Samuel O. L. (Samuel Otway Lewis) Potter.

Handbook of materia medica, pharmacy, and therapeutics, including the physiological action of drugs, the special therapeutics of disease, official and practical pharmacy, and minute directions for prescription writing online

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of naturally immune animals.

Ehrlich has shown that Behring' s law is valid also for the chemical poisons, Ricin and
Abrin, the respective toxalbumins of the ricinus palm and the jequirity bean. The blood
of animals slowly immunized by increasing doses of these toxins contains antitoxic sub-
stances named Antiricin and Antiabrin, which, if added to their respective poisons, will
attenuate and even neutralize the latter. These facts are advanced as proof that the
slowly increasing artificial immunity is not a simple tolerance acquired by the organism,
as Sternberg taught, but is due to the production of new antagonistic and defensive sub-
stances by file living cells of the organism.

Theories deduced from the observed facts are as follows : (i) That, as
the various pathogenic bacteria produce the causative toxins of their re-
spective diseases, so the organic cells of the body, reacting under the
stimulus of the poisons thus introduced, immediately proceed to elaborate
defensive antitoxins, which if produced in sufficient quantity will neu-
tralize the effects of the toxins. (2) That residual antitoxins remaining
in the blood after recovery render the animal immune for a time against
the disease. (3) That the immunizing and curative effects obtained by
the injection of the blood serum of an immunized animal into the circu-
lation of another animal are due — either to direct chemical neutralization
of the toxins themselves by the antitoxins so introduced (Behring, Kita-
sato), or to a particular influence exerted by the antitoxins upon the
living cells of the organism, which, being affected in two opposite direc-
tions, remain neutral to the disease (Buchner).

Specific action is a characteristic of the antitoxins with perhaps a few
exceptions ; which means that the serum from an animal inoculated with
the toxin of the diphtheria bacillus is effective only against diphtheria,
and the tetanus antitoxin only against tetanus. A dose of an antitoxin
followed by a dose of the corresponding toxin produces no effect from
either, the action of the one being rendered ineffective by the other.


The corresponding toxin and antitoxin may be mixed together outside
the body and then injected with like result, though of course there must
be a certain amount of antitoxin present to counteract a given dose of
toxin. The immunizing or vaccine property of the antitoxins, though
transient, are probably destined to be of considerable importance. In-
stances are already recorded in which epidemics of diphtheria in schools
were apparently stopped by vaccinating all the children therein with
diphtheria antitoxin.

An Antitoxic Serum is prepared as follows. Either a highly virulent
culture of the specific micro-organisms of the particular disease, or still
better, a strong toxin of tested strength prepared therefrom, is injected
into the cellular tissue of a suitable animal, generally a horse, at first in
very small quantity. The effect is soon shown by the onset of fever and
other symptoms of acute disease, which are known as the "reaction."
After an interval of time sufficient for recovery from these symptoms, the
injection is repeated with a stronger toxin or with a culture of greater
virulence, or with a larger quantity of the original toxin. With proper
care the amount injected may be gradually increased, until ultimately a
dose many hundred times greater than one which would have been fatal
at first can be given with impunity. This process is continued for several
months, or until the animal no longer " reacts " to the poison, and then
sufficient antitoxin is presumed to exist in its blood to render it immune
to the toxin and to the disease. After each inoculation the animal's
blood serum is tested as to its value by experiment on guinea-pigs of defi-
nite weights. When the desired degree of immunity is reached the ani-
mal is bled from the jugular vein under strict aseptic conditions, from 6
to 12 pints being taken from a horse, according to his size and general
condition. The blood is received in sterilized flasks, which are carefully
stoppered and stored on ice until the clot has separated from the serum.
The latter is tested to determine its value in antitoxin, has carbolic acid
added to it in the proportion of 0.5 per cent., and is bottled in vials
which contain in each the dose for one patient. The vials are labeled
with a statement of the number of normal antitoxin units per ccm. of the
contents, expressed in multiples of a standard normal serum. The effec-
tive antitoxin value of a serum intended for protective purposes is much
less than that of one intended for curative action, and the earlier in the
course of the disease that the latter serum is employed the smaller will be
the quantity capable of producing a certain remedial effect.

Serum-therapy properly means the prophylactic and curative treatment
of certain acute infectious diseases by the subcutaneous injection of a
blood serum containing an antitoxin specific to the particular disease.
As generally used, however, this term includes the treatment of the same
disorders by the toxins produced by attenuated cultures of their respective


microbes ; but these toxins, though sometimes grown on blood serum,
may be cultivated on other media, and are never administered in a serum
as the antitoxins invariably are. The antitoxins at present employed in
serum-therapy are those of diphtheria, tetanus, tuberculosis, erysipelas,
pneumonia, cholera, syphilis, and typhoid fever, but only the first three
have come into anything like general use. The toxin treatment is
described under the title Toxins.

Diphtheria Antitoxin, though not the first antitoxin discovered is
by far the first in practical importance. The bacillus of diphtheria was
discovered by Loeffler and Klebs in 1884, its toxic products were isolated
by Roux, and the antidote to them was found by Behring, who estab-
lished the preventive and curative properties of this antitoxin. In the
meantime Sidney Martin had proved the chemical identity of the labora-
tory toxins discovered by Roux with those produced in the body by the
bacillus. The clinical results obtained in Paris by the use of Behring's
diphtheria antitoxic serum were announced by Roux at the Buda-Pesth
Congress of Hygiene in 1894, and attracted universal attention. Since
then the statistics of diphtheria serum-therapy have grown voluminous,
have included a large number of reports from official and private sources
of the highest professional authority, and the weight of evidence has
steadily grown more and more favorable to this treatment.

The statistics first presented by Roux covered 300 cases of true diphtheria, treated at
the HSpital des Enfants Malades in Paris, with a mortality under the serum treatment
of 26 per cent., against a mortality of 51.7 per cent, in the same hospital during the pre-
vious iour years in 3971 cases, and a mortality of 60 per cent, in 520 cases during the
six months immediately preceding. Professor Virchow stated, at the last Christmas
file of the Empress Frederick Hospital in Berlin, that from April to November, 1895,
out of 335 diphtheria cases treated therein with the serum 305 were cured ; and that the
diphtheria mortality in that hospital, formerly 43 per cent., had declined to 9^ per cent,
under the antitoxin treatment. Professor Welch of Baltimore has collected and an-
alyzed the statistics available in July, 1895, covering 7,166 cases from 80 different sources,
and showing a general mortality under the antitoxin treatment of 17.3 per cent., against
a previous general mortality of 42 per cent. Tabulating the results according to the
time at which the treatment was commenced, he shows for 814 cases treated on the first
and second days of the disease a mortality of 5^ per cent. ; — for 531 cases treated on the
third and fourth days 15.2 per cent., — and for 286 cases treated after the fourth day 31.8
per cent. (Bulletin of the Johns Hopkins Hospital, 1895, No. vi.). Similar evidence is
presented in nearly every report published, and in estimating its weight it should be
remembered that these reports are not made by unknown men, but emanate from trained
clinicians and recognized professional authorities in the most populous centres of the
civilized world.

The clinical history of the disease under the serum treatment, as re-
corded by its observers, is equally favorable, and shows an extraordinary
decrease in the severity of the symptoms. The membrane loosens and
clears off rapidly, the temperature if high is lowered, and the pulse slows
and gains in force (Washbourn). Evident signs of distress vanished
within 24 hours, and apparent strength and good-humor took the place
of a previously low condition both mental and physical (Kossel). In no
case did the larynx become involved after the use of the serum if not so


previously, and many cases showing laryngeal symptoms recovered with-
out tracheotomy (Kossel). Even in the fatal cases life was prolonged

While diphtheria antitoxin properly prepared and used under aseptic
precautions is generally conceded to be harmless, some ill effects are re-
corded as caused by it. An urticarial eruption on the skin, also pains in
and swellings about the joints occur in about 5 per cent, of the cases, but
these symptoms are usually transient and without serious consequences.
Abscess at the site of the injection has occurred, but rarely forms if proper
aseptic measures are used. Welch states that over 100,000 injections
have been given, and that the serious mishaps directly attributable to the
serum can be counted on the fingers. Two deaths are recently reported,
one in Berlin and one in Oregon, as having occurred within a few minutes
after the injection of the antitoxin in healthy children.

The following seem to be established facts as to the use of antitoxin in
diphtheria. That the immunized serum is far more efficient as a curative
agent than any remedy heretofore employed, the general mortality of the
disease having been reduced by its use to about 1 7 per cent, from a pre-
vious rate of about 42 per cent. That a marked improvement in both
the local and general symptoms is usually noticed within 24 to 48 hours
after the injection of the serum. That the remedy has decided power to
prevent the spreading of the false membrane into the larynx and trachea.
That it is powerless to repair damage already done to the tissues by the
diphtheria toxins, hence the earlier that the serum is administered the
better are its results. That it is decidedly more efficient in the fibrinous
form of the disease than in the septic form, and in cases of simple infec-
tion than in those of double or mixed infection. That the |liability to
paralysis and albuminuria is not lessened but is perhaps somewhat in-
creased by this treatment, though genuine nephritis is less frequently seen
under its use than in cases treated, by other methods. That the serum
may cause certain untoward symptoms, as cutaneous eruptions, swellings,
etc., but that these are not serious and are not attended with danger to
life. That its injection is very rarely followed by serious local disturb-
ances, as abscess, and probably would never be complicated thereby if the
serum were always pure and used with strict aseptic precautions. That
recent improvements in the methods of preparation and more definite
knowledge as to the dose and manner of employment have made the later
reports even more favorable than the earlier ones. At the 1895 meeting
of the British Medical Association, Professor Klein made the statement
that " the scientific basis for the application of antitoxic serum is as
firmly founded and as thoroughly established as the use and application
of any known drug."

Local antiseptic treatment of the throat is still insisted on in connec-


tion with the serum injection in every case of the disease. If thoroughly
carried out in the incipiency it may destroy the dangerous streptococci
and other microbes, thereby preventing the mixed infection which proves
so virulent ; if continued throughout the case and during convalescence
it will minimize the danger of infecting other persons. In some in-
stances bacilli were found as long as two months after recovery.

Diphtheria Antitoxin is now prepared in all European countries and in the laboratories
of several boards of health, manufacturing druggists and others in this country. The
serum on the English market differs somewhat in strength, Aronson's being a highly
concentrated form obtained by precipitating the greater part of the inert constituents,
while Klein's is prepared by injecting both the toxins and the bacilli into the animal to
be immunized. The serum furnished by the British Institute of Preventive Medicine
contains 1,500 normal units in each 10 ccm. In Germany the preparation of the serum
is conducted by a private firm under the supervision of Professors Behring and Ehrlich,
and is tested by official experts before its distribution is permitted by the government
authorities entrusted with the control of its manufacture.

Behring' s Diphtheria Antitoxin is standardized in comparison with a
" normal therapeutic serum " of which one-tenth of a gramme will neu-
tralize one gramme of diphtheria toicin, and i ccm. of which is termed
equivalent to one "normal" or " immunizing unit." As distributed the
serum contains at least 100 such normal units in each ccm., the label on
every vial showing the potential strength of its contents, thus: "This
phial contains 6 ccm. of 100 times normal strength == 600 normal units."
Four different potentials are furnished, — one with a yellow label, possess-
ing 200 units, and intended only for prophylaxis, and three for therapeu-
tic employment, viz : (i) that with a green label, containing 600 units,
for use only in fresh cases on the first or second day; (2) that with a
■white label, possessing 1,000 units, to be used in more serious cases on
the first or second day, or in less serious cases of longer standing ; (3)
that with a red label, possessing 1,500 units, and meant for adults or for
very severe cases in children.

The doU for prophylaxis is 200 units, to be repeated after two or three
weeks if the case is still exposed to infection ; but this amount is too
small if the patient is in the incubation period of the disease. The im-
munity is only temporary, its duration depends on the quantity of anti-
toxin injected, and it gradually decreases as the latter is eliminated, but
it can be maintained for a long time by the repeated use of smaller doses
at short intervals.

The dose for curative purposes should be rather large than small, in
order to guard against a virulent infection, 200 to 300 units for a light
case, 500 to 800 for a severe or advanced one ; to be repeated on the
next or even on the same day if the case seems grave, until 800 to 1,000
or even 1,500 units have been given. The maximum quantity decided
on may be administered in one dose, and as a rule will not require to be
repeated. The necessary amount for any case can only be determined
by comparative estimation of the quantity of toxin present as indicated


by the symptoms ; remembering that this quantity increases rapidly with
every day after infection. The prognosis is unfavorable if the case is so
far advanced before treatment that the toxin has had time to accumulate
and to exert its paralyzing influence on the nervous apparatus of the heart.

Gibier's Diphtheria Antitoxin is prepared at the biological laboratory of the New
York Pasteur Institute from the lilood of horses made immune by injection for over 1
year with diphtheria toxin. Two forms are supplied, a liquid and a dry one. The
liquid product is supplied in bottles containing 5, 10 and 25 ccm. each, representing re-
spectively 500, 1,000 and 2,500 units. The smallest size is intended for immunizing
purposes, the medium one is a single curative dose for incipient cases, and the largest for
repeated injection and extended treatment in fully developed or grave cases. In the
latter the dose should be 25 ccm. at first, 25 ccm. more within 24 hours, and even
100 ccm. may be injected within a few days, the serum being entirely innocuous. The
dry form is a powder, one gramme of which is to be dissolved in 15 to 25 ccm. of
sterilized water in a sterilized vial, furnishing the equivalent of over 1,500 units. This
amount will sufEce for an incipient case, for a severe one two or even three times the
quantity may be used on the first day of treatment.

The injections are given by means of a sterilized hypodermic syringe, preferably in the
lateral part of the abdomen, after the site of injection has been carefully washed with a
4 per cent, solution of carbolic acid or a i per cent, solution of lysol. They are almost
painless, and subsequent massage is unnecessary as the swelling caused by the fluid disap-
pears quickly.

Gibier's Double Antitoxin is a serum obtained from a horse which has been im-
munized against streptococcus virus after having been previously rendered immune against
the diphtheria bacillus. It is supposed to contain both the diphtheria and streptococcus
antitoxins, and is intended for the virulent cases due to a mixed infection with these two
poisons, but it may be used in any case of diphtheria. It is supplied in vials containing
25 ccm. each, which quantity should be injected in two doses 12 hours apart in an
ordinary case ; but for severe cases the amount used should be 25 ccm. at first and 25 ccm.
more within 24 hours, to be repeated daily until 100 ccm. have been administered.

Concentrated Diphtheria Antitoxins, containing 200, 300 and 400 antitoxic units
to the ccm. , have been produced at the laboratory of the New York Board of Health.

Tetanus Antitoxin. Tetanus was one of the first diseases to be
studied successfully by the bacteriologists, and its antitoxin was the first
one prepared. Breiger (1880) showed that a crystalline substance of high
toxicity could be obtained from tetanic fluids, and that it would repro-
duce the symptoms of tetanus when injected into healthy animals. Rosen-
bach found the tetanus bacillus in human cases of the disease, and Nico-
laier demonstrated its existence in soils. Kitasato soon afterward obtained
pure cultures of the bacillus, and demonstrated the immunizing power of
the serum of animals inoculated with its toxin. As human tetanus is a
comparatively infrequent disease there are but few available statistics of
its treatment with antitoxic serum, all the reported cases numbering less
than a hundred ; but its previous mortality, as shown by the two largest
sets of statistics, covering 2,789 cases, was 88 per cent., which has been
reduced to 20 per cent, under the serum treatment (Kreiger). Dr. Marson
has reported a series of 38 cases so treated by various physicians, with 25
recoveries, a mortality of 34.2 per cent. In spite of its failure in many
instances, the antitoxic serum is unquestionably the most efficient remedy
known for this disease. As tetanus is only recognizable by symptoms due


to nerve lesions, which symptoms are not manifested until the nervous
system has been damaged by the toxin, an early diagnosis is impossible;
and when first seen by the physician the disease has usually advanced too
far for the curative action of the remedy to be available. For this reason,
and as the immunizing properties of this antitoxin are very potent, it is
advised that a preventive inoculation thereof should be given in all cases
where infection is possible, such as lacerated wounds soiled with earth or
rust, especially when occurring in those tropical countries where the disease
is most common. For this purpose a dose of 10 ccm. would suffice, if
repeated at intervals of two or three weeks. For curative purposes the
serum should be injected as soon as possible, the quantity being deter-
mined according to its stated strength, the gravity of the symptoms, the
patient's age and the time since infection. The shorter the time of in-
cubation or the more serious the symptoms, the larger should be the initial
dose. As a rule one injection should be given every other day, using a
smaller quantity at each repetition, so as to maintain sufficient immunity
and prevent relapse. Along with the serum treatment the usual remedial
measures should be employed, namely : excision of the part or the actual
cautery if the wound is recent, chloroform ansesthesia, chloral, etc. The
actual cautery, or the application of a strong solution of corrosive sub-
limate with tartaric acid, are the most efficacious means of neutralizing
the tetanus germs in the wound.

The tetanus antitoxin prepared by Dr. Gibier of the New York Pasteur Institute is
dispensed in dry form only, may be transported any distance without injury by heat or
frost, and is said to preserve its qualities for an indefinite time if Icept in a dark and dry
place. It represents as many antitoxic units as are contained in about 12 times its weight
of liquid serum. The powder is put up in 25 ccm. bottles, each containing 3 grammes,
to be filled with sterilized water when required for use, and shaken thoroughly until the
powder is dissolved. Each bottle then contains two doses of antitoxic solution, and this
amount is to be administered daily for four or five days, beginning on the very first appear-
ance of symptoms of the disease. For prophylactic use i or 2 ccm. of the solution
should be injected immediately after the infliction of a suspicious wound.

Tuberculosis Antitoxin has superseded Koch's tuberculin, which
was a toxin treatment, in the serum-therapy of tuberculous disease.
Boinet immunizes goats with injections of tuberculin, and claims to have
used the resulting serum in eight cases of tuberculosis with marked bene-
fit. Professor Maragliano, of Genoa, has treated 82 cases with a serum
similarly prepared. He reports that the cases of unmixed infection, with
circumscribed foci of disease, slight surrounding consolidation, and but
little fever, are distinctly benefited by the treatment and even some are
cured thereby ; but that those with much broncho-pneumonic consolida-
tion or with cavities do not show any great improvement.

Dr. Maragliano administers in apyretic cases or those.with slight fever i ccm. of the
serum every second day for the first ten days, then a similar dose every day for another
ten days, then two similar injections daily for the next ten days. If there is high fever
10 ccm. should be given at once, and after three days a daily injection of I to 2 ccm. if


the fever does not rise again, but if it persists a second dose of lo ccm. is given eight
days after the first one. Improvement is noticeable often within two weeks but sometimes
not until after two months have elapsed. Even when a cure seems complete the injec-
tions should be continued for at least a month and even for a year. General hygienic
measures must not be neglected, and the efficiency of the digestion must be especially
attended to.

Dr. Paul Paquin of St. Louis has reported upon 22 serious cases of this
disease, treated by him in the city hospital with a serum obtained from
horses immunized by injection of the toxins of the bacillus tuberculosis.
He states that a large percentage of these cases increased in weight from
5 to 16 pounds each during 6 to 8 weeks, and at the same time showed
other evidences of general improvement, without the use of tonics or any
special diet, only the regular fare of the city hospital or poor-house being
available for them. After the lapse of six months the entire 22 were alive,
all having improved and more than one-half the number having been dis-
charged from the hospital as well enough to work. Numerous reports from
other observers testify to good results obtained with Paquin's serum in the
worst cases, e.g., knee-joint tuberculosis (Cale), laryngeal tuberculosis
(Loeb), and acute pulmonary tuberculosis (Lemen).

The effects observed after injecting Paquin's serum include erythema,
urticaria, local swellings, pain, swelling and stiffness of joints, numbness,
pain in the spine, in the back of the head and in the stomach. The most
serious complication is a sudden disturbance of the circulation, caused
by the injection entering a vein or the muscular tissues, which requires
the prompt administration of cardiac stimulants, as alcohol, nitroglycerin,
etc. Over 3,000 injections were made in human subjects without one
serious accident.

Dr. Paquin administers a beginning dose of 10 minims, with strict aseptic precautions,

Online LibrarySamuel O. L. (Samuel Otway Lewis) PotterHandbook of materia medica, pharmacy, and therapeutics, including the physiological action of drugs, the special therapeutics of disease, official and practical pharmacy, and minute directions for prescription writing → online text (page 19 of 127)