The Nobel Prize in Physiology or Medicine 1939
Gerhard Domagk
The following account of Domagk's work is by Professor N. Svartz, member of the Staff of Professors of the Royal Caroline Institute.
Experiments in the treatment of
inflammatory conditions by means of drugs and chemicals are known
from earliest times, but for the most part the effects were nil
or at best insignificant. With certain of these conditions,
however, chemotherapy scored some first-class successes at an
early date. Mercury is a very ancient, active chemotherapeutic
agent, although it has now given place to more effective
preparations. Another therapeutic agent which has been in use for
a very long time is cinchona bark, the efficacy of which against
malaria became generally known in Europe during the 17th century.
Other experiments in anti-inflammatory treatment by chemical
methods for the most part yielded but meagre results.
It is only during the past few decades that further advances of
any great significance have been made in chemotherapy. In
particular, experimental investigations with arsenical
preparations and the successes achieved with these preparations
in cases of spirochaetic and trypanosome infections (relapsing
fever, syphilis, African sleeping-sickness) provided a powerful
stimulus to further experiments in the field of chemotherapy.
Salts of other metals have also proved valuable in the treatment
of specific types of inflammations - for instance, antimony salts
have been used very successfully with certain tropical diseases.
Particular mention must be made of the Bayer preparations
«Plasmochin» and «Atebrin» for malaria and
the preparation «Germanin» (Bayer 205) which has been
successfully used in cases of tropical sleeping-sickness. In
addition, bismuth salts have been found a very effective, though
by no means infallible, remedy against syphilis, and have largely
superseded mercury.
Thus, whereas it proved possible to attack certain diseases due
to protozoa and spirochaetes by means of chemical substances,
little success had been achieved with chemical preparations
against infections due to true bacteria, namely cocci and
bacilli. The theory that bacteria of the last-mentioned
categories could not be combated by chemical means therefore
continued to gain ground, and it was consequently assumed that
serotherapy was the most practicable method of treating
infections of this type.
Experiments with gold salts constituted an important phase in the
more recent development of chemotherapy. A number of bacterial
infections, e.g. septic conditions due to streptococci, rheumatic
infections, etc., were found to respond in some degree to these
salts, but it soon became clear that the effects varied very
widely, and when the doses were increased in an attempt to
produce a more vigorous effect serious symptoms of poisoning
frequently appeared.
During the past 15-20 years a great deal of work has been carried
out by various drug manufacturers with a view to producing less
toxic but at the same time therapeutically effective gold
preparations. The question of gold preparations and their
applicability was also investigated at the great research
laboratories of I.G. Farbenindustrie Aktiengesellschaft (Igefa)
at Elberfeld. The investigations here were part of a series of
experiments conducted with a view to discovering an agent
effective against streptococcal infections. The Igefa laboratory
department in which this research was carried out is under
Professor Gerhard Domagk, who planned and directed the
investigations involving experiments on animals. The chemists Dr.
Mietzsch and Dr. Klarer, working in close collaboration with
Domagk, provided various chemical preparations for these
investigations. It was decided to include sulphonamide compounds
among the preparations to be tested. These compounds had
previously been synthesized and had also been introduced into the
dyestuffs industry by Hörlein and his co-workers. However,
none of these compounds had been tested for their therapeutic
action.
During the investigations conducted by Domagk and his co-workers
4-sulphonamide-2', 4'-diaminoazobenzene hydrochloride, among
other substances, was tested. This preparation was subsequently
named Prontosil. The earliest published experiments with
Prontosil were begun in December 1932. The lethal dose, for mice,
of a certain strain of haemolytic streptococci, which had been
isolated from a patient suffering from blood poisoning, had
previously been determined. A number of mice were injected with
10 times the lethal dose of this bacterial strain, and
approximately half of them were given a specific quantity of
Prontosil 1 1/2 hours after being infected.
On 24th December, 1932, it was found that in an experiment begun
on 20th December, 1932, all the controls had died, whereas all
the mice which had been given Prontosil were alive and well. This
was the basis of the discovery which was destined to bring
undreamed-of advances in chemotherapy.
The results of these and subsequent experiments, which aroused
extra-ordinary interest, were not published until February 1935,
whereupon Prontosil and its effects rapidly became known
throughout the world. France was the first country apart from
Germany where Prontosil was subjected to practical tests
(Levaditi). Extensive experiments on, among other things, the
mode of action of Prontosil were then conducted in France
(Tréfouël, Nitti), America (Long, Marshall, and others)
and Britain (Colebrook, Kenny, and others). One result of these
investigations was the discovery that the favourable action of
Prontosil was mainly due to the sulphonamide component of the
preparation.
From the outset Prontosil was described as being effective
principally against streptococcal infections. Even in his first
publication, however, Domagk had reported that the preparation
had been found to have a therapeutic effect, although to a lesser
extent, in staphylococcal infections, and that certain types of
pneumonia had also responded to it.
At an early date sulphonamide preparations had proved extremely
effective against erysipelas, and subsequent investigations
completely confirmed this observation. Now, thanks to these
preparations, erysipelas can normally be treated without
difficulty.
It was also found that other streptococcal infections could be
dealt with by means of sulphonamide preparations, although for
the most part not so swiftly or surely as erysipelas. Although
suppuration in the pleural cavity and meningitis due to
streptococci are still serious diseases, they are much less so
than they used to be. The same applies to puerperal fever and
several other streptococcal infections. Even chronic general
septicaemia with endocarditis, a condition hitherto regarded as
incurable, has in isolated cases responded to sulphonamide
preparations.
In addition, brilliant results have been obtained with certain
infections not due to streptococci, namely gonorrhoea and
epidemic meningitis, and, as already mentioned, an effect has
also been shown with staphylococcal infections.
This preparation, which is so effective against various coccal
infections, has also been used with success in the case of
certain infections due to bacilli, e.g. cold infections.
Sulphonamide is therefore now the best known remedy against
infections of the urinary passages due to colon bacilli.
Preparations of this group are also effective against undulant
fever as well as, to a lesser extent, other bacillary infections
which will not be enumerated here.
The discovery of Prontosil opened up undreamed-of prospects for
the treatment of infectious diseases. Experiments with new
combinations of sulphonamide preparations were everywhere
conducted in the hope that new methods effective against other
diseases might be discovered. Contrary to expectation these
efforts were very quickly crowned with success.
Igefa reported that a new active sulphonamide preparation,
Uliron, had been produced. In addition, the report, published in
1938 by the chemical firm of May & Baker of Dagenham,
England, that a compound of pyridine and sulphonamide had been
synthesized and had proved effective against pneumonia, was of
major importance. This highly significant claim also proved
correct. The preparation in question was put on to the market as
M. & B. 693. It is now usually known as
Sulphapyridine. Sulphapyridine is so far the most
noteworthy derivative of Prontosil.
Simultaneously with the efforts to produce new sulphonamide
preparations research workers in various countries are busy
carrying out theoretical investigations into the mode of action
of these preparations and their side-effects. Domagk himself has
carried out some extremely fine investigations on these
questions. Research in this field has also been conducted in
France, Britain, America, Sweden, and other countries.
The foundations for this unprecedented expansion which
chemotherapy has undergone in the brief span of less than five
years were laid by Domagk and his co-workers. A new road leading
to effective treatment of diseases which in the past were often
fatal has been opened up. Reports on the most brilliant
therapeutic results with sulphonamide preparations are streaming
in from all parts of the world. Thousands upon thousands of human
lives are being saved each year by Prontosil and its derivatives.
Earlier, fruitless chemotherapeutic experiments often resulted in
despondency, but now even the most pessimistic have gradually
come to see the value of the results achieved. The imagination
reels before the prospects of new chemotherapeutic victories
which the sulphonamide preparations have unfolded before
us.
The award of the Nobel Prize for Physiology or Medicine for 1939
to Gerhard Domagk has honoured a discovery which means nothing
less than a revolution in medicine.
Professor Gerhard Domagk was awarded the 1939 Nobel Prize for
Physiology or Medicine for the discovery of the antibacterial
effects of Protonsil. Protonsil was the first of the so-called
sulpha preparations, which have proved to represent one of the
greatest therapeutic advances in the history of medicine.
Professor Domagk was prevented from accepting the prize at the
time by political conditions. In 1947 he received the gold medal
and the diploma.
Professor Domagk. It has become clear during the eight years that
have passed since it was decided to award you the Nobel Prize
that the sulphonamides have introduced a new era in the treatment
of infectious diseases. What Paul
Ehrlich dreamed of, and also made reality by using Salvarsan
in an exceptional case, has now, through your work become a
widely recognized fact. We can now justifiably believe that in
the future infectious diseases will be eradicated by means of
chemical compounds.
On behalf of the Caroline Institute I congratulate you most
warmly, and ask you to accept from His Majesty the King the medal
and the diploma.
From Nobel Lectures, Physiology or Medicine 1922-1941, Elsevier Publishing Company, Amsterdam, 1965
Copyright © The Nobel Foundation 1939
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