S. Weir (Silas Weir) Mitchell.

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UC-NRLF




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THE LIBRARY

OF

THE UNIVERSITY
OF CALIFORNIA



PRESENTED BY

PROF. CHARLES A. KOFOID AND
MRS. PRUDENCE W. KOFOID




SMITHSONIAN CONTRIBUTIONS TO KNOWLEDGE.

- 647



RESEARCHES



VENOMS OF POISONOUS SERPENTS.



BY

S. WEIR(_MITCHELL, M. D.,

.MEMBER OK THE NATIONAL ACADEMY OF SCIENCES, F. S. A. ; PRESIDENT OF THE COLLEGE OF PHYSICIANS

OK PHILADELPHIA.



EDWARD T. REICHERT, M.D.,

PROFESSOR OF PHYSIOLOGY IN THE UNIVERSITY OF PENNSYLVANIA.



[ACCEPTED FOR PUBLICATION, MAY, 1885.]



WASHINGTON:
PUBLISHED BY THE SMITHSONIAN INSTITUTION.

1886.




COMMISSION

TO WHICH THIS MEMOIR HAS BEEN REFERRED.

JOHN S. BILLINGS, M. D.,
HENRY G. BEYER, M. D.

SPENCER F. BAIRD,

Secretary S. I.



COLLINS PRINTING HOUSfi,
PHILADELPHIA.



PREFACE.



THE authors desire to express their multiple obligations to the Smithsonian
Institution. They have to thank the Army Medical Library for the valuable
Bibliography appended to this essay. With that to be found in Dr. AVeir Mitchell's
former essay, it completes the list of such knowledge up to January, 1885. They
desire also to thank Her Britannic Majesty's Indian Government for help in secur-
ing Indian serpent poisons. Among individuals they owe to no one so deep a debt
as to Vincent Richards, Esq., of Goalundo, British India. Without his untiring
aid the authors feel that it would have been impossible to have extended their
inquiries beyond our native snakes.

The excellent plates were drawn for the most part by Dr. J. Madison Taylor,
and thanks are due to Dr. Geo. A. Piersol's skill for the interesting micro-
photographs of blood-corpuscles attacked by venom. The authors are also indebted
to Dr. Guy Hinsdale for having made the tabulated reductions of kymographion
tracings.

S. WEIR MITCHELL,
EDWARD T. REICHERT.

PHYSIOLOGICAL LABORATORY OF THE
UNIVERSITY OF PENNSYLVANIA.



(Hi)



TABLE OF CONTENTS.



PAGE

PREFACE .......... iii

LIST OF ILLUSTRATIONS ........ ix

INTRODUCTION . . . . . . . . . .1

CHAPTER I.
PHYSICAL CHARACTERISTICS OF VENOM ....... 5

CHAPTER II.

THE CHEMISTRY OF VENOMS . .... 9

CHAPTER III.

THE EFFECTS OF VARIOUS AGENTS ON VENOM ...... 21

CHAPTER IV.

THE EFFECTS OF VENOM WHEN APPLIED TO Mucous OR SEROUS SURFACES . . .44

CHAPTER V.

THE EFFECTS OF VENOM ON THE NERVOUS SYSTEM ...... 48

CHAPTER VI.

THE GLOBULINS AND PEPTONES COMPARED AS REGARDS LOCAL POISONOUS ACTIVITY . 51

CHAPTER VII.

THE ACTION OF VENOMS AND THEIR ISOLATED GLOBULINS AND PEPTONES UPON THE PULSE-
KATE 56



Section I. The action of pure venom upon the pulse-rate . . ...

The action of pure venom upon the pulse-rate of normal animals
The action of pure venom upon the pulse-rate in animals with cut pneumo-



56
57



gastric nerves ...... 63

The action of pure venom upon the pulse-rate of animals in which sections of
the pneumogastric nerves and of the upper cervical portion of the spinal
cord had been made . . . . . . .66

'



v i TABLE OF CONTENTS.

PAGE

Section II The action of venom globulins upon the pulse-rate . . . .69

The action of venom globulins upon the pulse-rate of normal animals . 69

The action of venom globulins upon the pulse-rate of animals with cut pneu-

mogastric nerves ........ 74

The action of venom globulins upon the pulse-rate of animals with the pneu-

mogastric nerves and cervical .spinal cord cut ... 16

Section III. The action of venom peptones upon the pulse-rate ... 79

The action of venom peptones upon the pulse-rate of normal animals 79

The action of venom peptones upon the pulse-rate of animals with cut pneu-

mogastric nerves ...... 82

The action of venom peptones upon the pulse-rate of animals with the pneu-

mogastric nerves and cervical spinal cord cut . . . .83

CHAPTER VIII.

THE ACTION or VENOMS AND THEIR ISOLATED GLOBULINS AND PEPTONES UPON THE ARTE-

KIAL PRESSURE . . . . . . . . .85

Section I. The action of pure venom upon the arterial pressure . 85

The action of pure venom upon the arterial pressure of normal animals . 85

The action of pure venom upon the arterial pressure of animals with the

pneumogastric nerves cut ....... 92

The action of pure venom upon the arterial pressure of animals with the

pneumogastric nerves and cervical spinal cord cut . . .95

The action of pure venom upon the arterial pressure of animals with the

pnenmogastric, depressor, and sympathetic nerves and spinal cord cut 98

Section II. The action of venom globulins upon the arterial pressure . . . 102

The action of venom globulins upon the arterial pressure of normal animals 102
The action of venom globulins upon the arterial pressure of animals with

pneumogastric nerves cut . . . . . . .107

The action of venom globulins upon the arterial pressure of animals with

pneumogastric, depressor, and sympathetic nerves and spinal cord cut . 109

Section III. The action of venom peptones upon the arterial pressure . . .112

The action of venom peptones upon the arterial pressure of normal animals 112
The action of venom peptones upon the arterial pressure of animals with the

pneumogastric and depressor nerves cut ..... 114
The action of venom peptones upon the arterial pressure of animals with the
pneumogastric, depressor, and sympathetic nerves and cervical spinal
cord cut . . . . . . . . .116

CHAPTER IX.

THE ACTION OF VENOMS AND THEIR ISOLATED GLOBULINS AND PEPTONES UPON RESPIRATION 119

Section I. The action of pure venom upon the respiration . . . 119
The action of pure venom upon the respiration of normal animals . . 119
The action of pure venom upon the respiration of animals wkh the pneumo-
gastric nerves cut . . . . . . . 122

Section II. The action of venom globulins upon the respiration . . . 125
The action of venom globulins upon the respiration of normal animals . 125
The action of venom globulins upon the respiration of animals with the pneu-
mogastric nerves cut . . 129



TABLE OF CON TE NTS vii

PAGE

Section III. The action of venom peptones upon the respiration .... 130

The action of venom peptones upon the respiration of normal animals . 130
The action of venom peptones upon the respiration of animals with the

pneumogastric nerves cut ... ... 131

CHAPTER X.

PATHOLOGY . . 133



CHAPTER XI.

GENERAL CONSIDERATIONS ......... 153

BIBLIOGRAPHY ....... ... 159

DESCRIPTION OP PLATES ......... 181

INDEX . . 183



LIST OF WOOD-CUTS.



PAGE

Figure 1. Snake loop . ... . 3

Figure 2. Venom dried ..... ... 5

Figure 3. Muscle tissue altered by venom ... ... 147

Figure 4. Muscle tissue altered by venom ... . 147



(ix)



INTRODUCTION.



A FEW words of explanatory character in regard to the following essay may
not be out of place. From the time of Fontana, 1767, until the able essay of
Lucien Bonaparte, in 1843, on the chemistry of venom, there was no paper of
moment on serpent poisons. In January, 1861, one of us, S. Weir Mitchell,
published a long study of the venom of the Crotalus durissus, and in 1868 sup-
plemented it by a shorter contribution, in which he related some recent discoveries
of his own. and corrected certain errors of his former paper. These two essays
may be considered as constituting with Lucien Bonaparte's the foundation of the
later work in this direction, and perhaps as having left the study of venoms in as
definite a position as could be gained with the laboratory facilities of 1843 to 1868.

In 1872, the government of India enabled Sir Joseph Fayrer to publish a volume
of beautiful plates of the venomous snakes of India, to which was appended also
a series of investigations into the toxicology of their poisons. In 1872 the same
author and Dr. Lander Brunton contributed an admirable physiological study of
the effects of venoms. 1

In 1874, Vincent Richards, as chairman of a government commission, published
an excellent report on antidotes.

Dr. Wall's 2 thoughtful and suggestive book appeared in 1883. It is a compara-
tive study of the poisons of the colubrine and viperine serpents of India.

These, with a too brief study of the poison of our copperhead by Dr. Isaac
Ott, of Easton, Pennsylvania, sum up all of value which has been added to the
physiological literature of this most interesting subject.

Why it has won so few investigators is not far to seek. Even in India, where
the appalling loss of life from snake-bites has of late invigorated research, the
power and means of government were needed to overcome the obstacles which
surround such scientific effort from inception to close. But, if in a land where
snakes abound and professional snake-catchers can be had, it is yet not easy to
follow this pursuit with success, elsewhere it is a task set about with inconceivable
obstacles. The fear of serpents, the rarity of some species, the distances to which
they have to be carried, the mortality of caged specimens, and the great cost of

1 Proc. Roy. Soc. 1812, 1873, and 1875.

a Indian Snake Poisons; their Nature and Effects. A. J. Wall, M.D., F.R.ColJ.S., 1883.

1 April, 1886. ( I )



2 INTRODUCTION.

purchase and transportation, need only to be mentioned as indicating our own
difficulties. What had been done in India, sustained by a government, had to
be with us attempted by private individuals, aided by the Smithsonian Institu-
tion, without which it would have been impossible to succeed. Our work began
in the autumn of 1882, by extended efforts on our part, and that of the Smith-
sonian, to buy or otherwise get numerous living specimens of the American genera
of Thanatophidese. This quest was kept up by every means our ingenuity could
devise, and neither time nor money was spared. We succeeded in obtaining
a sufficient number of rattlesnakes, including Crotalw adamanteus and C. durissus.
We have had also enough of the Moccasin (Ancistrodon piscivorus). Our wants as
regards Ground Rattlesnakes, Copperheads, and Coral-snakes have been less com-
petently supplied, chiefly because these snakes are all small, so that to get enough
of their poison for study it was essential to have a great many snakes. We have
had in all about two hundred living serpents, and among them some superb
specimens, which yielded poison in large quantities. Thus one C. adamanteus
was eight and a half feet long and weighed nearly nineteen pounds. It furnished
on one occasion about one and a half drachms of venom.

It was thought desirable by Prof. Baird and ourselves to examine the poisons of
Indian serpents. To secure these the Secretary of State appealed to Her Majesty's
Indian government in our behalf. A courteous response was returned, and orders
given which resulted in our receiving a certain amount of Cobra venom. A more
constant and larger supply was due to the generous and untiring kindness of
Vincent Richards, Esq., M.R.C.S., of Goalundo, B. I.

The poison of the Daboia Russell ii, the Indian viper, we sought in vain to
secure. Government aid and private enterprise alike failed to secure a sufficient
quantity of the venom of this dreaded reptile. The other Thanatophidea?, of
Australia, and South America, still await more careful study, and our preliminary
report has already been the means of renewing interest in the chemical aspects of
this study in India.

Such of our serpents as were not cared for by the hospitality of the Philadelphia
Zoological Garden, were kept in large boxes, about four and a half feet high,
covered on top with removable wire network, and well-ventilated through wired
openings below. They were of course furnished with water, and if they declined
to eat, were fed at intervals, by artificial means, with raw beef chopped fine, and
passed down into the belly of the snake through a large glass-tube. Under this
treatment the deaths were fewer, and the supply of venom far better. Probably
this method could be usefully employed in zoological gardens, where many snakes
are lost owing to their indisposition to feed during the early months of captivity.

On all occasions, for forced feeding, or for the purpose of extracting venom, the
snakes were caught and held in the snake loop, Fig. 1. This is merely a staff,
having a leather strap so arranged that it can be drawn out into a loop in which
the serpent's neck is noosed, and so held. With this simple means all risk is
avoided, and with it serpents of any size and strength to be met with among our
Thanatophidea? can be safely held and easily manipulated.

For whatever reasons the study of snake venoms had not greatly advanced since



INTRODUCTION. 3

the last research of Fayrer and Lander Brunton until the authors of this paper
resumed the work in 1882. One of them (Dr. Mitchell) hud long felt that it
would be well to revise the toxicology of our American serpents which he had
begun in 18o8, and as the later English observers had in some points differed from

Fig. 1.




him, to learn if they or he were correct, or whether the divergence as to results
was due to variations in the qualities of the venoms employed. Then too he had
become conscious of certain errors in his former researches, and wished to aid in
correcting them, and in rilling up some of the gaps left in this branch of toxi-
cology by himself and others.

The authors started with a theory long held by Dr. Mitchell that snake venoms
are not simple in composition, but composed of two or more poisonous substances,
and that in the qualities and quantities of these agents would be found an expla-
nation of the differences between serpent venoms as to power to kill and mode of
causing death.

How fertile has been the germinal idea of this research must be judged of by
this present essay; which will, we trust, by leading thought and experiment in
new directions hasten the day when we shall be able to treat with success the
wretched thousands who now perish annually by snake-bite in India and elsewhere.

Some of our earlier results were so soon talked of and even noted in public
prints, that it seemed wise for this, and all other reasons, to state what we then
knew. This was done in a " Preliminary Report to the United States National
Academy of Sciences, in April, 1883." In this brief essay we announced our
proofs of the complex nature of snake poisons. The report was incomplete, and
in the light of our present more elaborate essay may be seen to contain several
erroneous statements.

It is not in the nature of things, that a research along such varied lines as
our present volume follows, though extending over several years, should be per-
fect in detail, or complete for all genera of Thanatophidians. It is our earnest



4 INTRODUCTION.

hope that it will be complemented and supplemented by some of the able staff of
the British Army Medical Service in the East Indies. There, only, is it possible
to find enough serpents, and all the various species which it will be desirable tc
review lexicologically from the new stand-point which we think we have estab-
lished.

We have forborne to overload this paper with comments on the later researches
of others, and have made the discussion of our own work as brief as was consistent
with clearness.

In writing of the various substances contained in venoms, we have given them
names which are fairly descriptive, but which, as in the case of the peculiar
peptone of Cobra, may perhaps excite criticism. Yet, however unsatisfactory our
method of nomenclature may be, any other plan of naming the curious bodies in
question would certainly have been even more misleading.



CHAPTER I.
PHYSICAL CHARACTERISTICS OF VENOM.

Physical Characteristics of Venom. All serpent venoms are more or less alike
in appearance when fresh. They are fluids varying in color from the palest amber
tint to a deep yellow. Dr. Wall describes the Cobra venom as being occasionally
colorless. This peculiarity we have never seen in the fresh poison of any of our
serpents, except once in the coral snake ; nor can the venom of one kind of snake
be distinguished with certainty by any physical peculiarity from that of any other,
however remote they may be in the scale of being.

When a fluid venom is allowed to dry slowly it presents . no specific distinctive
appearances. If desiccated too rapidly, it may look a little more gray and opaque
than is common, but usually it dries into a beautifully cracked mass, deceptively
like an aggregation of crystals, and which is well represented in Fig. 2.

Fig. 2.




In this state it is in solid yellow particles, very fragile, bright yellow, trans-
parent or translucent, and seemingly indestructible by time, since the dried venom
of the rattlesnake, for twenty-two years in Dr. Mitchell's possession, proved as
poisonous as that removed yesterday. It is equally unaltered by solution in
glycerin, which keeps it permanently in unchanged toxic force, as we shall here-



6 THE VENOMS OF CERTAIN THANATOPHIDE^E.

after point out. 1 Neither does it appear to be injured when dry by mingling it
with pure alcohol. In fact any of these three means, desiccation, glycerin, or
alcohol, preserves it well.

When fresh venom of any serpent is examined with the microscope it often
presents a variety of floating bodies which seem to be much alike in all cases, and
are very well shown in the plates of Dr. Mitchell's former paper and in Vincent
Richards's reports. In healthy serpents, but lately caged, there are fewest of
these solid ingredients, as has been noticed by Richards, by Wall, and by S. Weir
Mitchell. The question of the toxicity of these suspended solids has again drawn
our attention to them, and we have had yet more careful and repeated microscopic
examinations made by Prof. Formad. He found, like other observers, that the
venom of the more vigorous snakes has the least visible solid matter ; but, as in the
use of the fang, the mucus and floating solids of the mouth must be considered,
and, as in collecting venom from the snake, more or less of the mouth fluids mingle
with the venom, it was thought well to reconsider the nature of the floating solids
from the point of view of toxic activity. For the better study of the solids found
in venoms we examined numerous specimens, and placed many of these in the
hands of Prof. Formad, from whose notes we select the following observations :

A drop of fresh venom, taken directly from the Crotalus adamanteus, was examined
with a T V Zeiss. homog. immersion lens ; amplification 800 diameters. The most
striking appearance which first meets the eye is a granular material scattered about
in masses of various size and shapes, resembling those formed by bacteria. There
are also seen, in some cases, a few oval nucleated red blood-corpuscles, some leuco-
cytes resembling salivary corpuscles, and others corresponding to ordinary white
blood-corpuscles, the latter cells in an active state of amoeboid motion. There
were also observed several club-shaped epithelial cells covered with fine granular
material.

The granular matter first mentioned, and which seems to form the main solid
constituent of the venom, consists of two elements: Larger granules of an animal
or albuminous character, and a fine granular material of vegetable nature. The
albuminoid material is made up of minute particles ovoid, or somewhat irregularly
angular in shape, measuring about T7 ^^ of an inch in their longest diameters.
These ovoid particles are grouped side by side, from two to twenty in each collec-
tion, and are arranged so as to form single or double rows, or more often aggregated
into irregularly shaped clusters, which vary in size from -gfa to -g^rnr f an nic h ;
the smaller masses predominating. The particles just described are colorless,
refracting, and in general give the impression of bacteria. They are, however,
distinguished from the latter in that they do not multiply in cultures, or respond
to the aniline dye test for bacteria.

There are usually numerous bacteria in perfectly fresh venom. All the smaller
particles and granular material are micrococci, measuring on an average T7 | 7Tr of
an inch in diameter, are perfectly round or somewhat ovoid, and occurring singly,

1 Dr. Mitchell possessed a glycerin solution which was toxic after twenty years.



PHYSICAL CHARACTERISTICS OF VENOM. 7

in pairs, or in zooglcca masses. They arc less refracting, and paler than the
albuminoid particles described above, and respond promptly to the usual tests for
bacteria, viz: They multiply rapidly and absorb well the aniline dyes, thus form-
ing a marked contrast side by side with the animal granular material, which was
readily discolored under the influence of acid.

The epithelial cells seen in the venom are, as a rule, few in number, are squam-
ous or club-shaped, and in size not exceeding that of the red blood-corpuscle of
the serpent. Leucocytes are also few in number, and, as well as the epithelium, are
mostly covered with micrococci. A few of the white blood-corpuscles do not appear
to contain micrococci, and in fresh venom, especially upon the warming stage,
exhibit a quite active amoeboid motion. The venom of the moccasin presents the
same appearances.

If fresh venom stands but a short time exposed to the air the micrococci mulr
tiply with remarkable rapidity, forming large, pale, motionless clouds ; but, in
addition, multitudes of movable bacteria (the Bacterium termo and a bacillus
probably Bacillus sti-l>tU!*) gradually make their appearance. 1

The globulous masses, above described, may be collected by filtration, but as
this is often a difficult or even an impossible process with a fluid as viscous as pure
venom, and, as much is lost in the filter, another method was devised, and there-
after frequently used by us as an assistance in venorn analysis. A tube, about 5
millimetres wide and 200 to 400 m. m. long, has a bulb blown on it midway, or at
the top, and is then closed above in the blowpipe flame, and strongly heated
throughout. While hot, the lower end drawn to a point, is in like mariner sealed.
After being cooled the tip is broken within fresh venom, which is forced up into
the tube by atmospheric pressure. The end of the tube is then once more adroitly
sealed in the flame.

Thus prepared the tube is suspended, so that the solids of all forms settle in a
few days, while for this time, at least, the venom undergoes no such putrefactive
change as is inevitable when it is exposed to the air at our ordinary spring or
summer temperatures.

The solids, thus collected below, are easily separable from the supernatant venom
by breaking off the two ends of the tube and allowing the precipitate to escape,
with a minimum amount of liquid, from which washing in water easily separates
them.

The physical appearances of the venoms of the moccasin or of the rattlesnake,
tli us secluded from the air in these partial vacuum tubes, undergo some curious
changes of much interest.

The yellow coloring matter disappears from below upwards, and at last is seen
only at the top, where the venom is in contact with the small amount of air left in
the tube. At first, this change was presumed to be simply the rising of a pigment
of lesser gravity. But it was noticed that the layer of yellow was of no deeper
tint in its lessened bulk than when diffused. The fluid below it was left as



1 Fresh venom, putrefied from long standing, appears to lose at least a portion of its virulence.
But this is a point which is open to further observation.



8 THE VENOMS OF CERTAIN T H AN ATO P HI D E M.

clear and tintless as water ; but when re-exposed to the air once more became
yellow throughout, within one or two hours.

The yellow pigment of Cobra poison, when the dry poison was dissolved in water,
does not rise in the tube or disappear, but remains unaltered. It is desirable to
repeat these observations with fresh Cobra venom.

The cause of the disappearance and reappearance of the coloring matter of
venom we have not been able to explain to our satisfaction, and it is one of the
questions left open for inquiry.

The Specific Gravities of Venoms. The specific gravity of the venoms of our
own serpents is as follows :

Crotalus horridus 1.054

Crotalus atrox ........ 1.077

Crotalas adaraanteus 1.061

Ancistrodon piscivorus ....... 1.032

The specific gravity of Cobra venom is given by Wall at 1.058.
As to that of the Indian viper we can find no statement.
The losses of venom on drying were as follows:

C. adam. ....... 25.15 per cent.

C. atrox 25.1(5 "

Ancis. piscivorus . ..... 27.42 "



THE CHEMISTRY OF VENOMS



CHAPTER II.

THE CHEMISTRY OP VENOMS.

THE presence of alkaloids in venom, and especially of the ptomaines, has been
suspected, and these bodies have been repeatedly sought for in vain. Gautier is


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Online LibraryS. Weir (Silas Weir) MitchellResearches upon the venoms of poisonous serpents → online text (page 1 of 19)