NationalLibraryOfScotland/medical-history-of-british-india huggingface dataset:
62 Scientific Memoirs by
(b ) EXPERIMENTS IN WHICH THE INJECTION OF MINIMAL LETHAL DOSES
OF COBRA-VENOM WAS FOLLOWED BY THE INTRODUCTION OF
ANTIVENENE.
(1) Experiments in which the Antivenene was introduced in the same site as the
Venom.
Experiment II. —A fowl received a minimal lethal dose of dry cobra-
venom. Twenty minutes later 1 C.C. of antivenene was injected into the same
site, and four more doses of 0.5 C.C. were subsequently administered within the
course of the following four hours.
The usual symptoms of intoxication set in about three hours and one
quarter after the administration of venom, and death occurred about thirteen
hours later.
Here an amount of antivenene equivalent to 210 C.C. to a human subject
of 140 lbs weight failed to neutralise the action of a minimal lethal dose of
venom.
Experiment III. —A fowl received a minimal lethal dose of dried cobra-
venom. Twenty minutes later 1 C.C. of antivenene was injected into the
same site, and, during the course of the next three hours, three more doses of
0.5 C.C. were similarly administered.
Symptoms of intoxication appeared two and a half hours subsequent to
the introduction of the venom, and death occurred eight and a half hours
later.
(2) Experiments in which the Venom and the Antivenene were introduced at
sites widely distant from one another.
Experiment IV.—A fowl received a minimal lethal dose of cobra-venom
in the right leg, and twenty minutes later 1 C.C. of antivenene in the opposite
one. Three more doses of the remedy—one of 0.5 C.C. and two of 0.75
C.C., were administered during the course of the following three hours.
No symptoms of intoxication appeared during the course of that day.
On the following day they were present, but never became profound, and
recovery ultimately occurred.
Experiment V.—The procedure in this experiment, which was performed
with the same solution of venom and the same sample of antivenene at the
same time as the previous one, was of exactly like nature to that adopted
in it.
Symptoms of intoxication set in three hours after the administration of
the venom and death occurred eight hours later.
Medical Officers of the Army of India.
63
(c) EXPERIMENT IN WHICH THE INJECTION OF A DOUBLE MINIMAL
LETHAL DOSE OF COBRA-VENOM WAS FOLLOWED BY THE ADMIN-
ISTRATION OF ANTIVENENE.
Experiment VI.—A fowl received a double minimal lethal dose of dry
cobra-venom. Twenty minutes later a dose of 1 c.c. of antivenene was
administered, followed by three more doses of 0.5 C.C. during the course of
the following two hours, all the doses being introduced at the same site as the
venom.
Symptoms of intoxication appeared about half an hour after the injection
of the venom, and death occurred two hours later.
(d) EXPERIMENTS IN WHICH THE ANTIVENENE WAS ADMINISTERED PRE-
VIOUS TO THE INJECTION OF COBRA-VENOM.
Experiment VII.—A fowl received 2.5 c.c. of antivenene in four doses
during the course of one day. On the following day a minimal lethal dose of
cobra-venom was administered in the opposite leg without inducing any symp-
toms whatever. Six days later the administration of another minimal lethal
dose of venom was followed by the usual symptoms of intoxication and death.
Experiment VIII. —A fowl was treated with 2.5 c .c. of antivenene in four
doses. On the following day it received a double minimal lethal dose of dry
cobra-venom in the opposite leg.
Symptoms of intoxication came on during the course of the succeeding
night, and continued to be well marked during the next day, but after this
complete recovery ensued.
A week after the administration of the antivenene another double minimal
lethal dose of venom was administered, and was followed by the usual symptoms
and death.
We have here a series of eight experiments in which liquid antivenene
was employed in connection with minimal and double minimal lethal doses of
cobra-venom, and the fact that in four of these, including one case in which
the dose of venom was a double minimal lethal one, symptoms of intoxication
were either entirely suppressed or recovered from, affords conclusive evidence
that the material does really possess antidotal properties. The data also shows
that it differs from remedies such as bleaching powder and gold chloride in
acting as an antidote, not merely when administered so as to come into direct
Contact with the venom at the site of introduction, but also after absorption
into the circulation has taken place. Indeed, it would appear that it is after
absorption into the circulation that its activity is mainly exerted, for of the four
cases in which it was administered after the introduction of minimal lethal doses
of venom, the only one in which recovery ensued was one in which it had been
administered distally, and in two other cases of recovery after minimal and
double minimal lethal doses of venom it had not only been administered distally,
64 Scientific Memoirs by
but on the day previous to that on which the introduction of the venom took
place.
The result of Experiment I, in which the employment of antivenene as a
vehicle for the venom was followed by almost complete suppression of symptoms
of intoxication, cannot, in the face of the rest of the evidence, be taken as
a demonstration of the presence of any direct action of the antidote on the
venom, more especially when it is taken into account that, as will appear
when the phenomena presented by other experiments of like nature come to be
dealt with, the venom is certainly not necessarily deprived of active property by
mere solution in antivenene. The probable explanation of the almost complete
suppression of symptoms occasionally attending the employment of antivenene
as a vehicle for the venom is that the procedure necessarily places the remedy
at a relative advantage, not because it especially facilitates any direct action on
the venom, but because it favours the coincident absorption of antidote and
venom. The antecedent administration of antivenene in this set of experiments
certainly seemed to yield the best, and its administration subsequent to that of
the venom, even where direct contact of the two materials is provided for by
their introduction in the same site, the least satisfactory results. In those cases
in which a considerable period is allowed to intervene between the administra-
tion of the antidote and that of the venom, the absorption of the former must
have been fully accomplished ere that of the latter begins to take place, and,
consequently, any protective effects which may attend the presence of anti-
venene in the blood have had time to be produced before any venom has had an
opportunity of gaining access to the circulation. Where the poison and the anti-
dote are administered coincidently the results are not so likely to be uniformly
favourable, as they must necessarily be influenced both by the relative rates of
absorption of the two materials, and also by the relative rates at which they
are capable of producing their specific effects on the blood. Finally; where the
administration of the venom precedes that of the antivenene, the latter is placed
at a disadvantage, as the conditions are such as to allow of the possibility of the
absorption of sufficient venom to give rise to lethal changes in the blood ere any
equivalent antidotal change has had time to be produced.
I I . — R E S U L T S O F E X P E R I M E N T S O N T H E A C T I O N O F D R Y A N T I V E N E N E
AS AN ANTIDOTE TO COBRA-VENOM. THE SOLUTIONS WHICH
WERE EMPLOYED IN THIS SERIES OF EXPERIMENTS WERE, AS
PROFESSOR FRASER RECOMMENDS, OF SUCH STRENGTH THAT
1 C.C. CONTAINED 0.1 GRAMME OF ANTIVENENE.
(a) EXPERIMENTS IN WHICH THE VENOM WAS DISSOLVED IN THE
SOLUTION OF ANTIVENENE.
Experiment I.—A fowl received a dose of dry cobra-venom, amounting to a
little more than 13 times a minimal lethal dose in 1 c.c. of solution of antivenene.
Medical Officers of the Army of India.
65
Symptoms set in two hours later, and death occurred at three hours and
three quarters after the administration of the venom.
Experiment II.—A fowl received a dose of cobra-venom of equal amount
to that employed in the previous experiment dissolved in 1 C.C. of solution of
antivenene.
Death occurred three hours and forty minutes later.
Experiment III. —A fowl received a dose of cobra-venom, amounting to
six and a half times a minimal lethal dose in 1 C.C. of solution of antivenene.
Death occurred five hours later.
Experiment IV. —A fowl received a minimal lethal dose of cobra-venom in 1
C.C. of solution of antivenene.
Death occurred five hours later.
In the first two experiments of this series the duration of life was certainly
abnormally protracted in relation to the amount of venom which was employed,
but the results of the other two experiments appear to indicate that this must
have been merely dependent on obstructed absorption connected with the nature
of the vehicle. In fact, a solution of 0.1 gramme of dry antivenene in 1 C.C.
of water is so very thick and glutinous that it appears to be on the whole more
remarkable that death should have occurred so rapidly as it did in Experiment
IV, in which only a minimal lethal dose of venom was employed, than that it
should have been somewhat postponed in the first two cases.
(b) EXPERIMENTS IN WHICH THE INJECTION OF MINIMAL LETHAL DOSES
OF COBRA-VENOM WAS FOLLOWED BY THE INTRODUCTION OF
SOLUTIONS OF ANTIVENENE.
(1) Cases in which the Venom and the remedy were introduced in the same site.
Experiment V.—A fowl received a minimal lethal dose of cobra-venom.
Twent y mi nut es l at er, 1 C. C. of sol ut i on of ant i venene was i nj ect ed i nt o t he
same site, and four more doses of 0.5 C.C. were administered within the course
of the following five hours.
No symptoms of intoxication ever manifested themselves.
Experiment VI.— A
f o w l r e c e i v e d a m i n i m a l l e t h a l d o s e o f d r y c o b r a - v e n o m ,
and twenty mi nutes l ater, 1 C. C. of sol uti on of anti venene i n the same si te. Fi ve
more doses of 0.5 C.C. of the solution were administered during the course of
the next three hours.
Slight symptoms of intoxication appeared six and a half hours after the
beginning of the experiment, but were succeeded by recovery.
(2) Cases in which the Venom and the remedy were introduced at sites widely
remote from one another.
Experiment VII —A fowl received a minimal lethal dose of cobra-venom
in the right leg. Twenty minutes later 1 C.C. of solution of antivenene was k
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Scientific Memoirs by
injected into the opposite leg, and four more injections of 0.5 C.C. were similarly
administered during the course of the next five hours.
Symptoms of intoxication did not appear until the following day, and were
then only slightly marked, and on the next day complete recovery had
occurred.
Experiment VIII.—A fowl received a minimal lethal dose of cobra-venom
in the right leg, and twenty minutes later a dose of 1 C.C. of solution of anti-
venene in the left one. Four more doses of 0.5 C.C. were administered in the
left leg during the course of the next three hours.
Symptoms of intoxication began to appear about three hours after the
beginning of the experiment. They continued to be present during the course
of the following day, but were never profound, and on the third day recovery
had evidently set in and progressed steadily.
Experiment IX. —A fowl received an injection of a minimal lethal dose of
cobra-venom in the right leg, and twenty minutes later one of 1C . C . o f s o l u t i o n
of antivenene, followed by four more doses of 0.5 C.C. during the following two
hours and a half in the left leg.
Symptoms of intoxication gradually developed and became profound
during the course of the following day, and death occurred about 30 hours after
the beginning of the experiment.
This series of experiments, in which minimal lethal doses of venom were
followed by treatment with antivenene, seem clearly to indicate the superior
antidotal properties of the dry over the liquid form of the material, for we here
have recovery occurring in four cases out of five, whereas in the case of the
corresponding experiments with the liquid preparation, recovery only followed
in one out of four. The difference in the results is no doubt to be ascribed to
changes having occurred in the liquid preparation during transit to this country,
as Mr. Hankin has demonstrated that, in certain cases, the liquid contains an
abundance of schizomycete organisms, and in some has even a distinctly putre-
factive odour on arrival.
(c) EXPERIMENTS IN WHICH THE INJECTION OF DOUBLE MINIMAL LETHAL
DOSES OF COBRA-VENOM WAS FOLLOWED BY TREATMENT WITH
SOLUTION OF DRY ANTIVENENE.
Experiment X. —A fowl received a double minimal lethal dose of cobra-
venom. Twenty minutes later an injection of 1 C.C. of solution was admin-
istered in the same site, and was followed by five more doses of 0.5 C.C. within
the course of the following four hours.
Symptoms of intoxication began to appear about two and a half hours after
the injection of the venom, and progressed steadily and normally until they
terminated in death about seven hours later.
Medical Officers of the Army of India.
67
Experiment XI. —A fowl received a double minimal lethal dose of cobra-
v e n o m . T w e n t y m i n u t e s l a t e r a n i n j e c t i o n o f 1 C . C . o f s o l u t i o n o f a n t i v e n e n e
was introduced into the same site, and was followed by three more doses of
Specific sypmtoms of intoxication began to appear within two hours from
the beginning of the experiment, and death occurred about six hours later.
Experiment XII. —A fowl received a double minimal lethal dose of cobra-
venom. Twenty minutes later an injection of 1 C.C. of solution of antivenene
was introduced at the same site, and was followed by three more doses of
0.5 C.C. during the course of the next three hours.
Specific symptoms of intoxication began to appear within two hours after
the beginning of the experiment, and death followed about six hours later.
Experiment XIII. —A fowl received a double minimal lethal dose of cobra-
venom. Twenty minutes later an injection of 1 C.C. of solution of antivenene
was administered at the same site, and was followed by five more doses of
0.5 C.C. within the course of the next three hours. Slight symptoms of intoxi-
cation made their appearance between six and seven hours after the beginning
of the experiment, but they never became profound, and recovery ultimately
took place.
The results in this group of experiments go to show that the antidotal
power of antivenene is extremely limited, seeing that in only one instance
out of four, in which relatively very large doses were employed after only
double minimal lethal doses of venom, did recovery occur. In the case
of Experiment X, the quantity of antivenene which was administered was
equivalent to 245 C.C. of the solution, or 24.5 grammes of the dry prepara-
tion, for a man of 140 lbs. weight, and the only result of the treatment was
somewhat to delay the occurrence of death. A certain protraction of life
was also present in the other two cases in which recovery failed to occur,
but it is very probable that this was merely owing to retarded absorption
of the venom connected with the introduction of such relatively large
masses of the antidote into the same site as that into which it had been
injected. The proportion of active antidotal material contained in pre-
parations of antivenene would therefore appear to be very small indeed.
In the series of experiments in which minimal lethal doses of venom were
treated with masses of antivenene about 420 times as great, recovery occurred
in a ratio of 4 to 5, but when the ratio of antidote to toxin was reduced to 210,
that of recovery fell to 1 in 4.
( d) EXPERIMENTS IN WHICH ANTIVENENE WAS ADMINISTERED AT
VARIOUS PERIODS ANTECEDENT TO TREATMENT WITH COBRA-VENOM.
Experiment XIV.—One and a half gramme of dry antivenene was dissolved
K 2
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Scientific Memoirs by
in 15 C.C. of distilled water. Four fowls—( a), ( b), (c) and (d)—each received
3 C.C. of the solution, or 0.3 gramme of dry antivenene, during the course of
the day :—
(a) On the following morning, 13 hours after the injection of the last dose
of antivenene, a minimal lethal dose of cobra-venom was administered.
Hardly any symptoms of intoxication were ever perceptible, and complete
recovery soon occurred.
(b) A m i n i m a l l e t h a l d o s e o f v e n o m w a s a d m i n i s t e r e d 3 7 h o u r s a f t e r t h e
last dose of antivenene. Decided symptoms of intoxication appeared seven
hours later. On the following day they became profound, and death occurred
30 hours after the injection of the venom.
(c) A m i n i m a l l e t h a l d o s e o f v e n o m w a s a d m i n i s t e r e d 6 1 h o u r s a f t e r t h e
last injection of antivenene. Symptoms of intoxication appeared, but never
became profound, and recovery occurred.
(d) A minimal lethal dose of venom was administered 85 hours after the
last injection of antivenene.
Symptoms of intoxication appeared, and rapidly became profound, but after
they had remained so for 24 hours recovery gradually set in.
Experiment XV. —Four fowls ( a), (b), (c) and (d) were taken and each
was treated with 3 C.C. of solution of antivenene, the treatment not being
simultaneous, but on four successive days. On the fifth day after the beginning
of the experiment, a minimal lethal dose of venom was simultaneously adminis-
tered to each, that is, 120 hours after (a) , 96 hours after ( b), 72 hours after ( c),
and 48 hours after ( d), had been treated with the antidote, with the following
results :—
(a) Decided symptoms of intoxication occurred, but never became pro-
found.
(b) No symptoms whatever, save slight drowsiness, were ever perceptible.
(c) No symptoms, save temporary dulness, occurred.
(d) Symptoms were late in making their appearance, but for two days were
profound, after which recovery occurred.
Experiment XVI. —A fowl was treated with 2.5 C.C. of solution of anti-
venene, and 9 days later with a minimal lethal dose of cobra-venom.
The ordinary symptoms of intoxication appeared, and death occurred about
5½ hours after the administration of the venom.
Experiment XVII.—A fowl was treated with 2.5 C.C. of solution of anti-
venene, and 9 days later with a double minimal lethal dose of cobra-venom.
The ordinary symptoms of intoxication appeared, and death occurred
3¾ hours after the administration of the venom.
This series includes a total of 23 cases in which antivenene was administered
either before, along with, or subsequent to, the administration of lethal doses of
Medical Officers. of the Army of India.
69
cobra-venom, and in 13 of these death did not occur. Excluding the 4 cases
in which the antidote was employed as the medium for the introduction of the
venom, and in 3 of which the dose of the latter was relatively an excessive one,
together with the 2 last cases, in which a prolonged interval elapsed between
the introduction of the antidote and the venom, we have 13 cases of recovery
and 4 deaths out of a total of 17. These results are considerably better
than those which were yielded by the liquid preparation of antivenene, as, where
the latter was employed, the 7 cases, parallel to the above 17, gave only 3
recoveries.
The antecedent administration of the antidote unequivocally yielded the
best results, as out of 8 cases which were treated in this fashion, and in which
the period elapsing between the administration of the antidote and of a minimal
lethal dose of venom did not exceed five days, only 1 terminated fatally. On
the other hand, the absence of any appreciable direct action of the antidote
upon the toxin appears to be clearly indicated by the fact that a fatal result
ensued in all the four cases in which the former was employed as the medium for
the introduction of the latter, death occurring even in the case in which the
dose of venom was a minimal lethal one. The introduction of the antidote
subsequent to that of the venom gave more favourable results than in the case
of the liquid preparation, there being four instances of recovery out of a total of
eight experiments ; but, as has already been pointed out, the extreme limitation
of antidotal property was clearly indicated by the fact that, while three cases of
recovery occurred in the four experiments in which minimal lethal doses of
venom were employed, only one recovery occurred among the four in which the
dose was a double minimal lethal one. The results, as in the case of the
experiments in which the liquid preparation was employed, clearly show that the
action of the antidote is not a mere local one, like that of bleaching powder or-
gold chloride, depending on local contact with the venom at the site of intro-
duction and before absorption has taken place, but that it is a systemic one,
occurring after the venom has entered the circulation. Such a systemic anti-
dotal action may be conceived of as being exerted in several distinct ways.
Putting aside any direct action on the venom, of which we have already seen
ground for doubting the existence, the results may be regarded as dependent
either on a direct action on the blood rendering it unsusceptible to the influence
of the venom, or of an action primarily affecting the tissues and through them
telling on the properties of the blood. There appears to be some ground to
suspect that the action is a purely hæmic one, for it can be shown that the action
of the venom on specimens of blood outside the body is in certain respects
interfered with by the presence of antivenene. Be the action direct or indirect,
however, it is, at all events, quite clear that it differs from that exerted by cobra-
venom when habitually introduced into the system, in that the protection which