NationalLibraryOfScotland/medical-history-of-british-india huggingface dataset:
Medical Officers of the Army of India. 7 1
will still for a time be simultaneous ; but, being carried on at different rates,
the amount of antivenene which has entered the circulation will not for some time
bear the same ratio to the amount of venom which has entered it, as it did in the
previous case ; finally, when solutions of venom are introduced, not only apart
from, but antecedently to, solutions of antivenene, the latter must necessarily be
placed at still greater disadvantage. On the other hand, where the administra-
tion of the antidote precedes that of the venom by a period allowing of complete
absorption into the circulation ere absorption of the venom has begun to occur,
the antidote will evidently be placed at an even greater advantage than it is
when employed as a vehicle for the venom. Professor Fraser's data do not,
therefore, appear to afford conclusive proof that the antidotal property of anti-
venene is dependent on any direct action on the toxin, and those derived from
the present series of experiments seem to indicate, either that the action is not of
a direct nature at all, or that, if it be direct, it is one which is more efficiently
conducted after absorption of both toxin and antidote into the circulation.
III.—RESULTS OF EXPERIMENTS ON THE ADMINISTRATOIN OF PROFESSOR
FRASER'S ANTIVENENE AS AN ANTIDOTE TO DABOIA-VENOM.
(a) EXPERIMENT IN WHICH THE ANTIVENENE WAS EMPLOYED AS THE
MEDIUM FOR THE INTRODUCTION OF THE VENOM.
Experiment I.—A fowl received an injection of 0.01 gramme of dry venom,
an amount equivalent to a double minimal lethal dose when administered in 0.5
C.C. of distilled water, in a solution of 0.1 gramme of dry antivenene in 1 C.C.
of distilled water. No local muscular action occurred at the site of injection,
and no symptoms of acute intoxication appeared within 25 minutes after intro-
duction.
A second dose of like nature was now given, the injection being effected in
the opposite leg. No local muscular action attended the operation, and no
acute symptoms followed it, but the bird died during the course of the succeed-
ing night after having exhibited all the characteristic symptoms of chronic
intoxication by daboia-venom during the interval.
(b ) EXPERIMENTS IN WHICH THE ANTIVENENE WAS ADMINISTERED
PREVIOUS TO THE ADMINISTRATION OF VENOM.
Experiment II.—A fowl was treated with 2.5 C.C. of a solution of dry
antivenene, containing, as usual, 0.1 gramme per C.C.
On the following day it received 0.01 gramme of dry daboia-venom in 0.5
C.C. of water, or a double minimal lethal dose capable of inducing death by
acute intoxication.
Two minutes later it was attacked by furious general convulsions followed
by immediate death.
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Experiment III. —A fowl was treated with 2.5 C.C. of the usual solution of
dry antivenene, and on the following day received an injection of 0.005 gramme
of dry daboia-venom in 0.5 C.C. of water, or a minimal lethal dose for acute
intoxication.
Furious general convulsions set in, seven minutes later, and death took
place half a minute afterwards.
The result of these experiments is to show that antivenene derived from the
blood of animals which have been artificially immunised against cobra-venom
has no effect whatever as an antidote to daboia-venom. The absence of local
action and of symptoms of acute intoxication in the case of the first experiment
cannot be ascribed to any specific action on the part of the antivenene, as pre-
cisely similar results would have followed the introduction of similar doses of
the venom in a bulk of any viscid medium, equivalent to that of the medium
which was there employed ; and the subsequent fatal result clearly shows the
absence of any antidotal action averting the occurrence of the characteristic
intoxication attending the action of the venom when introduced in relatively
large bulk, but under circumstances prohibitive of the occurrence of acute
intoxication, The two remaining experiments, on the other hand, positively
demonstrate the powerlessness of the antidote, even when administered under the
most favourable circumstances, to modify the acutely intoxicant action of the
venom. The results are precisely what might have been anticipated from the
perfectly distinct properties of colubrine and viperine toxins, and are principally
noteworthy in connection with Calmette's assertion that his antivenene, prepared
from the blood of animals artificially immunised against the action of cobra-
venom, is an antidote against the action of the venom of all poisonous snakes,
whether colubrine or viperine in nature. It will be subsequently shown that the
antivenene present in the blood of animals which have been artificially
immunised against the action of. daboia-venom is quite incapable of affecting
cobra-venom.
B.—Experiments on the action of Calmette's Antivenene as an
antidote to Cobra-Venom.
The supply of antivenene was in this case obtained from three distinct
sources. The first sample consisted of a single bottle of the antidote, which had
been obtained direct from Calmette by Surgeon-Captain Maynard, which
he very kindly made over to me for experimental purposes. The second supply
was sent out to me by the Director of the Société Chimique des Usines du
Rhône, in Lyons, with a letter from Sir Joseph Fayrer asking me to test its
Medical Officers of the Army of India.
73
efficacy. The third sample, which, like the second, was contained in numerous
bottles, was very kindly sent to me by Mr. Hankin, who had obtained it direct
from Calmette, and regarded the material as of good quality and practically
sterile, and thus of a nature calculated to avoid the introduction of errors arising
in connection with the presence of putrefactive changes in composition.
I.—RESULTS OF EXPERIMENTS WITH THE ANTIVENENE OBTAINED
FROM SURGEON-CAPTAIN MAYNARD.
(a) EXPERIMENTS IN WHICH THE ANTIVENENE FORMED THE MEDIUM IN
WHICH THE VENOM WAS DISSOLVED.
Experiment 1.—A fowl received a minimal lethal dose of dry cobra-venom
dissolved in 1 C.C. of antivenene.
The normal symptoms of intoxication made their appearance, and termin-
ated fatally.
Experiment II.—A fowl received a double minimal lethal dose of dry
cobra-venom dissolved in I C.C. of antivenene.
Death occurred after the usual symptoms of intoxication.
( b) EXPERIMENTS IN WHICH THE ADMINISTRATION OF ANTIVENENE
FOLLOWED THAT OF VENOM.
Experiment III.—A fowl received a minimal lethal dose of dried cobra-
venom, and, 6 minutes later, an injection of 0.5 C.C. of antivenene in the opposite
leg.
The normal symptoms of intoxication followed in due course, and death
occurred about 11 hours after the beginning of the experiment.
Experiment IV.—A fowl received a double minimal lethal dose of cobra-
venom in one leg, and, 6 minutes later an injection of 0.5 C.C. of antivenene in
the other.
Symptoms of intoxication appeared about 4½ hours later, and death took
place 8½ hours after the beginning of the experiment.
II.—RESULTS OF EXPERIMENTS WITH THE ANTIVENENE OBTAINED
FROM LYONS.
(a) EXPERIMENTS IN WHICH THE ADMINISTRATION OF ANTIVENENE
FOLLOWED THAT OF VENOM.
Experiment I.—A fowl received a minimal lethal dose of cobra-venom in
one leg, and 20 minutes later an injection of 1 C.C. of antivenene in the
other.
Symptoms of intoxication appeared about 3½ hours after the injection of
the venom, and death occurred 4 hours later.
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Experiment II.—A fowl received a double minimal lethal dose of cobra-
venom in one leg, and 20 minutes later an injection of 1 C.C. of antivenene in
the other.
Symptoms of intoxication made their appearance an hour after the injec-
tion of the venom, and death occurred 11 hours later.
In the following two experiments the procedure was so far varied as, in
order to make them as far as possible comparable with those in which Professor
Fraser's dry antivenene was employed, a certain amount of the liquid was
dried off in a sulphuric acid chamber and given weights of the dried material
administered. Ten C.C. of the liquid yielded 0.822 gramme of dry residuum,
so that the proportion of solids is very considerably less than in Professor
Fraser's liquid preparation, in which each C.C. is equivalent to 0.1 gramme of
the dry one :-
Experiment III.—A fowl received a minimal lethal dose of cobra-venom,
and 20 minutes later an injection of 0.1 gramme of antivenene dissolved in
1 C.C. of water.
Symptoms of intoxication appeared 6 hours after the injection of the
venom, and death took place 24 hours later.
Experiment IV. —A fowl received a double minimal lethal dose of cobra-
venom, and 20 minutes later an injection of 0.1 gramme of antivenene dissolved
i n 1 C . C . o f w a t e r .
Symptoms of intoxication appeared 2 hours after the injection of the
venom, and death occurred 3 hours later.
(b) EXPERIMENTS IN WHICH THE ADMINISTRATION OF ANTIVENENE
PRECEDED THAT OF VENOM.
Experiment V. —A fowl received two doses each of 1 C.C. of antivenene
during the course of one day, and on the following morning a minimal lethal
dose of cobra-venom.
Symptoms of intoxication appeared about 6½ hours after the injection of
the venom, and death occurred 15 hours later.
Experiment VI. —A fowl received 2 C.C. of antivenene in the course of
one day, and on the following morning a double minimal lethal dose of cobra-
venom.
Symptoms of intoxication appeared about 3½ hours after the injection of
the venom, and death occurred II hours later.
Experiment VII.—A fowl received 0.2 gramme of dried antivenene in 2
C.C. of water during the course of one day, and, on the following one, a minimal
lethal dose of cobra-venom.
Symptoms of intoxication appeared 7 hours after the administration of the
venom. They continued to be present on the following day, but were never very
Medical Officers of the Army of India.
7 5
profound, On the third day they were less marked, and on the fourth complete
recovery seemed to have taken place.
Experiment VIII. —A fowl received 0.2 gramme of dried antivenene in 2
C.C. of water during the course of one day, and on, the following morning a
double minimal lethal dose of cobra-venom.
Symptoms of intoxication appeared 4 hours after the administration of the
venom, and death occurred 8 hours later.
III.—RESULTS OF EXPERIMENTS WITH THE ANTIVENENE RECEIVED
FROM MR. HANKIN.
As previous experience had shown that the administration of antivenene
antecedently to that of venom certainly gave the best results, in all the
experiments which have as yet been conducted with this supply of the antidote,
this has been the procedure which has been followed.
Experiment I.—A fowl received 3 C.C. of antivenene during the course
of one day, and on the following morning 0.001 gramme ofs cobra-venom, of
which 0.00075 gramme constituted a minimal lethal dose.
Symptoms of intoxication were late in appearing. They never became
profound, and recovery soon took place.
Experiment II. —A fowl received 3 C.C. of antivenene during the course
of one day, and three days later 0.001 gramme of cobra-venom of the same
lethal value as that employed in the previous experiment.
Symptoms of intoxication were late in appearing, but progressed steadily
onwards to a fatal termination about 17 hours after the administration of the
venom.
Experiment III .—A fowl received 3 C.C. of antivenene during the course
of one day, and four days later 0.001 gramme of the cobra-venom which was
employed in the previous experiments.
Symptoms of intoxication came on with abnormal rapidity ; general con-
vulsions began to occur 21 minutes after the injection of the venom, and death
occurred 15 minutes later.
Experiment IV. —A fowl received 3 C.C. of antivenene during the course
of one day, and five days later 0.001 gramme of cobra-venom of the same
strength as that employed in the previous experiments.
Symptoms of intoxication appeared 4 hours after the administration of the
venom, and terminated fatally 8½ hours later.
Experiment V.—A fowl received 12 C.C. of antivenene during the course
of three successive weeks.
Nine days after the last date on which antivenene had been administered
it was treated with 0.001 gramme of cobra-venom of the same lethal quality as
that which was employed in the previous four experiments. Symptoms of
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intoxication set in 2½ hours later, and death took place about 8½ hours after the
administration of the venom.
The result of the entire series of experiments with this antivenene was
very disappointing, and very inferior to that obtained with Professor Fraser's
preparations. When Professor Fraser's liquid antivenene was made use of, 8
experiments yielded 4 recoveries, and where his dry preparation was employed
23 experiments gave 13 recoveries, whereas here we have a series of 17 experi-
ments and only 2 recoveries, and both of these in cases in which the antidote
was used in relatively large bulk, and under the most favourable circumstances
by being administered antecedently, against minimal and slightly supra-minimal
lethal doses of venom. The material, as it reaches this country at all events,
would thus appear to be distinctly inferior in potency to Professor Fraser's pre-
parations, and to possess only very feeble antidotal properties. That it has a
certain antidotal power is indicated, not merely by the two cases of recovery
which occurred, but by the fact that in many of those which terminated fatally
both the onset of symptoms of intoxication and their subsequent progress
appeared to be distinctly retarded, and when employed along with free appli-
cation of bleaching powder or gold chloride at the site of entry of the venom
it may, no doubt, aid in averting the fatal effects normally following minimal
and slightly supra-minimal lethal doses of the latter, but, as an independent
antidote against the action of even minimal lethal doses or an adjuvant one
in dealing with cases where considerable doses have gained access to the system,
the result of the experiments gives no ground for regarding it as of any practical
value.
The transitory nature of the protection afforded by the access of even
very large quantities of antivenene to the system is once again clearly indicated
by the results of the experiments which were conducted with the material
obtained from Mr. Hankin, for, in the case of the first four of them, the adminis-
tration of antivenene was effected simultaneously, and the only case of recovery
after subsequent treatment with venom occurred when the latter was administered
after an interval of 24 hours only, while in the fifth the administration of an
amount of the antidote equivalent to the greater part of a litre to a man of
140 lbs. weight had left no appreciable protective effect after the lapse of an
interval of nine days from the date on which the administration was completed.
Medical Officers of the Army of India.
77
C.—Results on the action of the serum of the blood of the cobra
as an antidote to cobra-venom.
(a) EXPERIMENTS IN WHICH THE SERUM FORMED THE VEHICLE IN WHICH
THE VENOM WAS DISSOLVED.
Experiment I. —A fowl received a minimal lethal dose of dry cobra-venom
dissolved in 0.5 C.C. of fresh serum. The usual symptoms of intoxication
made their appearance, and death occurred 7 hours after the beginning of
the experiment.
Experiment II.—A fowl received a minimal lethal dose of dried cobra-
venom dissolved in 0.5 C.C. of fresh serum.
Death occur red 11 hours later.
Experiment III.— fowl received a double minimal lethal dose of cobra-
venom in 05 C.C. of fresh serum.
The usual symptoms appeared in due course, and death occurred 5 hours
after the beginning of the experiment.
Experiment IV.—A fowl received a quadruple minimal lethal dose of dried
cobra-venom in 0.5 C.C. of fresh cobra-serum.
The usual symptoms of intoxication occurred, but death did not take place
till the following day.
Experiment V. —A fowl received a minimal lethal dose of dried cobra-
venom in 0.5 C.C. of fresh serum.
No symptoms of intoxication appeared until 8 hours later. They sub-
sequently, however, became profound, and death appeared to be imminent
for the two following days. After this they diminished, and recovery ultimately
occurred.
Experiment VI.—A fowl received a minimal lethal dose of dried cobra-
venom in 0.5 C.C. of fresh serum.
No symptoms of intoxication appeared for more than 12 hours, but death
took place on the following morning within 24 hours from the beginning of the
experiment.
(b) EXPERIMENTS IN WHICH THE ADMINISTRATION OF SERUM FOLLOWED
THAT OF THE VENOM.
Experiment VII.—A fowl received a minimal lethal dose of dried cobra-
venom, and 20 minutes later an injection of 1 C.C. of fresh serum in the
same site.
The usual symptoms of intoxication followed, and death took place 9
hours after the beginning of the experiment.
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Experiment VIII.—A fowl received a minimal lethal dose of dried cobra-
venom, and, 20 mi nutes l ater, 1 C. C. of a sol uti on of dri ed serum, contai ni ng
0.1 gramme of the dry material to each C.C.
Four more doses of 0.5 C.C. of the solution were administered within the
course of the next 4 hours.
Symptoms of intoxication were late in appearing, but death occurred within
9 hours from the beginning of the experiment.
Experiment IX.—A fowl received a double minimal lethal dose of dried
cobra-venom, and after 20 minutes an injection of 1 C.C. of a solution of
dried serum of the same strength as that employed in the previous experiment.
Four more doses of 0.5 C.C. of the solution were administered during the
course of the following 4 hours.
Symptoms of intoxication were late in making their appearance, but death
occurred within 6 hours from the beginning of the experiment.
( c) EXPERIMENTS IN WHICH THE ADMINISTRATION OF SERUM PRECEDED
THAT OF VENOM.
Experiment X. —A fowl received 1 C.C. of fresh cobra-serum, and 2 days
later a minimal lethal dose of venom.
Symptoms of intoxication developed themselves rapidly, and death occurred
a little more than 7 hours from the beginning of the experiment.
Experiment XI. —A fowl received 1 C.C. of fresh cobra-serum, and 2
days later a double minimal lethal dose of venom,
Symptoms were profoundly developed within the course of 2 hours and
death occurred 5 hours after the beginning of the experiment.
Experiment XII. —A fowl received 2.5 C.C. of a solution of dried cobra-
serum, containing 0.1 gramme of the dry material per C.C., during the course
of one day. On the following morning a minimal lethal dose of cobra-venom
was administered.
The usual symptoms made their appearance and death took place 5 hours
after the administration of the venom.
Experiment XIII.—A fowl received 2.5 C.C. of a solution of dried cobra-
serum similar to that employed in the previous experiment, and on the following
day a double minimal lethal dose of venom.
Symptoms of intoxication appeared about 4 hours afterwards, and death
occurred 11 hours subsequent to the administration of the venom.
Experiment XIV.—A fowl, which for 8 months previous had been
recei vi ng weekl y i nj ecti ons of 1 C. C. of fresh cobra-serum, recei ved a mi ni mal
lethal dose of cobra-venom.
Symptoms of int oxication began to appear 5 hours later, and rapidly
became profound. For the next 2 days they continued to be so, the bird
Medical Officers of the Army of India.
7 9
appearing to be on the verge of dying, but on the following morning they had
somewhat diminished in intensity, and from this time onwards gradually wore off
until complete recovery had occurred.
Experiment XV.—A fowl, which for 9 months previous had been
receiving weekly injections of 1 C. C. of fresh cobra-serum, received a slightly
supra-minimal lethal dose of venom—0.001 gramme in place of 0.00075 gramme,
which constituted a minimal lethal dose of the stock of venom in use at the time.
Symptoms of intoxication came on 5 hours later. They developed rapidly,
but death di d not occur unti l 29½ hours after the admi ni strati on of the venom.
The above data certainly are not in favour of the belief which Professor
Fraser appears to entertain in the antidotal properties of cobra-serum. In onl y
2 experiments out of a total of 15 did recovery occur, and then only after
the development of prolonged and profound intoxication following minimal
lethal doses of venom. Moreover, even in these cases, it must remain doubt-
ful whether the result was dependent on any antidotal action exerted by the
treatment with serum, for isolated cases of recovery after normal minimal lethal
doses of venom do occasionally occur, apart from any treatment whatever,
and apparently owing to idiosyncratic variations in susceptibility.
In the case of the last two experiments, symptoms of intoxication were
certainly somewhat late in appearing, but this was probably merely owing to
retarded absorption connected with a certain .degree of abnormality in the
tissues, as the venom was introduced in areas which had previously formed
the sites of a very large number of injections of serum, some of which, at all
events, may well have given rise to a certain amount of irritation and conse-
quent tissue change.
It may appear at first sight that the doses of serum which were employed
in some of the experiments were too small to afford any satisfactory evidence
of the presence or absence of antidotal property, but it has to be taken into
account that the doses of venom dealt with were generally only minimal lethal
ones, and that, were the immunity of cobras to the action of cobra-venom
dependent on the normal presence of any material of the nature of antivenene
in their blood, even very small quantities of the latter must contain relatively
large amounts of the antidote. A cobra weighing less than 1 kilo will survive
treatment with an amount of venom sufficient to prove fatal to 1,000 fowls
o f 1 k i l o w e i g h t , s o t h a t , o n t h e t h e o r y t h a t t h e i m m u n i t y i s d e p e n d e n t o n t h e
presence of antivenene in the blood, comparatively small quantities of cobra-
serum ought necessarily to possess antidotal property very greatly in excess
of that present in equal bulks of serum derived from artificially-immunised
animals in which the immunity is of infinitely lower grade.
Taking the facts as they stand, they appear clearly to indicate that the
natural immunity of cobras is perfectly distinct in its nature from the artificial