THE
TOXINS AND VENOMS
AND THEIR ANTIBODIES
BY
EM. POZZI-ESCOT
AUTHORIZED TRANSLATION
BY
ALFRED I. COHN, PHAR. D.
_FIRST EDITION_
FIRST THOUSAND
NEW YORK
JOHN WILEY & SONS
LONDON: CHAPMAN & HALL, LIMITED
1906
Copyright, 1906
BY
ALFRED I. COHN
ROBERT DRUMMOND, PRINTER, NEW YORK
INTRODUCTION.
Our knowledge of the toxins is of quite recent date. It is hardly
twenty years since we began to acquire a knowledge of the facts that
are detailed in this volume, and to which modern medicine owes its most
recent and marvelous progress, particularly in serotherapy.
In this volume we have studied, besides the true toxins--substances of
cellular origin and of albuminoid nature and unknown composition--other
toxic substances, the nitrogenized alkaloidal bases introduced into
science through the researches of Selmi, Armand Gautier, and von
Behring, and which are highly hydrogenized nitrogenous crystallizable
principles of definite chemical composition--the products of the more
or less advanced breaking down of albuminoids.
Although these principles differ widely, by reason of their
physiological properties as a whole, from the toxic albuminoids, or
true toxins, it appears proper to consider them as products of the
advanced decomposition of these toxins--and in this respect their study
becomes imperative, the more so as they are very frequently encountered
together with the toxins, particularly in serpent-venoms, where their
action is exerted in addition to that of the true toxins.
In the first volume of this collection we dwelt on the essentially
reducing nature of the cellular functionation. To this
functionation--causing the splitting up or decomposition by hydrolysis
of nitrogenized albuminoid foods--is due the formation of these toxic
basic products within the organism, whether normally, or because of
certain pathological conditions.
This alone suffices to show that, during physiological life, oxygen
plays an essentially antitoxic rôle within the organism.
It is hoped that this succinct résumé, which it has been sought to
make as clear as possible, will be of service to those who, while
not scientists actively engaged in scientific progress, desire to be
abreast of the knowledge of modern evolution, but yet are not in a
position to consult original papers or large treatises.
CONTENTS.
PAGE
INTRODUCTION iii
PART I.
_GENERALITIES REGARDING TOXINS AND
ANTITOXINS._
CHAPTER I.
ALKALOIDAL TOXINS, PTOMAINES, AND LEUCOMAINES.
Alkaloidal products of cellular life 1
Ptomaines 4
Physiological action 5
Extraction 5
Classification, etc. 7
Leucomaines 10
Xanthic leucomaines 12
Creatinic leucomaines 13
Neurinic leucomaines 13
Indeterminate leucomaines 14
CHAPTER II.
TOXINS AND ANTITOXINS.
Toxins 15
Action of pathogenic bacteria 16
Action of toxins 17
Nature of toxins 18
Origin of toxins 20
Autointoxications 21
General mode of action 23
Constitution of toxins; Ehrlich's theory 24
Means of defense possessed by the organism
against the action of toxins 28
Pasteur's vaccination method 30
Virus action 30
Phagocytosis 32
Antitoxins 33
Mode of action 35
Formation; Ehrlich's theory 38
Serotherapy 41
PART II.
_THE TOXINS PROPER._
CHAPTER III.
I. VEGETABLE AND ANIMAL TOXINS. 42
Abrin 42
Ricin 44
Robin 45
Toxicity of the vegetable diastases 45
II. TOXINS FROM MUSHROOMS 46
Phalline 48
Symptomatology 49
Antidiastases 51
III. ANIMAL TOXINS 53
Peptotoxin 53
Alimentary Intoxications 55
Urinary toxins 57
Variation of urinary toxicity 59
Autointoxications (animal) 60
Glandular secretions 62
Suprarenal capsules 63
CHAPTER IV.
THE MICROBIAL TOXINS.
Pyogenic and pyretogenic properties 66
Anthrax toxin 67
Tubercular toxin 69
Diphtheria toxin 71
Tetanus toxin 76
Mallein 79
Typhoid toxin 80
Cholera toxin 82
CHAPTER V.
THE VENOMS.
General nature of venoms 85
Venomous serpents 87
Nature of serpent-venoms 88
Natural immunity towards serpent-venoms 90
Artificial immunity towards serpent venoms 91
Venoms of batrachians and saurians 92
Fish-poisons 95
Poisons of the hymenoptera 96
Poisons of scorpions 97
Poisonous blood and serums 98
Poisonous meats 100
TOXINS AND VENOMS.
PART I.
_GENERALITIES REGARDING TOXINS AND ANTITOXINS._
CHAPTER I.
ALKALOIDAL TOXINS, PTOMAINES AND LEUCOMAINES.
=Alkaloidal Products of Cellular Life.=
Before entering upon the study of the true toxins, which are products
of an alkaloidal nature and of unknown composition, it is necessary to
say a few words regarding the most definite of the toxic alkaloidal
principles that are frequently encountered under various conditions,
conjointly with the true toxins, particularly in venoms, and which,
furthermore, are closely allied to these albuminoid toxins.
These principles are formed in essentially reducing media, whether it
be within the body of the organism, and by the simple exercise of its
normal function, in which case the principles bear the generic name
_leucomaines_[1]; or whether due to the action of anaerobic microbes,
when they are designated as ptomaines.[2] These basic principles, which
are essentially the products of cellular secretion, are usually toxic,
and sometimes even extremely so.
[1] ARMAND GAUTIER: Sur les leucomaines, nouveaux alcaloides, dérivés
de la transformation des substances protéiques des tissus vivants.
_Bull. Soc. Chim._, 2e série, XLIII, p. 158.
[2] ARMAND GAUTIER: "Communication sur les bases d'origine
putréfactive." _Bull. Soc. Chim._ (2), XXXVII, p. 305.
As we shall presently see, ptomaines are essentially products formed
during putrefactive fermentation. The toxic properties of extracts from
the cadaveric fluids have long been known. Already in 1838 Panum[3] had
met with these products in snake venoms. Bergmann and Schmiedberg[4]
in 1868 isolated from septic pus a toxic substance which they named
_sepsin_; and almost at the same time Zuelzer and Sonnenschein[5]
reported having isolated from anatomical preparations an alkaloid
possessing mydriatic properties. It is, however, due particularly to
the researches of Selmi and Armand Gautier that we are now so well
informed regarding these toxic principles.
[3] _Virchow Archiv._, X, p. 301.
[4] _Medic. Centralblatt_, 1868, p. 497.
[5] _Berlin. Klin. Woch._, 1869, No. 2.
The labors of Armand Gautier were first published in his _Traité de
Chimie Appliquée à la Physiologie_; those of Selmi in the _Actes de
l'Académie de Bologne_.
At first sight, there appears to be a great difference between these
alkaloidal bases, the ptomaines and leucomaines, and the albuminoid
toxins proper. The toxic bases of the first two groups are quite
definite chemical products which can be generally obtained quite pure,
and frequently in crystalline form. The toxins proper, on the other
hand, are highly complex albuminoid substances which greatly resemble
the true diastases in all their properties.
Nevertheless, between the toxic alkaloids, ptomaines and leucomaines,
and the toxic albuminoids, or more properly toxins, there exists no
absolutely sharp line of demarcation, but there is a gradual passage
from the one to the other by every intermediary grade, as a result of
the breaking down of the albuminoid molecule.
We shall see, moreover, as we proceed, that these substances are
formed under coexistent circumstances, and that they are, hence, found
together, whether it be in virus or in snake venom.
We will first consider the ptomaines, and then the leucomaines.
=Ptomaines.=
This name is more specially reserved to designate those alkaloidal
substances, generally highly hydrogenized, that are formed outside
the organism, from the fermentative action of anaerobic microbes on
albuminoid substances.
These bases are generally volatile, with an intense and tenacious
purulent odor; often, however, they possess a floral odor (aubépine,
syringa), and even like that of musk. They combine readily with acids
and with the chlorides of the heavy metals, yielding crystallizable
salts.
The ptomaines afford no specific reaction whereby they may be readily
identified; and their identification is effected only after a
painstaking analysis.
We must here call attention, however, to several of their more common
properties, beginning with their basic character, their oxidizability
by the air and consequently their well-defined reducing power--a
property that led Selmi to propose a mixture of ferric chloride and
potassium ferricyanide as a reagent for their detection.[6] They are
precipitated by all the general reagents for the vegetable alkaloids.
Selmi has given several reactions, such as those afforded by sulphuric,
hydrochloric, and nitric acids, which appear, however, to apply much
more to the impurities present than to the bases themselves.
[6] Sulle ptomaïne od alcaloïdi cadaverici. Bologne, CLXXXVII, p. 11.
The physiological action of these bases varies greatly; in some
the action is an extremely toxic one, as in the case of neurine
and muscarine, which are true ptomaines; there are others, such as
cadaverine and putrescine, which are quite innocuous. The physiological
action of these bases, like that of the true toxins, is studied by
making hypodermic injections of solutions of the bases in healthy
animals, such as guinea-pigs, rabbits, and dogs.
In animals, the principal phenomena observed by Selmi to follow the
injection of the substances are the following: At first dilatation
of the pupil, then constriction; tetanic convulsions, soon followed
by muscular relaxation, and retardation, rarely acceleration, of
heart-beat; absolute loss of cutaneous sensibility; loss of muscular
contractility; paralysis of the vasomotors; greatly retarded
respiration; stupor, followed by death with the heart in systole.
It must be observed that in a number of cases where toxic researches
had been made in the past, these bases had been mistaken for poisons
which were believed to have been introduced into the organism with
criminal intent. No one will ever know how many have fallen victims in
the past to ignorance regarding the cellular mechanism!
The extraction of these bases is a tedious and difficult operation.
The materials must first be exhausted with water slightly acidulated;
then, after precipitating the albuminoids by boiling and defecating by
adding lead acetate, the liquid is evaporated to one-half its volume
and dialyzed in a vacuum.[7]
[7] ARMAND GAUTIER: _C. rend. de l'Académie des Sciences_, CXIV, p.
1256. _Ibid._, XCVII, p. 264, and XCIV, p. 1600.
Phosphomolybdate is then added to the dialyzed liquid, and the
precipitate formed, which now contains all the bases, decomposed by
boiling with lead acetate. After removing the excess of lead, there is
thus obtained a limpid solution of all the alkaloidal bases in the form
of acetates. These are separated by alcohol and by means of fractional
precipitations with various metallic salts, depending upon the known
properties of the bases.
In order to facilitate their study, the ptomaines have been grouped
under two distinct classes, the one embracing the cadaveric or
putrefactive ptomaines, of undetermined microbial origin, the other
containing the ptomaines formed by microbes of known character. Each
of these two groups is itself divided into subgroups, as shown in the
following table:
GROUP I.
=CADAVERIC PTOMAINES OF UNDETERMINED MICROBIAL ORIGIN.=
_a._ Amines.
_b._ Guanidines.
_c._ Oxamines (fatty or aromatic).
_d._ Amido Acids.
_e._ Carbopyridic Acids and analogues.
_f._ Undetermined Ptomaines.
GROUP II.
=PTOMAINES OF KNOWN MICROBIAL ORIGIN.=
_a._ Ptomaines extracted from microbial cells.
_b._ Ptomaines from pathological urines.
We will not here enter upon a detailed study of the bases belonging
to each of these groups. This subject is a vast one, requiring for
its treatment a volume devoted to it alone. We will here simply touch
upon the principal properties of several of the bases of each of the
subgroups named.
BASES OF GROUP I.
_a._ =Amines.=--Among these we find nearly all the fatty amines, such
as the methylamines and the cyclic alkaloids such as pyridine. They are
formed particularly by the putrefaction of fish.
Certain of these bases are very toxic, for instance trimethylene
diamine, the collidines, and the parvolines.
_b._ =Guanidines.=--Among the products of ordinary putrefaction there
has been found so far only methylguanidine, C{2}H{7}N{3}. This is a
highly toxic base of which 0.2 Gm. is fatal to a guinea-pig.
_c._ =Oxamines.=--Under this designation the following bases are
comprised: 1. Neurine bases; 2. oxygenized aromatic bases; 3. bases of
unknown constitution. Amongst them we find neurine and choline, which
are toxic, and betaine, which is innocuous. They are found particularly
in putrid fish.
_d._ =Amido Acids.=--These ptomaines, which are usually innocuous in
small quantities, are particularly the products of the decomposition
of albuminoid substances. Among them we find glycocoll, leucine, and
tyrosine, as members of this group.
_e._ =Carbopyridic and Carboquinoleic Acids.=--So far only one base
is known belonging to this group, and that is morrhuic acid, which is
found in the decomposed livers of codfish, and which is a powerful
appetizer and stimulant in disassimilation.
_f._ =Undetermined Ptomaines.=--Under this heading are classed certain
undetermined bases, such as those found in normal urines, and in
spoiled meats and bread.
BASES OF GROUP II.
_a._ =Ptomaines Isolated from Cultures of Pathogenic
Bacteria.=--Bacterial cultures contain, besides the true toxins, a
certain number of alkaloidal bases which sometimes possess considerable
toxicity.
In the cultures of streptococcus pyogenes there are found
trimethylamine and xanthic bases; in those of staphylococcus pyogenes
aureus are found xanthic bases and creatinine; while pyocyanine and
pyoxanthine are found in the cultures of bacillus pyocyaneus, etc.
_b._ =Ptomaines Isolated from Pathological Urines.=--Toxic ptomaine
bases have been found in the urines of a large number of diseases.[8]
It is quite probable that these bases are the results of a general
pathological condition due to some bacterial disease, the toxic
products of which are eliminated by the kidneys.
[8] GRIFFITHS: _C. rend. de l'Académie des Sciences_, CXV, pp. 285 and
667.
From the urines of epileptics Griffiths[9] isolated a colorless base
crystallizing in prisms having the formula C{12}H{15}N{5}O{7}, and
which was found to be exceedingly toxic; the same investigator isolated
from the urines of eczematous subjects a ptomaine which he named
_eczemine_,[10] and which is also highly toxic.
[9] E. POUCHET: Contribution à l'étude des matières extractives de
l'urine, _Thèse_, Paris, 1880; _Ibid._, _C. rend. de l'Académie des
Sc._, XCVII, p. 1560; BOUCHARD: _C. rend. Soc. de Biolog._, Aug. 12,
1882.
[10] GRIFFITHS: _C. rend. de l'Académie des Sciences_, CXVI, p. 1206.
In certain cases of cystinuria there are found in the urine sulphurized
ptomaines, and in measles the urine contains an undetermined ptomaine,
_rubedine_, which is very poisonous. _Typhotoxine_, a very toxic
ptomaine, has been isolated from the urine of typhoid patients;
_erysipeline_, a hardly less toxic base, exists in the urine of
erysipelatic subjects; while _spasmotoxine_, _tetanotoxine_, and
_tetanine_, exceedingly active alkaloids, are found in the urines of
tetanus patients.[11]
[11] BRIEGER: Untersuchungen über die Ptomaine, dritten Teil, p. 93;
_Berichte d. D. Chem. Gesellschaft_, 1886, p. 3159; 1887, p. 69.
As a general rule, all abnormal urines contain toxic bases; the kidneys
appear, in fact, to serve as a means of eliminating the toxic products
that form in large quantity whenever, and for whatever cause, the
organism ceases to functionate normally, whether it be as a whole, or
in any one of its parts.[12]
[12] CHARRIN: _Les poisons de l'urine_: Encyclopédie Léauté.
=Leucomaines.=[13]
[13] ARMAND GAUTIER: _Bull. Acad. de Médecin_ (2), XV, p. 115.
The leucomaines are basic substances, nearly allied to the ptomaines,
but still more closely related to the ureides. They are formed
directly or indirectly by the breaking down of protoplasmal
albuminoids. The agents that effect the breaking down are the
hydrolyzing ferments of the economy. It is well to recall here that
these phenomena of hydrolyzation occur within the cell itself and in
a practically reducing medium, as we have already stated. The inmost
mechanism of these phenomena cannot here be detailed; it will be found
described by Armand Gautier in the _Chimie Biologique_, and in his work
_Chimie de la Cellule Vivante_.[14]
[14] ARMAND GAUTIER: Leçons de chimie biologique. Published by Masson;
_Ibid._, Chimie de la cellule vivante. Also published by Masson.
The extraction of these bases is an extremely delicate operation. It is
necessary to operate with a large quantity of substance, say 50 kilos.
The substance is finely chopped, then exhausted with twice its weight
of water acidulated with acetic acid (0.2 Cc. per liter) and containing
a trace of oil of mustard, which is intended to act as an antiseptic.
The albuminoids are precipitated by boiling, the solution then
filtered, evaporated in a vacuum at 60° C., and the bases extracted
with 95-per cent. alcohol.
The alkaloidal bases obtained in this manner are separated by
crystallization from alcohol or by various other chemical methods, the
description of which we will not enter upon here.
In order to facilitate the study of the leucomaines they are classed
under three groups, according to their chemical affinities. These
groups are as follows:
1. =Xanthic Leucomaines.=--The bases of this group appear to have a
composition resembling that of uric acid. When hydrolyzed, they yield
urea and guanidine. They are weak bases, and exhibit both basic and
weakly acid properties. They all possess the common characteristic of
being precipitated by copper acetate in acid solution with heat, and by
ammoniacal silver nitrate in the cold.
According to Kossel, these bases are derived from the nucleo-albumins
which are found in the cell nuclei, and which are, as we know,
substances rich in nitrogen and phosphorus.
Among the bases of this group may be mentioned _adenine_,
C{5}H{5}N{5}, which is obtained from infusions of tea.[15] This base
is non-toxic; it was discovered by Kossel,[16] and it crystallizes
easily.
[15] KRUGER: _Bull. Soc. Chim._ (3), VIII, p. 687.
[16] KOSSEL: _Zeitschrift für physiol. Chim._, X, p. 248; and _Bull.
Soc. Chim._ (3), III, p. 239.
Some others of this group are:
_Guanine_, C{5}H{5}N{5}O, non-toxic, discovered by Unger;
_pseudo-xanthine_, obtained from muscular tissues; _sarcine_,
C{5}H{4}N{4}O, also but slightly toxic, discovered by Scherer;
_xanthine_, C{5}H{4}N{4}O{2}, which is found in many urines, and
which acts as a stimulant on the cardiac muscles; _paraxanthine_,
C{7}H{8}N{4}O{2}, a toxic base found in certain pathological
urines; _caffeine_ and _theobromine_, powerful diuretic bases; and
_carnine_, C{7}H{8}N{4}O{3}, from meat, a muscular stimulant like
caffeine.
2. =Creatinic Leucomaines.=--These have for their type guanidine; they
differ from the xanthic bases in that they are not precipitated by
copper acetate, but frequently are by ammoniacal silver nitrate. They
yield double salts with the chlorides of zinc and cadmium. To this
group belong _glycocyanine_, C{3}H{7}N{3}O{2}, and _glycocyanidine_,
C{3}H{7}N{3}O, both very toxic; _creatine_, C{4}H{9}N{3}O{2}, only
slightly toxic; _creatinine_, C{4}H{7}N{3}O; _lysatine_, which very
easily decomposes to form urea; _lysatinine_, _xanthocreatine_;
_arginine_, a vegetable base, etc.
3. =Neurinic Leucomaines.=--These have none of the characteristics of
the preceding bases; their type is neurine, a highly toxic base found
in the brain, nerves, and certain fish ova. These bases are sometimes
normally produced by the animal economy, and are also frequently the
result of microbic action. They are the result of the simple phenomena
of fermentative hydrolyzation of protagons and lecithins. Among these
bases are _choline_, a weak alkaloid, and _betaine_, which appears to
be non-toxic.
The former has the formula C{5}H{15}NO{2}; it was discovered
by Stocker. Wurtz synthesized it by combining trimethylamine and
glycol-monochlorhydrine, and treating the resulting hydrochloride with
silver oxide. Betaine, C{5}H{11}NO{2}, is found in beets; it was
discovered by Scheibler. Neurine is, chemically, trimethylvinylammonium
hydrate.
4. =Undetermined Leucomaines.=--Among these bases several are
important in more than one respect. For instance _spermine_, which is
found in the sperm, is a strong base possessing a powerfully dynamic
and tonic action on the nerves. It acts as an oxidizer. Spermine
was first obtained by Schreiner[17] from the sperm of mammifers in
which it occurs as a phosphate. It has the formula C{5}H{14}N{2}.
It was physiologically studied by Poehl, Tarchanoff, Weljaminoff,
and Joffroy.[18] _Plasmaine_, a toxic base found in the blood and
discovered by R. Wurtz,[19] has the formula C{5}H{15}N{5};
_protamine_, from fish milt, was discovered by Micocher.[20]
[17] _Liebig's Ann. der Chemie_, CXCIV, p. 68.
[18] _Journ. Soc. Phys. Chim. Russe_, 1893, No. 2; and _Bull. Soc.
Chim._ (3), XII, p. 243.
[19] _Leucomaines du Sang Normal_, Thèse, Paris, 1889.
[20] _Joh reab. de Thiérchen_, 1874, p. 341; Picard, _Ibid._, p. 355.
CHAPTER II.
TOXINS AND ANTITOXINS.
We have already seen, in the preceding chapter, that the microbes
and the cells of various organisms are capable of secreting definite
products of a toxic nature to which the names "ptomaines" and
"leucomaines" have been given. Researches, which were begun scarcely
twenty years ago, have shown that, besides these crystallizable and
definite products, we meet with basic non-crystallizable substances of
unknown composition, possessing special toxic properties, sometimes
even of extreme violence. These substances have been named "toxins."
At first this generic name was extended toward indefinite basic organic
products that could be isolated from tissues and tumors both normal and
abnormal; later on, however, the name was applied to toxic substances,
equally indefinite, isolated from the culture media of microbes and the
active constituent of various venoms.
It is only since 1885, when Charrin called attention to them, that
investigations began to be made regarding them. In 1888 Roux and
Yersin,[21] in their beautiful researches on diphtheria, pointed out
the diastatic nature of the properties of the active albuminoid matter
existing in the cultures of the specific bacilli of this disease. From
that period, these products began to take a more and more prominent
place, from year to year, in the study of pathological affections, and,
by developing the knowledge of immunity, they have opened a new path to
the investigations of therapeutic technic.
[21] ROUX and YERSIN; Mémoire sur Diphtérie. _Ann. Inst. Pasteur_,
1888-1889.
It is due to the knowledge of these principles that we have learned
that the infectious microbes, far from acting as they were believed to
do only a few years ago, and which Pasteur strongly maintained to be
by vital parasitism--such as would be the case with the carbonizing
bacteria which, according to Pasteur, act by diverting the oxygen,
or causing capillary embolisms--owe their pathogenic action to the
toxic substances which are the products of their secretion, and which
spread throughout the organism, even though the microbe frequently is
localized in a very circumscribed spot, as in tetanus and in diphtheria.
The idea of intoxication by these products has now replaced the idea of
the direct action of the microbe on the elements or the liquids of the
organism.
The occurrence that takes place in diphtheria and tetanus is one of the
best examples to cite in support of this view.
Here, in fact, the pathogenic microbe is found only in a very limited
area in the organism attacked--the false membrane, in the case of
diphtheria, or frequently only a slight wound in the case of tetanus,
and the microbe becomes localized there only. Now, in both cases,
there are general phenomena of toxic effects. There must hence be a
diffusion of toxic substances which, distributed by the blood, affect
the different systems and exert a toxic action on the entire organism.
It must be observed that the toxins act as toxic agents only when in
a condition to be introduced into the circulation subcutaneously.
The cause of this innocuousness of the toxins when given per os
has frequently been studied. It appears to be quite probable that
the cause of the attenuation of the morbid properties is due to
the intervention of the digestive microbes. Such is the opinion of
Levaditi and Charrin[22]; it is also the conclusion that is to be
drawn from the experiments of Mme. Metchnikoff and of Calmette[23] on
the modifications undergone by a vegetable toxalbumin, abrin, and by
serpent venoms, when these toxalbumins are inoculated with the bacillus
subtilis chromogenus. Moreover, Charrin and Lefèvre,[24] on the one
hand, and Nencki, Sieber and Somanowsky,[25] and Carrière,[26] on the
other hand, have discovered that the digestive ferments, particularly
trypsin, destroy, even though but little, the toxins secreted by
the Loeffler and Nicolaier bacilli. This is practically contrary to
the opinion of Behring and of Rauson,[27] according to which the
innocuousness of the microbial poisons when administered per os is due
exclusively to the lack of absorption.
[22] CHARRIN and LEVADITI: Le sort de toxines introduites dans le tube
digestif. _Journal de Physiologie et de Pathologie Générales_, 1898, p.
226.
[23] Citing Metchnikoff.
[24] _C. rend. de la Soc. de Biologie_, 1898.
[25] _Centralblatt für Bakt._, 1898.
[26] _C. rend. de la Soc. de Biologie_, 1899.
[27] _Deutsche Med. Wochenschr._, 1898, No. 8.
=Nature of the Toxins.=--The molecules of the toxins are very nearly
like those of the diastases. Like these, the toxins appear to have
a very complex, and very unstable, internal structure. Their mode
of action frequently depends, as in the case of the diastases, upon
the medium in which they occur. Again, like the diastases, they are
generally destroyed by the action of sufficiently prolonged heat, but
less easily, for there are certain toxins that resist a temperature
of 100° C. for an indefinite period. They are, like the diastatic
albuminoids, insoluble in strong alcohol, and are precipitated from
their solutions on the addition of this reagent. They easily adhere
to precipitates that form in liquids in which they occur in solution,
and possess the remarkable property of diastases in that imponderable
masses produce considerable results.[28]
[28] See POZZI-ESCOT: Les diastases et leurs applications, published by
Masson, 1900; and _Traité de Physico-chimie_.
Although closely allied to certain alkaloidal bases, the toxins are
sharply distinguished by the remarkable fact that their action is never
immediate, but is always preceded by a period of incubation, which may
be quite long.
Like the alkaloidal bases, they appear to result from the hydrolyzing
breaking down of albuminoids and nucleo-albumins, and they appear to
be intermediary, from a chemical point of view, between these bodies,
the general characters of which they retain, and the alkaloids proper,
or ptomaines, to which we have called attention, and the principal
chemical and physiological properties of which they possess.
No absolutely precise knowledge is had regarding the chemical nature
and constitution of these remarkable substances. A number of analyses
of these substances have been published which, in general, permit no
definite conclusion to be drawn.[29] I have, however, elaborated
several speculative ideas regarding this subject.[30]
[29] Regarding this see the works by KOCH and BRIEGER, _Deutsche
Medicin. Wochenschr._, Oct. 22, 1891.
[30] POZZI-ESCOT: Nature des Diastases. Published by J. Rousset,
Paris, 1903. See also Recherches de la Nature Chimique des Diastases
Oxydantes. _Revue génér. de chimie_, VII, pp. 129-136; and Aperçus
sur la nature chimique des Diastases, _Bulletin de l'Association
de Chimistes_, 1904, p. 769.--Propriétés Catalytiques de Quelques
Diastases; _Ibid._, 1904, p. 1247.
We must here call particular attention to the ideas of Ehrlich
regarding the constitution of the toxins. According to this scientist,
their molecules contain two functional groups; the one, to which he
has given the name "haptophore," is that which enables the toxin to
attach itself to any cellular element whatever, and which it then
renders non-toxic by means of the other, or "toxophore," group. We will
particularize farther on regarding this very important conception.
=Origin of the Toxins.=--These toxic bodies result either as the
products of the secretion of microbial life, or as the result of the
normal functionation of cellular life in the higher vegetable or animal
organisms.
They are the direct products of life, and do not result, as was
formerly believed, from a more or less profound modification of the
more or less complex albuminoids that serve as a food for the various
species of microbes, or for the cellular elements.
The vegetable toxins are less numerous than the animal toxins.
They are met with, nevertheless, in almost all mushrooms which are
reputed or known to be toxic; the seed of the castor plant contains a
very toxic vegetable albuminoid, as is likewise the case with Abrus
precatorius (jequirity-bean), and certain others.
The true physiological toxins occupy a very important place in the
realization of the conditions that govern health, sickness, and death.
We will see later on that they are met with in quite large number
in the bladder, whence they are voided in the urine. Their number
varies considerably, according to diverse influences (waking, slumber,
eating, fasting, fatigue, oxygen, brainwork, health, disease, etc.).
It is necessary here to observe that the renal system serves for the
purification of the entire organism, and that in the case of normal
life we will find in the renal system a large portion of the products
of the cellular secretion of the organism, and among the number there
are found, as we know, a certain number of alkaloidal bases. We will
take up later the subject of urinary toxicity.
=Autointoxications.=--The toxins are also encountered, and often in
some number, in the muscular tissues and in the blood, particularly
in those of batrachians, mureids, and saurians. In the organism these
toxins, developed by the activity of the various cells, may cause
autointoxication whenever, for one cause or another, their normal
elimination ceases. "Although there are an infinity of diseases,"
remarked Prof. Bouchard, "there are but a few ways of becoming ill." Of
these ways that of autointoxication is the most frequent. "What else
is it, then," says Prof. Charrin, "in the last analysis, but to die
from affections of the kidney, the liver, the heart, the lung, etc., if
it be not to succumb because of the lack of oxygen, the accumulation
of carbonic acid, the influence of the numerous urinary poisons, the
action of acids, of salts, of biliary pigments, or the effect of
noxious principles, which the hepatic cell must normally destroy or at
least attenuate."
These autointoxications, always due to poor elimination of toxic
principles, toxins formed in very great number in the organism, and
which the normal modes of evacuation or destruction do not eliminate,
are always found to be the cause of all diseases, even those that are
manifested by attacks of the cerebro-spinal axis, and that exhibit
variously mania, insanity, symptoms of hyperexcitability, etc.
These autointoxications are controlled by the nervous system, and
the latter alone is the cause of a larger number of maladies than
is generally believed; in fact, if the mechanism of nutrition be
reduced to its most simple elements, it will be seen to consist of the
penetration of the foods, of the plasmatic principles, to the cells;
of their transformation within the interior of the cells, and finally
the rejection of all the matter that could not be utilized. It is the
nervous system that commands or dominates this mechanism, that controls
the taking-up of assimilable elements and the elimination of toxic
principles, the fruit of assimilation or disassimilation, and in such a
manner, in fact, that this same nervous system can, at its will, cause
starvation, or intoxicate.
The marvelous cures obtained by magnetic methods are due to no other
causes than favorable changes in the nervous system.
=General Mode of Action.=--The toxins, of whatever kind, always behave
like diastases, in the sense that their definite action appears to be
absolutely independent of their mass, and that imponderable quantities
suffice to cause serious morbid affections and profound modifications
in nutrition.
Koch has shown that tuberculin is capable of affecting 60 trillion
times its weight of the living human being. According to Vaillard one
milligramme of tetanus toxin will kill a horse weighing 600 kilos.
These two examples show what an enormous power the toxins possess.
My views regarding the manner in which diastases act I have developed
at length in my work _Nature des Diastases_. The close analogy between
these substances and the toxins, an analogy upon which, moreover,
I have dwelt at some length, permits me to refer the reader who is
desirous of fuller details to the small work just mentioned.
The mode of action of diastases resembles singularly closely that of
the catalytic substances, and we will admit, for the moment, that they
act by intermediary combination, resulting in their rapid decomposition.
We owe to Ehrlich[31] a new conception relative to the nature and mode
of action of the diastases, and which to-day plays an important rôle in
all our conceptions regarding immunity.[32]
[31] EHRLICH: _Klinisches Jahrbuch_, 1897, VI. _Proceedings of
the Royal Society_, 1900, No. 482, p. 424. _Nothnagles' specielle
Pathologie und Therapie_, 1901, VIII, Schlussbetrachtungen, p. 163.
[32] To have a complete exposé regarding this question, it will be
profitable to consult No. 4 of this collection on _Sérums Immunisants_.
According to this scientist, the complex molecule of albuminoid
substances is constituted by a fixed central nucleus, and by a number
of lateral chains or receptors, fixed to this nucleus, which possess
diverse accessory functions, and which serve, particularly, for the
nutrition of the cells. These receptors have a great affinity for the
various substances necessary for the support of the living elements,
and they seize upon the alimentary substances, in normal life, just as
a leaf of the _Dionæa_ seizes a fly which serves as its food.
In these special conditions the receptors may attach themselves to
the complex molecules of albuminoid substances, such as the different
toxins.
Ehrlich supposes, as we have already seen, that a toxin contains two
special groups--a _toxophore_ group, which poisons, and a _haptophore_
group, which combines with the receptor. According to this theory,
the toxophore group of a toxin can act on an organism _only_ when the
haptophore group of the toxin encounters a suitable attachment or
receptor.
The receptors attached to the living protoplasmic molecule attract the
toxin, just as a lightning-rod attracts the lightning.
It is hence clearly proved that the toxigenic poisons exert their
noxious action on the cellular elements of sensitive organisms, by
entering into combination with these.
Experience has shown that they attach themselves, in a most rigorously
elective manner, to the tissues, and rapidly disappear from the general
circulation. Numerous facts, clearly established, attest the reality of
this fixation or attachment.
It is thus that von Behring and Wernicke[33] sought to ascertain
the quantity of antitoxin (we will see farther on that this name is
given to those substances which neutralize the activity of toxins
under certain conditions) which, introduced a certain time after the
introduction of the poison, will save the life of the animal. They
have experimented with diphtheria toxin, which we will study later,
and they have demonstrated that, if the antitoxic serum be introduced
immediately after the toxin, a dose of antitoxin twice as large as that
of the toxin suffices to effect a cure.
[33] VON BEHRING and WERNICKE: Zeitschrift für Hygiene, XII.
Eight hours after the administration of the toxin the dose must be
trebled, while after thirty-six hours it is necessary to have recourse
to a quantity of antitoxin eight times as great. These experiments
show that the curative action of the antitoxin is so much the less the
longer the period of time that has elapsed between the introduction
of the toxin and the antitoxin. This is because the toxin has become
so intimately attached to the tissues that the antitoxin introduced
has not the power to destroy the combination. These facts have been
confirmed by Donitz[34] and by the classic experiments of Decroly and
Rousse.[35]
[34] DONITZ: Ueber die Grenzen der Wirksamkeit des Diphtheria
Heilserums. _Deutsche Med. Woch._, No. 27, 1897.
[35] DECROLY et ROUSSE: _Arch. Int. de Pharmacodyn._, III and VI;
Masoin: _Arch. Intern. de Pharmacodyn._, II, 1903.
This is not, however, the case with cold-blooded animals, which,
generally, are not affected by injections of poisonous toxins. Thus
Metchnikoff[36] and his pupils have been able to show that the toxins
introduced into certain cold-blooded animals (Oryetes nasicorius) may
remain for several months without alteration in their circulation.
[36] METCHNIKOFF: _L'Immunité_, Paris, 1902; MORGENROTH: Zur Kenntniss
des Tetanus des Frosches. _Deutsche Med. Woch._, No. 35, 1898.
If we consider the facts of the theory of Ehrlich's lateral chains,
which we have mentioned, we are led to well-defined conclusions
regarding the mode of action of the toxins. In fact, since these toxins
exhibit a pronounced chemical affinity for the tissues, and while, on
the other hand, they can attach themselves only because of the presence
of certain functional groups of the protoplasmic molecules, this union
can take place only in certain specific centers. This has been fully
confirmed by experiments _in vitro_.
It is known, since the researches of Ehrlich,[37] Wassermann and
Takaki,[38] Marie,[39] Metchnikoff,[40] and a host of other scientists,
that this fixation is due to a clearly elective property. It is for
this reason that the tetanus toxin fixes itself only upon the nervous
tissue, and that in this action all passes as if the nervous tissue had
been provided with functional groups possessing an elective affinity
for the tetanic poison.
[37] EHRLICH: _Berl. Klin. Woch._, No. 12, 1898.
[38] WASSERMANN and TAKAKI: _Berl. Klin. Woch._, _Med._, p. 5, 1898.
[39] MARIE: Sur les Propriétés Antitoxiques aux Centres Nerveux de
l'Animal Sain. _Ann. Inst. Past._, 1898, p. 1.
[40] METCHNIKOFF: Recherches sur l'Influence de l'Organism sur les
Toxines. _Ann. Inst. Past._, 1899, p. 82.
=Means of Defense Possessed by the Organism against the Action of
Toxins.=--We have already seen that the renal organs serve for the
elimination of the toxins normally produced in the organism by the
simple play of its cellular mechanism. Experience has shown that the
toxins introduced from without into the circulation are generally
finally eliminated, even though in the meantime the modifications they
have imprinted on the economy may be transmitted hereditarily; and that
their influence on the general nutrition and the normal functionation
of the entire organism persists even after their elimination.
Much has been said regarding the elimination of these toxins by the
urine, but the experiments made by Métin, at the Institut Pasteur, have
shown the inaccuracy of this assumption, and it has been necessary to
seek another.
It has been remarked that oxidation destroys the toxins _in vitro_, and
it has been thought that a process resembling disinfection may well
take place within the tissues of the animal economy, but no decision
has been arrived at regarding the possible mechanism of this action,
which some attribute to the action of the oxidizing ferments of the
organism, or to the action of certain special cells.
According to Poehl, there is developed as destroyer a substance
possessing energetic oxidizing properties, which he has isolated and
named _spermine_, and which is found in most of the organic fluids
and particularly in the leucocytes, the special rôle of which we will
presently study.
There develops still another cause of elimination, or, to be more
exact, of the neutralization of the toxic principles in defense of the
organism against the toxins, and that is the formation of _antitoxins_.
It is well known that the term _virus_ has been reserved to designate
physiological liquids which were characterized, when first they were
known, by their property of transmitting to an organism certain
functional affections, but the true character of which is to expend
their toxicity upon the microbes which occur and are reproduced in the
organism, or upon the organized plastidulary granulations, as in the
case of the rabic virus, the special microbe of which has not as yet
been isolated.
Pasteur, when studying rabies, found that the brain and spinal marrow
of rabid animals contained the pure rabic virus in considerable
quantity, and that every particle of the marrow was capable of
imparting rabies to a perfectly healthy dog. After having ascertained
this fact, he found that he could _attenuate the action of the virus_,
either by passing the virus through certain animal organisms, such
as the monkey or rabbit, by gently heating, or even by allowing it to
oxidize and partially dry in the air, or else by submitting it to the
action of antiseptics or alternating electric currents of very high
tension.
Experiments have shown that a deadly virus, attenuated by one of the
means mentioned, may be injected, without danger of death, into the
living animal; and what is still better, the animal thus treated
acquires the power of resisting large doses of the virus, less and less
attenuated, and that it is possible to reach a point where the animal
economy may become habituated to very large doses of a highly virulent
virus without the organism experiencing any visible illness--that is,
the organism has been _vaccinated_ with regard to the particular virus.
Experiments have shown that this property is not peculiar to microbial
virus alone, but that it is common to the venoms the toxicity of which
is essentially due to some toxins, with the exception of those agents
noted.
The attenuated viruses act, as vaccins, through their soluble
constituents, which, either directly, by modifying the nutrition of
certain cells, or indirectly, by inducing reactions of the nervous
centers which preside over this nutrition, profoundly change the
conditions of life and give rise to the pathological condition--the
vaccined state.
Experiments by Behring and Kitasato[41] have shown that the tumors of
a vaccinated animal, freed from all organized matter visible under the
microscope by filtration through porcelain, contains principles capable
of directly or indirectly protecting other animals from the disease
caused by the corresponding virus. Meanwhile, experiments have shown
that the vaccinating matters are totally eliminated; nevertheless,
after their elimination, the immunity acquired remains with the animal,
which then continues to be protected against the corresponding virus.
[41] _Deutsche Med. Wochenschr._, 1890, p. 1113.
Interest in this subject has incited numerous researches with a regard
to bringing to light the mechanism of this immunization; and this will
form the subject of another volume of this collection. We may state
here, however, that there have been recognized two concurrent causes of
this preservative action; the one, called _phagocytosis_, results from
the fact that the microbe introduced into the vaccined organism becomes
incapable of producing its usual toxins, while on the other hand the
immunization renders the organism capable of secreting substances
possessing an activity contrary to that of the virus, in fact true
counter-poisons, comprised under the general name _antitoxins_.
=Phagocytosis.=--We have seen that an organism subjected to a toxic
invasion tends to protect itself by proper means of defense; and one
of those is the direct putting into activity of the living cellular
elements themselves, and in particular, the leucocytes, or white
corpuscles, found in more or less number, according to pathological
conditions, in the blood and lymphatic fluids.[42]
[42] It is necessary here to consult the work by LEVADITI: Le Leucocyte
et ses Granulations. _Scientia_, Naud, publisher, Paris, 1903; also
METCHNIKOFF: L'Immunité, Paris, 1902, Masson, publisher.
Metchnikoff has shown that the moment a foreign element, particularly
a microbe, enters the organism, these leucocytes come flocking from
all parts of the body, collect around the bacterial element, penetrate
it, and begin to digest it. These elements have received the name
_phagocytes_. The name _chemotaxis_ has been given to the property by
virtue of which they approach (positive chemotaxis) or move away from
(negative chemotaxis) certain substances which affect them powerfully.
Experiments have shown that the leucocytes are attracted by the
products secreted by pathogenic microbes, or saprophytes. Attracted by
the latter, the white corpuscles surround, envelop, and finally digest
them; and when it happens that all the pathogenic microbes within an
organism are absorbed, the organism survives, while in the contrary
case it succumbs.
Attention must be called to this attack by the white corpuscles within
the limits where they are normally confined. It is a pathologic
diapedesis--a leucocytosis provoked by the irritation of the
tissues--and caused either by the presence alone of foreign elements,
or by the soluble products secreted by them.
When, for any reason whatever, this phagocytic action is impeded,
the resistance of the organism to pathogenic infection ceases to be
effective, and the organism may therefore be invaded by the microbe.
Numerous causes may contribute to impede this action.
=The Antitoxins.=
We have seen that the second means of defense possessed by the organism
resides in the action of special products, true defensive secretions,
possessing an activity contrary to that of the toxins, and which are
secreted by the cells of the organism under the influence of the
vaccins.
This is a property common to every organism, and which is observed even
in non-vaccinated subjects, although in this case the secretion forms
with great difficulty and in small quantity.
When an organism subjected to the toxic action of a bacterial infection
does not succumb to the intoxication, it emerges from the test gifted
with a new property, which may be augmented by habituation, and which
borders on immunity.
At first we were content to vaccinate small animals in the laboratory,
but in proportion as the discoveries in this domain extended, and there
developed a need for large quantities of antitoxins, recourse was had
to the larger animals, particularly horses and cattle. From the moment
that large quantities of blood and antitoxic serum were at command,
search was made for a means of isolating the antitoxin and determining
its properties.
Experiments so far made have shown that the antitoxins are substances
of an albuminoid nature, of unknown composition, and which are very
closely united to the albuminoid substances of the serum. It must
be observed, however, that Behring and Knorr oppose the assertion
regarding the albuminoid nature of tetanic antitoxin, but their reasons
for this do not appear to be well founded.
In general, these antitoxins are precipitable with the globulins, and
possess quite considerable powers of resistance towards physical and
chemical agents. Thus they are destroyed only at a temperature above
60-65° C. Kept in the dry state, in the residue of evaporated serum,
and away from the light and all oxidizing action, it is possible to
preserve their activity for a very long time.
They are essentially humoral substances; they are found in the blood
of vaccinated animals, from which may be obtained antitoxic serums
with a specific but transient immunity; and they are also found in the
plasmas of the lymph and exudates, in aqueous tumors, and in the milk.
They are seldom found in the cells.
=Mode of Action.=--Frequent attention has been paid to the mode of
action of the antitoxins upon the toxins, a phenomenon of great
importance in relation to the phenomenon of immunity acquired against
the toxins. At the beginning of our knowledge on this subject, the idea
of a destruction of the toxin immediately suggested itself, and was
advanced by von Behring.[43] According to this scientist the antibody
inhibits the morbigenic action of the toxin by neutralizing the toxin,
combining with the latter to form a compound of a chemical nature which
is devoid of toxicity and without action on the organism. According to
this theory, the influence of the antitoxin on the toxin is direct, and
does not require the intervention of the living cellular protoplasm.
Such was also the belief of Prof. Ehrlich.[44]
[43] VON BEHRING and KITASATO: _Deutsch. med. Wochenschr._, 1890, p.
1113.
[44] EHRLICH: _Klin. Jahrb._ 1897, VI, p. 292.
Buchner, a little later, believed that the antitoxin, instead of acting
directly on the toxin, exercised a direct influence on the living
elements of the organism, preserving them from intoxication.[45]
[45] BUCHNER: _Münchener med. Wochenschr._, 1893, p. 480.
Such was also the opinion of Roux[46]; and Calmette demonstrated that a
mixture of venom and of a non-toxic antivenom recovered its toxicity on
being heated to 68° C, whereby the antivenom was destroyed (Calmette:
_Le Venin des Serpents_, Paris, 1897, p. 58); and Wassermann arrived at
the same result.[47]
[46] ROUX: _Annales de l'Institut Pasteur_, 1894, VIII, p. 724.
[47] WASSERMANN: _Zeitschr. für Hygiene_.
The array of proofs offered by these scientists, which we cannot here
enlarge upon without uselessly extending our subject, would tend to
make one believe, at first glance, that the antitoxin does not act
directly on the toxin, but at the present time Buchner's theory appears
untenable. Numerous researches have proved conclusively that the toxin
and the antitoxin have a specific affinity for each other, by virtue
of which these principles combine to form a substance free from all
toxicity, but unstable, and which may be decomposed by heat or certain
other factors.[48]
[48] J. DANZSY: _Annales de l'Institut Pasteur_, XVI, p. 331.
Some recent experiments by J. Martin and Cherry (_Proceedings of the
Royal Society_, 1898, LXIII, p. 423) have clearly brought out this
fact. These authors made mixtures of serpent venom with its antivenom,
which they filtered through a layer of gelatin, under the supposition
that, if the venom and its antivenom were not chemically combined,
the former alone would be able to pass through into the filtrate,
because its molecules are so much smaller. Martin and Cherry allowed
the venom and its antivenom to remain in contact for varying periods
before filtering. As the result of a series of experiments carried
out with this idea, they have demonstrated that the filtrate obtained
after allowing a few minutes' contact between the two substances,
was decidedly toxic, while that obtained after a contact of half an
hour was absolutely non-toxic. From this the authors conclude that
the antitoxin enters into chemical union with the venom, but that the
combination does not take place immediately, and requires a certain
length of time for its accomplishment.
Ehrlich and Knorr have demonstrated that the neutralization is less
rapid in dilute solutions than in concentrated ones.
Prof. Svante Arrhenius has completed our knowledge regarding the mode
of combination between the toxins and the antitoxins, by demonstrating
the occurrence of limited reactions analogous to the etherification of
an alcohol by an acid, and in such a manner that there always exists,
in a mixture of these two substances, a certain quantity of free toxin
and antitoxin. This is an important modification of the general ideas
held in this respect.[49]
[49] SVANTE ARRHENIUS: La Physico-chimie des Toxines et des
Antitoxines. _Conférences de la Société chimique de Paris_, May 20,
1904. See also MADSEN AND ARRHENIUS: Testkrift red indivulsen of
Stotens Serum Institut. Copenhagen, 1902.
It appears necessary to bring here more clearly in evidence the fact
that _the antitoxin inhibits the noxious action of the toxin, even
outside the living organism, by uniting with it to form a compound in
identically the same manner as when a strong base and a strong acid are
brought together_. As we have seen, all the conditions of environment
that favor or retard the formation of salts, in a like sense influence
the neutralization of the toxin by its antitoxin.
=Formation of Antitoxins.=--Ehrlich's theory of side chains, to which
reference has already been made, furnishes us with an explanation of
the formation of the antitoxins in tumors. Let us suppose that, in
the organism, a cell had come into contact only with certain toxic
molecules incapable of compromising its life, and that the only result
was the immobilization of the receptors which are united with the
haptophore groups of the opposing toxins. It is known that, by virtue
of a property inherent in all living organisms, during the phenomena
of reparation, there is generally an overproduction of the neoformed
parts. In the case we here speak of, as the receptors fill an important
function in the nutrition of the opposing cellular elements, once they
become united with the toxic haptophores, they become incapable of
filling their normal function of nutrition. Under these conditions the
cells develop so large a quantity of receptors that, filling the cells,
and not finding any more room, they spread into the blood and other
liquids of the organism.
Under these conditions, every new injection of toxin into the organism
is absorbed into the blood where it meets with the free receptors which
possess great avidity for the haptophore group of its molecule, and the
two groups immediately unite, before the haptophore group of the toxin
has been able to attack and intoxicate a cellular element.
We thus see that the receptors which, when in a free state in tumors,
play the rôle of antitoxics or antitoxins, become, within the cellular
elements themselves, the vehicle of intoxications. Figuratively
speaking, so long as these fixators are attached to the molecule of the
living protoplasm they attract the toxin.
According to this ingenious conception, the formation of antitoxins is
hence absolutely independent of the action of the toxophore elements on
the cellular elements, and it suffices that these possess receptors or
side chains capable of uniting with the haptophore groups of the toxin.
This explains why it has been possible to produce antitoxins from
toxins which have lost some of their toxic properties, but which have
preserved their property of uniting with antitoxic substances. Ehrlich
gives the name _toxoids_ to those modified toxins that have lost their
toxophore groups, while the haptophore group, the producer of the
immunizing substance, is still preserved intact.
According to Metchnikoff's theory, which is very similar, it seems
quite possible that the phagocytes, thanks to the facility with
which they absorb poisons, occupy an important place as producers of
antitoxins. It has not been possible so far to verify this theory in
our at present imperfect knowledge regarding this subject. The domain
of immunity has, however, made brilliant conquests during these last
few years, so that we should not despair of arriving at a definite
solution before long.
In the vaccinated animal the antitoxin is reproduced, and it is
possible to obtain several times, from the vaccinated animals,
successive portions of antitoxic serum.[50] The protective power
of these antitoxins is absolutely marvelous. An animal accustomed
gradually to the tetanic virus yields a serum containing an antitoxin a
thousand times more active than the virus.
[50] CH. SALMONSEN et TH. MADSEN: Réproduction de la substance
antitoxique. _Ann. Inst. Pasteur_, XII, p. 762. ROUX et VAILLARD:
_Ibid._, 1893, p. 83.
According to Vaillard, a quintillionth of a cubic centimeter of this
antitetanic serum suffices to preserve one gramme of living mouse from
the effects of a dose of tetanic serum that would otherwise be surely
fatal.
In the animal, the antitoxins are eliminated mostly by the fluids of
the body, and particularly by the urine. Ehrlich has demonstrated that
they also pass into the milk, and this fact is confirmed by a large
number of observers. It explains the immunity acquired by nurslings,
and which is transmitted by the milk.
=Serotherapy.=--The search for antitoxins and their rôle in the
etiology of infectious diseases are fundamental points in actual
therapy. It has been demonstrated that the serums of certain vaccinated
animals enjoy very extended antitoxic therapeutic properties; for
instance, the serum of vaccinated rabbits is an antivenom towards
erysipelas; and the sterilized cultures of the pneumococcus or of the
Bacillus pyocyaneus prevents infection of carbuncle (anthrax).
The antivenomous serum of the ass immunized by injections of increasing
doses of the venom of the terrible naja is a perfect prophylactic and
curative, not only as regards the venom of this serpent, but also
against that of the crotalus, trigonocephalus, and viper.
We shall take up the study of serotherapeutics in another volume of
this collection.
PART II.
_THE TOXINS PROPER._