NationalLibraryOfScotland/medical-history-of-british-india huggingface dataset:
15
With the temperature at 103.3, 0.5 gram of crushed 1905 tablets was ad-
ministered in water by the mouth at 1-30 P.M. and the temperature recorded
every half hour till 4-30.
Temperature at
1-30
103.3
,,
, ,
2-5
102.1
,,
,,,
2-30
102
,,
, ,
3
102.5
,,
, ,
3-30
102.8
, ,
, ,
4
103.2
,,
, ,
4-30
103.2
From the above noted figures it will be seen that the temporary reduction
of temperature was practically equal in each case, and the 1905 tablets may be
said to have retained their activity in full when tested against freshly made
tablets.
Phenacetinum-cum-Caffeina Tablets.
Each tablet contains four grains of phenacetin and one grain of caffeine.
CAFFEINE.
A separation was effected between the phenacetin and the caffeine by
utilising their different solubilities. Caffeine is soluble in water in the propor-
tion of 1 in 68, whereas phenacetin is practically insoluble in water (1 in 1,700).
By crushing and dissolving the tablets as far as possible in water, and then
filtering, a solution of caffeine was obtained containing phenacetin only to the
extent of 1 in 1,700, the undissolved phenacetin being left on the filter.
Two solutions were made, A of 2.5 grams of old (1905) tablets, (contain-
ing 0.5 gram of caffeine) in 50 c. c. of water, well filtered, equalling a one per
cent, solution of caffeine, and B of the same strength made in the same way
with fresh (1910) tablets.
(1) EFFECT ON STRIPED MUSCLE OF FROG WHEN APPLIED LOCALLY.
(See Plate IV.)
A nerve muscle preparation was arranged for recording contractions and
a normal curve first recorded. Then 0.25 c.c. of a ten-fold dilution of solution
A with normal saline solution was applied to the muscle, and a curve taken
immediately after the application. This curve was almost the same height as
the normal curve but about double its length. The muscle was then washed
with normal saline and a five-fold dilution of solution A applied in the same way
16
and a contraction recorded. This was lower and slower than the previous two
and relaxation was not complete. After Washing the muscle a two-fold dilution
(containing 0.5 per cent. caffeine) was applied. This caused a considerable
shortening of the muscle. A contraction was recorded which was very flat with
incomplete relaxation. The muscle was again washed and undiluted solution A
was applied, causing great contraction, the base line being now above the level
of the highest part of the normal contraction. A contraction was recorded,
which was also very flat and showed incomplete relaxation. These results are
shown in Chart No. 1, Plate IV.
The experiment was repeated with a fresh muscle nerve preparation and
solution B, the results being identical, and being shown in Chart No. 2,
Plate IV.
(2) ACTION ON ISOLATED HEART OF PITHED FROG. (See Plates V and VI.)
The heart was isolated and arranged for recording contractions on a slow-
ly moving drum. A normal tracing was first made (No. 1, Plate V). 0.5
c.c. of solution A was then allowed to flow over the heart (No. 2). The
effect became apparent in six seconds, the contractions gradually diminishing
in amplitude and. the diastole becoming greatly prolonged, up to as much as
5.8 seconds (Nos. 3 and 4). At the end of two minutes the contractions
were regular but only from 0.6 to 0.75 of the normal amplitude, and the
diastole was regular lasting just under two seconds (No. 5). At 2 minutes 40
seconds a second dose of 0.5 c.c. was applied, but no further effect was
perceptible (Nos. 6 and 7).
The experiment was repeated with a fresh frog's heart, using solution B.
The normal tracing was first taken (No. 1, Plate VI), and then the drug
applied (No. 2). The effect was similar but not so marked as with solution
A, and was recovered from to a greater extent (Nos. 3 and 4). At two
minutes a second dose was applied (No. 5), which apparently almost paralysed
the heart (Nos. 6, 7, and 8).
(3) VASO-DILATOR ACTION ON PERIPHERAL VESSELS OF PITHED FROG.
Pithed frog and apparatus arranged as stated on page 2. The frog was
perfused with normal saline solution until bloodless and then the saline solution
traversing the peripheral circulation was measured during successive five
minute periods. When the flow had become approximately constant and
uniform, normal saline solution containing 2 per cent. of solution A, was
17
perfused and the amount coming away in successive five minute periods was
similarly measured. The results obtained are noted below :—
Amount passed in successive 5 minute periods in c.c.
Normal Saline
Solution.
Saline containing
Solution A.
7 0
80
70
85
6 8
85
74
81
72
78
The experiment was repeated with a fresh frog, using first normal saline
solution and then saline solution containing 2 per cent. of solution B. The
figures obtained were as follows :—
Amount passed in successive 5 minute periods in c. c.
Normal Saline
Solution.
Saline containing
Solution B.
21
33
25
37
30
42
30
44
30
45
30.5
46
46
(The pressure under which the solutions were perfused was kept constant
in both experiments.)
The results of the foregoing experiments would appear to show that the
caffeine in the old tablets has retained most of its activity, but compared with.
that in the fresh tablet it shows a slight degree of deterioration and loss of
activity.
18
Phenacetin.— The undissolved phenacetin from solution A, was dried and
weighed and tested against that from solution B, in rabbits whose temperature
bad been artificially raised and no difference in antipyretic action could be
detected between the two.
P i l . P l u m b i c u m O p i o ( F i v e g r a i n s ) .
Each pill contains 0.243 gram of Lead Acetate and 0.04 gram of Opium.
The activity of both substances was investigated, pills of 1907 and 1910 being
tested against each other.
Solubility and rapidity of solution.—Two dishes each containing 100 c.c.
of distilled water were kept at a temperature of 37 Centigrade. In one was
placed a fresh pill and in the other an old pill and both were observed for one
hour.
In the case of the old pill, the outer coating began to dissolve at 13
minutes and at the end of an hour the whole of the outer coat was dissolved
and a small amount of the pill substance had dissolved. At the end of 24
hours about half the pill had disintegrated.
The outer coating of the new pill showed the first signs of dissolving at
20 minutes and the whole coating and a small amount of the pill had dissolved
at the end of an hour. After 24 hours about half the pill had disintegrated,
some being dissolved and some remaining as a sediment.
The solubility was similarly tested with a 0.5 per cent. solution of Hydro
chloric Acid, and here the old pill broke up slightly more rapidly than the
new, the whole of the old and the greater part of the new having disin-
tegrated at the end of an hour.
A 0.5 per cent. solution of Sodium Carbonate was also used and in this the
old pill showed a slightly more rapid disintegration.
One hundred c.c. of water at 100 Centigrade disintegrated the old pill in
6 minutes and the fresh pill in 7 minutes.
Lead Acetate being soluble in water, a one per cent. solution was made by
crushing and dissolving one pill in 24.3 c.c. of water, giving a solution of 0.01
gram per c.c.
Solution A was made with old pills, solution B being of equal strength
made with fresh pills.
The coagulating action of these on albumin, and their action on the blood
vessels of the frog and also on the muscular power and irritability of the frog
were then compared.
(1) COAGULATION OF ALBUMIN.
Both were found to coagulate albumin.
19
On doing a quantitative test with Esbach's tubes, using an albuminous
solution of known strength and taking the same amount of solution A and
solution B, both produced the same amount of coagulum.
(2) ACTION ON EXPOSED MESENTERY OF FROG.
Both solutions produced a similar effect, namely, first a slight dilatation
of the vessels followed after between six and seven minutes by gradual slowing
and. finally stasis of, the circulation, with a slight white deposit on the surface
of the mesentery, probably due to coagulation of albumin.
(3) INTRA-PERITONEAL INJECTION IN FROG.
One c.c. of solution A was injected into one frog and the same amount of
solution B into another. No effects were observed during the following three
hours, the muscular power remaining unimpaired and the reflexes normal.
The dose was increased up to 4 c.c. of one per cent. solution without
producing any effect either in the case of solution A or solution B.
Solutions were next made from both the old and the fresh pills as follows.
Five pills were crushed and dissolved in 20 c.c. of water. Then sulphuretted
hydrogen was passed through the solution to precipitate the lead in solution
as lead sulphide. The solution was then thoroughly filtered to get rid of the
lead, the filtrate containing no lead and being clear and yellowish in colour.
Solution C was made from the old pills and solution D from the fresh pills.
(4) INTRA-PERITONEAL INJECTION OF LEAD-FREE SOLUTION.
Four c. c. (equal to 0.04 gram of opium) of solutions C and D respectively
were injected into two frogs.
In the case of solution C the following events were noted. Diminution of
reflexes was first perceptible 15 minutes after the exhibition of the drug. This
gradually became more marked and at one hour and forty minutes the reflexes
were greatly diminished and very slow. The frog was unable to walk and
response to stimulation was very late. At 1 hour 45 minutes no response could
be elicited to any stimulus applied to the legs. At 1 hour 50 minutes head
spasm occurred, five spasms being counted in one minute, each followed by a
relaxation of the muscles. At two hours from the injection of the drug and.
thereafter, any stimulus caused spasmodic contractions, but the frog was unable
to move except when stimulated, This condition persisted for two hours more.
Next day the frog had recovered and was apparently normal.
Solution D produced similar effects but more quickly. Diminution of
reflexes was perceptible in five minutes from the injection. The frog could
20
still walk but had stopped jumping. At 13 minutes the frog could only move
about slowly. The corneal reflex was normal and the pupil not contracted.
When placed on its back it could still regain its normal position. At 16 minutes
it was unable to right itself but made slow movements when in its normal posi-
tion. The first spasms appeared at 25 minutes and at 35 minutes there was
a continuous spasm lasting for nearly five minutes. Any stimulus applied to
the frog or even any movement of its containing cage produced a spasm.
Apart from these spasms the frog was unable to move, and the pupil was in a
state of contraction. This condition lasted from minute 35 to minute 56, after
which no response or spasm was evoked by any stimulus. The frog was dead in
one hour after the injection of the drug.
(5) EFFECT WHEN GIVEN BY THE MOUTH TO RABBITS.
Twenty c. c. of solution C was given to one rabbit and 20 c.c. of solution
D to another, being introduced into the stomach by a tube.
Condition on receiving the drug.
SOLUTION C RABBIT.
Temperature
.
.
101
Respiration
.
.
58
Pupil
.
. . normal
SOLUTION D RABBIT.
Temperature
.
.
100.8
Respiration
.
.
60
Pupil
.
.
. normal
AFTER ONE HOUR.
Temperature
.
.
101
Respiration
.
.
.
Pupil
.
.
. normal
Temperatur
.
.
101
Respiration
.
.
5 6
Pupil
. .
. normal
Both animals were kept under close observation for four hours, but no
effects attributable to the drug were observed.
(6) ACTION ON FROG ' S MESENTERY.
0.25 c.c. of solution C was applied to the mesentery and the application
was followed at once by some engorgement of the vessels which appeared a
deeper red under the microscope and also showed perceptible dilatation.
Solution D gave rise to the same effects but the engorgement and dilatation
were more marked, the smaller vessels appearing bright red and considerably
increased in calibre.
From the foregoing results I conclude that the lead in the old pills has not
undergone deterioration and is practically as active as the lead in the fresh pill.
21
The opium in the old pills, however, has decomposed considerably and is
much less active than that in the fresh pills.
In rapidity of solution and ease of disintegration there is practically no
difference between the old and the fresh pills.
Pil. Hydrargyri Subchloridi Co.
Some experiments were first made to compare the ease and quickness of
solution of the old pill with that of the fresh.
(1)
Two DISHES EACH CONTAINING 100 C.C. OF A 5 PER CENT. SOLUTION OF
HYDROCHLORIC ACID IN WATER WERE KEPT AT 37° CENTIGRADE.
In one was placed a fresh pill and in the other an old pill and both were
observed for an hour.
The old pill showed no sign of dissolving, only two cracks having formed
in the coating.
The fresh pill showed some melting of the coating in five minutes and the
whole of the coating had dissolved off in ten minutes, but the pill itself re-
mained undissolved, the fluid remaining quite clear.
(2)
THE EXPERIMENT WAS REPEATED WITH A 5 PER CENT. SODIUM CARBONATE
SOLUTION.
The old pill showed some cracks in the coating at 15 minutes and in half
an hour the coating was entirely dissolved. At the end of an hour the liquid
close to the pill showed some brown discoloration, indicating some slight solu-
tion of the pill itself.
In the case of the fresh pill the coating took half an hour to dissolve
completely and the brown discoloration was rather more marked than in the
case of the old pill.
(3)
THE EXPERIMENT WAS REPEATED WITH BOILING WATER.
The old pill was entirely broken down into fine suspended matter in be-
tween eight and nine minutes.
The fresh pill only took five minutes to disintegrate.
Physiological action.
(4) PURGATIVE ACTION ON MAN.
Two laboratory attendants who volunteered for the experiment and were
of approximately the same weight received an old and a fresh pill respectively
at 3-30 P.M.
22
The recipient of the old pill had one motion at 8 Pm., hard and yellowish.
At 6-30 A.M. he passed a small quantity of soft solid fæces followed by a large
quantity of yellow liquid. No griping or loss of appetite was complained of.
The recipient of the fresh pill passed one motion at 7 P.M., soft but fairly
normal in appearance. He passed a second motion at 9 P.M. consisting almost
entirely of yellow liquid, and a third motion at 10-30 P.M. consisting of a large
quantity of yellow liquid containing a small amount of solid fæcal matter.
He complained of loss of appetite and also of griping which lasted four hours.
(5) PURGATIVE ACTION ON DOGS.
Two old pills were crushed and given in suspension to a dog weighing 18
kilos, at 11-30 A.M. At 12-33 the dog vomited about two ounces of greenish
matter mixed with froth and mucus. At 3-30 it defecated once, a small hard
greenish-black mass. At 6 P.M. it again vomited a small quantity of greenish
frothy matter. It passed no more fæces during the 24 hours following the
administration of the drug.
Two fresh pills were crushed and given to a dog weighing 19 kilos at
11-40 A.M. This dog did not vomit and passed one small liquid yellowish
motion at 8 P.M. No further action took place during the 24 hours following
the administration of the drug.
Conclusions.— The old pills break up and dissolve more slowly than the
fresh. They appear to have retained most of their capability of producing
purgation and show little deterioration when tested against the fresh pill.
Soda Mint Tablets.
The physiological action of Sodium Bicarbonate and Peppermint on the
secretion of gastric juice is so complicated as to be outside the scope of this
investigation.
Clinical experiments with the old and the fresh tablets in cases of acid
dyspepsia showed no difference between their respective activities.
The chemical report on the Sodium Bicarbonate is favourable, and Pepper-
mint is present although its amount cannot be determined.
Sodium Chloride Soloids.
Each soloid is said to contain thirty grains, equal to 1.944 grams of Sodium
Chloride. They were first tested for loss of weight and substance.
(1) Loss OF WEIGHT.
Four soloids taken at random were found to average 1.914 grams, a loss of
weigh t of 30 milligrams per soloid.
23
( 2 ) O N E S O L O I D W A S D I S S O L V E D I N 1 0 0 C . C . O F D I S T I L L E D W A T E R , G I V I N G A
SOLUTION WHICH SHOULD BE 1.944 PER CENT.
This was titrated against Standard Solution of Silver Nitrate and was
found to correspond to a 1.845 per cent. solution, showing a loss of 99 milli
-grams of Sodium Chloride per soloid.
The difference between the results obtained in experiments (1) and (2) is
probably due to some of the loss of Sodium Chloride being made up for by
absorbed moisture.
(3) A 0.75 PER CENT. SOLUTION BY WEIGHT WAS MADE WITH FRESH PURE
SODIUM CHLORIDE AND ALSO WITH THE SOLOIDS AND EACH WAS DILUTED
WITH DISTILLED WATER UNTIL IT PRODUCED PERFECT AND COMPLETE
HÆMOLYSIS OF HUMAN RED BLOOD CORPUSCLES.
Complete hæmolysis was only produced in the case of the fresh salt when
it had been diluted up to four volumes. In the case of the soloid solution, a
dilution to 3.8 volumes produced complete hæmolysis.
These results, with those obtained by the Chemical Examiner, show that
the Sodium Chloride soloids, except for a very minute loss of substance, have
not undergone deterioration.
Tinct. Camph. Co. Tablets.
One ounce of Tinct. Camph. Co. contains two grains of opium, two grains
of Benzoic Acid and one and a half grains of Camphor.
One tablet is equal to fifteen minims and therefore contains one-sixteenth
of a grain (equal to 0.004 gram) of opium. Ten tablets contain, therefore,
0.04 gram of opium.
Two solutions were made. Solution A consisted of 20 tablets dissolved.
in 50 c.c. of water and contained 0.0016 gram of opium per c.c. Solution B
(control), of the same strength, consisted of 300 minims of fresh Tinct. Camph.
Co. made up to 50 c.c. with distilled water.
Having no means of separating out the constituents of Tinct. Camph. Co.
one was compelled to take the combined action of the composite preparation.
(1) INTRA-PERITONEAL INJECTION IN FROG.
Two frogs were taken, one receiving an injection of one c.c. of solution A
and one an injection of the same amount of solution B. Both frogs were kept
under observation for four hours and in neither case was any deviation from the
normal detected.
24
( 2 ) T H E S A M E E X P E R I M E N T W A S R E P E A T E D W I T H A L A R G E R D O S E .
Two frogs were taken. Frog X received an injection of five c.c. of solution
A intra-peritoneally, frog Y receiving five c.c. of solution B.
In the case of frog X no deviation from the normal was observed, the
animal responding to stimuli and behaving in a perfectly natural manner during
the four hours it was kept under observation.
Frog Y showed effects very soon after the exhibition of the drug. Five
minutes after, it was unable to jump normally when stimulated, and could only
move at a walk.
At nine minutes, on the hind legs being pinched or pricked, they were
withdrawn very slowly after a considerable interval. At twelve minutes the
hind legs were stretched out and then retracted, after which the frog remained
in this position. When placed on its back it was unable to right itself. After
twenty minutes it ceased to respond to any cutaneous stimulation, and the cor
-neal reflex was greatly impaired and retarded, the eyes being closed very slowly.
From minute 25 to minute 33 spasmodic contractions of all the muscles occurred
four times at intervals of about two minutes. After minute 33 the frog remain
-ed quiet and no more spasms occurred. Respiration which had ceased to be
perceptible ten minutes after the injection of the drug again became visible at
one hour 20 minutes and the frog gradually recovered although next day the
reflexes were still sluggish.
(3) EFFECT WHEN LOCALLY APPLIED TO EXPOSED MESENTERIC VESSELS
OF PITHED FROG,
Two frogs were pithed and the abdomen opened enough to permit of a loop
of intestine and its attached mesentery being drawn out on a slide and kept
under observation with the low power of a microscope.
To the mesentery of frog X, 0.2 c.c. of solution A was applied and to that
of frog Y, 0.2 c.c. of solution B.
Frog X.—No change was at first apparent, and the earliest perceptible
alteration in the calibre of the mesenteric vessels was noticed 15 minutes after
the application of the drug. The change observed was some engorgement and a
slight increase in the calibre of the larger vessels, not however affecting the
capillaries. The state of the vessels remained the same for 53 minutes when
the circulation which had been getting slower and slower in the capillaries
stopped altogether, and became almost stationary in the larger vessels.
It again became free on the application of normal saline solution.
25
Frog Y .—No effect was visible for five minutes when slight dilatation of
the larger vessels became perceptible. The smaller capillaries remained undi
-luted. At 15 minutes circulation was still free with fairly well marked dila
- t a t i o n o f t h e l a r g e r v e s s e l s b u t n o e n g o r g e m e n t .
At 35 minutes engorgement of the larger vessels was fairly well marked
but circulation was still free. Circulation became slightly slower up to one
hour, but at once recovered on the application of normal saline solution.
These results would indicate a very marked deterioration and loss of activity
on the part of the tablets, when tested against and compared with the fresh
drug.
Tinct. Digitalis Tablets.
The effects of Digitalis which were chosen for investigation and comparison
were the following :—
(1) Its somewhat complex action on the heart, as indicated by the increase
in the power of the systole and the lengthening of the diastole when the drug
is exhibited in therapeutic doses, and by irregularity and even stoppage of the
heart when it is subjected to the influence of excessive doses.
(2) Its vaso-constricting effect as observed microscopically in the vessels of
the frog's mesentery after local application, and as shown by perfusion experi
-ments.
(3) Its irritant effect when applied to the peritoneal surface of the frog's
intestine.
Four solutions were made, two of old tablets and two, as controls, of cone
-sponding strength of fresh tincture.
Solution A, equal to a strength of 0.4 minims per c.c., was made by
dissolving eight tablets (each tablet equals five minims of tincture) in 100 c.c.
of distilled water. Solution was very slow and at the end of twenty-four hours
the tablets were only half dissolved. They were then broken up with a glass
rod and the solution well shaken and stirred, but twenty-four hours later a con
- s i d e r a b l e a m o u n t o f i n s o l u b l e d a r k - g r e e n s e d i m e n t r e m a i n e d , t h e s u p e r n a t a n t
fluid being clear and pale green in colour.
Solution B was made by adding 40 minims of fresh Tinct. Digitalis to
95 c.c. of distilled water and making up to 100 c.c. with water.
Solution C, of ten times the strength of A, was made by triturating 20
tablets in 25 c.c. of water, giving a strength of 4 minims per c.c.
Solution D was 100 minims of fresh tincture made up to 25 c.c. with
distilled water.
Both solutions C and D were filtered to get rid of the insoluble suspended
matter.