NORTHWESTERN
UNIVERSITY
LIBRARY
EVANSTON
ILLINOIS
PRINCIPLES OF THERAPY UNDER MODERN BIOLOGY
BY HENRY BIXBY HEMENWAY, A.M., M.D.
Evanston, 111. ^
Reprinted from International Clinics, Vol. II, Twenty-third Series.
Copyriffht, 19I3. by J. B. Lippincott Company, Philadelphia. Pa.
PRINCIPLES OF THERAPY UNDER MODERN BIOLOGY *
BY HENRY BIXBY HEMENWAY, A.M., M.D.
Evanston, 111.
De. Galton tells us in his " Memories " that, when he was
sixteen years old, in the Birmingham General Hospital, he had at
one time practically under his sole care no less than sixteen fractures^
dislocations, or other injuries of the arm. A medical acquaintance
of the speaker, in giving his professional history, said that at the
age of sixteen he went to study with a country doctor. After four
months his preceptor told him that he was prepared to enter practice
on his own account, as he had learned well nigh all that his preceptor
could teach him. Accordingly at the age of seventeen he " hung out
his shingle," and he did well in practice. Thirty-five years ago it
was customary for leading schools of medicine in this country to
require only two years' attendance upon courses of lectures, each last¬
ing four months, as the requirement for graduation. Contrast this
with the four or five years now prescribed ; and remember that to-day
many schools are demanding a preliminary course of two years in a
literary college, and that all exact at least a high-school education,
whereas formerly there was practically no request for more than
such rudimentary training as was given in the district school. Re¬
member, further, that the school year is twice as long as formerly.
Yet, owing to the tremendous advance made in the science of
medicine, it is likely that the recent graduate, thirty-five years ago,
was better qualified, as judged by the then state of the science, than
is the graduate of to-day, when we consider the sum total of knowl¬
edge obtainable now.
Objection is sometimes made to the length of time now spent
in medical education, hut as the courses are arranged very many
feel that too little is devoted to therapeutics, and the subject of pre¬
ventive medicine is barely touched. Formerly all that was needed
of the practitioner was a knowledge of the human body and its ail-
• Delivered before the Knox County, Dlinois, Medical Society, April 17, 1913.
1
2
INTEENATIONAX CLINICS
ments, with the gross action of drugs. To-day we realize that a
knowledge of the human body requires a broad acquaintance with
biology and zoology, as well as with many other branches of science.
How many physicians know an Anopheles mosquito from a midge?
Do general practitioners recognize the essential differences between
the typhoid house-fly and the stable species which is being identified
with infantile paralysis ? Are they acquainted with the life history
of the various disease-carriers among the members of the animal
kingdom? Then, too, much light is shed upon human ailments by
the study of the diseases of the lower animals. Hor must we forget
that much of our recent great advance has depended upon non¬
medical men. Pasteur was a chemist, and the zoologist Metchnikoff
made his discovery of phagocytosis in his study of the nutrition of
the amœba. To-day as never before, medicine is a learned pro¬
fession. Ho other vocation demands such a breadth of culture.
What does all this mean to us who left our college halls decades
ago? It means that the man who has not studied harder since he
graduated than he did before has dropped behind. To use a slang
expression, he has become " a back number," even though he may
be more expert than he was in his earlier years of practice. There
are too many commercial men in the profession, and too few phy¬
sicians of the higher standard. It follows then that the legal require¬
ments for entering the profession should be based, not upon the
curriculum of the second-rate schools, but upon that of the best, and
examinations for license should be strict. The object of education
is to fit us to meet emergencies, not to cram the mind with facts and
theories. The examination questions, therefore, should be calculated
to show training rather than knowledge of unimportant points in
anatomy or chemistry.
Every physician, as a part of his daily duty, should be a research
worker. A knowledge of how to tackle a subject is more important
than a knowledge of individual facts. This is a point well recog¬
nized by university men, but absolutely beyond the ken of the
political license examiners who unfortunately compose some of the
different state boards. Of what possible value, in determining the
real qualifications of a candidate to practise medicine, can such a
question be as that recently propounded by a certain board—" De¬
scribe minutely how a transverse section of a normal human appendix
THERAPY HHDBR UODEBH BIOLOOY
3
would differ from a like section through the duodenum of a rabbit " Î
The same board also asked : " Show how alcohols are derived from
water." By way of contrast permit a recital of the experience of a
candidate for the degree of Doctor of Philosophy in one of our
leading universities. His oral examination began with general ques¬
tions, and constantly approached details; but the examiners did
not particularly care whether or not he knew the minutiae. They
were trying to determine how he would approach the subject, and
whether he actually knew what he was claiming to know, or was
" bluffing " at what he did not know. An incompetent man who
spends a few days cramming with the aid of a collection of license
questions may pass a text-book examination. Only the competent
man may endure tests of training.
In the Atlantic Monthly, January, 1913, Mr. G. M. Stratton
says: "Of two Kip Van Winkles awakening to-day, the physician
would find his old methods as rust eaten and useless as his instru¬
ments; the lawyer, after a few hours with new statutes, would feel
at home in any of our courts." Routine is a mental soporific which
makes many men into Kip Van Winkles, only they never wake up.
How can the older graduate keep up with the advance in medical
science ? First, by reading leading medical journals and text-books.
But this is not enough. He must pass frequent examinations in the
subjects thus studied. These examinations are the natural result of
attending medical societies, where in the mutual discussions he will
correct erroneous conclusions and receive more light. Secondly, no
medical practitioner can possibly afford to neglect frequent attend¬
ance upon medical societies. If he does, he will surely find within
a few years (imless he is intellectually blind, or asleep) that he is
dropping behind and taking his place in the rear end of the procession,
among the stragglers. Nor is mere attendance at the meeting suffi¬
cient. He must be willing to betray ignorance by asking questions,
and expose himself to the purifying fire of fraternal interchange
of ideas. The man who writes a paper, on an average, leams
thereby more than those who listen to its reading.
Sometimes it is possible for the practitioner to take a month or
two at some medical college. If so, do not let the utilitarian idea of
" the practical " take him too frequently to the clinic. He has been
attending clinics all his years of practice. What he needs is to get
4
INTERNATIONAL CLINICS
back to the fundamental sciences upon wbich his practice must be
based. The laboratory is far more important for him than is the
surgical amphitheatre.
Because of the simplicity of surgical art, its spectacular char¬
acter, and the relatively greater compensation, surgery has received
attention to the neglect of the far more important field of medical
healing. In consequence there is too much tmcertainty in the minds
of medical practitioners. In answer to a question, a recent graduate
from a leading medical school said that in pneumonia, for example,
he was taught to try this, and, if it did not work, to try something
else. This very uncertainty has passed from the minds of phy¬
sicians, so-called, to those of their patients. It has become the sub¬
ject of frequent jokes. Patients want something definite, not ex¬
perimentation. In consequence, they listen to the positive, though
often false, claims made by schismatics, quacks, and charlatans.
We must not blame them. The fault is with ourselves.
Successful therapeusis must depend upon a clear idea of what is
to be accomplished. This means that we must make a correct diag¬
nosis, know the cause of disease, and how the cause works. Such a
knowledge will point the way in which to look for a proper remedy,
and tell us what we may hope to do, and what is apparently im¬
possible. Cabot has recently shovra,^ by postmortems in the Massa¬
chusetts General Hospital, that in grave diseases there is a very
large percentage of error in diagnosis. In general practice this per¬
centage is undoubtedly very much greater. Such a fact calls for
honest refiection in solitude by each of us.
MICROBIC CHARACTERISTICS
We find that a large proportion of diseases are caused by microbio
organisms, either plant or animal. These microbes have various
life histories, fairly constant for each species. Thus, some bacteria
grow only in the absence of air, while others die in the absence of
this same element Some thrive only in acid media. Others cannot
develop or live in the presence of acid. The fact, then, that a certain
drug is bactericidal for one species does not by any means indicate
that it is so for all. Using the term in its broad signification, as
^Journal A. M. A., Dec. 28, 1912, p. 2295.
THEEAPY TJNDEE MODEEN BIOLOGY
5'
referring to bacteria and protozoa, it is unreasonable to expect that
any one antiseptic will be equally efficient for all cases.
MECHANICAL EFFECTS
The fever of malaria is occasioned, apparently, by the mechan¬
ical shock produced when the matured protozoön explodes, setting
free the newly-formed plasmodia. This is a direct effect of the germ
of the disease. So, also, the mechanical injury to the red corpuscles
of the blood may be charged to the direct effect of the organism, and,
without considering any poison produced by the protozoön, we may
thus account for much of the anaemia of malaria. Simply to combat
the poison of the disease will not remove the distressing symptoms.
The germ itself must be killed. Again: In membranous croup the
diphtheria plant by its growth obstructs the larynx. The symptom
is a direct result of the growth. Owing to the nature of the
epithelium upon which it grows the plant may be easily displaced
and produce complete occlusion. Because of the lack of circulation
little poison can be absorbed. On the other hand, when the plant is
located in the nose, with its free circulation, ample opportunity is
offered for the absorption of the toxin. The mechanical obstruction
is of very minor importance, and the symptoms are chiefly those of
the poisoning. Here it is necessary to defend the system against
the effect of the toxin. This we do by the administration of an
antitoxin. If the antitoxin also acts as a bactericide, this is in¬
cidental. The mere holding in check of the destructive action of the
toxin permits the ordinary defences of the body to attack the bacteria.
ENTEANCE OF GBEMS TO CELLS
So far as we know, it is not possible for a bacterium to enter a
healthy cell. It is possible that, after the cell wall may be broken
down by the (chemical ?) action of a toxin, a bacterium may enter
the partially-ruined cavity, but Such a broken shell offers also free
access for other substances. In marked distinction from the ■'^'^re-
going, protozoa frequently enter the cells of the body, and ai'^ thus
protected from harm while they are maturing their destiuctive
schemes. It is practically useless to attempt, by the use of quinine.
6
INTEENATIONAI, OEIKIOS
the destruction of the hœmatozoôn of malaria so long as it is fortified
behind the walls of the red corpuscle. We make the attack when
the newly-formed individuals are free in the blood plasma.
EITTBAITCE TO BODY
Since bacteria cannot by their own power force themselves into
healthy tissue, to gain entrance they must attach themselves to some
friendly agent. Many enter the body with our food. Others take
advantage of some bruise of membrane, or minute injury caused by
previous disease. Not infrequently the bacteria may be carried from
place to place by insects, and perhaps inserted by the hypodermic
needle of a mosquito. In all these cases the insect is a simple carrier
of the infection. The danger of infection decreases with the passage
of time since the insect has come in contact with the diseased body
or culture. The species of the carrier is not material, for the
methods of propagation for bacteria are practically uniform.
CAEEIEES VEESTJS HOSTS
In the case of many protozoa, on the other hand, the insect may
be more than a simple carrier. Take the sleeping-sickness of Africa,
for example. This is due to a trypanosome which propagates
asexually in tlie body of an infected patient to whom it has been
communicated by a tsetse-fiy. If such a fiy bites a patient, he may
be able to communicate the disease by biting another person within
from twenty-four to forty-eight hours. During this period the fiy
acts as a simple carrier, just as is the fiea a carrier of the bacillus
pestis. After forty-eight hours the fiy is incapable of communicat¬
ing the disease for a period of about seventeen days, during which
the Protozoon is undergoing sexual reproduction in the body of the
insect Thereafter for two months the fly is again an infective agent
It has not been shovra that any other insect, aside from the different
species of the Glossina, can thus serve for the sexual development of
kthe Protozoon. In like manner the stegomyia mosquito is the only
knov^ \ intermediary host for yellow fever ; the culex mosquito harbors
filaria*'! and the various species of the anopheline mosquitoes alone
permit the sexual cycle of development for malarial parasites. Any
insect possessing the nature of a hypodermic needle, by extracting
THERAPY TJHDEB MODBEN BIOLOGY
Y
blood laden Avith plasmodia and carrying it to a healthy person may
be a disease carrier. Only special varieties may be intermediary
hosts.
PROTOZOAL ENTRANCE TO THE BODY
It is not likely that bacteria upon healthy skin or mucous mem¬
branes may thus enter the body. A Solution of continuity is neces¬
sary for the entrance of the germ. Kot so in the case of some
protozoa. Dourine, sometimes called horse syphilis, is a disease which
is very fatal to horses. It was formerly supposed that it was always
commimicated through copulation. It is generally fatal to horses in
from six months to a year. An epidemic among the horses and mules
on the Canal Zone was carefully studied in the laboratory of the
Sanitary Department, and the record of results may be found in
different numbers of their monthly bulletin. Briefly, it was found
that the trypanosome of the disease when placed on perfectly sound
skin or mucous membrane enters the body and infects the animal.
Flies {Musca domestica) are able to infect a healthy animal two
hours after feeding upon a diseased nose. Since the Musca does not
bite, this spread of the disease is due to the motile power of the
trypanosome. Two mules in the Zone, which were inoculated with
virus attenuated by passage through guinea-pigs, went through the
disease to recovery, and the trypanosomes disappeared from the
system. Subsequent inoculations, either with the attenuated virus or
with a malignant strain, failed to infect the animals. These re¬
sults, representing more than two years' investigation by the Zone
laboratoiy, are at least encouraging. If, as seems probable, the
Spirochœte pallidum is also protozoan, these observations as to the
horse disease may be important relative to human syphilis.
ANTIPROTOZOAL TREATMENT
The foregoing indicates the more forcibly that treatment of
protozoal diseases must be directed against the germ itself rather
than again&t the poisons and their effects. In this regard an im¬
portant lesson is taught by the African sleeping-sickness. This dis¬
ease normally has a mortality of ninety per cent, or more. Atoxyl
given in efficient doses kills the trypanosome in very many cases, and
8
INTEENATIONAL CLINICS
this treatment results in over eighty per cent, of recoveries. Efficient
treatment, then, lessens the possibility that new cases shall arise, for
it lessens the possibility that the fly may imbibe the peculiar microbe.
It is found, however, that if the drug be used in repeated small doses
the trypanosomes become immune, not only to atoxyl but also to
other arsenical compounds. This specific immunity is transmitted
to subsequent generations of the germ, as tested through many suc¬
cessive generations. Unsuccessful treatment in these cases, there¬
fore, seems to substitute a race of immune trypanosomes for those
which are subject to treatment. What clearer demonstration is
needed of the urgency for definiteness in therapeusis? We should
hnow what we are doing or attempting to do.
BACTERIAL ANTAGONISMS
It is well known that milk, when left to itself, sometimes sours
and remains sour for a long time before becoming putrid. Some¬
times it putrefies rapidly after souring. At other times it becomes
rancid without having previously developed the lactic acid to an
appreciable degree. The souring may be due to any one of several
organisms, among them being the different strains of lactic acid
bacilli and yeast germs. The putrefaction is also due to bacteria. If
the milk be inoculated with the lactic acid bacilli, especially with
the Bulgarian strain, the multiplication of these bacilli occurs rapidly,
and in such a presence the putrefactive bacteria are impotent. Eor
this reason when sour milk or buttermilk is used medicinally it should
always be thus artificially " started." When thus properly handled
the milk attains a pure sourness without danger of rancidity.
Putrefaction is the result of the destructive action of certain
bacteria upon proteid substances. Many of the products of putre¬
faction are distinctly poisonous to the animal body. Thus many
of our common ailments are the result of such proteid destruction
within the laboratory of the intestinal canaL We are all familiar
with the sallow complexion, the dull headache, the disordered appe¬
tite, and the drowsiness which so often accompany the condition.
Sometimes the disturbance is intensified, and we find vomiting and
diarrhœa, fever, and possibly a prostration which ends in death.
Knowing the bacterial origin of the disorder we may administer
THEEAPY XJNDEK MODEBN BIOLOGY
9
antiseptics. Tlius we may destroy many of tlie bacteria, but we are
unable to kill all. Many of our drugs simply hinder the bacterial
operations, without exterminating them. This drug medication,
therefore, is like a housecleaning. The weak bacteria are kiUed,
but the more resistant are left, and, having gotten rid of their weak
brothers who were in the way, those who are left may more easily
multiply as soon as the drug is vsithdrawn. The Bible tells of an
evil spirit which when cast out wandered through dry places, and
then returned to his former abode, which he found swept and
garnished. He therefore found seven other spirits, more wicked
than himself, and they entered in. The comment is that the last
state of that man was worse than the first. This lesson may well be
applied to the treatment of intestinal putrefaction by intestinal
antiseptics alone. On the other hand, we may take advantage of the
hostility between the lactic acid bacilli and the putrefactive bacteria.
By administering buttermilk, artificially produced, we drive out the
putrefactive germs, and in their place substitute those which are
harmless.
[Putrefaction must not be confused with fermentation. Fer¬
mentation is a process by which carbohydrates are broken up. This
is hindered by their normal digestion- HormaUy the digestion of
starchy foods by the ptyalin admixed continues in the stomach for
about half an hour after the meal, but the ptyalin cannot work in a
distinctly acid medium. Buttermilk, taken with the meal, may
thus hinder amylaceous digestion and favor fermentation.]
It does not seem reasonable to expect that the action of capsules
or tablets containing dry bacteria will be as efficient as fresh
cultures. In the dry stage many of the germs are probably in spore.
It is claimed that the Bulgarian strain of lactic bacilli form no spores.
It takes time for them to become active. When they start to grow
they are relatively weak, and it would be possible for the putrefactive
germs to prevent, or impede, the lactic development. Buttermilk is
nutritive, and fiUed with active bacilli. Sometimes, when the taste
of the sour milk is repulsive to the patient, the use of the tablet may
be permitted.
A similar use of the lactic acid bacillus has long been tried in
membranous croup, for example. It was formerly supposed that the
dissolving action of the lactic acid upon the diphtheria plant was the
10
INTEENATIOITAL CLINICS
chief value. Now we know that in addition the lactic acid bacillus
is antagonistic to the Klebs-Löffler bacillus. In a like manner a
culture of the lactic acid is useful in that hête noire of dentists, pyor-
rhœa alveolaris. Berthelot has found also that the lactic acid bacillus
is antagonistic, even in vitro, to the meningococcus. There are
carriers of this disease as there are carriers of that of diphtheria.
In all such cases a nasal spray of fresh lactic acid culture should be
used effectively.
In a similar manner Professor Ravenel advises the use of a
spray of a culture of staphylococci in diphtheria carriers. This
seems to be efficient.
ANTISEPTICS VBESTTS BACTEBTAT, THEEAPY
The ordinary antiseptic is efficient in proportion to the size of
the dose, and its action is very limited as to time. Moreover, the
antiseptics may produce positive injury to the animal cells. The
lesions which are thus produced favor the further harmful effects
of the disease-producing microorganism. Further, the use of the
antiseptic may hinder the natural defenders of the body. Hydrc^en
peroxide is an efficient antiseptic m vitro. In actual use it is often
followed by an increase in the severity of the infection. I suspect
that the reason for this is that the individual cells of the body take
up so much oxygen that the normal phagocytic action is mechan¬
ically hindered. The swelling of other cells interferes also with the
circulation, and the phagocytes cannot get into the battle. Swelling
of the tissues may frequently be observed.
In the case of indolent ulcer hydrogen peroxide acts well to
cleanse the surface, but it is common that the ultimate effect is dis¬
appointing. Yeast poultices have been despised as " old women's
remedies," but in the light of modem biology we may possibly have
greater respect for this kind of treatment It is not impossible that
the old-fashioned " bread-and-milk " poultice may owe its efficiency
partly to the culture of the lactic acid bacillus which wiU most surely
be produced. If that be so, why not use the culture intelligently?
Local infections, caused by bacteria which do not thrive in lactic
acid media, would therefore yield to the local injections of cultures of
the lactic baciUi.
THEBAPY FITDBIt MODEBIT BIODOOT
11
ATTENUATED VIBUS
It has long been observed that one attack of certain diseases serves
to prevent future similar illnesses. Taking advantage of this fact,
our forefathers were accustomed to inoculate healthy persons with
the germs of smallpox. Then came 4iie discovery of Jenner, and the
use of the cowpox germ, which is apparently an attenuation of that
of smallpox. Thus we get a general rule in such cases that a person
may be protected against a severe disease by inoculation with an
attenuated viruis. The attenuated virus is weaker in toxins, but
active in producing phagocytosis. This protection may be attained
even after infection and during incubation. How ? Probably
variola is a protozoal disease, so we shall use a protozoal illustration.
In the asexual development of the malarial plasmodiiim each adult
produces from six to twenty plastids. In the tertiary form each
generation occupies two days in development. Ross estimates that
an adult person weighing 142 poimds will not show malarial fever
until such a time as 150,000,000 plastids are free in his blood at
one time. He estimates that the Plasmodium vivax increases at least
tenfold in each generation. Taking the various powers of the differ¬
ent numbers, and multiplying by 1000, it will be seen that with a
start of five plasmodia the fever stage woiild be reached in twelve
days; that for six germs in ten days; that for ten in eight days;
and that for fifteen in six days. These times we designate the
" incubation period." How applying this reasoning to the smallpox,
we realize that a naturally-produced infection would not be likely to
contain many germs at the start, and the incubation would naturally
be long. On the other hand, vaccination would start with many
germs, and the incubation period would consequently be very short
The production of immunity by vaccination would therefore be suffi¬
ciently rapid to probably head off the more severe disease. A similar
reasoning would apply to the curative action of bacterins against
their particular diseases, though because bacterins are dead, and in¬
capable of multiplying, relatively larger doses must be injected.
The specific organism producing rabies is not known, but the
disease is successfully treated by the use of a virus attenuated by
drying. The spinal cord of a rabetic rabbit is dried, and the length
of time consumed in drying determines its virulence. For the
12
INTEENATIONAL OEINICS
first treatment it is customary to use a cord which has been dried for
fourteen days in the dark at a temperature of 23° C. Every second
or third day a stronger virus is injected, ending with a three-day
virus. In this way the natural defences of the body are built up to
meet the onslaught of the infection.
It is very unfortunate that the term " vaccine " has become com¬
monly used with reference to distinctly differing principles. Its use
should be strictly limited to inoculations with attenuated living
germs, leaving the designation " bacterins " to describe inoculations
with killed bacteria. This will serve to suggest to the mind the
distinction in method of action between the two classes of products.
PHAGOCYTOSIS
The chief defence of the body against infection is found in the
phagocytes. As a part of their normal nutrition these cells engulf
and destroy proteid substances. When a phagocyte meets with a
bacterium it surrounds and digests the germ, thus checking further
danger from that individual. This phagocytic power is not limited,
as many seem to think, to the white corpuscles found in the blood.
It is common also in lymph-cells and the cells of the deeper struc¬
tures of the skin, and of various glands. The phagocytic power
varies in a given person from time to time and with regard to
different bacteria. It may be active for the typhoid germ and weak
for the streptococcus, or vice versa. Burnet says that quinine in
0.002 pen cent, solution acts as a stimulant to the phagocytic power,
but in 0.1 per cent, solution it depresses this action. Peptones are
powerful stimulants, and iodoform also acts as a stimulant. On the
other hand, the phagocytic power may be paralyzed by opium or by
cold. This being so, the use of opium to control the pain of in¬
flammation is contra-indicated. But it may be asked if the good re¬
sults achieved by application of cold in local inflammations do not
disprove the statement that cold paralyzes phagocytosis. Most bac¬
teria do not develop well until a certain elevation of temperature is
reached. Cold therefore retards bacterial development The few
bacteria which come in contact with the blood-plasma may be easily
mastered by phagocytes which have not come under the influence of
the cold. These few bacteria also stimulate the phagocytic power of
THERAPY UNDER MODERN BIOLOGY
13
the system against that particular strain. The cold acts then by
giving more time in which to build up the bodily resistance.
Bier's hypersemic method consists in causing local increase of
circulation, thus bringing more phagocytes to battle with the disease
germs; and cupping has a like effect. To specially protect against
infection in cases of abdominal operations many surgeons inject
warmed blood-serum into the peritoneum.
VISCOSITY OF BLOOD
It frequently happens that in local inflammations there is an
increase in the viscosity of the blood. This increased viscosity re¬
tards the circulation. In such cases the free use of citric acid or
the citrates, which reduce the viscosity, tends to bring more leuco¬
cytes into the battle, and thus aids nature in combating the dis¬
ease. Thus, in cases of a " brawny swelling," which is distinctly
local, in boils and similar troubles, aS well as in pneumonia, citric
acid and the citrates are most valuable aids in treatment. On the
other hand, in a septicaemia, where the bacteria are floating free in
the blood-plasma, we should expect that this use of citric acid would
be absolutely negative.
TOXINS AND ANTITOXINS
When a pathogenic bacterium is introduced into the body, and
there begins to multiply, it also develops its peculiar poison or toxin.
In the case of diphtheria bacilli this poison is excreted and readily
soluble. The same is true of the toxin of tetanus, which shows a
special affinity for nerve-cells. The toxin of the typhoid bacillus is
not excreted, but it is set free by the destruction of the bacillary
cell. Such poisons are called endotoxins. The toxins are not imme¬
diately poisonous to the tissues, in the same sense as strychnia is
poisonous. Toxins resemble diastase in mode of action, and take
time for incubation. As the toxins come in contact with the animal
body specific antitoxins are produced. The phagocytes seem to be
the chief, if not the only, source of these antitoxins. Apparently the
antitoxin enters into a loose chemical union with the free toxin. If
toxins and antitoxins, properly mixed, are introduced into the
body together the effect is practically nil. If the administration of
14
mTEBNATIOXAI. OUITIOS
the antitoxin precedes that of the toxin, the antibody is prepared
to neutralize the toxin at once, and the effect is nil. This is the
case in the ordinary prophylactic treatment. If the toxin has
already made its union with body-cells the administration of the
antitoxin will be without effect. This is well shown in the case of
tetanus. The antitoxin does not draw the toxin away from the
nerve-cells to which it has united. In actual practice, even though
the nervous elements show the pernicious effects of the poison, we
administer antitoxin to neutralize the free toxins which may still be
produced.
DOSE OF ANTITOXIN
When a person is infected by a disease microbe he is not made
immediately ill. The very few microbes first introduced must have
time in which to multiply and produce their toxin. Remembering
that bacteria propagate by division, and that the multiplication may
occur once an hour under favorable circumstances, we may see that,
without making allowance for destruction of any of the bacteria,
one germ may become 160,000 within twenty-four hours. It would
therefore take a very much smaller dose of antitoxin to neutralize
the toxin produced by the original bacteria than it would after a
few days. Five hundred units of diphtheria antitoxin is ordinarily
suficient for prophylaxis; 5000 should be regarded as a minimum
dose used for curative purposes. Since the production of antitoxin
begins soon after the toxin is excreted, the dose of antitoxin ad¬
ministered does not need to be exactly proportional to the number
of bacteria. The disease approaches a crisis when there is an increas¬
ing quantity of free toxin; lysis begins when the antitoxin supply
passes that of the toxin.
LOCATION FOE ANTITOXIN INJECTION
Since the antitoxin acts exclusively upon the free toxin, not only
should it be introduced early, if it is to be used at all, but the location
of its use is important. The injection of antitoxin starts a race
between the antagonists. If the toxin reaches the susceptible cells
and there works its injury, the administration of the antitoxin is
relatively useless. Injections into the cellular tissue require much
time for their absorption. From the peritoneum absorption is less
THERAPY UNDER MODERN BIODOGY
15
slow. Injections into the veins are much more efficient; but in
such diseases as tetanus and meningitis even intravenous injections
are too slow. It is the nervous centre which needs special protection
in these maladies. Intravenous injections dissipate the antitoxin
over the entire body. In the treatment of meningitis the injections
must be into the lumbar spine. Tetanus antitoxin is more efficient
when injected into the brain itself. Since this is hardly practicable
in human cases we must be content with injections into the spinal
fluid.
MANUFACTURE OF ANTITOXIN
Since the antitoxin has not been isolated for any disease, what
we really mean in speaking of the preparations used medicinally is
a serum, generally derived from the horse, and containing the anti¬
toxin. The dose is reckoned according to its neutralizing power,
and may be relatively very different from the bulk or weight, being
standardized to a known unit of toxin. The investment required,
the amount of time demanded, the facilities needed, all conspire to
make it practically impossible for the private laboratory to pre¬
pare these antitoxic sera for ordinary use. The same is true of the
various true vaccines. On the other hand, the high degree of scien¬
tific care requisite, and trust imposed, show that only the products
of houses of well-known reliability should be used. Properly pre¬
pared, such medicinal agents must be relatively expensive. Cheap¬
ness is no recommendation for the product of any firm. Baeterins,
on the other hand, may be prepared at moderate expense in any
well-equipped biologic laboratory.
OPSONINS AND BAOTERINS
Citron has shown that rabbits which had been inoculated with
the extract from dead hog-cholera bacilli furnished a serum which
was protective for guinea-pigs, though the bacilli would grow in that
same serum. There are other examples of this same phenomenon.
This indicates that an antitoxin is not of itself bactericidal. When,
however, the killed bacteria are injected into the system, they arouse
a reaction which shows itself in increased phagocytosis. Wright
considers that this is due to a principle of the serum which prepares
the bacteria for consumption by the phagocytes, and calls it an
16
INTEEWATIONAJL CLINICS
opsonin. The followers of MetdmikofiE do not deny that such a
principle is found in the serum, but they think that they have demon¬
strated that it originates in the phagocytes themselves, and that it
is simply a manifestation of the digestive power of those cells. They
further affirm that it is a cell secretion, and therefore that it is
only found in the serum after the cells have been injured. Be
that as it may, this stimulation of phagocytosis is strictly specific.
The power may be great for one bacterium but weak for another.
Of course, when the killed bacteria are injected they are accompanied
by their specific toxins. The immediate effect of the injection is
an intensification of the symptoms of the disease. This is the stage
of depression, which precedes the beneficial action. Living bacteria
also stimulate the opsonic power. It is thus that vaccination with
attenuated living germs acts as a prophylactic measura In case of
illness vaccination with unattenuated living germs would hardly be
advisable in therapeutic practice. Heither would the injection of
dead germs be advisable when there is a general bactersemia—^where
the system is already overburdened with the effects of the toxins,
and the phagocytes are unable to cope with the multitude of living
germs. On the other hand, when the infection is local, and relatively
few phagocytes have an opportunity to come in contact with the
bacteria, we may find this bacterin treatment especially valuable.
Thus, in a localized tuberculosis, as in the joint, or on the skin, or in
corneal tuberculosis, the bacterin treatment may be very helpful. In
a general tuberculosis it seldom helps, and often proves a serious
detriment. Antistreptococcus serum apparently owes its efficiency
to its opsonin content, not to antitoxin.
LOCATION FOE BACTERIAL INJECTIONS
It must be remembered that the modus operandi for bacterins is
very different from that of antitoxins. With antitoxins we use a
large dose to start with, and inject as close to the place where the
toxin does its work as circumstances will allow. The bacterins
produce their results by slowly coming in contact with the phagocytes.
We therefore begin with small doses, and the place for injection is
selected with reference to slow absorption. Since the phagocytes
near the diseased area are already almost overwhelmed by living
THEEAPY UNDER MODERN BIODOGY
17
bacteria, we find a place at a distance, to stimulate the general
phagocytic power of the system. The subdermal cellular tissue of
the back is a favorite place chosen, and the size of the dose is in¬
creased as the powers of the body are raised to withstand the effect of
the dose.
BACTERINS SPECIFIC
Since this opsonic action is specific, it follows that there must
be an exact bacterial diagnosis. If the disease be one which is
definitely recognized, such as typhoid fever, a stock vaccine may
properly be Used. If the exact germ be not recognized, the bacterin
used might better be prepared from cultures from the individual
case.
There are many staphylococcus species, just as there are many
varieties of diplococci. No one should think of treating a typical
case of pneumonia with cultures of the diplococci of meningitis and
gonorrhœa, but because of the diagnostic difficulty of determining
streptococci and staphylococci in their exact species many are accus¬
tomed to take stock mixtures of different strains of bacterins. The
result must be like firing a scattering load of shot from a gun. It
may be that some of the shot may strike; it is quite as likely that
none take effect. A good marksman uses a rifle rather than a
shotgun.
An old doctor down in Indiana used to keep a large bottle in his
office. Whenever any medicine was left from one of his prescriptions
he poured it into this bottle. When he was in doubt as to what
medicine to prescribe, he poured a phial full from this general
receptacle. He remarked that he " got about as many cures from
this as from anything which he used." Somewhat similarly a com¬
mercial house has recently put upon the market a mixture of the
germs of many diseases. That this shotgun mixture sometimes hits
the case cannot be doubted, but what is the use of putting fine bird-
shot in with the bullets which are fired at a lion ? Shotgun prescrip¬
tions always proclaim ignorance. They are like the mystified wander¬
ings of the Babes in the Wood. This masquerading of indefiniteness
under color of scientific progress should be emphatically condemned.
Let us now apply these general principles to a few specific
ailments. ' i
18
INTEBNATIOWAI- CLIiaCS
FUEUNCUL08IS
In furunculosis we have to do chiefly with the multiplication,
locally, of staphylococci. The toxin is not important, so that it
is not worth while to bother with an antitoxin. We need to stimu¬
late phagocytosis. This may be done by improving general condi¬
tions of circulation and nutrition. If epeciflc treatment be required
we should look to the opsonic influence of injections of dead bacteria.
Since staphylococcus is a generic name, not specific, the exact bac¬
terium which is involved may be a matter of question. We may, for
convenience, use a stock vaccine made from several strains of
staphylococci. If the result is not satisfactory it is no evidence
against the value of bacterin therapy. We should use autogenous
bacterins, made from cultures of the individual bacteria isolated in
pure culture from the patient. Even here, because it might be
possible that two species of staphylococci are growing side by side,
one being pathogenic and the other not, it would be better to make
the vaccine from a culture of a mixture of germB isolated at different
times and by differing methods.
DIPHTHERIA, TREATMENT
It would be possible for a person to die from a disease with
which he had not been infected. Infection only takes place when
the specific microbe enters the body. An individual who was entirely
free from the Klebs-Löffler bacillus would nevertheless die from
diphtheria should a sufficient dose of the toxin be inoculated. The
clinical picture of such a case would vary from a typical one chiefly
by the absence of the plant. Practically the plant may be considered
as outside of the body, or more correctly as " inter," not " intra."
The great trouble is caused by the absorption of the toxin. The
identity of the microorganism is definite. An injection of antitoxin
is clearly indicated. Ordinarily the injection should be into the
muscles; in urgent cases it should be intravenous. Since the growth
is easily reached, we may aid in the destruction of the plant by
sowing the seeds of another plant. Staphylococcus cultures may
not be easily obtained when wanted. Lactic acid cultures are found
everywhere. Since relatively few bacteria enter the system, phago¬
cytosis may be practically ignored.
THXBAPT TTITDEB MODSBN BIOLOOT
19
DIPHTHERIA, PEOPHTLAZIS
For diphtherial prophylaxis it has been customary to depend
upon injections of antitoxin. Since horse serum is the vehicle for
most antitoxins, and the protection of the antitoxin is not lasting,
it may well be suspected that the susceptibility to anaphylaxis thus
produced may outweigh the beneficent results. It is more than
possible that the effect of the antitoxin may be to mask an infection.
Because the toxin is robbed of its power, a weak growth of the
bacilli might be permitted to go on undetected, and thus we may
get our diphtheria carriers. It might be well, as a routine procedure,
to use cultures of lactic bacilli sprayed into the nose and throat in
every prophylactic case.
TYPHOID FEVEE
In typhoid fever we have a very different condition with which
to deal. Here we have a local infection in the intestines, where
most of the bacteria are produced and the toxin manufactured.
There is also a general bacteraemia. An antitoxic serum has not
given satisfaction for prophylaxis, and its results in treatment may
be questioned. A human serum, obtained from blisters on patients
during lysis, has sometimes seemed to give good results. What is
especially indicated in such a case is a limitation of bacterial
development and stimulation of phagocytosis. For prophylaxis, as
in the case of the army and navy, or for travelling men, where
general hygienic conditions may be somewhat uncertain, repeated
vaccinations with dead typhoid bacilli cultures give good protection,
lasting perhaps about four years. In case of typhoid in the family
such a measure is not necessary in the same sense aS we find it
possibly advisable to use diphtheria anfitoxin. Typhoid prophylaxis
in the family should depend upon general hygienic precautions.
Since the bacteria gain entrance to the body through the in¬
testines, and since they do not fiourish in acid media, the free use
of acidulated drinks is a prophylactic and curative measure. Fresh
milk, being an excellent culture medium for the typhoid bacilli, is
contra-indicated, but buttermilk may be useful. A portion of the
disturbance caused in this disease is probably due to the action of
other putrefactive bacteria, and these cannot work in the presence
20
INTEENATIONAL CLINICS
of an ample culture of the lactic bacillus. Since the typhoid
bacteria are foimd freely circulating in the blood, and thus affording
ample opportunity for phagocytosis, and since vaccination with dead
bacilli also introduces the endotoxin, bacterin therapy may be of
questionable propriety, especially at the height of the diseñe. If
it be used, the opsonic index must be closely watched.
PNEUMONIA
In pneumonia we have essentially a local growth of bacteria,
with a tendency toward stasis of blood. Much of the seriousness of
the disease is due to the mechanical effect of the congestion, checking
circulation, and aeration of the blood. Poisons which are normally
eliminated through the lungs, or are destroyed by oxidation, remain
to oppress the body. The most important indication here is to
relieve the congestion by reducing the viscosity of the blood. This
can be accomplished by the use of citric acid and the citrates.
Secondly, we must stimulate the specific phagocytosis. This may
be done with inoculations of dead cultures of the pneumococcus.
Since the pneumococcus is frequently assisted in its diabolical work
by the streptococcus or staphylococcus, it may be best to use those
bacterins also. So far as I know, a successful antitoxin for pneu¬
monia has not been produced, but even were it obtainable it must
apparently be of minor importance to the bacterin.
DEUG MEDICATION
Finally, biologic products, though important in modem treat¬
ment of disease, by no means remove the necessity for the use of
dmgs. Symptoms must be relieved as they arise. Biologic remedies
are expensive, and easily deteriorate. Often they may not readily
be obtained. Hot seldom equally good results may be secured by
the use of simple medicaments intelligently prescribed. When
ordered carelessly or according to an unreasoning routine, much
harm may be done. Remember the words of Duclaux : " With
Pasteur chemistry invaded the field of medicine, probably never to
leave it." The therapeutic problems of the future are largely chem¬
ical: how to kill the protozoa without injury to the patient; to
produce antitoxins outside of animal bodies; and, chiefly, the nu-
THEEAPY triTDEB MODEEN BIOLOGY
21
trition of the phagocytes, to render them still more efficient. We
may not all do the original work, but we may and should keep in¬
formed as to the progress which is being made in our most noble
science and art.
In conclusion, the tabulated statement here given will show at a
glance the gist of the article:
General Indications
Therapeaais Prophylaiis
Protozoal diseases Drug zoacides Vaccination (7)
/ Antitoxin (?)
I Bacterin (?)
Bacterial antagonists Bacterial antagonists
{Bacterins Bacterins
Antitoxin (?)
Opsonic sera (?)
Bacteria producing ■
Toxins Antitoxin
Administbation
Antitoxins.—Large initial dose, repeated in progressively smaller doses, pro re
nata.
Vaccines.—Small dose, possibly repeated after all symptoms have disappeared.
Bacterins.—Small initial dose, followed by progressively increasing doses.
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