NationalLibraryOfScotland/medical-history-of-british-india huggingface dataset:
26
They report that, in the case of those who received the Quinine in a dilu
-tion of 1 in 10, elimination ended within 48 hours after the last injection ; and
that in the other case elimination was pronounced for four or five days after the
last injection. It is difficult to explain the differences in elimination shown in.
Tables A and. B. Judging from the in vitro experiments, there is no reason.
why Quinine urea should be better absorbed than Quinine hi-hydrochloride:
It would appear, moreover, that Quinine urea has not fulfilled the hopes
entertained of it ; for Giemsa34 has recently recommended the combination of
Quinine hydrochloride with urethane for hypodermic injection. Urethane
and antipyrine increase the solubility of Quinine hydrochloride, new chemical
products being formed from which, it is thought, Quinine is liberated in the
body. Gaglio35 recommended the urethane solution as being neutral, non-irri-
tating and stable : after its hypodermic injection he recovered from 30 to
50 per cent . in the urine and concluded that it was rapidly and completely
absorbed. Schmitz, 21 however, has been unable to confirm these results ;
giving the urethane solution hypodermically to a patient daily for seven days,
he found the daily amount eliminated was only 16.1 per cent. on an average.
Recently Giemsa34 seems to have given up the use of Quinine-urea in favour of
this urethane solution of Quinine hydrochloride, the advantages he puts forward
for the latter being : that it will stand boiling for an hour and is not de-
composed by heat like Quinine urea while being sterilized, that it is well
absorbed, that it has a similar re-action to that of the tissue fluids and that its
intramuscular injection is almost painless. In the antipyrine solution of
Quinine hydrochloride, quinopyrin is formed, which according to Santesson
is less toxic than Quinine, but according to Stofella is useless. 36 Regarding
these solutions resulting in the formation of new compounds Marshall 3 6
s t a t e s
that they should be looked upon with suspicion. Moreover, it should be noted
that their miscibility with ox blood-serum is no greater than that of solutions
of simple Quinine hydrochloride itself. Solubility in water is merely of advan-
tage during the process of injecting ; it is solubility or miscibility in serum that
favours absorption.
Clinically, one striking pint about the hypodermic administration of
Quinine is the sudden great increase recently in dosage by this method. A few
years ago the hypodermic dose of Quinine was usually given as from four to six
grains ; at present the dose is generally from ten to fifteen grains—the same
as when given by the mouth. This indicates that absorption after oral adminis
tration is at least as complete as after hypodermic. In comparing the two
methods of administration there remains therefore only the question of prompt-
ness of action. Smythe's14 experience is that after hypodermic injection Quinine
is slowly absorbed and that its elimination takes weeks ; that 20 grains injected
27
in the flanks give protection from malaria for at least a month. According to
Megaw,15 the temperature of malarial patients takes about twelve hours longer in
coming to normal when treated by the hypodermic method than when Quinine
is given by the mouth; from this it is assumed absorption is slower from the
subcutaneous tissues than from the mucous membrane of the gastro-intestinal
tract. Scott 16 has come to the conclusion that the hypodermic (intramuscular)
mode of administration of Quinine has no special value in the treatment of
acute cases of malarial fever owing to slowness of absorption. The results
obtained by Cohen3 7
a r e i n t e r e s t i n g f r o m t w o p o i n t s o f v i e w : t h e y s h o w t h e
conclusions arrived at by an advocate of Quinine injections, and they were
obtained by the use of Quinine urea which was so strongly recommended by
Giemsa and Schaumann. Cohen states that 15 grains of Quinine urea, if
injected during or within four hours after a paroxysm of malarial fever, were
readily absorbed and procured freedom from fever for a period of from six to
thirteen days: he, however, admits that Quinine by the mouth is "equally
efficacious". His statements that the Quinine urea was readily absorbed from
the point of injection and that freedom from fever was obtained for from six to
thirteen days are hardly consistent.
The evidence, so far, casting doubt upon the alleged therapeutic value of
the subcutaneous administration of Quinine can be summarised as follows:—
I.—ABSORPTION.
(1) Experimental. —The behaviour of Quinine solutions when mixed with
ox blood-serum suggest the possibility of very dilute solutions of Quinine (1—150)
but the unlikelihood of concentrated solutions, such as ordinary Quinine hypo-
dermic injections, being readily absorbed: it suggests the probability that most
of the Quinine in hypodermic injections is thrown out of solution at the point
of injection, is combined with albumen in an oxidised but unstable form and is
gradually liberated from this combination.
Mariani's13 experiment, in which he recovered from rabbit's muscle 66.5
per cent. of the dose of Quinine (Quinine hi-hydrochloride 1 in 5) injected 17
hours before the rabbit was killed, is positive proof that Quinine was deposited
at the point of injection, and that most of the Quinine was still lying at the
point of injection 17 hours after the injection was made.
The experiments on Quinine elimination in the urine give very little
information regarding Quinine absorption. One point which seems to be
definitely settled is that the amount of Quinine eliminated in the urine after
hypodermic injection is invariably less than that after oral administration. By
F
28
the advocates of hypodermic injection, the diminution in Quinine excretion is
attributed to greater cleavage of Quinine in the body after absorption from the
seat of injection. The results of different experimenters vary considerably,—as
one would expect seeing that the degree of dilution of the Quinine solution both
before and after injection (and consequently the amount of Quinine thrown
out of solution at the point of injection) is subject to considerable variation.
(2) Clinical. —There is a considerable amount of evidence that absorption is
no better after hypodermic than after oral administration; and that, however
useful hypodermic injections may be for prophylaxis, hypodermic medication is
not so good in the treatment of malaria as oral. Reference has already been
made to the recent great increase in the dose of Quinine when given
hypodermically and to the observations of Smythe and Scott.
II.—PROMPTNESS OF EFFECT.
(1)
Experimental.—Mariani 13
after injecting one gramme of Quinine
bi-hydrochloride dissolved in ten cubic centimetres of water found that the
maximum elimination of Quinine in the urine occurred between the sixth and
twelfth hours after injection; and that, after injecting one gramme of the same
salt dissolved in two cubic centimetres of water, the maximum elimination
occurred between the ninth and eighteenth hours. It has already been
stated that after oral administration during fasting the maximum elimina-
tion of Quinine occurs between the third and sixth hours; and during or soon
after meals, between the sixth and twelfth hours. It is evident therefore, if per-
missible to draw conclusions regarding absorption from Quinine elimination in
the urine, that maximum absorption and consequently maximum therapeutic
effect is obtained later after hypodermic injection (in dilutions at least up to
1 in 10 which include all Quinine hypodermic injections as ordinarily given)
than after oral administration.
(2) Clinical. —The results obtained by Megaw 15 point to absorption being
slower from the subcutaneous tissues than from the gastro-intestinal mucous
membrane.
Minimum-Lethal Dose experiments on Guinea-pigs with Quinine
bi-hydrochloride by oral and subcutaneous administration.
Reid Hunt3 3
h a s s h o w n t h a t t e m p e r a t u r e m a y h a v e a g r e a t i n f l u e n c e o n t h e
results of such experiments on small animals. Experimenting by subcutaneous
injections on mice, be found that doses otherwise non-lethal were fatal on cold
days. All the following experiments were carried out at a temperature within
the limits of 71°—76° F., so that they should be strictly comparable so far as
temperature is concerned.
29
Table VII.
A.—MINIMUM-LETHAL DOSE BY ORAL ADMINISTRATION.
(After fasting 24 hours.)
Weight of
animal in
grammes.
Actual
dose in
grammes.
Dose per
kilogramme of
animal in grammes.
Result.
550
0.165
0.3
Recovery. Distinct effects.
620
0.217
0.35
Recovery. Distinct effects.
510
0.204
0.4
Recovery. Very severe effects.
610
0.244
0.4
Recovery. Very severe effects.
600
0.240
0.4
Died in 6-7½ hours.
470
0.2115
0.45
Died in 8 hours.
520
0.234
0.45
Died in 6 hours.
500
0.25
0.5
Died in 21 hours.
B. —MINIMUM-LETHAL DOSE BY ORAL ADMINISTRATION.
(Immediately after food.)
Weight of
animal
in grammes.
Actual
dose in
grammes.
Dose per
kilogramme of
animal in grammes.
Result.
630
0.252
0.4
Recovery. Slight effects.
630
0.2835
0.45
Recovery. Slight effects.
660
0.295
0.45
Died in 11 hours.
500
0.25
0.5
Died in 6¼ hours.
500
0.25
0.5
Died in 6—7 hours.
F 2
30
C.—MINIMUM-LETHAL DOSE BY SUBCUTANEOUS INJECTION.
( Dilution 1 in 150. )
Weight of
animal
in grammes.
Actual
dose in
grammes.
Dose per
kilogramme of
animal in grammes.
Result.
730
0.073
0 . 1
Recovery. Very slight effects.
590
0.118
0.2
Recovery. Marked effects.
710
0.1775
0.25
Recovery. Very severe effects.
570
0.1596
0.28
Recovery. Very severe effects.
490
0.147
0.3
Died in 7½ hours.
620
0.186
0.3
Died in 7 hours.
D.—MINIMUM-LETHAL DOSE BY SUBCUTANEOUS INJECTION.
(Dilution 1 in 2. )
Weight of
animal
in grammes.
Actual
dose in
grammes.
Dose per
kilogramme of
animal in grammes.
Result.
475
0.1425
0.3
Recovery. * Marked effects.
610
0.244
0.4
Recovery. Slight effects.
550
0.275
0.5
Recovery. Distinct effects.
510
0.306
0.6
Died in 23½ hours.
660
0.396
0.6
Died † in 4 hours.
650
0.455
0.7
Died in 19½ hours.
580
0.522
0.9
Died in 9—11 hours.
* This animal was a weakling and was accidentally chosen for experiment.
† At the post-mortem examination, much exudate was found in the loose tissue at the point of injection.
31
E.—MINIMUM-LETHAL DOSE BY SUBCUTANEOUS INJECTION.
(Dilution 1 in 8. )
Weight of
animal
in grammes.
Actual
dose in
grammes.
Dose per
kilogramme of
animal in grammes.
Result.
570
0.171
0.3
Recovery. Slight effects.
590
0.236
0.4
Recovery. Slight effects.
580
0.29
0.5
Recovery. Distinct effects.
560
0.246
0.6
Recovery. Marked effects.
410
0.336
0.6
Died in 8½ hours.
The minimum-lethal doses, therefore, sufficiently accurate for comparative
purposes are as follows:—
By oral administration (fasting)
.
. =.45 gm. per kilo.
„ „(after food)
.
.
= . 5 „ „
By subcutaneous injection 1—150
.
.
=.3 „ „
„ „ 1—2
.
.
=.6 „ „
„ „ 1— 8
.
.
=over .6 „ „
The higher minimum-lethal dose shown by these results for injections of
1 in 8 dilution, as compared with 1 in 2, is probably explained by my having
carried out the experiments with 1 in 8 dilution last of all; for, having observed
that diffusion of the injected fluid by massage or movement on the part of the
animal had some effect —although slight—on the results, the animals that
received injections of 1 in 8 dilution were kept quiet in the hands for five or
ten minutes after injection. The lethality, and therefore the absorbability, of
Quinine are in the following order, beginning with the most lethal mode of
administration:—
(1) Subcutaneous injection in extreme dilution (1—150);
(2) Oral administration during fasting;
(3) Oral administration with or soon after food;
(4) Subcutaneous injection in the strengths generally used for hypoder
-mic injection (1 in 2 and 1 in 8).
And as that mode of administration which is most lethal to the animal
would almost certainly be the most lethal to any parasite in the animal's blood
or tissues, it follows that the therapeutic value of the different modes of
administration is also in the order given for lethality. As will be evident later,
the subcutaneous injection of Quinine in extreme dilution (or rather, as it
should be called, subcutaneous infusion) is not feasible for clinical reasons; so
for all practical purposes, if it is permissible to generalise from those experi-
ments on guinea-pigs, Quinine by the mouth is of greater therapeutic value
in respect of amount of absorption than subcutaneous Quinine injections.
32
With the object of getting some idea as to the relative promptness of action
attained by the different methods of administration, the time of appearance of
the various toxic symptoms in each experiment was carefully noted,—with the
following results.
Table VIII.
Minimum-Lethal Dose Experiments on Guinea=pigs.
Order in which Toxic symptoms Appeared.
(Quinine Bi-Hydrochloride.)
Time after ad-
ministration.
ORAL ADMINISTRATION.
SUBCUTANEOUS INJECTION.
Fasting.
Dose= about .45
gm. per kilo.
With food.
Dose =about
.5 gm. per kilo.
1-150.
Dose= about
.3 gm. per kilo.
1-2.
Dose= about
.6 gm. kilo.
1-8.
Dose=about
.6 gm. per kilo.
¾ hour..
. . .
...
. . .
. . .
1
"
. . .
. . .
Convulsions
. . .
. .
2 hours.
...
. . .
Inability to
stand.
. . .
. . .
2½ "
Unsteadiness
. . .
...
...
. . .
3
"
...
Unsteadiness
. . .
. . .
. . .
3 ½ "
T w i t c h i n g s
and "starts"
...
...
...
. . .
4
"
. . .
Twitchin g s
and "starts"
...
. . .
. . .
4½ "
Convulsions
...
. . .
. . .
Unsteadiness
5 "
...
...
...
. . .
T w i t c h i n g
and starts.
6
. . .
...
Unsteadiness
. . .
6 ½ "
. . .
Convulsions
. . .
...
. . .
8
"
...
. . .
...
Convulsions Convulsions
Recovery un-
der 24 hours
if dose sub-
lethal.
Recover un-
der 24 hours
if dose sub-
lethal.
Recovery under
24 hours if dose
sub-lethal.
Recovery took
at least 30
hours if dose
. . .
From this table it is evident that, as regards promptness of effect, the
various modes of administration stand in exactly the same order as that given
for lethality or absorbability. The time at which the various toxic symptoms
appeared in the case of suicide (already described) by swallowing four drachms
of Quinine, which is about the minimum lethal dose for man, corresponded so
33
closely with that given in this table that probably all the results tabulated
here hold good approximately for man. Other reasons that justify the applica-
tion of this table to man are the following:—
The maximum elimination of Quinine in man's urine after Quinine by
the mouth during fasting occurs between the third and sixth hours
(Mariani1 3
) .
The maximum elimination of Quinine in man's urine after Quinine by the
mouth after food occurs between the sixth and twelfth hours (Mariani 1 3
) .
The maximum elimination of Quinine in man's urine after a subcutane-
ous injection of one gramme of Quinine bi-hydrochloride (1) dissolved in
ten cubic centimetres of water occurs between the sixth and twelfth
hours, and (2) dissolved in two cubic centimetres of water occurs
between the ninth and eighteenth hours (Mariani.1 3
) .
These results obtained by Mariani correspond in a very striking manner
with the appearance of convulsions in the guinea-pigs in the minimum-lethal
dose experiments.
The results tabulated above may therefore be taken as practically conclu-
sive; and they show that the oral administration of Quinine affords more
prompt action of the alkaloid than does the subcutaneous.
The following curves give a graphic representation of the absorption of
Quinine after administration in the various methods already referred to, the
dose of Quinine being taken to be the same in each case:—
Curves of Quinine Absorption after various Methods
of Administration.
34
Subcutaneous Quinine infusions being debarred, Quinine by the mouth.
with or soon after meals suggests itself as particularly suited for the treatment
of malaria in which sporulation is irregular, and also for prophylaxis. Quinine
by the mouth while fasting would be serviceable two or three hours before a
paroxysm where sporulation recurred regularly.
In the curve representing absorption when Quinine is given with meals.
(absorption in such a case according to Mariani l3 is at its height between the
sixth and twelfth hours) it will be noticed that absorption from the fifth to the
thirteenth hour, i.e. , for eight hours, is higher than it ever reaches when an or-
dinary Quinine hypodermic injection containing the same dose of Quinine is
given. It follows therefore that Quinine given with (or soon after) meals three
times a day every eight hours, will keep the amount of Quinine in the body at
a higher level than one could ever hope to do by giving similar doses of
Quinine hypodermically in the usual concentrated solutions.
Local and Post=mortem Changes found in the Guinea=pigs
used for the Minimum-Lethal Dose Experiments.
A few minutes after injection into the subcutaneous connective tissue,.
the skin overlying the injection become discoloured and yellow, and soon an
area of skin corresponding to the size of the injection had undergone necrosis.
—killed directly by the action of the Quinine. The epidermis and hairs
o v e r t h i s a r e a c o u l d b e p e e l e d o f f b y r u b b i n g i t w i t h t h e b l u n t e d g e o f a k n i f e . I f
the animal survived, a red raw ulcer resulted; no pus was seen, possibly owing
to the tissues at the base and edge being saturated with Quinine which checks
diapedesis of leucocytes. In one case, where the injection had been large,
necrosis had extended on the deeper surface through all the abdominal muscles
right down to the peritoneum. The layer of muscle underneath the injection
was invariably necrosed and looked like washed gray leather. Not infre-
quently the yellow necrosed mass became surrounded by an inflamed indurated
area prior to the eschar being cast off. Even Quinine solutions so dilute as
1 in 150 had a severe necrotic action on all tissues with which they came in
contact: the superficial muscular layer of the abdominal wall was invariably
necrosed, as was also the skin, the result being generally, if the animal sur-
vived, a huge ulcer occupying the greater part of the surface of the abdominal
wall. This extensive ulceration and necrosis preclude Quinine infusions from
clinical use.
If any blood vessels happened to be included in the eschar, they appeared
like black threads and could easily be picked out in the pale necrosed tissues:
the blood they contained was invariably clotted. In several instances, includ-
35
ing cases both of oral and subcutaneous administration, hæmorrhagic erosions
were found in the stomach,—particularly in guinea-pigs that had survived soma
twenty hours or so after injection. One guinea-pig which had received
Quinine by the mouth was found to have had an extensive hæmorrhage in the
lower part of the large intestine. These hæmorrhages are most probably due
to engorged capillaries giving way. In typical cases, the ventricles of the heart
were found empty and pink in colour (therefore not contracted or in rigor) ;
both auricles were enormously distended with dark venous blood ; and all large.
veins were engorged with blood.
Hypodermic Injections in General and those of Quinine in
Particular.
A substance, to be suited for hypodermic injection, should satisfy the
following requirements :—
(1) It should be capable of being easily sterilized, e.g., stand boiling.
(2) Its solution ready for injection should be in small bulk, i.e., the sub-
stance should be very active pharmacologically and be very soluble
in water, saline or other menstruum.
(3) It should be capable of rapid and thorough absorption, i.e., its solu-
tion in the concentration in which it is injected should be compa-
tible with serum and lymph.
(4) It should be non-injurious to the tissues locally.
(5) It should be non-irritating.
Now, examining Quinine according to this standard, it is evident that one
only of these five requirements is satisfied. Quinine can be got into sufficiently
small bulk for injection, but in this concentration it cannot be absorbed rapid-
ly or thoroughly, and it is irritating and very injurious to the tissues at the
point of injection. Regarding sterilization, none of the salts of Quinine
stands heating well. Quinine is therefore fundamentally unsuited for
hypodermic use.
Further, Quinine injections, although devoid of any therapeutic advantage
over administration by the mouth, are not infrequently attended by serious
complications, mutilation and dangers.
(1) Necrosis.—From the rapidity with which this occurred in the guinea-
pig experiments and from the rapid yellow discolouration of the skin, it
is practically certain that this necrosis is due to the direct action of the
Quinine, which even in a dilution of 1 in 150 kills outright all tissues
which by diffusion it reaches. Thrombosis could not possibly produce necrosis
so rapidly.
36
(2) Thrombosis.— If by accident some solution is injected into a blood vessel,
rapid thrombosis and possibly embolism results. Thrombosis, however, occurs in
vessels which have not been directly injured by the hypodermic needle ; for, all
vessels in the necrosed area contain clotted blood. If, therefore, the injection is
made near a large blood vessel, thrombosis in that vessel may cause ischæmic
paralysis.
(3) Paralysis.—Besides ischæmic paralysis from thrombosis of a large
artery, paralysis may also occur from direct destruction of a nerve near which
the Quinine may have been injected. Quinine has no specific affinity for any
special tissue, such as strychnine and nerve cells : if in sufficient concentration
it is a poison to all forms of living matter. According to Sollmann 4 Quinine
will kill a nerve if applied directly to it ; according to Kobert, 25it kills what-
ever it reaches—nerve, skin, etc.
(4) Ulceration. —If the necrosed area reaches skin the eschar must
necessarily be thrown off, and leave an ulcer. In intramuscular injections,
the necrosed area does not reach skin, so no ulceration results ; the necrosed
area is ultimately converted into a fibrous nodule in the muscle. If the needle
during injection is kept parallel to the skin surface, ulceration will infallibly
occur ; for the Quinine by diffusion reaches the surface and includes the
skin in the necrosed area.
(5) Tetanus. —The occurrence of tetanus as a not infrequent sequel to
Quinine injections has long been recognised; but a definite explanation of
this phenomenon has not yet been given. The convulsions which occur in
Quinine poisoning are recognised as distinctly epileptiform, and not tetanic ; 3 9
so the opinion of some that the tetanic symptoms are simply a manifestation of
Quinine poisoning may be dismissed at once as untenable. But even with
reference to true tetanus there are two ideas regarding the mode of infection.
The more generally accepted one is that tetanus spores are introduced during or
after the injection of Quinine ; the other is that tetanus spores are already
existent in a latent condition in the body and that they are stirred into activity
by the trauma or the Quinine at the time of injection. In support of the latter
idea, Tarozzi: 4 0
h a s s h o w n t h a t t e t a n u s s p o r e s c a n l i v e f o r o v e r t h r e e m o n t h s i n
the liver or kidney in a latent condition, but are gradually destroyed ; and by
an artificial trauma lie was able to induce these spores to germinate and produce
" spontaneous tetanus." Regarding infection during or after injection several
points have to be considered. If pure tetanus cultures are introduced into the
blood or organs of the body, the spores are soon destroyed unless conditions
favouring their multiplication are present:41 the bacilli and spores by themselves
in the tissues form relatively bland foreign bodies, and are slowly taken up by the