NationalLibraryOfScotland/medical-history-of-british-india huggingface dataset:
37
leucocytes, possibly hours or, as stated by Tarozzi, months after injection.
Factors which favour multiplication of tetanus bacilli in the body, according to
Vaillard,42 are—(1) much dirt introduced into the wound, (2) all means that keep
leucocytes away from the inoculated spot, (3) means which afford mechanical
protection to the bacilli, (4) the addition of certain chemicals, e.g., lactic acid,
(5) severe mechanical lesions, e.g., fracture and contusion, and (6) the introduc-
tion of certain saprophytes. As regards tetanus following Quinine injections,
the first and fifth of these factors may be dismissed at once, and probably also
the sixth, as tetanus has occurred even after scrupulous care in sterilising the
injection—quite sufficient to destroy all saprophytes—had been taken. That
Quinine can keep leucocytes away from the inoculated spot is well recognised
(Binz) :11 and this action of Quinine is accentuated in two other ways—(1)
Quinine causes impairment of phagocytosis (Golgi), 43 and (2) diminishes the
number of leucocytes in the body, 3 gramme of Quinine sulphate being capable
of reducing the number of leucocytes by 7 per cent. in six hours (Marshall,4
Sollmann6 ) . T h e c o a g u l u m a t t h e s e a t o f i n j e c t i o n m a y p o s s i b l y a f f o r d s o m e
mechanical protection to tetanus spores, but it can also favour their development
in another way—phagocytes may be diverted from the relatively bland spores
to the more irritating coagulum. Heddæus 44 has reported the occurrence of
tetanus after the subcutaneous injection of gelatine, where probably the same
causes, mechanical protection and diversion of leucocytes, were at work.
Quinine is generally included with lactic acid among the chemical agents that
favour tetanus. A probable explanation of its action is suggested by my serum
compatibility experiments. In the coagulum formed by adding Quinine solu-
tions to ox blood-serum, Quinine was precipitated in an apparently oxidised
form in combination with proteids (cf. Rossbach's33 experiments on the com-
pound formed by the combination of Quinine and albumen, and Kerner's 2
experiments with dihydroxyl-quinine formed by acting on Quinine with
permanganate of potassium). It is possible therefore that tetanus spores in-
troduced at the time of injection may be included in interstices of the coaguolum
produced by the Quinine and in a favourable fluid medium deprived of its oxygen.
The action of Quinine in inhibiting the oxidation of guaiacum" in the ordinary
blood test, in inhibiting the so-called " acid fermentation of the blood" " and in
diminishing the synthesis of hippuric acid in the kidney perfusion4 6
" e x p e r i m e n t s
may be similarly explained : oxygen is used up in the Quinine albumen com-
pound, and none is available for guaiacum, for the blood or for the nourishment
of the renal cells, respectively. Regarding sterilisation of Quinine injections,
it should be noted that all bacilli are not equally susceptible to the action of
Quinine : anthrax spores for instance are fairly refractory (Koch) 4 8 ;
t e t a n u s
spores may be likewise.
G2
38
Intramuscular Injections.
Intramuscular injections in no way differ essentially from subcutaneous.
Possibly absorption is slightly more energetic owing to a more active blood
and lymph circulation and less pain is occasioned, but the same destructive
and necrotic changes occur as in the subcutaneous proper. Kleine 2 2
r e p o r t s t h a t
the tissues after subcutaneous injection, especially if intramuscular, look
severely damaged for a long time after injection ; and Mariani 1 3
m a d e t h e s a m e
observations in his rabbit experiments (intramuscular injections). These inju-
rious effects are hidden from view : necrosis does not reach the skin, so no ulcera-
tion follows. Paralysis, however, whether from thrombosis of blood vessels or
from direct destruction of nerve fibres, is more liable to occur after
intramuscular injections.
Quinine solutions so dilute as 1 in 150 and containing sufficient Quinine
to be of any therapeutic value could not possibly be injected intramuscularly.
Such solutions would therefore have to be injected into the subcutaneous
connective tissue, as a Quinine infusion. The rapid and thorough absorption
that would follow such a Quinine infusion is more than counterbalanced by
the large ulcer that would infallibly result. Further, we have in the intra-
venous injection of Quinine a method which will give still greater Quinine
concentration in the blood without any of the special dangers of Quinine
infusions.
Intravenous Injections of Quinine.
The intravenous method of administering Quinine was introduced by
Bacelli,49 who used a solution containing Quinine hydrochloride, 1 ; sodium
chloride, .075 ; distilled water, 10 parts. This solution, however, the strength of
which is about 1 in 10, did not find favour, and certainly the serum compati-
bility experiments would lead one to expect the introduction of this concen-
trated solution intravenously to be attended with grave danger. The addition
of sodium chloride does not increase the compatibility of Quinine hydrochloride
with ox blood-serum.
If a Quinine salt is to be safely introduced intravenously, it must be in a
dilution of 1 in 150 at least. Preferably the Quinine salt (e.g . about seven
grains of Quinine bi-hydrochloride) should be dissolved in two or three pints
of normal saline. In this dilution there is no danger of thrombosis or preci-
pitation : the toxins in the blood are also diluted and their elimination favoured
—this mode of administration being specially indicated in malignant types of
malaria. Such solutions have been infused intravenously with good effect in
cases of pernicious malaria. If there is any tendency to hæmoglobinuria, I
39
should recommend the substitution of Quinine alkaloid for Quinine bi-hydro-
chloride ; as the alkaloid delays hæmolysis, while the acid salts of Quinine are
strong hemolytic agents. 5 0
By this method of administration the special dangers of the subcutaneous
injection, of Quinine are avoided. There is no danger of necrosis, paralysis,
ulceration or thrombosis. It is also very doubtful if the introduction of
tetanus spores with the intravenous Quinine infusion, in a bulk of two or three
pints, would produce any harm. Pure tetanus cultures introduced into the
blood are soon destroyed unless conditions favouring their multiplication are
present.41 Of the five factors already mentioned which would favour their
multiplication, only one—the presence of the chemical agent Quinine itself —
would be operative in intravenous infusion ; and the Quinine would probably
be in too great dilution to favour the development of tetanus bacilli.
The average amounts of Quinine eliminated in the urine after intravenous
injection are, according to Mariani, 13 20.54 per cent. on the first day, 6.33 per
cent. on the second and 1.07 on the third. These results lead one to suppose that
the therapeutic action of the intravenous administration of Quinine is not so
fleeting as one might expect.
While investigating the hemolytic action of Quinine and its salts I
devised a method of injecting Quinine alkaloid intravenously by dissolving it
in 33 per cent. alcohol (in saline), the strength of the injection fluid being about
1 in 135. 50 As one grain of Quinine alkaloid thus requires a bulk of about
eight cubic centimetres, this mode of injecting Quinine is not likely to be of use
clinically ; so only a short description is required.
First of all, the strength of alcohol which can safely be added to blood
serum was determined : it was found that 33 per cent. alcohol is miscible with ox
blood-serum provided that in the final mixture not more than 10 per cent. alcohol
is present. In the next place the solubility of Quinine alkaloid in 33 p er cent.
alcohol was estimated : it was found that 2 gramme Quinine alkaloid is solu-
ble in 2.7 cubic centimetres of 33 per cent. alcohol, i.e., about 1 in 135. It will
be noted that this solution is more concentrated than solutions of soluble
Quinine salts which can be used with safety for intravenous injection. Lastly
the miscibility of this Quinine alcoholic solution with ox blood-serum was
studied : it was found that half a cubic centimetre of Quinine alcoholic solution
is miscible with two cubic centimetres of ox serum. It seemed probable there-
fore that this Quinine alcoholic solution could be injected intravenously
without any change occurring in the blood, provided the quantity injected
met with four times its own bulk of blood. These limits of safety were based
on the changes which occurred in vitro alter standing twenty-four hours, and
not on any changes that occurred immediatly on mixing the proposed. injection
40
with serum; so that the figures given are well within the actual limits of
safety.
Quinine alkaloid in doses up to .03 gramme per kilogramme of animal
weight, dissolved in 33 per cent . alcohol (in normal saline) was injected intra-
venously in rabbits without any ill-effects being observed to follow. A dose
of .03 gramme per kilogramme of animal weight would correspond to a
dose of 2.1 grammes (32½ grains) of Quinine alkaloid to man. The injec-
tions, moreover, were not made slowly but as quickly as with any other
solution. Quinine alkaloid is no doubt precipitated as it enters the vein, but
it is in such a fine state of sub-division that, even if it could reach capillaries.
before being re-dissolved in the blood-serum, it could cause no obstruction.
In passing, it may be noted that, by first dissolving Quinine alkaloid in
a minute amount of absolute alcohol and then adding normal saline to make a
dilution of 1 of Quinine alkaloid in 2,000 or 5,000, a rapid and easy solution
of the alkaloid is obtained for intravenous infusion. To dissolve Quinine
alkaloid directly in water or saline is a very slow and laborious process.
Rectal Administration of Quinine.
Quinine enemata .—Quinine enemata are probably used as often for
amœbic dysentery as for malaria. In the former case, absorption is not
desired; in the latter, absorption is our object. The chief drawback to Quinine
rectal injections is that Quinine salts, and particularly the more soluble salts,
are so irritating to the mucous membrane that they are generally quickly
returned. Prolonged retention is necessary for the efficient action of these
injections whether they be given for amœbic dysentery or for malaria. In
order to get sufficiently long retention, it is always necessary to add opium,
belladonna or cocaine to the injections. Yet these substances, although they
prolong retention, are apt to retard absorption. It is necessary, of course, before
giving a Quinine enema to clear out the bowels with a simple enema.
According to the National Dispensatory, 10an enema of Quinine hydrochloride.
in the same dose as by the mouth has nearly the same therapeutic effect as when
given by the mouth, provided the Quinine salt in the enema is given in watery
solution. This view of Quinine enemata appears to be too optimistic, Kleine 12.22
after giving an enema consisting of two grammes of Quinine hydrochloride in
100 cubic centimetres of water found the average Quinine elimination in the
urine to be 17.5 per cent., maximum elimination occurring between the
fourth and tenth hours. He concluded that elimination and probably absorp-
tion from an enema containing a soluble Quinine salt are considerably smaller
than those which take place when Quinine is given by the mouth; and
that with a Quinine preparation which is not easily soluble absorption must be
41
much smaller still, for peristalsis is poor and the Quinine is merely in sus-
pension. These results have been confirmed by Flamini 23 who, after an enema
containing two grammes of Quinine tannate, found 2.65 per cent. only elimi-
nated in the first 24 hours; and also by Giemsa and Schaumann 5 who after
giving an enema containing one gramme of Quinine alkaloid with mucilage
of acacia and tincture of opium found only 5.177 per cent. eliminated in the
urine in the first 24 hours. From these results Giemsa and Schaumann infer
that Quinine enemata are little suited for the treatment of malaria, because—
even if sufficiently long retained—Quinine absorption is quite insufficient,
and particularly so if Quinine salts which are not easily soluble are employed.
As carbonic acid and bile appear to play such a prominent part in the
absorption of Quinine from the small intestine, it is possible that the addition
of these to enemata would help absorption. Kerner5 1
s e e m s t o h a v e o b t a i n e d
quite good results with carbonic acid, the salt used being Quinine hydrochloride.
The amount of Quinine he found eliminated in the urine is given in the
accompanying table, which is self-explanatory.
Table IX.
Elimination of Quinine in Urine after Quinine Enemata.
Quinine hydrochloride.
HOURS.
¼
½
¾ 1
3
6
12
24
36
48
1 per cent. solution in 150 c.c. of
water.
...
1
4
9
16
16
14
9
2
...
1 per cent. solution in 150 c.c. car-
bonated water; and 100 c.c. more
carbonated water injected one
hour later.
1
5
5
10
19
28
15
5
4
. . .
Further investigations regarding Quinine enemata are necessary. So far as
our present knowledge takes us, the best results are obtained by using Quinine
hydrochloride in a dilution of about 1 in 50 of water with tincture of opium or
belladonna or cocaine added, and injected as high as possible. Even under the
most favourable circumstances, when retention has been sufficiently long, we
cannot expect as much from Quinine enemata as from Quinine by the mouth.
Quinine suppositories.— These are very irritating and useless in the treat-
ment of malaria. Binz 1 1
s t a t e s t h a t , w i t h t h e r e c t u m p r e v i o u s l y w a s h e d o u t
and the suppository passed high up with the finger, retention beyond one
hour is very exceptional.
42
SUMMARY OF CHIEF RESULTS AND CONCLUSIONS.
Solutions of Quinine Salts and Moulds.
The sulphate is not the only salt of Quinine that is liable to infection with
moulds, and the moulds which infect solutions of Quinine salts are not limited
to the genus Penicillium. Quinine is not so inimical to the higher fungi as to
the lower yeast forms.
Miscibility of Quinine Salts with Ox Blood=serum.
The salts of Quinine most soluble in water, even in a dilution of .1 in
100 are not miscible with ox blood-serum. The three salts, Quinine bi-
hydrochloride, Quinine bi-hydrobromide and Quinine urea, most frequently
used for subcutaneous injection and in the dilution most frequently employed,
mixed with an equal volume of ox blood-serum, in a few minutes at 17°C.
result in the formation of a solid gelatinous mass. Quinine bi-hydrobromide
even in a dilution of 1 in 20 produces a mass of curdy consistence. Quinine
salts in the dilutions usually employed are quite unsuited for hypodermic use.
The deposit which forms in vitro on adding a concentrated solution of
Quinine salt to blood serum seems to contain Quinine in altered form, oxidised
and combined with proteid. Mixing equal volumes of blood-serum and
Quinine hydrochloride 1 in 20, it is found that slightly over half the Quinine
is in solution and slightly under half is contained in the deposit. The greater
the dilution of Quinine salt, the less the deposit that forms on mixing with
blood-serum; and therefore presumably the greater the amount of Quinine
that remains in solution.
Solubility of Quinine Alkaloid in Ox Blood=serum and in Ox Bile.
Quinine alkaloid is soluble 1 in 625 of ox blood-serum, i.e., nearly three
times as soluble in ox blood-serum as in ordinary water.
Quinine alkaloid is soluble 1 in 183 of ox bile, i.e., about nine times as.
soluble in ox bile as in ordinary water.
Absorption of Quinine.
Too much reliance must not be placed on the amount of Quinine elimina-
tion in the urine as a gauge of the amount of Quinine absorbed, especially
when different modes of Quinine administration are being compared. Lethality
varies directly with thoroughness of absorption and is a reliable measure of the
amount of absorption when comparing different modes of Quinine administra-
tion.
43
Oral Administration.—Under ordinary circumstances, most of the Quinine
administered by the mouth is absorbed from the small intestine; a small amount
possibly from the stomach, especially if administered while fasting and in the
form of a salt easily soluble in water; and also a relatively small amount from
the large intestine.
Affections of the gastro-intestinal tract and liver have a marked influence
on the amount of Quinine absorbed, as have also the food contents of the gastro-
intestinal tract and the degree of solubility of the Quinine salt employed.
Absorption is retarded if Quinine is given with or soon after food and also if the
less soluble preparations of Quinine are administered. Rapid and energetic
absorption is best obtained by giving a soluble Quinine salt during fasting:
gradual and prolonged absorption is attained by giving one of the less soluble
salts of Quinine with or soon after meals, absorption under such conditions.
being maintained at a considerable level for some eight hours. Hence, where
sporulation is regular, a soluble Quinine salt should be given, during fasting,
two or three hours before a paroxysm; in other cases, one of the less soluble
preparations of Quinine, with or soon after meals, every eight hours. Carbonic
acid, like bile, probably plays an important part in the process of Quinine
absorption.
The administration of soluble Quinine salts in capsules is bad: gastric
irritation and trouble may follow. Where Quinine causes gastric irritation, the
least soluble salts of Quinine, e.g., tannate, should be given.
Large doses., e.g. , 15 grains three times daily, give better therapeutic results
than fractional doses, e.g ., four grains every two hours day and night. In
cases where Quinine by the mouth does not produce the desired effect, attention
should be directed to the condition of the gastro-intestinal tract and liver.
Subcutaneous (including intramuscular ) administration .—Quinine salt
solutions in the concentration usually employed for hypodermic injection, when
mixed with blood-serum produce a coagulum which contains Quinine in altered
form.
Quinine is precipitated at the seat of injection and over 66 per cent. of
the amount injected intramuscularly has been recovered 17 hours afterwards
from the muscles at the site of injection.
The amount of Quinine eliminated in the urine after this mode of ad-
ministration varies between wide limits.
Urethane, antipyrine and sodium chloride, although they increase the
solubility of Quinine hydrochloride in water, do not increase the miscibility of
that Quinine salt with ox blood-serum; and the new compounds formed in
such solutions are of doubtful therapeutic value.
44
As regards guinea-pigs, the lethality (and therefore absorbability ) of
Quinine by the several modes of administration is in the following order, be-
ginning with the most lethal mode of administration: (1) subcutaneous injec-
tion in extreme dilution (1 in 150), (2) oral administration during fasting, (3)
oral administration with or immediately after food, and (4) subcutaneous
injection in the strengths generally used for hypodermic injection (1 in 2 and
1 in 8). The oral administration of Quinine also affords more prompt thera-
peutic action of the alkaloid than does the subcutaneous, the subcutaneous injec-
tion of Quinine in extreme dilution (1 in 150) being excluded for clinical
reasons. Further, subcutaneous injections are followed by various compli-
cations and mutilation. Intramuscular injections are attended by the same
drawbacks as subcutaneous proper; and although ulceration rarely occurs, they
are more liable than the latter to be followed by thrombosis and paralysis.
The harmony between the results of various observations on man and
those of my experiments on guinea-pigs justify the inference of general applic-
ability—that subcutaneous and intramuscular Quinine injections, in solutions
of the usual strength (1 in 1 to 1 in 10) are inferior to Quinine by the mouth
in rapidity of action and thoroughness of absorption, and that they are liable to
be attended by grave complications, mutilation and dangers. Quinine and
its salts are, moreover, fundamentally unsuited for hypodermic use. This mode
of Quinine administration should therefore be abandoned.
Intravenous injections of Quinine. —Great dilution (at least 1 in 150) is
necessary in order to avoid the dangers special to Quinine. The Quinine, e.g .,
seven grains of Quinine bi-hydrochloride, should be dissolved in two or three
pints of saline. This mode of administration is called for in cases of
emergency, e.g ., pernicious malaria with coma or other cerebral symptoms;
and in such cases this extreme dilution affords the additional advantage of
attenuating the toxins and favouring their elimination. In this dilution
intravenous injections of Quinine are quick and sure; and, judging from the
subsequent Quinine elimination in the urine, their action is not fleeting:
they are attended by no risks peculiar to Quinine, but merely by those attend-
ant on intravenous infusions generally.
Quinine alkaloid itself, instead of one of its salts, should be used where
there is any tendency to or fear of hæmoglobinuria: the alkaloid delays
hæmol
ysis its acid salts are powerful hemolytic agents. A solution of the
alkaloid can be obtained rapidly and easily for intravenous infusion by first
dissolving the alkaloid in a minute amount of absolute alcohol and then
adding normal saline to make a solution of 1 in 2,000 or 5,000.
Intravenous injections of Quinine alkaloid dissolved in 33 per cent.
alcohol (in saline) in a strength of about 1 in 135, have been made quickly