NationalLibraryOfScotland/medical-history-of-british-india huggingface dataset:
26
(1) ACTION ON ISOLATED HEART OF PITHED FROG. (See Plate VII.)
Heart isolated and. arranged for recording contractions on a drum moving
slowly and at a constant rate. Contractions were recorded for five minutes
before the application of the drug (No. 1). 0.5 c.c. of the clear supernatant
fluid of solutioc A was then allowed to flow slowly over the heart and the
contractions were recorded for five minutes (No. 2). The tracing showed a
slight increase in amplitude of the contraction and a very slight slowing of the
heart. Solution A was then shaken up and 0.5 c.c. of the turbid. fluid was
allowed to flow over the heart and the contractions recorded for five minutes
(No. 3). There was no perceptible change in the curve. The heart and its
surroundings were then washed with normal saline solution and 0.5 c.c. of
solution B applied. to the heart with no apparent difference in the contractions
(No. 4).
(2) ACTION ON ISOLATED HEART OF PITHED FROG. (See Plates VII
and VIII.)
The arrangements were as in (1), but the stronger solution C was used and
instead of being allowed to flow over the surface of the heart it was injected
into the right auricle. Normal contractions were first recorded for five minutes.
0.5 c.c. of solution C was then injected into the right auricle with a hypodermic
syringe fitted with a very fine needle. The effect was instantaneous. The
ventricle contracted firmly and stopped beating and only a small auricular con
-traction was maintained (No. 1, Plate VII).
At the end of nine seconds slight ventricular contractions began again
and these increased in volume during the next 24 seconds, when the curve
produced showed the same amplitude as before the exhibition of the drug, the
relaxation between the auricular and ventricular contractions being however
much less marked and relaxation not always being of equal completeness
(No. 2).
Fifty-five seconds after exhibition of the drug, the contractions began to
show irregularity, a second contraction occurring before the relaxation of the
previous one was complete (No. 3). At 2 minutes 15 seconds the first pro
- l o n g e d d i a s t o l e o c c u r r e d . ( N o . 4 ) . T h e r e a f t e r t h e t r a c i n g s h o w e d g r o u p s o f
from two to twelve contractions with incomplete relaxation, each group being
separated by a prolonged diastole (No. 5). With the exception of some groups
of single contractions, each contraction being followed by a prolonged diastole,
this characterises the record up to the end of the experiment, 25 minutes after
the exhibition of the drug. During the last 10 minutes the contractions
gradually became feebler.
27
The experiment was repeated with solution D, normal contractions were
first recorded for five minutes (No. 1, Plate VIII). 0.5 c.c. of solution. D
was then injected into the right auricle. The heart at once stopped beating,
with the ventricle in complete contraction (No. 2). At the end of 25 seconds
feeble auricular contractions began and at the end of 60 seconds very slight
ventricular contractions were seen. At the end of five minutes the contractions
were again well established and regular but smaller than normal (No. 3).
At eight minutes the prolongation of the diastole first appeared (No. 4), and
from this point to the finish of the record at 27 minutes, the contractions
showed this characteristic. The contractions were both single and arranged in
groups of two, three and four, the majority being single or in pairs (No. 5).
The amplitude was normal from 9 minutes 30 seconds to 25 minutes when the
contractions began to diminish and show great irregularity (No. 6).
(3) ACTION ON ISOLATED HEART OF PITHED FROG. (See Plate VIII.)
In this experiment a frog was used to whose heart solutions A and B had
already been applied externally with practically no effect.
The heart was beating normally and a tracing was first recorded at this
stage. 0.5 c.c. of solution D was then injected into the right auricle. The
effect was instantaneous. The ventricle stopped beating and remained firmly
contracted, very slight auricular contractions being still perceptible (No. 1) .
This condition persisted as long as the record was maintained, namely, 25
minutes.
The probable explanation of the difference in the results of this experiment
and those of the previous experiment is that some of the previously applied
Digitalis had already been absorbed and the combined effect of that and of the
dose now injected was sufficient to account for the more severe effect.
(4) ACTION ON ISOLATED HEART OF PITHED FROG. (See Plate IX.)
Arrangements as before. A normal tracing was first taken (No. 1, Plate
IX). 0.5 c.c. of solution C was then allowed to flow over the surface of the
heart. No effect was perceptible until 3' 36" after the application of the drug,
when considerable slowing of the beat, increased amplitude, and a marked in
-crease in the auricular contraction became evident (No. 2). This was main
-tained for 1' 40", the contractions being mostly in pairs with an exaggerated
and prolonged relaxation between each pair (No. 3). For the next three
minutes there was considerable irregularity (No. 4), but this gradually passed
off and at the end of fifteen minutes from the first injection the action was,
again regular (No. 5). This regularity was maintained till the end of the
experiment.
28
(5) .ACTION ON ISOLATED HEART OF PITHED FROG. (See Plate IX.)
Arrangements as before. A normal tracing was first taken (No. 1, Plate
IX). 0.5 c.c. of solution D was then allowed to flow over the surface of the
heart. A considerable slowing of the beat was at once produced with an in
-crease in the force of the systole (No. 2). The prolonged diastole seen in
experiment (4) was not apparent here and the heart continued to beat regularly,
with a slightly prolonged " systolic plateau " to the end of the experiment 20
minutes after the application of the drug (Nos. 3 and 4).
(6) VASO-CONSTRICTION EFFECT, AS OBSERVED MICROSCOPICALLY IN
INTER-DIGITAL MEMBRANE OF FROG.
Two frogs were pithed and an inter-digital membrane of each fixed under
a microscope. Frog X received 0.5 c.c. of solution C injected into its dorsal
lymph sac, frog Y receiving 0.5 c.c. of solution D similarly.
In neither case could any change in the calibre of the vessels of the mem.
brane be made out during fifteen minutes' observation.
(7) VASO-CONSTRICTOR EFFECT AS OBSERVED MICROSCOPICALLY IN MESEN-
TERY OF PITHED FROG- AFTER LOCAL APPLICATION OF DRUG-.
Two frogs (X and Y) were pithed and the mesentery of each placed on the
stage of a microscope and kept moist with normal saline solution. Two minims
of solution C was applied to mesentery of frog X and the same amount of
solution D to that of frog Y. In X on the application of the drug the circula
-tion which had been very slow, occasionally showing only a pulsatile movement,
instantaneously became very active, but no change in the diameter of the
vessels was apparent for 9 minutes when a slight narrowing became perceptible.
This diminution in the diameter became more marked up to 14 minutes but
never approached in degree that shown in frog Y. Fourteen minutes after the
application of the drug an appearance of inflammation was seen. This became
much more intense during the following 5 minutes and the vessels began to
dilate again. Half an hour after the application there was intense inflamma
-tion over the area to which the drug had been applied, with considerable
dilatation of the vessels, but the circulation was still rapid.
In the case of Y, to which fresh Tinct. Digitalis (solution D) had been
applied, the circulation which had been similar to that seen in X, immediately
became very rapid and a considerable degree of constriction of the arterioles
and to a less extent of the small veins was at once apparent. This constriction
increased for a period of 6 minutes, after which the calibre of the vessels
29
remained unaltered during the rest of the experiment. The membrane and
adjacent intestine were kept under observation for 30 minutes after the applica
-tion of the drug and no sign of inflammation or irritation was seen.
(8) EFFECT ON PERIPHERAL VESSELS, AS SHOWN BY PERFUSING VESSELS
OF PITHED FROG WITH DRUG.
Pithed frog and apparatus arranged as stated on page 2. Several prelimi
-nary experiments were done to determine the best perfusing fluid, the optimum
pressure, the time taken to render the frog bloodless, the best strength of the
drug in the perfusing solution, and some other minor points. At first Ringer's
solution was used, but later it was found that normal saline solution, which
took much less time to prepare, gave equally good results. The best marked
effects were got with normal saline solution containing 6 per cent. of solution
A and solution B.
The following figures were obtained.: (The frog was perfused with normal
saline solution until bloodless, and then the saline solution traversing the peri
-pheral circulation was measured during successive 5 minute periods. When
the flow had become approximately constant, normal saline solution containing
6 per cent. of solution A was perfused and the amount traversing the
peripheral circulation in. successive 5 minute periods was similarly measured.)
Amount passed in successive
Normal Saline Solution.
5 minute periods in c.c.
Saline containing Solution A.
30
22
34
19
34
16
29
17
28
14
26
24.5
22.5
26
2 5
30
The experiment was then repeated with a fresh frog, using first normal
saline and then saline containing 6 per cent. of solution B, the figures obtained
being as follows :—
Amount passed in successive 5 minute periods in c.c.
Normal Saline Solution.
Saline containing Solution B.
21
22
24
23
27
15
27
24
27
24
26
22
26
20
This also shows a certain amount of vaso-constriction, but not to such a
degree as that produced by the tablet solution (Solution A).
This result was not what was anticipated, so it was verified by repeating
the experiment with four more frogs, but in each case, although the ratio was
not exactly the same, the general results approximated to those shown above,
indicating that the tablet solution when perfused has a slightly more vaso
- c o n s t r i c t i n g e f f e c t t h a n h a s t h e f r e s h s o l u t i o n .
(9) Toxic ACTION ON ANIMALS WHEN EXHIBITED IN EXCESSIVE DOSES.
Two guinea-pigs were taken each weighing as nearly as possible 500 grams
(precise weights 487 and 496 grams respectively). One received 2 c.c. of
solution C and the other 2 c.c. of solution D hypodermically, each thus getting
4 minims of Tinct. Digitalis, equal to 8 . 8 minims per kilo, i.e., 20 times the
maximum pharmacopeal dose, calculating this as 30 minims for a .man of 75
kilos.
Both animals were kept under observation for 48 hours. Except that for
the first two hours they remained huddled up in one corner of their cage and
did not move about freely, they showed no symptoms or signs of any sort, and
at the end of 48 hours and also 5 clays later they were both apparently
a perfectly normal condition.
In the light of the foregoing experiments, the tablet preparation of Tinct.
Digitalis would appear to have deteriorated a considerable extent when
31
compared with the fresh preparation, but the deterioration does not affect all
its actions equally. In its action on the heart, which is its most important one
therapeutically, it shows a distinctly weaker effect, and its action on peripheral
vessels, when applied locally to the exposed mesentery, is weaker and at the
same time more irritating. On the other hand, perfusion experiments show
that its vaso-constricting power is slightly greater than that of the fresh
preparation. The administration of very large doses to guinea-pigs without any
evil effects indicates the absence of any undesirable toxic bodies from both
tablets and fresh drug.
To summarise .—The experiments performed indicate that the tablet has
deteriorated considerably when compared with the fresh drug, except in regard
to its vaso-constricting effect when perfused through the peripheral circulation.
Tinct. Opii Tablets (10 minims).
Ten tablets were dissolved in 100 c.c. of distilled water and at the end of
24 hours a thick light brown fluid was obtained containing much brownish
matter in suspension. This was filtered, the clear filtrate being solution A.
A control solution of identical strength was made by diluting 100 minims
of fresh Tinct. Opii with distilled water to 100 c.c. making a clear brown
solution, solution B.
Both these solutions ought to contain an identical amount of Morphine,
v iz ., 0.044 gram.
(1) INTRA-PERITONEAL INJECTION IN FROG-.
Two frogs were taken, frog X received 1 c.c. of solution A (0.00044 grains
Morphine), and frog Y received 1 c.c. of solution B.
Frog X showed no sign of being affected by the drug during the four hours
it was kept under observation.
Frog Y, 15 minutes after injection of the drug, sat quietly and did not
respond to slight stimuli. To strong stimuli it responded, but with a percep
-tible latent period. At 45 minutes the frog was apparently comatose and
responded only to very strong stimuli. This condition persisted to the end of
the experiment. The pupil remained normal throughout.
(2) THE ABOVE NOTED EXPERIMENT REPEATED WITH A TEN-FOLD DOSE,
Solutions of double the strength of solutions A and B were prepared,
solution C being made from the tablets and solution D from the fresh Tinct,
Opii.
32
Two frogs were taken, frog X got 5 c.c. of solution C and frog 5 c.c. of
solution D.
Frog X, 20 minutes after the injection, was moving about freely and
responded normally to stimuli. At 60 minutes the condition was practically
the same. At 2 hours and 5 minutes movements in response to stimuli were
not quite so marked, but there was no delay of response. This condition per
sisted to the end of the experiment. The pupil remained normal throughout.
Frog Y, 22 minutes after the injection, had ceased to make any spontaneous
movements and responded very slowly and feebly to stimuli. Very slight con
-traction of the pupil was present. At 52 minutes stimuli produced. convulsive
movements, and spasmodic contractions occurred at intervals during the next
hour. At two hours and seven minutes after the injection respiration had
ceased and the frog was apparently dead, although on opening the body the
heart was found still to be beating. It is well known, however, that frogs can
recover after very large doses of Morphine and after their respiration has been
stopped for several hours.
(3) VASO-DILATOR EFFECT ON VESSELS OF EXPOSED MESENTERY OF
PITHED FROG.
Two frogs were pithed and a loop of intestine with its attached mesentery
brought out and fixed under the low power of a microscope. 0.2 c.c. of
solution C was applied to one and 0.2 c.c. of solution D to the other.
In the case of solution C, the application of the drug was followed
immediately by a perceptible dilatation of both the larger vessels and the
capillaries. Thirteen minutes later slowing of the circulation in the capillaries
became apparent, dilatation of all the vessels remaining about the same. At
40 minutes the vessels had returned to their original calibre and circulation
had stopped completely in the smaller capillaries. At 55 minutes circulation
in the larger vessels was still taking place but much more slowly, and it
gradually came to a standstill in the course of the next half hour.
In the case of solution D, application of the drug was at once followed
by dilatation of all the vessels, but to a greater extent than in the case of
solution C.
Three minutes after application the larger vessels had dilated to about twice
their original calibre. Some of the capillaries showed an appearance of
engorgement, but the circulation remained quite free. Some of the smallest
capillaries showed a very marked increase in size. At 28 minutes dilatation
was still maintained, but the circulation was much less rapid and there was a
tendency to stasis in some of the vessels, specially the capillaries. At
33
43 minutes the circulation had almost stopped and complete stasis occurred
within an hour.
(4) EFFECT WHEN GIVEN BY THE MOUTH TO RABBITS.
Two rabbits of 478 and 464 grams were taken and to one (X) five tablets
crushed in 30 c.c. of water were administered by a stomach tube, the other (Y)
receiving 50 minims of fresh Tinct. Opii in 30 c.c. of water. Both animals
were kept under observation for five hours.
X's temperature before receiving the drug was 101.2. No difference in
temperature, contraction of pupil or other effect of the drug was apparent
throughout the experiment.
Y's temperature was 101.2 before receiving the drug. At 25 minutes after
administration slight contraction of the pupils was perceptible. At 70
minutes the animal was sitting quietly with eyes half shut and appeared rather
dizzy, staggering slightly when pushed. The temperature had dropped to 100.2.
At 1 hour and 40 minutes the pupil contraction had passed off and the animal
was moving about occasionally. Thereafter no further effects were noticed.
These results would indicate that, although by no means on a par with the
fresh tincture in physiological effect, the tablets have retained a portion of their
activity. They cannot, however, be regarded as a satisfactory substitute for
the fresh tincture.
Zinc Sulphate.
These one grain tablets were tested against fresh pure zinc sulphate
obtained from Messrs. Baird and Tatlock.
(1) CHEMICAL TESTS.
( a )
S o l u t i o n s o f e q u a l s t r e n g t h ( 5 p e r c e n t ) o f t a b l e t s a n d o f f r e s h s a l t
give a similar reaction with Ammonia, both giving a precipitate which dis
- s o l v e d i n e x c e s s .
( b )
B o t h s o l u t i o n s w e r e p r e c i p i t a t e d b y B a r i u m C h l o r i d e .
( c )
B o t h s o l u t i o n s w e r e p r e c i p i t a t e d b y A m m o n i u m S u l p h y d r a t e .
(2) COAGULATION OF ALBUMIN.
An aqueous solution containing 4 per cent. of egg albumin was prepared
and two Esbach tubes were filled with it up to the U mark. One tube was
filled up to the R mark with 2.6 per cent. solution of tablets, the other being
similarly filled up with 2.6 per cent. solution of fresh salt. The tubes were
shaken and allowed to stand for 24 hours, the precipitate being thus given
time to settle. The precipitate was the same in both tubes, viz., 0.025 per cent.
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The experiment was repeated with undiluted beaten up and filtered egg
albumin and again the solution of the tablets and that of the fresh salt gave
the same result, viz., 0.24 per cent.
(3) EMETIC ACTION ON DOGS.
Thirty grains being taken as a dose for a man of 75 kilos, this works out at
0.4 grain (0.026 gram) per kilo as an emetic.
Two solutions of different strengths were made, both with the tablets and
with the fresh salt.
Solution A .
.
.
.
.
2.6 per cent. Tablets.
" B.
.
.
.
.
.
2.6
" Fresh Salt.
" C .
.
.
•
.
26
"
Tablets.
" D
.
26
"
Fresh Salt.
Two dogs were taken and weighed, one weighing 3.02 kilos and the other
16.41 kilos. To the smaller one 0.078 gram of tablet was given by the mouth,
i.e., 3 c.c. of solution A. It was kept under observation for six hours, but no
effects attributable to the drug were seen.
To the larger dog 0.853 gram of fresh salt was given, i.e., 3.3 c.c. of solu
-tion B. The dog was kept under observation for six hours and showed no
signs of vomiting or salivation.
Two days later the experiment was repeated, reversing the drugs, i.e., the
small dog receiving the fresh salt and the larger one the tablets.
The small dog, 10 minutes after receiving the drug, began to bark and
yawn and passed urine three times during the first hour and a quarter. There
-after its behaviour was quite normal.
The larger clog, 9 minutes after receiving the drug, began to show signs of
uneasiness, swaying about and trembling. At 11 minutes it vomited once, a
small quantity of frothy thick fluid. It kept shaking its head to and fro for
15 minutes after this, and then lay down quietly, remaining quiet and showing
no further signs of any action on the part of the drug.
The Zinc Sulphate tablets appear to be in all respects equal to the fresh
salt and show no sign of having deteriorated.
Hypodermic Tablets.
Apomorphinum Hydrochloridum (0.1 grain =0.0065 gram).
The solubility of this salt is one in sixty in water. In its action it is
emetic, acting on the central nervous system. Locally applied it diminishes
35
and finally abolishes the irritability of both striped and cardiac muscle in the
frog.
A solution of 0.005 gram per c.c. was made by dissolving 5 old tablets in
6.5 c.c. of distilled water—solution A. A control solution B of equal strength
was made from the new (1910) tablets.
Solubility .—The fresh tablets entirely dissolved in 30 seconds when
shaken up in the water. The old tablets took 25 minutes to dissolve, with
constant shaking. The colour was the same in each case, namely, light green,
the solution of the fresh tablets being clear and that of the old ones slightly
turbid. Twenty-four hours later both solutions had become dark green.
(1) EMETIC ACTION ON DOGS.
A dog weighing 17.9 kilos received hypodermically 1.79 c.c. of solution A.
=0.0005 gram per kilo) at 12-50 P.M. Salivation and symptoms of nausea set
in at 12-54, and at 12-54'-30" the dog vomited. Considerable muscular weak
- n e s s w a s p r e s e n t , t h e d o g b e i n g u n a b l e t o s t a n d . I t c o n t i n u e d t o r e t c h a t
intervals and vomited again at 1-8. Evidences of nausea persisted till
2-50 P.M. after which the dog was apparently normal.
To another dog weighing 16.8 kilos, a hypodermic injection of 1.6S c.c.
of solution B =0.0005 gram per kilo) was administered at 12-45 P.M. The
dog began to vomit 1 minute 45 seconds after receiving the injection and
vomited 13 times in 20 minutes. At first undigested food was vomited, but
later only greenish yellow frothy mucus. The animal was unable to stand and
the eyes were injected. There was constant retching and the dog made
efforts to vomit at intervals of about 2 minutes up till 2 P.M. After 2 the
dog was able to stand, but there was still considerable nausea. It urinated.
once at 1-20 P.M. By 4 P.M. the animal had apparently returned to its normal
state.
(2) DIMINUTION OF IRRITABILITY OF STRIPED MUSCLE OF FROG.
A muscle nerve preparation was dissected out and arranged for recording
the minimum effective Stimulus, as indicated by the distance between the
primary and the secondary coil. Using two Hensen cells in series and an in
- d u c e d c u r r e n t a n d g r a d u a l l y i n c r e a s i n g t h e d i s t a n c e b e t w e e n t h e p r i m a r y a n d
secondary coil, the greatest separation of the coils which still gave an effective
stimulus was 20 c.m.
Two c.c. of solution A was then allowed to flow over the muscle, and the
greatest separation of the coils compatible with an effective stimulus was then
found to be 17 c.m.
F2