 mgm. dissolved in water and given by

stomach tube

TIME PULSE OBSERVATIONS
4.10 P.M. 126

4.15 Administration of arecoline
hydrobromide.

4.30 126

4.31 Defecation; feces of soft con-

sistency and in small quantity.'

4.45 126
4.55 114
5.05 114

5.15 120

AI
,u‘i
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a
.0"
.M
0 wt
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. I
ll
' .4:
I
a".
ell
a
vi:
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U
I
f
A
c
1
Q

H 142 H

D08 No. 12 March 1, 1945
Female

8.5 kgm. body weight

Temperature: 101.6 F

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight

Total dose: 27.2 mgm. dissolved in water and given by

stomach tube

Results:

.TIME PULSE OBSERVATIONS

3.35 P.M. 150

3.44 Administration of arecoline
hydrobromide.

3.52 150

3.54 Defecation. Animal shows increase
respiration.

4.00 Emesis.

4.02 144

4.12 132

4.15 Defecation; feces of soft
consistency.

4.21 126

4.31 114

4.41 126

4.51 114

5.01 120

5.11 120

H 143 -

Dog N0. 13 March 7, 1945

Female

7 kgm. body weight

Temperature: 101.0 F

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight

Total dose: 22.4 mgm. dissolved in water and given by
stomach tube

Results:

TIME PULSE OBSERVATIONS
1.35 P.M. 132

1.45 Administration of arecoline
hydrobromide.

1.55 128

1.57 Defecation; feces of soft
consistency.

2.00 132

2.15 120

2.20 132

2.25 Defecation; feces of liquid

consistency and accompanied by mucus.
2.26 120
2.35 108
2.45 120

A‘

3 '1-
I

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v

I a:
.\i
.14
-

1' ‘
.. [22

T n
;.F-‘
l.-w v.
r

.
.I'w‘

hell.
I

‘l‘!:1
{Jioi

'ah,‘

I
ow to.

"in-J

- 144 -

D08 NO- 14 March 14, 1945
Male

11 kgm. body weight

Temperature: 101.3 F

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight

Total dose: 35.2 mgm. dissolved in water and given by

stomach tube

Results:

TIME PULSE OBSERVATIONS

3.10 P.M. 120

3.20 Administration of arecoline
hydrobromide.

3.30 108

3.37 Emssis; fairly large amount of
foodstuff.

3.39 Defecation; feces of soft con—
sistency.

3.40 102

3.43 Emssis; liquid material and foamy.

3.44 Micturition.

3.46 Defecation; scanty and repeated.

3.55 102

3.56 Defecation; feces somewhat liquid.

4.05 114 Mucus is expelled from anus.

4.20 108

4.30 114 Mucus is expelled from anus.

H 145 a

D08 N0. 15 March 19, 1945

Male

13 kgm. body weight

Temperature: 101.2 F

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight

Total dose: 41.6 mgm. dissolved in water and given by
stomach tube

Results:

TIME PULSE OBSERVATIONS
4.10 P.M. 102

4.15 Administration of arecoline
hydrobromide.

4.25 84

4.35 72

4.38 Emssis; fairly large amount of
foodstuff.

4.45 66

4.55 66 Animal seems to be depressed.

5.05 66

5.25 60 Animal still depressed.

5.35 54 " " "

5.40 Salivation.

5,45 60

5-55 60

6.05 66

Dog N0. 16

Female

9 kgm. body weight

Temperature: 103.0 F

Drug:
Dose:

Total

H 146 H

March 20, 1945

arecoline hydrobromide

3.2 mgm. per kgm. body weight

dose: 28.8 mgm. dissolved in water and given by

stomach tube

Results:

TIME
3-35
3-37

3.45
3.55
4.05
4.15
4. 25

4.35
4.45

4.55
5-05
5.15
5-35
5.35

108
108
108
102

84

OBSERVATIONS

Administration of arecoline

hydrobromide.

Animal is quiet.

Animal shows trembling movements

on his rear legs.

_ 147 H

Dog No. 17 March 22, 1945
Female

24 kgm. body weight

Temperature: 103.5 F

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight

Total dose: 76.8 mgm. dissolved in water and given by

stomach tube

Results:

TIME PULSE OBSERVATIONS

3.25 P.M. 108

3.30 Administration of arecoline
hydrobromide.

3.39 Defecation; feces of soft con«
sistency.

3.40 108

3.49 Defecaticn.

3.55 108

3.57 Defecation; feces somewhat liquid.

3.58 Micturition.

4,02 Defecation; liquid feces and scanty.

4.05 102

4.10 Defecaticn followed by small quan-
tity of mucus.

4.13 Micturition.

4.20 102

4.30 102

_ 148 -
Dog No. 17 (cont'd.)

TIME PULSE OBSERVATIONS
4.40 P.M. 90

5.00 108

5.08 Micturition.

5.15 114

H 149 -

Dos No. 17 March 28, 1945
Male

11 kgm. body weight

Temperature: 100.4 F

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight

Total dose: 35.2 mgm. dissolved in water and given by

stomach tube

Results:
TIME PULSE OBSERVATIONS
8.45 A.M. 72
9.10 Administration of arecoline
I hydrobromide.
9.20 84
9.24 Defecation; feces somewhat liquid.
9.25 - Nausea followed by emesis; foamy
material.
9.30 78
9.40 72
9.50 72
9.51 Defecation; feces of liquid con—
sistency and accompanied by mucus.
10.00 66
10.15 66

10.30 72

_ 150 .

Dog No. 28 April 16, 1945
Male

11 kgm. body weight

Temperature: 102.4 F

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight

Total dose: 35.2 mgm. dissolved in water and given by

stomach tube

Results:
TIME PULSE OBSERVATIONS
9.35 A.H. 132
9.45 Administration of arecoline
hydrobromide.
9.51 Defecation; feces of soft con—
sistency.
9.55 120
10.00 Defecation; feces of liquid con~
sistency scanty and repeated.
10.05 96
10.15 78
10.20 Micturition.
10.25 78
10.33 Defecaticn
10.35 78
10.45 66
11.10 72 Nausea
11.11 Nausea followed by emesis.
11.20 72

11.30 84

_ 151 _

Dos N0. 29 April 18, 1945

Male

13.5 kgm. body weight

Temperature: 100.3 F

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight

Total dose: 43.2 mgm. dissolved in water and given by
stomach tube

Results:

TIME PULSE OBSERVATIONS
10.25 A.M. 84

10.30 Administration of arecoline
hydrobromide.

10.40 66

10.45 Emssis.

10.48 Emssis; foamy material.

10.50 Defecation; feces blood tinged.

10.51 84

11.00 108

11.08 Micturition.

11.10 90

11.20 96

11.30 96.

11.40 90

Dog N0. 30
Male

805 kgm. bOdy weight

Temperature: 102.4 F

April 20, 1945

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight

Total dose: 27.2 mgm. dissolved in water and given by

stomach tube

Results:

TIME
10.30 A.M.

10.35

10.45
10.46

10.48
10.50

10.54
10.55
10.58

11.00
11.10

PULSE
114

114

96
84

OBSERVATIONS

Administration of arecoline

hydrobromide.

Defecation; feces of soft
consistency.

Micturition.

Defecaticn; feces of liquid
consistency.

Defecation; feces of liquid
consistency and scanty.

Emesis; fairly large amount of
foodstuff.

Emssis; scanty and foamy liquid

material.

_153_

Dog N0. 30 (cont'd.)

TIME PULSE OBSERVATIONS

11.12 A.M. Emssis; liquid and foamy material.
11.17 Emssis; liquid and foamy material.
11.20 96

11.30 90

11.40 66

11.55 84

Dog N0. 32

Male

11.5 kgm. body weight

Temperature: 102.0 F

_ 154 _

April 19, 1945

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight.

Total dose: 36.8 mgm. dissolved in water and given by

stomach tube

Results:

TIME
9.10
9.20

9.30
9.40
9.50
9.57

10.00
10.10
10.14
10.16
10.19
10.20
10.30
10.40
10.50
10.52

126
114
102

102
96

84
84
78
84

OBSERVATIONS

Administration of arecoline

hydrobromide.

Defecation; feces of soft
consistency.

Nausea.

Emesis.
Defecaticn.

Micturition.

Emssis; small quantity of liquid

material and foamy.

.01

iv'

e
.1

Dog No. 36 April 28, 1945

Male

8.5 kgm. body weight

Temperature: 101.2 F

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight

Total dose: 27.2 mgm. dissolved in water and given by
stomach tube

Results:

TIME PULSE OBSERVATIONS
9.15 A.M. 132

9.25 Administration of arecoline
hydrobromide.
9.32 Emssis; fairly large amount of
foodstuff.
9-35 90
9.36 Emssis; liquid material and foamy.
9.41 Defecaticn and nausea.
9.45 88
9-55 95
10.05 102
10.15 108
10.25 126
10.35 120
10.45 114

10.55 114

-155...
Dog N0. 36 (cont'd.)

TIME PULSE OBSERVATIONS
11.05 A.M. 114

11.15 96
11.25 114
11.35 120

11.45 168

_ 157 .

Dos NO- 37 April 28, 1945

Male

12 kgm. body weight

Temperature: 101.5 F

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight

Total dose: 38.4 mgm. dissolved in water and administered by
stomach tube

Results:

TIME PULSE OBSERVATIONS
9.35 A.M. 102

9.40 Administration of arecoline
hydrobromide.
9.50 104
10.00 96
10.10 96
10.11 Defecation; feces of soft
consistency.
10.20 72 I
10.30 78
10.40 54
10.43 Defecation and micturition.
10.50 60
11.00 84
11.10 72
11.20 84
11.30 96
11.40 95

11.50 96

* 158 —

Dog No. 38 April 28, 19H5

Male

6 kgm. body weight

Temperature: 101.5 F

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight

Total dose: 19.2 mgm. dissolved in water and given by
stomach tube

Results:

TIME PULSE OBSERVATIOYS

9.50 A.M. 90

10.00 Administration of arecoline
hydrobromide.

10.10 90

10.20 96

10.30 102

10.no 90

10.50 108 Nausea and salivation.

10.55 Defecation; feces of soft
consistency.

11.00 84

11.10 72

11.13 Defecation; feces of liquid
consistency.

11.18 Emssis; accompanied with foamy

material.

_ 159 a

Dog No. 38 (cont'd.)

TIME PULSE OBSERVATIONS
11.20 72
11.30 72
11.no 120
11.h5 Eicturition.

11.50 120

Dog No. 39 April 28, 19h5

Male

11 kgm. body “eight

Temperature: 101.0 F

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight

Total dose: 35.2 mgm. dissolved in water and given by
stomach tube

Results:

TIME PULSE OBSERVATIONS
10.10 A.M. 126

10.30 Administration of arecoline
hydrobromide.

10.n0 125

10.50 inn

11.00 102

11.10 96

11.20 8%

11.30 72

11.40 Defecation.

11.u1 96

- 161 -

Dog No. 40

Male

12 kgm. body weight
Temperature: 102.? F

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight

April 28, 19M5

Total dose: 38.4 mgm. dissolved in water and given by

stomach tube

Results:

TIME PULSE
1.uo .m. 102

OBSERVATIONS

1.50 Administration of arecoline
hydrobromide.

1.52 Defecation; feces of soft
consistency.

1.53 'Hicturition.

1.55 Emssis.

1.58 Defecation; feces of liquid

consistency.

2.00 168

2.03 Emssis.
2.10 96

2.12 I Defecation.
2.20 96

2.30 96

2.40 96

2.50 8H

3.00 8h

— 162 —
Dog No. “0 (cont'd.)

TIME PULSE OBSERVATIoNS
3.10 P.E. 84

3.20 96
3.30 120
3.no 96
3.50 90
n.00 84
n.10 102

1+. 20 102

a 163 _

Dog No. 41 April as, 19u5

Male

11+ kgm. body weight

Temperature: 103.2 F

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight

Total dose: HH.S mgm. dissolved in water and given by
stomach tube

Results:

TIME PULSE OBSERVATIONS
1.50 P.M. Inn

1.58 Administration of arecoline
hydrobromide.

2.02 Defecation; feces of soft
consistency.

2.03 Emssis.

2.05 132

2.15 120

2.25 120

2.35 120

2.h5 132

2.55 120

3.05 120

3.15 132

3.25 132

3.35 120

~164—
Dog No. #1 (cont'd.)

TIME PULSE OBSERVATIONS
3.u5 P.M. 120
3.55 120
4.05 138
n.15 Inn

a 165 _

Dog No. A} April as, 19u5

Male

5.5 kgm. body weight

Temperature: 100.2 F

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight

Total dose: 20.8 mgm. dissolved in water and given by
stomach tube.

Results:

TIME PULSE OBSERVATIONS
2.20 Pgfl. 88

2.28 Administration of arecoline
hydrobromide.
2.35 Defecation; feces of soft

consistency.

2.40 102

2.50 76

2.51 Defecation; feces of liquid

consistency.

2.55 Emssis.

3.00 80

3.10 80

3.20 96

3.30 120

3.40 80

3.50 80

4.00 92

h.lo 120

4.20 80

— 166 -

Dog No. “5 ‘ April 28, 19u5

Male

6 kgm. body weight

Temperature: 101.6 F

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight

Total dose: 19.2 mgm. dissolved in water and given by
stomach tube

Results:

TIME PULSE OBSERVATIONS
3.00 Pom. 108

3.10 Administration of arecoline
hydrobromide.

3.20 126

3.27 Micturition.

3.30 11h

3.fl0 108

3.50 90

4.00 102

“.02 Defecation.

4.10 102

4.20 98

4.30 98

“.90 120

h.u2 Emssis

n.5o 120

_ 167 _

Dog No. #6 April as, 1945

Male

13 kgm. body weight

Temperature: 100.6 F

Drug: arecoline hydrobromide

Doss: 3.2 mgm. per kgm. body weight

Total dose: 41.6 mgm. dissolved in water and given by
stomach tube

Results:

TIME PULSE OBSERVATIONS
3.15 P.M. 132

3.22 Administration of arecoline
hydrobromide.

3.30 luO

3.33 Micturition.

3.u0 135

3.Ml Defecation; feces of soft
consistency.

3.92 Emesis.

3.49 Defecation; feces of liquid con—

sistency and scanty and repeated.

3.h6 Defecation.
3.50 152
4.00 152

“.10 160

— 168 ~

Dog No. #6 (oont'd.)

TIME PULSE OBSERVATIONS
4.20 P.M. Defecation.

n.20 152

n.30 152

n.uo 152

n.50 152

a 169 _

Dog No. #7 April as, 19u5

Male

18 kgm. body weight

Temperature: 101.2 F

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight

Total dose: 57.6 mgm. dissolved in water and given by
stomach tube

Results:

TIME PULSE OBSERVATIONS
3.45 P.M. 120

3.50 Administration of arecoline
hydrobromide. ‘

4.00 102

“.05 Defecation; feces of soft
consistency.

n.10 102

n.20 96

4.29 Defecation; liquid feces,

scanty and repeated.

4.30 102
u.uo 96
“.49 Emssis.

n.5o 96

_ 17o _

Dog N0. 48 April 28, 1995
Male

19.5 kgm. body weight

Temperature: 101.6 F

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight

Total dose: 96.4 mgm. dissolved in water and given by

' stomach tube

Results:

TIME PULSE OBSERVATIONS
2.00 P.M. 102

2.05 Administration of arecoline
hydrobromide.

2.15 102

2.20 Emssis; fairly large amount of
foodstuff.

2.25 88

2.35 88

2.45 89

2.48 Micturition.

2.55 68

3.05 68

3.15 as

3.25 60

3-35 72

3.45 64

— 171 ~

Dog No. 48 (cont'd.)

TIME PULSE OBSERVATIONS
3.55 P.‘. 54
4.05 64
4.15 64

4.25 64

_ 172 _

Dog No. 49 May 3. 1995

Male

8 kgm. body weight

Temperature: 101.9 F

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight

Total dose: 25.6 mgm. dissolved in water and given by
stomach tube

Results:

TIME PULSE OBSERVATIONS
8.55 A.M. 96

9.02 Administration of arecoline
hydrobromide.

9.12 120

9.19 Emssis.

9.20 Defecation; ssmi~liquid feces.

9.22 90

9.30 89

9.31 Emssis; liquid and foamy material.

9.35 Emssis; foamy material.

9.90 78

9.43 Defecation; feces of liquid
consistency.

9,49 Emssis; scanty and foamy material.

9.50 108

10.00 90

10.10 108

-173-
Dog Ho. 99 (cont'd.)

TIME PULSE OBSERVATIONS
10.20 A.M. 119

10.30 108
10.40 108
10.50 108

11.00 102

Dog No. 50

Male

10 kgm. body weight

Temperature: 102.0 F

a 17d _

May 3, 1995

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight

Total dose: 32 mgm. dissolved in water and given by

stomach tube

Results:

TIME
9.05
9.07

9.14
9.21
9.24

9.25
9.35
9.95
9.50
9-55
10.05
10.15
10.25
10.35
10.45

10.55

A.M.

PULSE
132

156

126
138
150

150

OBSERVATIONS

Administration of arecoline

hYdIObromidee

Emssis.

Defecation; feces of soft

consistency.

Micturition.

- 175 _

Dog No. 51 May 3, 1945

Male

11 kgm. body weight

Temperature: 101.8 F

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight

Total dose: 35.2 mgm. dissolved in water and given by
stomach tube

Results:

TIME PULSE OBSERVATIONS
9.15 A.M. 102

9.29 ' Administration of arecoline
hydrobromide.

9.32 90
9.92 73
9.47 Defecation.
9.52 78

10.02 72

10.15 78

10.18 Emssis.

10.25 66

10.35 60

10.45 60

10.55 72

_ 175 _

Dog N0. 52 May 5, 1945

Female

8 kgm. body weight

Temperature: 102.2 F

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight

Total dose: 25.6 mgm. dissolved in water and given by
stomach tube

Results:

TIME PULSE OBSERVATIONS
9.50 A.M. 84

9.55 1 Administration of arecoline
hydrobromide.
10.05 84
10.08 Emssis.
10.15 66
10.25 72
10.35 89
10.45 84
10.55 84
11.05 84

11.15 72

Dog No. 53

Female

10 kgm. body Weight

Temperature: 103.0 F

a 177 _

May 5. 1995

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight

Total dose: 32 mgm. dissolved in water and given by

stomach tube

Results:

TIME

9-55
10.00

10.15
10.20

10.25
10.35
10.45
10.55
11.05
11.15
11.25

A0“.

150

132
180
144
150
144

132

OBSERVATIONS

Administration of arecoline

hydrobromide.

Defecation; feces blood tinged

and micturition.

- 173 _

Dog No. 59 June 4, 1945

Male

11.5 kgm. body weight

Temperature: 101.9 F

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight

Total dose: 36.8 mgm. dissolved in water and given by
stomach tube

Results:

TIME PULSE OBSERVATIONS
10.00 A.M. 120

10.05 Administration of arecoline
hydrobromide.

10.15 108

10.17 Defecation; feces of soft
consistency.

10.25 84

10.30 Defecation; feces of semiusolid
consistency.

10.35 90

10.45 72

10.55 72

11.05 60

11.15 89

11.25 60

a 179 a

Dog Ho. 55 June 4, 1945

5 kgm. body weight

Temperature: 102.0 F

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight

Total dose: 16 mgm. dissolved in water and given by
stomach tube

Results:

TIME PULSE OBSERVATIONS
10.10 A.M. 114

10.15 Administration of arecoline
hydrobromide.

10.25 144 Animal is excited.

10.26 Defecation; feces of soft
consistency.

10.35 96

10.45 120

10.52 Defecation; feces of liquid
consistency.

10.55 108

11.05 108

11.15 120

11.23 Defecation; feces of liquid
consistency.

11.25 75

11.35 144

11.45 96

~ 180 ~

DOS N00 56 June 4, 1945

Female

6.5 kgm. body weight

Temperature: 101.6 F

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight

Total dose: 20.8 mgm. dissolved in water and given by
stomach tube

Results:

TIME PULSE OBSERVATIONS
10. 20 A.M. 120

10.25 Administration of arecoline
hydrobromide.

10.26 Nicturition.
10.35 144

10.42 Defecation.
10.45 120

10.55 126

11.05 108

11.15 108

11.25 102

11.35 96

11.45 102

DOS N0. 57 June 4, 1945
Female
7.5 kgm. body weight
Temperature: 103.2 F
Drug: arecoline hydrobromide
Dose: 3.2 mgm. per kgm. body weight
Total dose: 24 mgm. dissolved in water and given by

stomach tubc

Results:

TIME PULSE OBSERVATIONS
9.50 A.M. 120

9.53 Administration of arecoline
hydrobromide.
9.56 Defecation; fairly large amount

of feces and micturition.

9.58 Defecation; feces of semi—liquid

consistency.

10.05 126 I

10.19 Defecation; scanty and repeated
mucus.

10.15 108

10.25 120 Mucus, scanty but repeated.

10.35 114

10.45 120

10.55 120

1

1

— 182 ~

D08 NO- 58 June 4, 1995

Female

8.5 kgm. body weight

Temperature: 102.2 F

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight

Total dose: 27.2 mgm. dissolved in water and given by
stomach tube .

Results:

TIME PULSE OBSERVATIONS
9.45 A.M. 96

9,49 Administration of arecoline
hydrobromide.

9,56 Defecation; feces of soft
consistency.

9.58 Emssis; fairly large amount

of foodstuff.

10.00 60

10.08 Emssis, somewhat liquid and foamy.

10.10 60

10.19 Defecation; scanty and repeated
feces of liquid consistency.

10.20 60 Mucus, scanty but repeated.

10.30 78

10.40 90

10.50 90

11.00 90

11.10 96

Dog N00 59

Female

10 kgm. body weight

Temperature: 102.2 F

- 1g} _

June 9, 1945

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight

Total dose: 32 mgm. dissolved in water and given by

stomach tube

Results:

TIME

9-55
9.58

10.10
10.12

10.13
10.20
10.23

10.30
10.40
10.50
11.00
11.15

A.M.

PULSE
96

90

90

84
84
90
90
96

OBSERVATIONS

Administration of arecoline

hydrobromide.

Defecation; feces of soft
consistency.

EmesiB e

Defecation; feces of liquid

consistency.

- 184 —

Dog No. 60 June 9, 1945

Female

8 kgm. body weight

Temperature: 102.2 F

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. bOdy weight

Total dose: 25.6 mgm. dissolved in water and given by
stomach tube

Results:

TIME PULSE OBSERVATIONS
10.20 A.M. 132

10.23 Administration of arecoline
. hydrobromide.
10.30 Defecation; feces of soft
consistency.
10.35 102
10.38 Defecation; liquid feces and scanty.
10.93 Defecation; feces of liquid

consistency.

10.45 108

10.99 Defecation; scanty, repeated, liquid
feces accompanied by mucus.

10.55 126

11.05 132

11.15 132

Dog N0. 61 June n, 19h5
Female

6.5 kgm. body weight

Temperature: 101.8 F

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight

Total dose: 20.8 mgm. dissolved in water and given by

stomach tube

Results:

TIME PULSE OBSERVATIONS

3.15 P.L. 96

3.20 Administration of arecoline

hydrobromide.

3.29 Defecation and micturition.
3.30 — 84

3.33 Defecation and micturition.
3.40 84

3.43 Defecation; feces of liquid

consistenCy, scanty and repeated.

3.50 96
4.00 89
4.04 Emssis.
9.10 78
4.20 72
4.30 90
4.40 72

4.50 96

~ 186 -

Dog No. 62 June 4, 1945

Female

10 kgm. body weight

Temperature: 101.9 F

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight

Total dose: 32 mgm. dissolved in water and given by
stomach tube

Results:

TIRE PULSE OBSERVATIONS
3.25 P.M. 120

3.29 Administration of arecoline
hydrobromide.

3.40 126

3.42 Defecation; feces of soft
consistency.

3.45 Micturition.

3.50 126

4.00 102

9.10 96

4.18 Emssis.

4,19 Defecation; feces accompanied

with mucus.

4.20 126
4.30 . 132
4.40 108

5.15 102

- 137 _

908 30- 53 June 9, 1945

Female

15.5 kgm. body weight

Temperature: 103.6 F

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight

Total dose: 49.6 mgm. dissolved in water and given by
stomach tube 1

Results:

TINE PULSE OBSERVATIONS
10.15 A.M. 144

10.18 Administration of arecoline
hydrobromide.

10.25 Emssis; foodstuff.

10.26 Defecation; feces of semi~liquid
consistency.

10.27 Emssis, liquid and foamy material.

10.28 ' 60

10.38 66

10.42 Defecation; feces of liquid

consistency, scanty and repeated

and accompanied with mucus.

10.48 96
10.58 120
11.08 126
11.18 138
11.30 150

11.40 150

— 188 —

Dog No. 69 June 9, 1995

Female

10 kgm. body weight

Temperature: 101.4 F

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight

Total dose: 32 mgm. dissolved in water and given by
stomach tube

Results:

TIME PULSE OBSERVATIONS
10.10 Adi . 96

10.19 Administration of arecoline
hydrobromide.

10.24 Emssis.

10.25 72

10.30 Defecation.

10.32 Micturition; animal seems to

be depressed.

10.35 60

10.45 60

10.46 Micturition.

10.47 Emssis.

10.55 60

10.59 Defecation; liquid feces and
followed by mucus.

11.05 60

11.15 66

--189—

Dog N00 64 (CORE'do)

TINE PULSE OBSERVATIONS
11.30 A.M. 72
11.40 78

11.50 84

~190—

DOS No. 55 June 11, 1945

Female

12 kgm. body weight

Temperature: 101.8 F

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight

Total dose: 38.9 mgm. dissolved in water and given by
stomach tube

Results:

TILE PULSE OBSERVATI ONS
2.10 .N. 96

2.18 Administration of arecoline
hydrobromide.
2.28 96
2.38 84
2.98 78
2.58 90
3.08 108
3.18 78
3.28 90
3.38 78
3.48 72
3.58 72
4.08 72
4.20 72

4.35 78

DOS NO- 65 June 11, 1945

Female

6.5 kgm. body weight

Temperature: 101.2 F

Drug: arecoline hydrobromide

Dose: 3.2 mgm. per kgm. body weight

Total dose: 20.8 mgm. dissolved in water and given by
stomach tube

Results:

TIME PULSE OBSERVATIONS
2.05 P.U. 84

2.15 Administration of arecoline
hydrobromide.

2.25 78

2.30 Emssis.

2.35 60

2.36 Defecation.

2.45 60

2.55 60

3.05 60

3.15 60 Mucus expelled from anus, scanty

and repeated.

3.25 66
3.35 78
3.95 90
3.55 96

4.05 90

PROTOCOLS OF CLINICAL EXPERIMENTS
WITH ARECOLINE HYDROBROMIDE AT A
DOSAGE RATE OF 4.8 MGLI. PEP. KGM.

a 198 a

Dog No. 32 April 27, 1945

11.5 kgm. body weight

Temperature: 101.5 F

Drug: arecoline hydrobromide

Dose: 4.8 mgm. per kgm. body weight

Total dose: 55.2 mgm. dissolved in water and given by
stomach tube

Results:

TIME PULSE OBSERVATIONS
10.35 A.M. 108
10.90 Administration of arecoline

hydrobromide.

10.50 96

11.00 102

11.10 114

11.11 Emssis.

11.19 Defecation; feces of soft
consistency.

11.20 96

11.28 Micturition.

11.29 Defecation; feces of liquid
consistency.

11.30 90

11.40 96

‘ 11.95 Emssis.

11.55 108

Dog No. 55 (cont'd.)

TIRE PULSE OBSERVATIONS
3.42 78
3.52 72
4.02 60
4.20 84

4.30 90

-203...

Dog No. 57 June 19, 1945

Female

7 kgm. body weight

Temperature: 109.0 F

Drug: arecoline hydrobromide

Dose: 9.8 mgm. per kgm. body weight

Total dose: 33.6 mgm. dissolved in water and given by
stomach tube

Results:

TIME PULSE OBSERVATIJYS
10.30 A.M. 138

10.35 Administration of arecoline
hydrobromide.

10.49 Defecation; feces of soft
consistency.

10.45 132

10.51 Defecation.

10.55 120

11.05 96

11.06 Emssis.

11.14 Defecation; liquid material

followed by expulsion of mucus.
11.15 114
11.25 120
11.35 138

~ 204 1

Dog No. 58 June 19, 1945

Female

8.5 kgm. body weight

Temperature: 102.9 F

Drug: arecoline hydrobromide

Dose: 9.8 mgm. per kgm. body weight

Total dose: 40.8 mgm. dissolved in water and given by
stomach tube

Results:

TIME PULSE OBSERVATIONS

10.35 A.M. 102

10.38 Administration of arecoline
hydrobromide.

10.40 78

10.49 Defecation; feces of soft

consistency.

10.51 Emssis.

10.55 Defecation accompanied with mucus.
10.58 72

11.07 Emssis.

11.08 66

11.18 72 Copious mucus expelled from anus.
11.28 78

11.45 102

11.50 102

- 305 _

DOS NO- 59 June 20, 1945

Female

10.5 kgm. body weight

Temperature: 102.2 F

Drug: arecoline hydrobromide

Dose: 9.8 mgm. per kgm. body weight

Total dose: 50.4 mgm. dissolved in water and given by
stomach tube

Results:

TINE PULSE OBSERVATIONS
9.40 A.M. 108

9.44 Administration of arecoline
hydrobromide.
9.54 96
10.09 78
10.06 Defecation; feces of soft

consistency.

10.14 78

10.15 Emssis.

10.24 66

10.34 78

10.37 Defecation; liquid material.
10.44 72

10,54 84

11.04 96

11.20 102

11.35 84

Dog N0. 60

Female

9 kgm. body weight

Temperature:

r0

0

C\
1

June 20, 1945

Drug: arecoline hydrobromide

Dose: 4.8 mgm. per kgm. body weight

Total dose: 93.2 mgm. dissolved in water and given by

stomach tube

Results:

TIME
9.50
9.54

10.00
10.04
10.14
10.24
10.34
10.94
10.54
11.04
11.21
11.38

1:
Oak.

PULSE

162

150
144
150
132
144
144
144
156
144

OBSERVATIONS

Administration of arecoline
hydrobromide.

Defecation;semi~solid feces.

Dog No. 61

Female

7 kgm. body weight

Temperature: 102.1 F

207 ~

June 12, 1945

Drug: arecoline hydrobromide

Dose: 4.8 mgm. per kgm. body weight

Total dose: 33.6 mgm. dissolved in water and given by

stomach tube

Results:

TIME
9.28
9.30

9.35

9.46

9.52

9.56
10.06
10.16
10.26
10.36
10.46
10.56
11.06
11.16
11.26
11.36

A.M.

PULSE
108

108

90
96
96
90
132
84
90
9O
90
89

96

OBSERVATIONS
Administration of arecoline
hydrobromide.

Defecation; feces somewhat liquid.

Defecation, scanty and repeated.

Mucus SXpelled from anus.

Dog No. 62 September 15, 1945
Female
11 kgm. body weight
Temperature: 100.0 F
Drug: arecoline hydrobromide
Dose: 9.8 mgm. per kgm. body weight
Total dose: 52.8 mgm. dissolved in water and given by
stomach tube
Results:
TILE PULSE OBSERVATIONS
10.05 .E. 132
10.25 Administration of arecoline
hydrobromide.
10.29 Nausea followed by emesis.
10.35 66 Animal seems to be depressed.
10.36 Nausea followed by emesis.
10.38 Defecation; liquid and scanty feces.
10.41 Nausea and foamy material is vomited.
10.43 Defecation; scanty and liquid feces.

Animal seems to increase respiration.

10.45 72

10.47 Nausea. Respiration is increased.
10.55 72 Mucus material expelled from anus.
11.05 78

11.15 78 Mucus material.

11.25 90

11.35 96

11.50 120

12.00 116

.. 209...

Dos NO- 53 August 23, 1945
Female

16.5 kgm. body weight

Temperature: 102.6 F

Drug: arecoline hydrobromide

Dose: #.8 mgm. per kgm. body weight

Total dose: 81.2 mgm. dissolved in water and given by

stomach tube

Results:

TIME PULSE OBSERVATIONS

2.30 P.n. 96

2.34 Administration of arecoline
hydrobromide.

2.un inn

2.45 Defecation; feces of soft
consistency.

2.h7 Micturition.

2.50 Emssis; material somewhat liquid
and scanty foamy.

2.5“ 178 Animal seems to be depressed.

3.0M 60

3.08 Mucus material expelled from anus.

3.1“ 90 Copious mucus material.

3.2% 96

3.34 108 Animal is more active.

3.uu 96

~ 210 -

Dog No. 64 September 15, 1945
Female
6 kgm. body weight
Temperature: 102.0 F
Drug: arecoline hydrobromide
Dose: ”.8 mgm. per kgm. body weight '
Total dose: 28.8 mgm. dissolved in water and given by
stomach tube

Results:

TIME PULSE ’ OBSERVATIONS
10.10 A.M. 90

10.20 Administration of arecoline
hydrobromide.
10.29 Defecation; feces of soft

consistency.

10.30 90

10.31 Micturition.

10.u0 72

10.41 Defecation; feces of liquid
consistency.

10.50 90

11.00 72

11.10 84 Mucus material expelled from anus.

11.20 90

11.30 90

11.50 72

12.00 84

~ 211 w

Dog No. 65 June 20, 1945

Female

10.5 kgm. body weight

Temperature: 101.1 F

Drug: arecoline hydrobromide

Doss: 4.8 mgm. per kgm. body weight

Total dose: 52.“ mgm. dissolved in water and given by
stomach tube

Results:

TIME PULSE OBSERVATIONS
9.u5 A.M. an

9.M8 Administration of arecoline
hydrobromide.
9.55 78
10.05 ’ Defecation; feces of soft
consistency.
10.08 66
10.10 Micturition.
10.14 Defecation; scanty and semialiquid
material.
10.18 66
10.28 MS
10.38 #8
10.48 60
10.50 60
11.08 5h
11.2u 72

11.uo 96

Dog No. 66

Female

6.5 kgm. body weight
Temperature: 101.1 F

Drug: arecoline hydrobromide

Dose: u.8 mgm. per kgm. body weight

June 20, 1945

Total dose: 31.2 mgm. dissolved in water and given by

stomach tube

Results:
TIE PULSE OBSERVATIONS
9.55 A.u. 102
9.59 Administration of arecoline
hydrobromide.
10.09 78
10.11 Defecation; feces of soft
consistency.
10.l9 72
10.29 66
10.39 72
10.4% Defecation.
10.49 60
10.50 Micturition.
10.58 Emssis.
10.59 72
11.09 54
11.25 5h
11.uo 72

PROTOCOLS OF CLINICAL EXPERIMENTS WITH NEI-JURAL
AT A DOSAGE RATE EQUIVALENT TO
ARECOLINE HYDROBROMIDE 3.2 MGM. PER KGM.

Dog No. 19

Female

/

Temperature:

Drug:

Dose:

Total

fa)

March 28, 19“5

c kgm. body weight

101.2 F

nemural in tablets

equivalent to 3.2 mgm. of arecoline hydrobromide per
kgm. body weight

dose: 1.?“ tablets of nemural (equivalent to 19.2 mgm.

of arecoline hydrobromide)

Results:

TIME PULSE OBSERVATIONS

10.50 A.M. 96

10.55 Administration of nemural in so—
1ution and given by stomach tube.

11.05 120

11.10 Emssis.

11.1“ Defecation; feces of soft consistency.

11.15 102

11.20 Micturition.

ll.-5 102

11.26 Emssis; liquid and foamy material.

11.27 Defecation; feces somewhat liquid.

11.35 96

11.37 Defecation; liquid feces, scanty and-
repeated. Animal is depressed;
shows nausea.

11,M5 8“

11.55 60

Dog No.

Male

20

12 kgm. body weight

Temperature:

Drug:

Dose:

Total

Resul

nemural in tablets

101.0 F.

March 28, 19“5

equivalent to 3.2 mgm. of arecoline hydrobromide per

kgm. body weight

dose: 3.89 tablets of nemural (equivalent to 38.“ mgm.

of arecoline hydrobromide)

ts:

TIME
1.uo
2.10

PULSE

P.M. 120

90
9O
90
8“
8“

90

an
an

OBSERVATIONS

Administration of nemural in so—

lution and given by stomach tube

Emssis

Dog No. 21

Male

March 29, 19“5

9.5 kgm. body weight

Temperature: 101.“ F

Drug: nemural in tablets
Dose: equivalent to 3.2 mgm. of arecoline hydrobromide per
kgm. body weight
Total dose: 3.08 tablets of nemural (equivalent to 30.“ mgm.
of arecoline hydrobromide
Results:
TIRE PULSE OBSERVATIONS
9.35 A.M. 8“
9.50 Administration of nemural in so~
lution given by stomach tube.
9.55 Emssis; liquid material and foodstuff.
10.00 8“
10.05 Defecation; feces of soft consistency.
10.07 Emssis; liquid and foamy material.
10.10 8“
10.18 Micturition.
10.20 8“ Animal seems to be depressed. Mucus
expelled from anus.
10.30 102
10.“c Sc
10.50 8“
11.00 8“
11.10 8“
11.20 8“ Animal is very quiet, somewhat

depressed.

-216—

Dog No. 22 March 30, l9“5
Male
5.5 kgm. body weight
Temperature: 102.5 F
Drug: nemural in tablets
nose: equivalent to 3.2 mgm. of arecoline hydrobromide per
kgm. body weight
Total dose: 1.78 tablets of nemural (equivalent to 17.6 mgm.
of arecoline hydrobromide)
Results:
TIME PULSE OBSERVATIONS
10.20 A.M. 90

10.30 Administration of nemural in so—

lution given by stomach tube.

10.35 Defecation; feces of soft consistency.

10.“o a“

10.“2 Defecation; feces of liquid con~
sistency.

10.“3 Emssis; fairlv large amount of
foodstuff.

10.“7 ' Defecation; liquid scanty and re-
peated.

10.50 72

10.52 Emssis.

10,5“ Defecation; liquid feces and ac—

companied with mucus.

11.00 72

_ 217 _

Dog No. 22 (cont'd.)

TIME PULSE OBSERVATIONS

11.05 A.M. Defecation; scanty and repeated;
mucus.

11.10 66

11.20 72

11.30 a“

ll.“0 8“

- 218 ~

Dog No. 23 March 31, 19“5
Male
10 kgm. body weight
Temperature: 101.0 F
Drug: nemural in tablets
Doss: equivalent to 3.2 mgm. of arecoline hydrobromide per

kgm. body weight
Total dose: 3.2“ tablets of nemural (equivalent to 32 mgm. of

arecoline hydrobromide)
Results:

TIME PULSE OBSERVATIONS

9.55 A21. 72

10.05 Administration of nemural in so—

lution given by stomach tube.

10.15 66

10.2“ Defecation; feces of soft consistency.

10.26 Emssis.

10.27 100

10.30 102

10.31 Defecation; liquid feces.

10.35 120

10.“3 132

10.55 96

11.00 Defecation; feces of liquid con—
sistency and blood tinged.

11.05 96

11.25 60 Animal is depressed.

11.55 s“

_ 219 _

Dog No. 2“ March 31, 19u5
Female
8.5 kgm. body weight
Temperature: 100.6 F
Drug: nemural in tablets
Dose: equivalent to 3.2 mgm. of arecoline hydrobromide per
kgm. body weight
Total dose: 2.“7 tablets of nemural (equivalent to 27.2 mgm.
of arecoline hydrobromide)
Results:
TIME PULSE OBSERVATIONS
10.00 A.u. 96
10.11 Administration of nemural in so—

lution given by stomach tube.

10.20 90
10.30 78
10.“0 78
10.“3 Defecation; feces of soft consistency.
10.55 84
11.05 8“
11.25 78

11.55 a“

~ 220 ~

Dog No. 28 April 10, 1945
Male
9.5 kgm. body weight
Temperature: 101.2 F
Drug: nemural in tablets
Dose: equivalent to 3.2 mgm. of arecoline hydrobromide per
kgm. body weight
Total dose: 3.08 tablets of nemural (equivalent to 30.“ mgm.
of arecoline hydrobromide)
Results:
TIME PULSE OBSERVATIONS
9.“5 A.M. 108
.55 Administration of nemural in solution.

given by stomach tube.

10.05 96

10.15 78

10.20 Defecation; feces of soft consistency.
10.25 66

10.32 Emssis.
10.35 72

10.“5 72

10.55 73

11.05 78

11.15 8“

11.30 8“

11.“5 s“

Dog No. 29 April 11, l9“5
Male
12.5 kgm. body weight
Temperature: 101.0 F
Drug: nemural in tablets
Dose: equivalent to 3.2 mgm. of arecoline hydrobromide per
kgm. body weight
Total dose: “.16 tablets of nemural (equivalent to “C mgm.
of arecoline hydrobromide)
Results:
TIRE PULSE OBSERVATIONS
10.15 A.M. 73
10.27 Administration of nemural in so~

lution given by stomach tube.

10.35 66

10.38 Nausea followed by emesis.

10.“5 66

10.52 Defecation; feces of soft consistency.
10.5“ Salivation.

10.55 90 Nausea.

11.05 78

11.15 66

11.25 66

11.35 60

11.45 66

Dog No. 30

Male

8 kgm. body weight
Temperature: 101.“ F

Drug: nemural in powder

April 12, 19“5

Dose: equivalent to 3.2 mgm. of arecoline hydrobromide per

kgm. body weight

Total dose: “6.8 mgm. of nemural (equivalent to 25.6 mgm.

of arecoline hydrobromide)

Results:
TIME PULSE
9.00 A.M. 120

9.15

9.19

9.22

9.2 90
9.30

9.35 81+
9.“5 90
9.55 75
10.05 66
10.15 72
10.25 90
10.35 78

10.“5 78

Administration of nemural in so-
lution given by stomaflitube.
Defecation; feces of soft consistency.
Emssis; foodstuff.

Animal seems to be depressed.
Defecation; liquid feces, scanty

and repeated.

Dog N0. 31 April 13, 19“5

Male

12 kgm. body weight

Temperature: 101.5 F

Drug: nemural in powder

Dose: equivalent to 3.2 mgm. of arecoline hydrobromide per
kgm. body weight

Total dose: 6“.3 mgm. of nemural (equivalent to 38.“ mgm.

of arecoline hydrobromide)

Results:
TIME PULSE OBSERVATIONS
10.30 A.M. 120
10.“7 Administration of nemural in sea
lution given by stomach tube.
10.52 Defecation; feces of soft consistency.
10.56 Defecation; fairly large amount
of feces.
11.00 120 Nausea.
11.01 Emssis; food material and foamy.
11.03 Defedation; feces somewhat liquid.
11.07 Emssis; liquid and foamy material.
11.09 Emssis and defecation.
11.10 126
11.12 Defecation and micturition.
11.16 Emssis; liquid and foamy material.
11.20 102
11.30 78
11.“o a“
11.53 8“

1‘.)

Do; No. 3
Male

11 kgm. body weight
Temperature: 101.2 F

Drug: nemural in powder

April 13, inhr

/"/

Dose: equivalent to 3.2 mgm. of arecoline hydrobromide per

kgm. body weight

Total dose: 70.2 mgm. of nemural (equivalent to 35.2 mgm.

of arecoline hydrobromide)

Results:
TIME PULSE
2.20 P.M. 108

2.30

2.35

2.“0 102
2.50 7a
3.00 8“
3.10 a“
3.20 72
3.30 72
3.“0 s“
3.50 72
“.00 78
“.10 7s
“.12

“.20 7a

11.30 an

OBSERVATIONS

Administration of nemural in so~

lution given by stomach tube.

Nausea.

Nausea followed by emesis.

a 225 _
Dog No. 32 (cont'd.)

TIME PULSE OBSERVATIONS
“. “5 P .M . 66

“.55 Defecation and micturition.

Dog No. 33 April 15, 19“5
Male
7 kgm. body weight
Temperature: 101.8 F
Drug: nemural in powder
Dose: equivalent to 3.2 mgm. of arecoline hydrobromide per
kgm. body weight
Total dose: “0.9 mgm. of nemural (equivalent to 22.“ mgm.
of arecoline hydrobromide)
Results:
TIME PULSE OBSERVATIONS
10.20 A.M. 120
10.25 Administration of nemural in sou

lution given by stomach tube.

10.30 Defecation; semi~solid feces.

10.31 11“

10.“1 Defecation; feces of soft consistency.
10.“5 96

10.“6 Emssis.

10.“8 Emssis.

10.5“ Emssis, liquid and foamy.

10.55 90

10.59 Defecation; liquid feces, scanty

and repeated.
11.03 Nauseant state.

11.05 102

Dog No. 33 (cont'd.)

TIME
11.15 A.M.
11.25

11.35
11.“5

PU

To.
Hi.-

96
96
8“
8“

OBSERVATIONS

Dog No. 3“ April 23, 19“5

Female

9 kgm. body weight

Temperature: 102.0 F

Drug: nemural in powder

Dose equivalent to 3.2 mgm. of arecoline hydrobromide per
kgm. body weight

Total dose: 52.8 mgm. of nemural (equivalent to 28.8 mgm.
of arecoline hydrobromide)

Results:

TIME PULS OBSERVATIONS

10.35 A.E. 102

10.“5 Administration of nemural in sou

luticn given by stomach tube.

10.53 Defecation; feces of soft consistency.
10.58 Defecation.

11.00 108

11.07 Defecation; feces somewhat liquid,

scanty and repeated.

11.10 90

11.12 Nausea.

11.15 Defecation; liquid feces.

11.20 11“

11.2“ Defecation; liquid feces accompanied
with mucus.

11.30 120

11.“0 120

a 229 _

Dog No. 35 April 2“, 19“5

Male

11 kgm. body weight

Temperature: 100.0 F

Drug: nemural in powder

Dose: equivalent to 3.2 mgm. of arecoline hydrobromide per
kgm. body weight

Total dose: 6“.3 mgm. of nemural (equivalent to 35.2 mgm.

of arecoline hydrobromide)

Results:
TIHE PULSE OBSERVATIONS
9.35 A.M. 72
9.“3 Administration of nemural in so~
lution given by stomach tube.
9-55 50
9.57 Nausea followed by emesis.
10.05 5“
10.15 5“
10.26 Defecation; feces of soft consistency.
10.30 60
10.“0 56
10.50 56
11.00 52
11.15 “8

_ 23o _

Dog No. 36 u 1, 1945

9)
V.

Male
8.5 kgm. body weight
Temperature: 99.6 F
Drug: nemural in tablets
Dose: equivalent to 3.2 mgm. of arecoline hydrobromide per
kgm. body weight
Total dose: 2.“7 tablets of nemural (equivalent to 27.2 mgm.
of arecoline hydrobromide)
Results:
TIME PULSE OBSERVATIONS
10.30 A.M. 126
10.37 Administration of nemural in so—
lution given by stomach tube.
'10.“2 Defecation; feces of soft consistency,

repeated several times.

10.“5 Emssis; foodstuff.
10.“s 96
10.“? Defecation; feces somewhat liquid,

scanty and repeated.

10.50 Emssis; liquid and foamy material.
10.52 Micturition.

10.57 60

11.00 Defecation; liquid feces accompanied

with mucus.
11.02 90
11.15 120

Dog No. 36 (cont‘d.)

TIME PULSE DESTINATIONS

11.23 A.M. 132

11.35 120
ll.“5 132 Animal is trembling.
11.5“ 132

12.02 138

Dog No. 37

Male

13 kgm. body weight
Temperature: 101.0 F

Drug: nemural in powder

Dose: equivalent to 3.2 m

kgm. body weight

any 1, 19“5

gm. of arecoline hydrobromide per

Total dose: 76 mgm. of nemural (equivalent to “1.6 mgm. of

arecoline hydrobromide)

Results:

TIEE PULSE
5.23 r.s. 11“
5-29

5.39 11“
5.“0

5.“9 96
5.59 96
6.00

6.07

6.09 S“
6.19 8“
6.29 90
6.39 a“
6.“s

6.“9 96

6.59 108

OBSERVATIONS

Administration of nemural in so-

lution given by stomach tube.

Defecation; feces of soft consistency.

Defecation; feces of soft consistency.
Defecation; liquid feces, scanty

and repeated.

Defecation; blood tinged feces.

Dog No. 38 Nay 1, 19h5

Male

6 kgm. body weight

Temperature: 101.5 F

Drug: nemural in tablets

Dose: equivalent to 3.2 mgm. of arecoline hydrobromide per
kgm. body weight

Total dose: 1.94 tablet of nemural (equivalent to 19.2 mgm.

of arecoline hydrobromide)

Results:
TIME PULSE OBSERVATIONS
5.20 P.M. 144
5.25 Administration of nemural in so«
lution given by stomach tube.
5.35 168
5.36 Emssis.
5.41 Micturition.
5.u5 156
5.47 Defecation; feces of soft consistency.
5.51 Defecation; feces somewhat liquid.
5-55 155
5.5 Emssis; liquid and foamy materiel.
6.05 146
6.09 Defecation; liquid feces and scanty.
6.15 156
6.25 156

6.30 Defecation; blood tinged feces.

_ 234 -

Dog No. 38 (cont'do)

r—J

Ins PULSE OBSERVATIONS
6.35 PJJ. 163

6.44 Nauseant stage.

6.M5 168 Animal is trembling.
6.55 162

-235...

00g No. #0 may 2, 1945

Male

12 kgm. body weight

Temperature: 101.5 F

Drug: nemural in tablets

Dose: equivalent to 3.2 mgm. of arecoline hydrobromide per
kgm. body weight

Total dose: 3.89 tablets of nemural (equivalent to 38.5 mgm.
of arecoline hydrobromide)

Results:

E OBSERVATIONS

U)

TImE PUL
10.10 as. 84
10.20 A Administration of nemural in so—

lution given by stomach tube.

10.30 108

10.31 Emssis.

10.35 Defecation; feces of soft consistency.

10.40 Defecation; semiuliquid feces.

10.h0 60

10.M8 Defecation; liquid feces, scanty
and repeated.

10.50 Micturition.

,10.52 62

10.55 Animal seems to be depressed.

11.00 60

11.1 78

Dog N0. ”0 (cont'd.)

TIME PULSE OBSERVATIONS

11.20 A.M. sh

11.3u 13s
11.u2 96
11.51 90

12.00 78

a 237 _

Dog N0. ”1 May 2, 1945
Male
13 kgm. body weight
Temperature: 104.“ F
Drug: nemural in tablets
Dose: equivalent to 3.2 mgm. of arecoline hydrobromide per
kgm. body weight
Total dose: ”.22 tablets of nemural (equivalent to ”1.6 mgm.
of arecoline hydrobromide)
Results:
TIME PULSE OBSERVATIONS
10.10 A.M. 132
10.28 Administration of nemural in sou

lution given by stomach tube.

10.30 Emssis; somewhat liquid.
10.35 Emssis; food material.
10.38 108

10.48 54 Animal is quite depressed.
11.00 126

11.01 Defecation and micturition.
11.1“ 120

11.15 Nauseant stage.

11.19 Animal starts trembling.
11.26 126

11.38 126 Animal is trembling.

11.nu 132

11.55 138

12.03 132 Animal is trembling.

Dog No. #3 May 1, 1945
Male
7 kgm. body weight
Temperature: 101.5 F
Drug: nemural in tablets
Dose: equivalent to 3.2 mgm. of arecoline hydrobromide per
kgm. body weight
Total dose: 2.27 tablets of nemural (equivalent to 22.“ mgm.
of arecoline hydrobromide)
Reevlts:
TIME PULSE OBSERVATIONS
5.30 P.M. 120
5.36 Administration of nemural in so~

lution given by stomach tube.

5.h0 Defecation
5.50 90
6.00 108
6.10 108
6.20 80
6.30 102
6.M0 78
6.50 72

7.00 84

8 kgm. body weight

Temperature: 101.0 F

Drug: nemural in tablets

May 1, 1945

Dose: equivalent to 3.2 mgm. of arecoline hydrobromide per

kgm. body weight

Total dose: 2.59 tablets of nemural (equivalent to 25.6 mgm.

of arecoline hydrobromide)

Results:
TIME
12.u5
12.50

12.55
12.56
1.00
1.05
1.10
1.20
1.21
1.30
1.40
1.50
2.00
2.10
2.20
2.30

PULSE
P0110 108

90

120
126

120
96
90
96
96

108

108

OBSERVATIONS

Administration of nemural in so-
lution given by stomach tube.
Defecation; feces of soft consistency.

Emssis.

Defecation; feces of soft consistency.

Emssis; liquid material is expelled.

Emssis; liquid and foamy material.

Animal starts trembling.

Animal is trembling.

Dog No. 46

Male

13 kgm. body weight

Temperature:

Drug:

Dose:

Total

Resul

nemural in tablets

101.0 F

— 240 —

May 2, 1945

equivalent to 3.2 mgm. of arecoline hydrobromide per

kgm. body weight

dose: 4.22 tablets of nemural (equivalent to 41.6 mgm.

of arecoline hydrobromide)

ts:

TIME
1.05
1.07

1.12
1.15
1.18
1.22
1.25

H
O

\N
L)

1.33
1.35
1.40
1.45

J

1-55
2.05
2.15

~

[‘3

TO
\0

P.M.

PULSE
132

144

150

OBSERVATIONS

Administration of nemural in so~
lution given by stomach tube.

Defecation and micturition.

Defecation; feces of soft consistency.
Defecation; somewhat liquid and scanty.
Defecation; liquid feces, canty ‘
and repeated.

Emssis; liquid and foamy material.

Defecation and c0pious mucus.

Defecation; liquid feces and mucus.

- 2&1 _

Dog No. 47 May 2. 1945
Male
17 kgm. body weight'
Temperature: 101.4 F
Drug: nemural in tablets
Dose: equivalent to 3.2 mgm. of arecoline hydrobromide per
kgm. body weight
Total dose: 5.52 tablets of nemural (equivalent to 54.4 mgm.
of arecoline hydrobromide)
Results:
TIME PULSE OBSERVATIONS
12.50 P.E. 120
12.5 Administration of nemural in so~

lution given by stomach tube.

1.05 120

1.14 ‘ Defecation; feces of soft consistency.

1.15 168

1.17 Emssis; fairly large amount of
foodstuff.

1.25 165

1.35 132

1.45 120

1.55 120 Animal starts trembling.

2.05 126

2.15 126

2.25 120

2.28 Defecation; feces somewhat liquid,
mucus.

2.43 156

DOS No. ”3 May 1, 1945
Male
12.5 kgm. body weight
Temperature: 101.6 F
Drug: nemural in tablets
Dose: equivalent to 3.2 mgm. of arecoline hydrobromide per
kgm. body weight
Total dose: 4.26 tablets of nemural (equivalent to 40 mgm.
of arecoline hydrobromide)
Results:
TIME PULSE OBSERVATIONS
5.44 P.M. 96
5.47 Administration of nemural in so»

lution given by stomach tube.

5.54 102

6.03 Defecation; feces of soft consistency.
6.04 102

6.14 90

6.15 Defecation and micturition.

6.24 96

6.34 72

6.44 72

6.54 78

7.00 96

Dos No. 49 May 11, 1945
Hale
7.5 kgm. body weight
Temperature: 102.2 F
Drug: nemural in tablets
Dose: equivalent to 3.2 mgm. of arecoline hydrobromide per
kgm. body weight
Total dose: 2.43 tablets of nemural (equivalent to 24 mgm.
0f arecoline hydrobromide)
Results:
TIME PULSE OBSERVATIONS
10.25 .2. 132
10.28 Administration of nemural in so~

lution given by stomach tube.

10.35 125

10.45 102

10-46 Defecation; feces of soft consistency.
10.55 103

11.05 90

11.10 Hicturition.

11.11 Defecation.

11.15 96

11.25 90

11.35 90

I 11.45 102

—- 244..

Dog No. 50 May 11, 1945
Male
8 kgm. body weight
Temperature: 105.0 F
Drug: nemural in tablets
Dose: equivalent to 3.2 mgm. of arecoline hydrobromide per
kgm. body weight
T0tal dose: 2.59 tablets of nemural (equivalent to 25.6 mgm.
of arecoline hydrobromide)
Results:
TIME PULSE OBSERVATIONS
10.20 A.M. 180
10.26 Administration of nemural in so—

lution given by stomach tube.

10.35 156

10.36 Emssis.

10.39 Defecation; feces of soft consistency.

10.45 102

10.51 Defecation; somewhat liquid, scanty
and repeated.

10.55 90

11.05 90

11.15 64

11.25 108

11.35 132

11.45 120

Dog No. 55 June 7, 1945

Female

5 kgm. body weight

Temperature: 101.2 F

Drug: nemural in tablets

Dose: equivalent to 3.2 mgm. of arecoline hydrobromide per
kgm. body weight

Total dose: 1.62 tablets of nemural (equivalent to 16 mgm.

of arecoline hydrobromide)

Results:
TIUE PULSE OBSERVATIONS
1.45 P.M. 120
1.50 Administration of nemural in so~

lution given by stomach tube.

2.00 108
2.10 102
2.20 90
2.30 108
2.40 90
2.50 90
2.58 Defecation and micturition.
3.00 120

\D
(J\

3.10

DOS No. 55 June 7, 1945
Female
6.5 kgm. body weight
Temperature: 102.3 F
Drug: nemural in tablets
Dose: equivalent to 3.2 mgm. of arecoline hydrobromide per
kgm. body weight
Total dose: 2.11 tablets of nemural (equivalent to 20.8 mgm.
of arecoline hydrobromide)
Results:
TIME PULSE OBSERVATIONS
1.35 P.M. 120
1.40 Administration of nemural in so—

lution given by stomach tube.

1.43 Defecation; feces of soft consistency.
1.50 Defecation.

1.50 102

2.00 73

2.01 Emssis.

2.09 Defecation; liquid feces, scanty

and repeated.

2.10 78
2.20 76
2.30 90
2.40 114
2.50 96
3.00 108

3.10 108

Dog No. 57 June 12, 1945
Female
7.5 kgm. body weight
Temperature: 103.4 F
Drug: nemural in tablets
Dose: equivalent to 3.2 mgm. of arecoline hydrobromide per
kgm. body weight
Total dose: 2.43 tablets of nemural (equivalent to 24 mgm.
of arecoline hydrobromide)
Results:
TIRE PULSE OBSERVATIONS
9.30 A.M. 126
9.40 Administration of nemural in so—

lution given by stomach tube.

9.50 126
9.52 Defecation; feces of soft consistency.
9.54 Defecation; feces of semi—liquid
consistency.
10.00 120
10.09 Defecation; blood tinged feces
and mucus.
10.10 120
10.20 Copious mucus eXpelled from anus.
10.30 120
10.40 120
10.50 132
11.00 120
11.20 125

11.30 132

Dog N0. 58

Female

8.5 kgm. body weight

Temperature: 102.0 F

Drug: nemural in tablets

June 12, 1945

Does: equivalent to 3.2 mgm. of arecoline hydrobromide per

kgm. body weight

Total dose: 2.47 tablets of nemural (equivalent to 27.2 mgm.

of arecoline hydrobromide)~

Results:
TIME
9.35
9.43

9.53
9.5”
9-55
10.00

10.03
10.13
10.15

10.23
10.33
10.43
10.53

A.

*d

L":
U)
[‘1

\O
O\

60

60
72
72

OBSERVATIONS

Administration of nemural in so~

lution given by stomach tube.

Defecation; feces of soft consistency.
Nausea followed by emesis.
Defecation; liquid feces, scanty

and repeated.

Defecation; liquid, scanty and

repeated.

Copious mucus expelled from anus.

Dog No. 58 (cont'd.)

TIME PULSE OBSERVATIONS
11.03 72

11.13 72
11.23 72

11.35 90

- 350 a

Dos NO- 59 June 12, 104:
Female
10 kgm. body weight
Temperature: 100.8 F
Drug: nemural in tablets
Dose: equivalent to 3.2 mgm. of arecoline hydrobromide per
kgm. body weight
Total dose: 3.24 tablets of nemural (equivalent to 32 mgm.
of arecoline hydrobromide)
Results:
TIME PULSE OBSERVATIONS
2.00 Pdf. 120
2.09 Administration of nemural in so~

lution given by stomach tube.

2.18 Emssis.

2.19 108

2.29 78

2.30 efecation; feces of soft consistency.
2.39 73

2.49 72

2.50 Defecation; semi—liquid feces.
2.59 S4

3.09 73

3.19 84

3.29 96

3.40 102

Doe No. 60 June 12, 1945
Female
8 kgm. body weight
Temperature: 101.0 F
Drug: nemural in tablets
Dose: equivalent to 3.2 mgm. of arecoline hydrobromide per
kgm. body weight
Total dose: 2.59 tablets of nemural (equivalent to 25.6 mgm.
of arecoline hydrobromide)
Results:
TIxE PULSE OBSERVATIONS
2.05 P.n. 126
2.11 Administration of nemural in so~

lution given by stomach tube.

2.20 126
2.30 inn
2.uo 126
2.50 120
3.00 132
3.10 156
3.25 150

3.h0 15o

Dos NO- 51 June 7, 1945

Female
6.5 kgm. body weight
Temperature: 102.0 F
Drug: nemural in tablets
Dose: equivalent to 3.2 mgm. of arecoline hydrobromide per
kgm. body weight
Total dose: 2.11 tablets of nemural (equivalent to 20.8 mgm.
of arecoline hydrobromide)
Results:
TIME PULSE OBSERVATIONS
1.n5 P.M. 108
1.4? Administration of nemural in so~

lution given by stomach tube.

1-57 90

1.59 Defecation; feces somewhat liquid.
2.06 Defecation; liquid consistency.

2.07 108

2.12 Defecation; liquid feces and scanty.
2.17 102

2.27 108

2-37 90

2.#7 132

3.00 108

3.10 120

Dos NO- 62 June 12, 19a;
Female
10 kgm. body weight
Temperature: 100.3 F
Drug: nerrural in tablets
Dose: equivalent to 3.2 mgm. of arecoline hydrobromide per
kgm. body weight
Total dose: 3.24 tablets of nemural (equivalent to 32 mgm.
of arecoline hydrobromide)
Results:
TIHE PULSE OBSERVATIONS
2.00 P.X. 120
2.06 Administration of nemural in so~

lution given by stomach tube.

2.14 Emssis.

2.15 Defecation; feces of soft consistency.
2.16 103

2.25 Defecation; liquid feces.

2.26 96

2.32 Defecation; liquid feces and reheated.
2. 6 108

-.M6 96

2.53 Cepious mucus expelled from anus.

2.56 103

3.06 iuu

3.16 138

3.26 132

\N
O
4:
O
H
N
c \

Dog No. 63

Female

15 kgm. body weight

Temperature:

I

Drug: nemural in tablets

102.8 F

_ 254 -

June 13, 1945

Dose: equivalent to 3.2 mgm. of arecoline hydrobromide per

kgm. body weight

Total dose: 4.87 tablets of nemural (equivalent to 48 mgm.

of arecoline hydrobromide)

Results:
TIME
9-15
9-27

9.30
9.33

9.37
9.45
9.46
9.47
9.53

9.57
10.07
10.17
10.27

10.37
10.50

A.M.

PULSE
13s

66

84

108
150
138
132
150
150

OBSERVATIONS

Administration of nemural in so-
lution given by stomach tube.
Defecation; feces of soft consistency.
Emesis; fairly large amount of
foodstuff.

Animal is depressed.

Emssis.

Defecation; feces blood tinged.

Defecation; liquid feces, blood

tinged and accompanied by mucus.

Animal is depressed.

_255_

Dog No. 64 June 13, 1945
Female
9.5 kgm. body weight
Temperature: 101.0 F
Drug: nemural in tablets
Dose: equivalent to 3.2 mgm. of arecoline hydrobromide per
kgm. body weight
Total dose: 3.08 tablets of nemural (equivalent to 30.4 mgm.
of arecoline hydrobromide)
Results:
TIME PULSE OBSERVATIONS
9.15 A.M. 96
9.24 Administration of nemural in so-

1ution given by stomach tube.

9.3} Defecation; feces of soft consistency.
9.34 78

90”} Emssis.

9.44 78

9.45 Defecation; liquid feces accompanied

by mucus.

9.54 72
10.04 72
10.08 Defecation; liquid feces, scanty and

repeated followed by expulsion
of mucus.

10.14 72

10.24 84

_ 256 -

Dog No. 64 (cont'd.)

TIME PULSE OBSERVATIONS
10.34 102
10.35 Defecation; liquid feces accompanied
by mucus.

10.48 84

_ 257 _

Dog No. 65 June 15, 1945
Female
10.5 kgm. body weight
Temperature: 102.5 F
Drug: nemural in tablets
Dose: equivalent to 3.2 mgm. of arecoline hydrobromide per
kgm. body weight
Total dose: 3.41 tablets of nemural (equivalent to 33.6 mgm.
of arecoline hydrobromide)
Results:
TIME PULSE OBSERVATIONS
2.40 P.M. 78
2.50 Administration of nemural in so-

lution given by stomach tube.

2.55 Emssis; foodstuff and liquid material.
3.00 78
3.10 78
3.20 90
3.25 Defecation; feces of soft consistency.
3.30 72
3.40 66
3.50 72
4.00 66
4.10 60
4.20 66

4.35 72

Dog No. 66

Female

7 kgm. body weight

Temperature:

Drug:

Dose:

Total

nemural in tablets

101.1 F

_ 258 _

June 15, 1945

equivalent to 3.2 mgm. of arecoline hydrobromide per

kgm. body weight

does: 2.27 tablets of nemural (equivalent to 22.4 mgm.

of arecoline hydrobromide)

Results:

TIME

2.45 P.M.

2.47

2-57
2.58
3-07
3.17
3-27
3.37
3.47
3-57
4.07
4.17
4.27

PULSE

120

120

S4
96
9O
9O
9O
84
78
78
78

OBSERVATIONS

Administration of nemural in so-

1ution given by stomach tube.

Defecation; feces of soft consistency.

PROTOCOLS OF CLINICAL EXPERIMENTS WITH NEMURAL
AT A DOSAGE RATE EQUIVALENT TO
ARECOLINE HYDROBROMIDE 4.8 MGM. PER KGM.

.. 259...

Dog No. 32 ' May 8, 1945
Male
11.5 kgm. body weight
Temperature: 100.0 F
Drug: nemural in tablets
Dose: equivalent to 4.8 mgm. of arecoline hydrobromide per
kgm. body weight
Total dose: 5.60 tablets of nemural (equivalent to 55.2 mgm.
of arecoline hydrobromide)
Results:
TIME PULSE OBSERVATIONS
9.20 A.M. 102
9.37 Administration of nemural in so-

lution given by stomach tube.

9.4? 132
9.49 Emssis.
9.51 Defecation; feces of soft consistency.
9.54 Micturition.
10.00 84
10.10 78
10.20 96
10.30 84
10.31 Defecation; feces somewhat liquid.
10.40 78
10.50 72 Copious mucus expelled from anus.
11.00 90 " " ” " "
11.10 66 N " " " "

11.20 72

- 260 —

Dos NO- 36 May 8, 1945

Male

8.5 kgm. body weight

Temperature: 101.4 F

Drug:

Dose:

Total

nemural in tablets
equivalent to 4.8,mgm. of arecoline hydrobromide per

kgm. body weight

dose: 4.14 tablets of nemural (equivalent to 38.8 mgm.

of arecoline hydrobromide)

Results:

TIME PULSE OBSERVATIONS
9.35 A.M. 102
9.45 Administration of nemural in so-
lution given by stomach tube.
9.50 96
(10.00 108
10.10 Emssis.
10.11 114
10.20 96
10.30 84
10.40 90
10.50 102
11.00 108
11.10 96
11.20 96
11.30 108

- 261 —

Dog No. 37 May 7, 1945
Male
11.5 kgm. body weight
Temperature: 101.0 F
Drug: nemural in tablets
Dose: equivalent to 4.8 mgm. of arecoline hydrobromide per
kgm. body weight
Total dose: 5.60 tablets of nemural (equivalent to 55.2 mgm.
of arecoline hydrobromide)
Results:
TIME PULSE OBSERVATIONS
1.35 P.M. 126
1.40 Administration of nemural in so—

1ution given by stomach tube.

1.50 126

1.52 Defecation; feces of soft consistency.

2.00 120

2.01 - Defecation and micturition.

2.10 108

2.12 Defecation; liquid feces, scanty
and repeated.

2.20 108

2.30 108

2.35 Defecation; liquid feces, scanty
and repeated.

2.40 132

2.45 Micturition.

2.50 120 Copious mucus from anus.

- 262 -

Dog No. 37 (cont'd.)

TIME PULSE OBSERVATIONS

3.00 P.M. 108 mucus from anus.

3.10 108

3.20 102 Mucus, scanty and repeated.
3.30 96

3.40 102

_ 263 _

Dog No. 38 May 7, 1945
Male
5.5 kgm. body weight
Temperature: 102.3 F
Drug: nemural in tablets
Dose: equivalent to 4.8 mgm. of arecoline hydrobromide per
kgm. body weight
Total dose: 2.69 tablets of nemural (equivalent to 26.4 mgm.
. of arecoline hydrobromide)
Results:
TIME PULSE OBSERVATIONS
1.40 P.M. 108
1.45 Administration of nemural in so-

lution given by stomach tube.

1.50 96
1.52 ‘ Defecation; feces of soft consistency.
1.55 Defecation; feces of soft consistency.
2.00 120
2.05 Mioturition.
2.10 102
2.20 108
2.30 102
2.35 Defecation; liquid feces, scanty
and repeated.
2. 44 144
2.50 108
2.59 Defecation; liquid feces, scanty

and repeated.

- 264 _

Dog No. 38 (cont'd.)

TIME PULSE OBSERVATI ONS

3.00 P.M. 120 Mucus expelled from anus.

3.10 132

3.19 Defecation accompanied by mucus.
3.20 120

3.30 126

3.40 120

Dog NO. 40 May 7, 1945
Male
12.5 kgm. body weight
Temperature: 101.2 F
Drug: nemural in powder
Dose: equivalent to 4.8 mgm. of arecoline hydrobromide per
kgm. body weight
Total dose: 109.6 mgm. of nemural (equivalent to 60 mgm.
of arecoline hydrobromide)
Results:
TIME PULSE OBSERVATIONS
10.35 A.M. 96
10.37 Administration of nemural in so—

lution given by stomach tube.

10.43 Emssis.

10.44 Defecation; feces of soft consistency.
10.45 102

10.47 Defecation; semi-liquid consistency.
10.48 Emssis; foamy material.

10.55 72

10.59 Micturition.

11.05 90

11.15 90

11.20 Copious mucus expelled from anus.
11.25 120

11.35 108

11.45 90

11.50 Mucus blood tinged.

— 266 -

Dos NO- 43 May 7, 1945
Male
6.5 kgm. body weight
Temperature: 102.4 F
Drug: nemural in powder
Dose: equivalent to 4.8 mgm. of arecoline hydrobromide per
kgm. body weight
Total dose: 56.6 mgm. of nemural (equivalent to 31.2 mgm.
of arecoline hydrobromide)
Results:
TIME PULSE OBSERVATIONS
10.25 A.M. 84
10.35 Administration of nemural in so—

lution given by stomach tube.

10.45 102
10.46 Defecation; feces of soft consistency.
10.55 72
11.05 84
11.15 78
11.25 78
11.35 78

11.45 78

_ 267 _

Dog No. 45 May 9: 1945

Kale

8.5 kgm. body weight

Temperature: 100.3 F

Drug:

Dose:

Total

nemural in tablets

equivalent to 4.8 mgm. of arecoline hydrobromide per
kgm. body weight

does: 4.14 tablets of nemural (equivalent to 40.5 mgm.

of arecoline hydrobromide)

Results:

TIME PULSE OBSERVATIONS

10.25 A.M. 84

10.39 Administration of nemural in so-
lution given by stomach tube.

10.48 Defecation; feces of soft conSistency.

10.50 96

11.00 54

11.10 66

11.20 98

11.22 Defecation; liquid feces, scanty
and repeated.

11.25 Emssis.

11.30 72

11.40 140

11.50 156

Dog No. 48

Male

12.5 kgm. body weight

Temperature: 102.4 F

Drug: nemural in tablets

268 -

June 13, 1945

Does: eQuivalent to 4.8 mgm. of arecoline hydrobromide per

kgm. body weight

Total dose: 6.09 tablets of nemural (equivalent to 60 mgm.

of arecoline hydrobromide)

Results:
TIME

9.15
9.18

9.24
9.25
9.28
9.38
9.44
9.48
9.58
10.08
10.09

10.18
10.28
10.38
10.51
11.00

A.M.

PULSE
114

90
72

78
72

72
6O
66
84

84

OBSERVATIONS

Administration of nemural in so-
lution given by stomach tube.
Defecation; feces of soft consistency.

Micturition.

Defecation; somewhat liquid.

Defecation; liquid feces, scanty

and repeated, accompanied by mucus.

_ 259 _

Dog N0. 55 June 15, 1945
Female
5 kgm. body weight
Temperature: 101.4 F
Drug: nemural in tablets
Dose: equivalent to 4.8 mgm. of arecoline hydrobromide per
kgm. body weight
Total dose: 2.44 tablets of nemural (equivalent to 24 mgm.
of arecoline hydrobromide)
Results:
TIME PULSE OBSERVATIONS
2.45 P.M. 90
2.53 Administration of nemural in so—

lution given by stomach tube.

3.01 Defecation; feces of soft consistency.
3.03 90

3-13 73

3.20 Emssis.

3-23 90

3.33 66

3-“3 78

3.53 66

4.03 66

4.17 72

4.35 84

Dog No. 57

Femal

8

8.5 kgm. body weight

Temperature: 102.4 F

Drug:

Dose:

Total

Resul

nemural in tablets

_ 270 _

July 2, 1945

equivalent to 4.8 mgm. of arecoline hydrobromide per

kgm. body weight

dose: 4.14 tablets of nemural (equivalent to 40.8 mgm.

of arecoline hydrobromide)

ts:
TIME

1-55
2.00

2.10
2.12
2.20
2.28

2.30
2.38
2.40
2.50
3.00
3.10
3.20
3.30

POM.

PULSE
144

132

132

130

108
102
114

96
102
108

OBSERVATIONS

Administration of nemural in so-

lution given by stomach tube.
Defecation; feces of liquid consistency.
Animal is restless.

Defecation; liquid feces, scanty

and repeated.

Emssis.

Mucus material expelled from anus.

_ 271..
Dog No. 57 (cont'd.)

TILIE PULSE OBSERVATIONS
3.40 Pd! . 108

3.50 102

4.00 120 Mucus

Dog No. 58

Female

7.5 kgm. body weight

Temperature:

Drug:

Dose:

Total

Resul

nemural in tablets

101.2 F

July 2, 1945

equivalent to 4.8 mgm. of arecoline hydrobromide per

kgm. body weight

dose: 3.65 tablets of nemural (equivalent to 36 mgm.

of arecoline hydrobromide)

ts:

TIME
2.10
2.13

2.20
2.22
2.24
2.25
2.26

2-35
2.38

2.45
2.55

3.01

3-05

P.M.

PULSE
120

an

78

84
84

9O

OBSERVATIONS

Administration of nemural in so-
lution given by stomach tube.
Defecation; feces of soft consistency.
Defecation; somewhat liquid.
Defecation; liquid feces, scanty
and repeated.

Defecation;

liquid feces, scanty

and repeated.

Defecation; feces blood tinged and

accompanied by copious mucus.

Dog No. 58 (cont'd.)

TIME PULSE OBSERVATIONS

3.15 P.M. 72

3-25 72
3-35 78
3.45 84
3.55 78 Mucus expelled from anus.

4.05 84

Dog No. 59 September 18, 1945
Female
10.5 kgm. body weight
Temperature: 100.4 F
Drug: nemural in powder
Dose: equivalent to 4.8 mgm. of arecoline hydrobromide per
kgm. body weight I
Total dose: 92.3 mgm. of nemural (equivalent to 50.4 mgm.
of arecoline hydrobromide)
Results:
TIME PULSE OBSERVATIONS
10.15 A.M. 96
10.20 Administration of nemural in so—

lution given by stomach tube.

10.30 90

10.33 Defecation; feces of soft consistency.
10.35 Defecation; somewhat liquid.

10.40 90

10.43 Emssis.

10.50 72

11.00 78 Copious mucus expelled.

11.10 84

11.20 84

11.28 Emssis; liquid and foamy material.
11.30 84

11.40 90 Mucus expelled from anus.

- 275 _

Dog No. 60 August 23, 1945
Female
8 kgm. body weight
Temperature: 103.2 F
Drug: nemural in tablets
Dose: equivalent to 4.8 mgm. of arecoline hydrobromide per
kgm. body weight
Total dose: 3.89 tablets of nemural (equivalent to 38.4 mgm.
of arecoline hydrobromide)
Results:
TIME PULSE OBSERVATIONS
2.38 P.M. 138
2.41 Administration of nemural in so—

lution given by stomach tube.

2.48 Defecation and micturition.

2.50 Defecation; feces of soft consistency.
2.51 162

3.01 120

3.11 144 Mucus material expelled from anus.
3.21 150

3.31 180

3.41 150

_ 275 -

Dos NO- 61 June 18, 1945

Female
6.5 kgm. body weight
Temperature: 101.4 F
Drug: nemural in tablets
Dose: equivalent to 4.8 mgm. of arecoline hydrobromide per
kgm. body weight
Total dose: 3.26 tablets of nemural (equivalent to 31.2 mgm.
of arecoline hydrobromide)
Results:
TIME PULSE OBSERVATIONS
,2.25 P.M. 96
2.30 Administration of nemural in so-

lution given by stomach tube.

2.40 84

2.46 Defecation; feces of soft consistency.
2.50 78

3.00 72

3.07 Defecation and micturition.
3.10 84

3.20 102

3.30 114

3.40 102

3.50 90

4.00 84

4.15 90

...277..

Dog No. 63 June 18, 1945
Female
15.5 kgm. body weight
Temperature: 102.4 F
Drug: nemural in tablets
Dose: equivalent to 4.8 mgm. of arecoline hydrobromide per
kgm. body weight
Total dose: 7.55 tablets of nemural (equivalent to 74.4 mgm.
of arecoline hydrobromide)
Results:
TIME PULSE OBSERVATIONS
2.35 P.M. 120
2.51 Administration of nemural in so-

lution given by stomach tube.

3.01 108

3.09 Defecation and micturition.

3.11 96

3.20 Defecation; feces of soft consistency.
3.21 120

3.31 102

3.41 126 Defecation; liquid feces and repeated.
3.44 Copious mucus expelled from anus.

3.51 114

4.01 90 Iucus expelled.

4.15 96

_ 278 _

D08 NO- 64 June 18, 1945
Female
10.5 kgm. body weight
Temperature: 102.4 F
Drug: nemural in tablets
Dose: equivalent to 4.8 mgm. of arecoline hydrobromide per
kgm. body weight
Total dose: 5.11 tablets of nemural (equivalent to 50.4 mgm.
of arecoline hydrobromide)
Results:
TIME PULSE OBSERVATIONS
2.30 P.n. 96
2.35 Administration of nemural in so~

lution given by stomach tube.

2.45 102

2.47 . Defecation; feces of soft consistency.

2.55 84 Animal seems to be depressed.

2.56 Micturition.

3.01 Emssis.

3.03 Defecation followed by expulsion
of mucus.

3.05 90 Animal is quite depressed.

3.15 90 Copious mucus expelled.

3.25 102

3-35 73

3.45 84 Copious mucus expelled.

3-55 95

4.15 108

- 279 -

Dog No. 65 JU1Y 11: 1945
Female
10 kgm. body weight
Temperature: 102.4 F
Drug: nemural in powder
Dose: equivalent to 4.8 mgm. of arecoline hydrobromide per
kgm. body weight
Total dose: 82.2 mgm. of nemural (equivalent to 45 mgm. of
arecoline hydrobromide)
Results:
TIME PULSE OBSERVATIONS
10.15 A.M. 96
10.19 Administration of nemural in so—

lution given by stomach tube.

10.29 108

10.31 ‘ Emssis.

10.35 Defecation; liquid feces.

10.39 84

10.45 Animal is depressed. Respiration
accelerated. Trembling.

10.48 Defecation; liquid feces repeated
and followed by 00pious mucus.

10.49 90

10.59 78

11.09 78

11.19 108

11.29 120

11.39 120

11.49 108

- 28o -

Dog N0. 66 July 11, 1945
Female
7.5 kgm. body weight
Temperature: 100.9 F
Drug: nemural in powder
Dose: equivalent to 4.8 mgm. of arecoline hydrobromide per
kgm. body weight
Total dose: 65.8 mgm. 0f nemural (equivalent to 36 mgm.
of arecoline hydrobromide)
Results:
PULSE

TIME OBSERVATIONS

10.15 A.M. 126

10.21 Administration of nemural in so-
lution given by stomach tube.
10.25 Defecation; feces of soft consistency.
10.27 Defecation; feces of liquid consistency.
10.31 126
10.32 Defecation; liquid feces, scanty
and repeated.
10.41 120
10.51 126
11.01 102
11.04 Emssis; liquid material and foamy.
11.05 Mioturition.
11.09 Emssis; foamy material.
11.11 78 Animal is depressed.
11.21 84
11.31 96
11.41 96

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