- --.. Si’., .

PROCEEDINGS OF THE AMERICAN SOCIETY FOR

PHARMACOLOGY AND EXPERIMENTAL THERA-
PEUTICS
FIRST ANNUAL MEETING

Harvard Medical School, Boston, December 29 and 30, 1909

Edited by the Secretary, DR. REID HUNT

December 29, a business meeting was held at which a constitu-

tion was adopted and officers were elected.
On December 30 the following demonstrations were given at a
joint meeting with the American Physiological Society.
The mutual antagonism between . magnesium and barium. D.
R. Joseph and S. J. Meltzer.
Demonstration of anaphylactic immobilization of the lungs in
guinea pigs. J. Auer and P. Lewis.
A simple respiration apparatus. W. H. Schultz.
A demonstration of the method of respiration by continuous
intratracheal insufflation. S. J. Meltzer.
After these demonstrations the following papers were read and
discussed, President John J. Abel in the chair.

On the Pharmacological Action and Antiseptic Value of Certain

Benzoic Acid Derivatives. A. S. Loevenhart and A. Arkin.
From the Pharmacological Laboratory, University of Wis-
consin.
The following products were studied:

(1) Sodium ortho-iodbenzoate, CUH4<’ -

- . COONa

- - /1=0
(2) Sodium ortho-iodosbenzoate, C,H<
- - - ‘COONa
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(3) Sodium ortho-iQdoxybenzoate, CtIJ4#{231} ,o
‘COONa
 - 5

570 PROCEEDINGS

The first has very little antiseptic action, while the second and
third are antiseptics of considerable strength for the organisms
studied, namely, B. typhosus, B. coli, Staphylococcus aureus,
B. pyocyaneus. Under the conditions of our experiments typhoid
bacilli were killed by iodbenzoate in , by iodosobenzoate in
and by iodoxybenzoate in solution, in 24 hours at
370 C. B. coli is killed in the same dilutions. Hence the germi-
cidal property of these substances is dependent upon the active
oxygen combined with the iodine.
The iodosobenzoate also kills staphylococcus aureus in
solution. Toward this organism it is about five times as powerful
as iodoxybenzoate.
The presence of proteid (4 per cent gelatin, or 83 per cent dog
serum) did not diminish the antiseptic action of these sub-
stances. When used locally, subcutaneously or intraperitoneally
the iodosobenzoate is quite irritating, but the iodoxybenzoate is,
on the other hand, quite bland. On intravenous injection neither
of these products causes more than an insignificant diminution
in hamoglobin or red blood corpuscles, but a leucocyt-#{244}sis is pres-
ent in about 50 per cent of the cases.
Work is under way to establish the therapeutic value of these
substances, the authors being aided by a grant from the Rocke-
feller Institute.

Studies upon the Action of Certain Salts on the Isolated Intestines.

M. V. Tyrode. From the Pharmacological Laboratory of
Harvard Medical School.

Strips of rabbit’s small and large intestines kept alive in the

author’s nutritive medium and tested by different methods showed
an increased motor activity when magnesium sulphate, sodium
sulphate and sodium phosphate were applied to the mucous sur-
face of the strips but a decreased activity was observed when
these salts were applied to the peritoneal surface and this was
particularly well marked after magnesium sulphate.
 -r-------’ ‘ - - - -r--5-5’5 -‘-- --- - -- ‘-v--

PROCEEDJNGS 571

Central Vasomotor Effects. T. Sollmann and J. D. Pilcher. From

the Pharmacological Laboratory, Western Reserve Uni-
versity.

An organ is left in connection with the vasomotor center, but

separated from the circulation, and perfused artificially. Cardiac
effects, and direct actions on the vessels, are thus excluded, there-
by permitting the study of the activity of the vasomotor center.
The response of this center to physiological and pharmacological
conditions is under investigation. The following results on the
central vasomotor control of the spleen were reported.
Stimulation of afferent nerves, asphyxia, cardiac stoppage and
cerebral anemia gave constriction. Slight hemorrhage causes
constriction; in severe hemorrhage this is overshadowed by injury
and eventual paralysis of the center. Saline infusion generally
causes constriction. Compression of the thoracic aorta usually
causes constriction (in the dog), together with some degree of
injury. In a few dogs it caused dilation. Suprarenal generally
causes dilation as the pressure is returning to normal. Small
doses of strychnine cause constriction, large doses dilation.
Chloroform causes dilation; if the heart is weakened, there may
be asphyxial constriction. Nitrites cause constriction. Curare
causes constriction or is negative. The effects of phenol, ergot
and small doses of aconite are slight and inconstant. Pituitary
is negative or causes slight dilation. Atropin is negative or gives
slight constriction. Veratrum, cevadin and strophanthus pro-
duce slight constriction. Cyanide, nicotin and large doses of
aconite give powerful constriction.

The Inhibition of the Pancreas. Charles Wallis Edmunds From

the Pharmacological Laboratory, University of Michigan.

The- pancreatic secretion produced by secretin is inhibited by

the vaso-constricting action of adrenalin, nicotine, pituitary
extract, and strychnine. When these drugs do not cause vaso-
constriction they do not inhibit the pancreas. After the injec-
tion of adrenalin the pancreas may not regain the normal volume
572 PROCEEDINGS

for five minutes and with pituitary extract it maybe eight minutes,
which facts explain why the inhibition persists after the blood
pressure has returned to the normal height.
If the high blood pressure produced by adrenalin is lower#{231}d by
secretin to the normal height or below, the inhibiting action of
adrenalin is not removed because the lowering of the blood pres-
sure is due to weakening of the heart and not to vaso-dilation.
Barium chloride may inhibit or accelerate the pancreatic flow
depending upon whether it constricts the pancreatic vessels or
dilates them and thus increases the blood supply to the organ.
No evidence could be found for the presence of two substances
in adrenalin-one raising the blood pressure and the other inhibit-
ing the pancreas, as it was found that whenever adrenalin raised
the blood pressure it always caused inhibition.
When the pancreas is stimulated by pilocarpine its activity is
inhibited not only by adrenalin but also by fresh injections of
pilocarpine provided the blood supply of the organ is lessened in
amount by the slowing of the heart produced by the pilocarpine.

Caffein Tolerance.’ By William Salant and J. B. Rieger. Labora-

tory of Pharmacology, Bureau of Chemistry, Department
of Agriculture, Washington, D. C.

Increased resistance to caffein has been observed after the

repeated administration of gradually increasing doses given to
cats, dogs and rabbits. Cats survived quantities that were 60
to 70 per cent more than the fatal dose, dogs 30 to 33 per cent
and rabbits 15 to 20 per cent. Some dogs stood much larger
doses without untoward effects.

The Toxicity of Caffein.2 By William Salant and J. B. Rieger.

Laboratory of Pharmacology, Bureau of Chemistry, Depart-
ment of Agriculture, Washington, D. C.

Dogs were the most susceptible. Eleven centigrams injected

subcutaneously produced symptoms. and in some cases proved to

‘Published by permission of tbe Secretary of Agriculture.

2 Published by permission of the Secretary of Agriculture.
 PROCEEDINGS 573

be fatal. The dose by mouth was somewhat larger. Fourteen

to fifteen centigrams per kilo killed some dogs within a few hours.
Cats proved more resistant to caffeine. 0.15 to 0.155 Gm. caffeine
per kilo injected subcutaneously produced symptoms in 10 to
15 minutes and death in a little over an hour. Rabbits and
guinea pigs stood much larger doses. After the subcutaneous
injection of 0.2 Gm. per kilo of rabbits symptoms such as in-
creased reflexes and tremors soon developed, but it required about-
0.27 to 0.28 Gm. per kilo to produce death which usually happened
within one one to four hours from the time of injection. The re-
sistance of guinea pigs was found to be about the same as that of
rabbits. Tests have also been made on pigeons and on frogs.
In the pigeon caffeine is somewhat toxic in dosesof 0.14 to 0.15 Gm.
per kilo. Frogs vary considerably in their reaction to caffeine.
Five to six milligramswere toxic in frogs weighing about 45 grams,
which is equal to about one decigram per kilo, or approximately
double the quantity of the surely fatal dose.
The influence of the mode of introduction on the toxicity of
caffeine has been studied in some detail in our experiments. Our
results show that this factor is especially important in the rabbit.
We found that the dose required to produce death was about
25 to 30 per cent greater when given by mouth than when injected
subcutaneously. The fatal dose per os was 0.35 to 0.36 Gm. per
kilo of rabbit. In intravenous injection, about 3 cc. of 2 per cent
caffeine injected slowly into the ear vein of rabbits weighing about
1 kilo produced convulsions. The fatal dose, however, was fully
16 centigrams per kilo. Intramuscular injections of caffeine were
also tried. It was found that by this path the dose was not
much greater than when injected intravenously. Two decigrams
per kilo proved fatal within a few hours.
Experiments on chronic caffeine intoxication made on rabbits,
dogs and cats have shown that doses too small to produce symp-
toms were sufficient to produce decided effects on the nutrition of
the animal. Loss of flesh and strength were frequently observed
in such animals, terminating in death. The changes found on
autopsy show inflammation and ulceration of the intestines and
especially of the stomach. It may be remarked in this connec-
574 PROCEEDINGS

tion that diarrhaa and intestinal putrefaction, were frequent

symptoms, especially in dogs.
Finally, experiments were also made of rabbits, to ascertain
the effect of starvation. When starved four or five days the
resistance to caffeine was markedly diminished. The fatal dose
was about 30 per cent less than in well fed rabbits.

The Influence of Alcohol on the Composition of Urine. William

Salant and C. F. Hinkle. Department of Biological Chem-
istry, Columbia University.

Experiments on dogs which were given 3 to 5 cc. of alcohol per

kilo diluted to 50 or 70 per cent showed moderate diminution of
the excretion of total nitrogen and of total sulphur. The reduc-
tion of the amount of total and inorganic sulphates was well
marked. Ethereal suiphates were on the contrary greatly increased
after alcohol, although in one dog a diminution was observed
under similar conditions. There was also a marked diminution
of indican, after alcohol. The urinary chlorides varied in differ-
ent individuals but there was a marked tendency to retention
after large amounts of alcohol. There was also considerable
diminution in the elimination of phosphates. In some dogs the
amounts were fully 30 per cent less than in the control periods.

The Biological and Chemical Assay of Ergot. H. C. Wood, Jr.

Pharmacological Laboratory, University of Pennsylvania.

The method used for determining the activity of ergot physio-

logically was based on the use of blood pressure, the average rise
for t-en minutes after the injection being taken as the physiological
figure. Comparative tests having shown that the amount of
benzol soluble matter in the fluid extract of ergot bears a close
relation to the physiological activity of the specimen, a method
of chemical assay on this fact was suggested. The residue
obtained by extracting the fluid extract with benzol yields a
nitrogenous body on prolonged shaking wit-h dilute acids, which
is highly active.
 55 5 - ‘P-- --- -.

PROCEEDINGS 575

Strophanthin Absorption from the Gastro-intestinal Tract. R. A.

Hatcher. Pharmacological Laboratory, Cornell University
Medical School.

Strophanthin is not absorbed from the alimentary canal of the

rat, and the absorption is extremely irregular in the cat and the
dog and apparently so in man.

The Effect of Certain Drugs upon the Toxicity of Acetphenetidin

and Para-Amidophenol. Worth Hale. Division of Pharma-
cology, Hygienic Laboratory, U. S. Bureau of Public Health,
and Marine Hospital Service, Washington, D. C.

A series of feeding experiments were carried out to determine

what effect the combination of caffeine citrate, sodium bicarbon-
ate, codeine, and morphine sulphate, with acetphenetidin and
para-amidophenol would have upon the toxicity of the latter
drugs. White mice kept under the same conditions of tempera-
ture, food, etc., were fed upon cakes made up with cracker meal
to which the drugs under investigation had been added. The
mice fed in this way were divided into two classes-namely those
receiving no drug or a drug uncombined with others, which class
served as a control, and a series which received these drugs in
combination.
The following summary indicates the drugs used, the approxi-
mate daily dose, and the results of such feeding.
SERIES I
DAYS I4VD

Plain cakes 44.25

Caffein citrate.. 36.5
002 gm.
Sodium bicarbonate 30.0
0.02 gm.
Codeine 48.5
001 gm.
Morphine sulphate 38.0
0.002 gm.
Acetphenetidin 16.75
0.05 gm.
.eetphenetidin 9.75
0.06 gm.
Para-amidophenol ........................................... 19.75
0.04 gm.
 - -. - S -:

576 PROCEEDINGS

SERIES II

COMBINATION O DRUGS DAYS LIVED

Acetphenetidin and caffein citrate 11.50

005gm. 0.02 gm.
Acetphenetidin and caffein citrate 7 75
0.06gm. 0.02gm.
Acephenetidin and sodium bicarbonate 13-75
0.05gm. 0.02gm.
Acetphenet.idin and sodium bicarbonate 10.75
0.06gm. 0.02gm.
Acetphenetidin and codeine 8.25
0.05gm. 0.01 gm.
Acetphenetidin and morphine sulphate 20.25
0.05gm. 0.002 gm.
Para-amidophenol and caffein citrate 1300
0.04gm. 0.02 gm.
Para-amidophenol and sodium bicarbonate 13.5
0.04gm. 0.02 gm.
Para-amidophenol and codeine 11.25
0.04gm. 0.01 gin.

These results indicate that the toxicity of acetphenetidin and

para-amidophenol is almost always increased by the addition of
small non-toxic amounts of other drugs such as were used in these
experiments.

The Effects of Urea and Hypertonic Solutions on the Circulation.

J. A. E. Eyster, Pharmacological Laboratory, University of
Virginia. (Read by title.)

On Insufflation of the Lungs with Hydrogen, Carbondioxide and

Air. C. C. Guthrie. Laboratory of Pharmacology and
Physiology, University of Pittsburg. (Read by title.)

On the Use of Phenolsulphonephthalein in Estimating the Function

of the Kidneys. L. G. Rowntree and J. T. Geraghty.
Pharmacological Laboratory, Johns Hopkins University and
The Genito-Urinary Clinic, Johns Hopkins Hospital.

Phenolsulphonephthalein administered subcutaneously is ex-

creted quantitatively in the urine; in health 60 to 80 per cent
of a 3 to 12 mg. dose being recovered in two hours as estimated
 PROCEEDINGS 577

by the Duboscq colorimeter. In disease of one or both kidneys

the degree to which the function is impaired can be estimated
by a decrease in the amount of drug excreted. The drug is non-
toxic, non-irritant, and first appears inside of ten minutes and
these small doses are entirely excreted in from two to two and a
half hours.

On the Behavior of Certain Arsenical, Antimony a-nd other Corn-

pounds in the Treatnwnt of Experimental Nagana. J. J.
Abel and L. G. Rowntree. Pharmacological Laboratory,
Johns Hopkins University.

The authors have met with success in the treatment of experi-

mental nagana in rats, mice, guinea pigs, rabbits and dogs by
the use of certain arsenical and antimony compounds, among
which may be named, dimethylamidophenylarsenoxide, hexame-
thyltriamidotriphenylarsine, the arsenic compound of thiogly-
coffic acid, the antimony compound of thioglycollic acid, the
sodium salts of the two last named and a compound which is ap-
parently the amide of an antimony compound obtained by the
interaction of the ethylester of thioglycollic acid with antimony
oxide and subsequent treatment with ammonia. This compound
is here described for the first time to the best of the authors’
knowledge. The best results have been obtained with thiogly-
collic and thioglycollic ester compounds whose salts can be admin-
istered hypodermically without inducing a local reaction. Other
syntheses were attempted and other compounds were tested.
Details concerning methods of preparation of these compounds
and the results obtained in their use will be described in detail
in the near future.
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