NationalLibraryOfScotland/medical-history-of-british-india huggingface dataset:
CONTENTS.
PAGE.
Introduction . .
. . . . . . . . . . .
. . .
1
Peculiarities of Quinine and its salts . .
. . . . . . . .
. .
3
Their solubility in water.
Their deterioration (heat, light, moulds).
Compatibility of Quinine salts with blood-serum.
. . . . . .
. . .
6
.Solubility of Quinine alkaloid in blood-serum . . .
. . . .
. . . 11
Solubility of Quinine alkaloid in bile. . .
. . . . . . . . 11
Absorption of Quinine . . . . . .
. . . . . . . 13
Quinine elimination in the urine as a gauge of the amount of Quinine absorbed
. . . . . .
. . .
. .
. 13
Lethality as a measure of the amount of Quinine absorbed . . . .
. .
. 15
A. Oral administration . . . . . . . . . . .
. . . 15
Seat of absorption of Quinine . . . . .
. . .
. . . 15
Factors influencing absorption from the gastro-intestinal tract
. .
.
. . .
. . . 18
(1)
F o o d c o n t e n t s o f t h e g a s t r o - i n t e s t i n a l t r a c t .
(2)Affections of the gastro-intestinal tract.
(3)Affections of the liver.
(4)The solubility of the Quinine salt employed.
The value of the lethality gauge as compared with Quinine elimination
in the urine as a measure of Quinine absorption.
(5)Carbon dioxide.
(6)Single large doses of Quinine as opposed to divided or " fractional " doses.
The efficacy of Warburg's tincture explained
. . .
22
B. Subcutaneous (including intramuscular) administration
. .
. 22
Miscibility of Quinine salt solutions with blood-serum : coagulum formation if the Quinine
salt solution is concentrated .
. .
.
.
23
Precipitation of Quinine at the seat of injection
.
. .
24
Variability in amount of Quinine eliminated in the urine. Effect of degree of concentra
tion of the Quinine injection on elimination .
.
. . . 25
Quinine hydrochloride solutions containing urethane, antipyrine or sodium chloride
. .
26
Facts, (a) experimental and (b) clinical, casting doubt upon the alleged therapeutic advan
tages of hypodermic injections of Quinine, as regards (1) amount of absorption and (2)
promptness of effect .
.
. 26
Minimum-lethal dose experiments on guinea-pigs to test the relative amount of absorption
and promptness of action of Quinine after (1) oral and (2) subcutaneous administration
Reasons justifying the application of these results to man
. . . .
28
Graphic representation (curves) of Quinine absorption after various methods of adminis
tration
. .
33
Local and post-mortem changes in the guinea-pigs used in the minimum-lethal dose experi
ments .
.
,. .
. 34
Quinine fundamentally unsuited for hypodermic injection .
.
.
35
Dangers peculiar to Quinine when administered hypodermically
. .
3 5
Intramuscular injections of Quinine
. .
38
Intravenous injections of Quinine.
. . .
38
Bacelli's solution of Quinine hydrochloride containing sodium chloride
.
38
Great dilution not only necessary in order to avoid the dangers noted after subcutaneous
injections of Quinine but in itself beneficial in malignant malaria by attenuating .the
toxins and favouring their elimination . .
.
.
.
33
2
CONTENTS— concluded .
PAGE.
If any tendency to hæmoglobinuria Quinine alkaloid itself should be used. Acid salts of
Quinine dangerous
.
. 38
The therapeutic action of intravenous injections of Quinine not so fleeting as one might
expect
.
.
.
.
.
.
.
39
Quinine alkaloid dissolved in 33 per cent. alcohol (in saline) in a strength of about 1 in
135 for intravenous injection
.
.
.
.
.
3 9
D. Rect al admi ni st r at i on of Qui ni ne
.
.
.
40
Enemata—
Difficulties: irritation, short retention, etc. Of small therapeutic value in malaria: com-
paratively little absorbed even if retained. The use of a soluble Quinine salt essential.
Suppositories —
Irritating and useless in the treatment of malaria.
Summary of chief results and conclusions . .
.
.
42
References .
.
.
.
.
.
45
QUININE AND ITS SALTS: THEIR SOLUBILITY
AND ABSORBABILITY.
T HE administration of Quinine, although so old and well tried a remedy,
is still beset with many difficulties and feelings of uncertainty on the
part of the physician regarding the rapidity and certainty of action of a given
dose of the alkaloid, by whichever channel that dose is administered. This is
due mainly to our want of knowledge regarding the physical, chemical and, in
particular, physiologico-chemical peculiarities of Quinine and its salts. The
factors influencing the absorption of Quinine from the gastro-intestinal tract
have been neglected; and even the relative therapeutic or prophylactic value
of the various methods of administration of Quinine is still unsettled.
By many it is assumed that Quinine is absorbed chiefly from the stomach,
the intestines taking little or no part in the absorption. Malanin,1 in 1868,
pointed out the insolubility of the compound formed by Quinine and bile acids,
and took for granted that, when this alkaloid was administered by the mouth, as
much of it as was not absorbed from the stomach became inert on coming in
contact with bile in the intestines and was thus eliminated in the fæces. A
similar action was ascribed to bile acids by Kerner.2 Lauder Brunton,3 on
account of the precipitation from a mixture of Quinine and bile acids of this
salt, which is sparingly soluble, except in an excess of bile, recommended clear-
ing out the liver by administering an emetic and a cholagogue purgative before
giving Quinine in the treatment of malaria. According to Sollmann, 4 Quinine
is fairly readily absorbed from the stomach: Giemsa and Schaumann, 5 however,
have come to the conclusion that most of the Quinine given by the mouth is
absorbed from the small intestine. Marshall6 states that most of the Quinine
passes into the duodenum: and Dixon7 is of the opinion that after entering the
duodenum Quinine is under ordinary circumstances absorbed rapidly; but, if
there is excess of alkali in the duodenum, Quinine is precipitated, forming with
the bile acids insoluble salts which are passed unchanged in the fæces.
When there is so little agreement regarding the fate of Quinine in the
gastro-intestinal tract, it is not surprising to find an explanation of the marked
variations in the absorption of Quinine—so often encountered in clinical
practice, sometimes even in the same individual and when using the same salt
of this alkaloid—wanting, and the reason of the efficacy of a preparation like
Warburg's tincture still shrouded in mystery. Warburg's tincture has been
described as "merely Quinine concealed in a farrago of inert substances."
To this description Maclean's (Netley) reply8 was—"I have never seen a single
dose of Quinine given alone to the extent of 9½ grains sufficient to arrest an
2
exacerbation of remittent fever, much less prevent its recurrence ; while no-
thing is more common than to see the same quantity of the alkaloid in Warburg's
tincture bring about such results." According to Sollmann 4 the substances—
aloes, rhubarb, camphor, gentian and aromatic substances which are combined
with the alkaloid in Warburg's tincture, "probably aid in the absorption of the
Qui ni ne; " and Cushny9 st at es t hat t hey promot e Qui ni ne absorpt i on by act i ng
on the stomach and that capsicum and piperine have a similar reputation as ad-
juvants in Quinine treatment. The view expressed in the National Dispensa-
t o r y 1 0 i s t h a t Q u i n i n e a b s o r p t i o n i s h a s t e n e d b y t h e p r e v i o u s a d m i n i s t r a t i o n o f
purgatives, of which a combination of rhubarb and aloes acts best.
Regarding the relative value of the various methods of Quinine adminis-
tration, it will suffice in these introductory remarks to refer to only two—oral
and hypodermic. Most authors of text-books of pharmacology and therapeutics-
assume that Quinine given by the hypodermic method is rapidly and effectively
absorbed. Cushny9 recommends this mode of administration in cases of emer-
gency ; Sollmann4 states that by hypodermic injections, deep into the gluteal
muscles, rapid action is secured ; Binz11 is of the opinion that absorption is
thorough and quick. Many clinicians have expressed similar views. Recent
experiments and clinical observations, however, have cast doubt upon the
orthodox belief that hypodermic injections of Quinine, as of other medicinal
agents, mean more rapid and more concentrated action than is possible with ad-
ministration by the mouth. In Italy and Germany attempts have been made
to solve this problem by laboratory methods. Kleine, 12 on finding a smaller
percentage of Quinine eliminated in the urine when the alkaloid was injected.
subcutaneously than when given by the mouth, came to the conclusion that
absorption was less in the former instance and that the hypodermic method was
therefore of less therapeutic value than the oral. Mariani 13 made an intramus
cular injection into the leg of a rabbit, with a solution of .201 gramme of the
bi-hydrochloride of Quinine in one cubic centimetre of water, and from the
muscle of the rabbit which was killed seventeen hours after the injection he
recovered .1 gramme of anhydrous Quinine or 66.5 per cent, of the amount
injected. The results of Giemsa and Schaumann5 agree with those of Kleine :12
they found that after oral administration the amount of Quinine eliminated in
the urine was 38.5 per cent. of the dose administered and that after hypo-
dermic injection the amount eliminated was only 19.2 per cent. ; but they
regard this difference in the elimination of Quinine as clue not to less absorption,
but to a greater destruction of Quinine in the body when administered by hypo-
dermic injection than when given by the mouth. From the clinical aspect, the
subject has been investigated principally in India. Smythe14 states that
Quinine injected hypodermically is slowly absorbed and is eliminated in the
3
urine for many weeks after administration; and that 20 grains injected into
the flanks will protect an individual from malaria for the following month at
least. According to Megaw 1 5
t h e t e m p e r a t u r e o f p a t i e n t s s u f f e r i n g f r o m
malaria takes about twelve hours longer in coming to normal when treatment
is by hypodermic injections (bi-hydrochloride of Quinine in doses of
10 grains) than when Quinine is given by the mouth, and consequently that
absorption is slower from the subcutaneous connective tissue than from the
mucous membrane of the stomach. Scott1 6
r e g a r d s t h e h y p o d e r m i c m e t h o d
(intramuscular) as of no special value in the treatment of acute cases of
malarial fever, owing to slowness of absorption; but he considers this method
particularly useful as a preventive of frequently recurring attacks of ague.
The authors of the National Dispensatory1 0
a c k n o w l e d g e t h a t t h e t e n d e n c y
of hypodermic injections to produce "pain, inflammation, gangrene and even
fatal tetanus more than counterbalances the advantages of facility of adminis-
tration and promptness of effect" and recommend that this method of adminis-
tration should be restricted to cases in which delay would be dangerous. The
importance of determining whether or not this "promptness of effect" is really
obtained by the hypodermic method is obvious.
In an endeavour to throw some light on these debated points regarding the
absorption of Quinine, this work has been undertaken. The alkaloid and its
salts employed in the various experiments were obtained direct from Merck
(Darmstadt) and therefore in unopened bottles.
Peculiarities of Quinine and its Salts.
Unfortunately, as the composition of many of the salts of Quinine varies
with different manufacturers and as the details (temperature, etc. ) regarding
the conditions under which the results given by various analytical chemists
have been obtained are not alway given, there is much uncertainty regarding
the chemical properties, e.g., solubility, of some of these compounds. As
those used in my investigations were obtained from Merck, I have, whenever
possible, followed his analyses17 in the following table:—
Table 1.
Quinine preparations.
Percentage of
anhydrous
Quinine base.
Solubility of 1
part in parts of
cold water.
Reaction
of
solution.
REMARKS.
Q. bi-hydrochloride .
74.8
.66
Faintly acid Recommended for hypoder-
mic injection.
Q. bi-sulphate .
.
58.12
10
ditto
Originally called "neutral
sulphate."
C
4
Table I—contd.
Quinine preparations.
Percentage of
anhydrous
Quinine base.
Solubility of 1
part in parts of
cold water.
Reaction
of
solution.
REMARKS.
Q. bi hydrobromide .
60.0
7
Faintly acid Recommended for hypoder
mic injection.
Q. urea (carbamide) .
70.0
1
ditto
Recommended for hypoder
mic injection.
Q. hydrochloride
.
81.7
37
Neutral
Q. sulphate
. .
72.8
8 0 0
ditto
Q. lactate .
. .
75.0
10
ditto
Recommended for hypodermic injection.
Q. hydrobromide .
.
76.6
45
ditto
Recommended for hypoder
mic injection.
Q. cacodylate .
.
62.0
under 10
ditto
Q. phosphate
. .
76.5
784
ditto
Acicular crystals like the
sulphate but harder and
denser.
Q. quinate
.
.
58.7
under 10
ditto
Recommended for hypoder
mic injection.
Q acetate .
. .
84.3
over 2,000
ditto
Q. carbonate
.
8 0 . 2 over 2,000
ditto
Q tartrate
.
.
79.4
1,000
ditto
Q. tannate
.
.
31.0
over 2,000
ditto
Composition stated to be
very variable.
Q. salicylate
.
.
6 8 . 8
2,30
ditto
Q. arsenate (basic)
.
68.0
over 2,000
ditto
Q. arsenite. .
85.0
over 2,000
ditto
Q. valerianate .
.
75.8
100
ditto
Q. benzoate
.
.
72.6
373
ditto
Q formate (basic)
.
87.5
under 20
ditto
Recommended for hypoder
mic injection.
Q. alkaloid
.
. 85 . 7
1,670
Feebly basic
Practically all of these Quinine preparations require to be kept in well
stoppered bottles, because of the readiness with which they part with water of
crystallisation or take up moisture from the atmosphere. They' also require
5
to be protected from heat and light. At a low temperature, they keep
indefinitely : exposed to heat, they are liable to lose water of crystallisation and
to become decomposed. Exposed to sunlight they acquire—whether in the
solid form or in solution—a yellowish or brown colour. Flückiger18 named this
brown product "quiniretin" and found it had the same composition as
Quinine, but was destitute of its alkaline re-action ; and, although soluble
in acids, it could not neutralise them. Heat seems to accelerate this change
in Quinine ; and boiling, whether for purposes of sterilization or of hastening
solution, produces this change in some of these Quinine preparations in a
few minutes. Quinine, hydrochloride, besides being much more soluble than
Quinine sulphate, contains a larger proportion of Quinine base and is much
less irritating to mucous surfaces (stomach and rectum) : its, solutions are less
likely to become mouldy, but are said10 to be much less stable than those of
the sulphate.
Besides deterioration due to exposure to heat and light, solutions of
Quinine salts are prone to become infected with moulds. In the literature
on the subject solutions of Quinine sulphate alone are spoken of in this
connection. According to Marshall,6 "Quinine in general is fatal to moulds,
but on standing exposed to the air solutions of Quinine sulphate quickly
become infected with the common Penicillinm, which grows rapidly."
Solutions of the various Quinine salts were kept in stoppered tube-bottles in
the laboratory (Edinburgh University) for over three months, the bottles being
opened and examined periodically. The sulphate solutions were the most liable
to mould infection. The solution of Quinine sulphate with tartaric acid became
infected very quickly and showed luxuriant mould growths under two weeks.
Flavouring agents, such as syrupus aurantii, still further favour the growth of
moulds, especially Penicillium glaitcum. In these experiments the growth of
moulds was not limited to the solution of Quinine sulphate and the genus of
fungus was not confined to Penicillium. In luxuriance of mould growth,
solutions of Quinine quinate and Quinine bi-hydrobromide ranked next to
those of the sulphate. Growths were also present, but scanty, in solutions of
bi-hydrochloride, bi-sulphate, urea bi-hydrochloride, lactate and arsenite.
The genus Mucor, as judged from zygospore formation, was present in one
or two instances, but the Perisporiaceœ predominated. Both genera,
Aspergillus and Penicillium with their respective gonidiophores were in
evidence, the former being almost as common as the latter. Perithecia,
indicating the less frequent mode of reproduction, were observed in solutions
of bi-hydrobromide, lactate and arsenite. It would appear therefore that
Quinine is not so inimical to the higher members of fungi as to the lower.
yeast forms, which are said6 to be as susceptible as bacteria to its action.
c 2
6
Compatibility of Quinine Salts with Blood=Serum.
With the object of obtaining some information as to what actually
happens when solutions of Quinine salts are injected subcutaneously or enter
the blood stream, the behaviour of such solutions with ox blood-serum was
investigated in vitro.
If .01 gramme of a Quinine salt, e.g., bi-hydrochloride, bi-sulphate, bi-
hydrobromide, urea bi-hydrochloride, lactate, etc., is added direct in the form of
a powder to one cubic centimetre of ox blood-serum in a test tube, a coarse curdy
precipitate takes place. This precipitate, produced by
adding one part of Quinine salt to 100 parts of ox
blood-serum is not merely precipitated alkaloid, as it is
insoluble in excess of serum.
As no further progress could be made by adding the
dry Quinine salts to the serum, solutions of various
strengths of the Quinine salts were prepared and the
effects produced by adding one cubic centimetre of these
solutions to one cubic centimetre of ox blood serum ob-
served. The following table gives the results, one cubic
centimetre of Quinine salt solution being in each instance
mixed with one cubic centimetre of blood-serum. The upper line opposite
each salt indicates the results got immediately on mixing Quinine salt solution
with serum; the lower line the effects produced after standing 24 hours:—
Table II.
Chief Quinine salts
used for hypodermic
injection.
DILUTION OF QUININE SALT SOLUTION.
1-2.
1-10.
1-50.
1-100.
1-200.
Q. bi-hydrochloride .
Gray syrupy
liquid.
Precipitate
Precipitate
Faint haze
No change.
Gelatinous mass Gelatinous mass Deposit
Faint deposit Haze.
Q. bi-sulphate
Precipitate
Haze
Faint haze
No change.
Deposit
Deposit
No deposit
Mere cloudiness.
Curdy preci-
pitate pro-
duced by
adding a
Quinine
salt in
powder
form to ox
blood-
serum.
7
Table II— contd.
Chief Quinine salts
used for hypodermic
injection.
DI LUTI ON OF QUI NI NE SALT SOLUTI ON.
1-2.
1-10.
1-50.
1-100.
1-200.
Q. bi-hydrobromide
.
Precipitate . Precipitate . Faint haze . No change.
Gelatinous mass Deposit
. Faint deposit
.
Haze.
Q. urea (carbamide)
.
Gray syrupy
liquid.
Precipitate . Precipitate . Faint haze . No change.
Gelatinous mass Curdy mass . Deposit
. Faint deposit
.
Haze.
Q. hydrochloride .
Precipitate . Faint haze
.
No change.
Deposit
. Faint deposit
.
Haze.
Q. lactate
. .
Precipitate . Precipitate
.
Faint haze . No change.
Deposit
. Deposit
. Faint deposit
.
Haze.
Q. hydrobromide . .
Precipitate . Faint haze . No change.
Deposit
. Faint deposit
.
Haze.
Q. quinate . . .
Precipitate
Precipitate . Faint haze . No change.
Deposit
. Deposit
. No deposit . Faint haze.
Q. cacodylate
. .
Precipitate
.
Precipitate . Faint haze . No change.
Deposit
.
Deposit
. No deposit . Faint haze.
Q. formate . .
Precipitate . Faint haze . No change.
Deposit
Faint deposit
.
Haze.
Solutions of Quinine hydrochloride prepared with the addition of
antipyrine, urethane or sodium chloride, respectively, as recommended for
hypodermic or intravenous use, were tested in the same way, but they showed
no greater compatibility or miscibility with ox blood-serum than did simple
solutions of Quinine hydrochloride itself.
Using dilutions of Quinine salts of 1 in 20, the results were the same
as under 1 in 50 in above table, only more pronounced, with the exception of
Quinine bi-hydrobromide which even in this dilution of 1 in 20 produced a
thick semi-solid mass of jelly consistence. This behaviour of the bi-hydro-
bromide is the more remarkable as it contains a comparatively low percentage
of anhydrous Quinine base. The bi-hydrobromide therefore appears to be
the least compatible with ox blood-serum.
The above re-actions were carried out at laboratory temperature (12°C.).
The effect of incubating the mixture of Quinine salt solution and serum at
37°C. was tested in a few instances and the result was an acceleration of the
changes that were seen to occur at laboratory temperature.
Giemsa and Schaumann5 having observed the behaviour in vitro of
saturated solutions of some of these salts of Quinine with (1) pig blood-serum
and (2) human blood-serum have recorded very similar results.
A series of tubes was next prepared to compare the relative amount of
precipitate and deposit formed by adding solutions of the strength of 1 in 80
of each of these Quinine salts to ox blood-serum. Two tubes showed no
deposit, but only a flocculent precipitate in suspension—quinate and cacody-
late: of the tubes presenting a deposit, the bi-sulphate showed the least
deposit and the least opacity of the supernatant fluid. On referring to the
table giving the percentage of anhydrous Quinine base in Quinine salts it
will be noticed that the quinate, cacodylate and bi-sulphate are exactly those
salts which contain the smallest percentage of Quinine base. A second
series of tubes were therefore prepared using solutions of the same salts
having a strength of 1 of Quinine base in 80. Judging from the amount
of deposit and the degree of transparency of the supernatant fluid, the acid
salts of Quinine seemed the most compatible with the serum; but the re-
actions of the mixtures containing the acid salts were found to be very faintly
acid. Of the neutral salts of Quinine there seemed to be slightly greater
miscibility with serum on the part of the quinate and cacodylate.
As the salts used for these re-actions have been specially chosen as
those generally recommended for subcutaneous injection, the results tabulated
strongly suggest an utter unsuitability, especially in the dilutions usually
employed, of Quinine salts for hypodermic injection. The three salts most
frequently used, bi-hydrochloride, urea bi-hydrochloride and bi-hydrobromide,
and in the dilutions most frequently employed produce in a few minutes at
body temperature when mixed with ox blood-serum a gelatinous mass.