Salvarsan

The invention:

The first successful chemotherapeutic for the treatment
of syphilis

The people behind the invention:

Paul Ehrlich (1854-1915), a German research physician and
chemist
Wilhelm von Waldeyer (1836-1921), a German anatomist
Friedrich von Frerichs (1819-1885), a German physician and
professor
Sahachiro Hata (1872-1938), a Japanese physician and
bacteriologist
Fritz Schaudinn (1871-1906), a German zoologist



The Great Pox

The ravages of syphilis on humankind are seldom discussed
openly. A disease that struck all varieties of people and was transmitted
by direct and usually sexual contact, syphilis was both
feared and reviled. Many segments of society across all national
boundaries were secure in their belief that syphilis was divine punishment
of the wicked for their evil ways.
It was not until 1903 that bacteriologists Élie Metchnikoff and
Pierre-Paul-Émile Roux demonstrated the transmittal of syphilis to
apes, ending the long-held belief that syphilis was exclusively a human
disease. The disease destroyed families, careers, and lives,
driving its infected victims mad, destroying the brain, or destroying
the cardiovascular system. It was methodical and slow, but in every
case, it killed with singular precision. There was no hope of a safe
and effective cure prior to the discovery of Salvarsan.
Prior to 1910, conventional treatment consisted principally of
mercury or, later, potassium iodide. Mercury, however, administered
in large doses, led to severe ulcerations of the tongue, jaws,
and palate. Swelling of the gums and loosening of the teeth resulted.
Dribbling saliva and the attending fetid odor also occurred. These
side effects of mercury treatment were so severe that many pre-
ferred to suffer the disease to the end rather than undergo the standard
cure. About 1906, Metchnikoff and Roux demonstrated that
mercurial ointments, applied very early, at the first appearance of
the primary lesion, were effective.
Once the spirochete-type bacteria invaded the bloodstream and
tissues, the infected person experienced symptoms of varying nature
and degree—high fever, intense headaches, and excruciating
pain. The patient’s skin often erupted in pustular lesions similar in
appearance to smallpox. It was the distinguishing feature of these
pustular lesions that gave syphilis its other name: the “Great Pox.”
Death brought the only relief then available.


Poison Dyes

Paul Ehrlich became fascinated by the reactions of dyes with biological
cells and tissues while a student at the University of Strasbourg
under Wilhelm von Waldeyer. It was von Waldeyer who
sparked Ehrlich’s interest in the chemical viewpoint of medicine.
Thus, as a student, Ehrlich spent hours at this laboratory experimenting
with different dyes on various tissues. In 1878, he published
a book that detailed the discriminate staining of cells and cellular
components by various dyes.
Ehrlich joined Friedrich von Frerichs at the Charité Hospital in
Berlin, where Frerichs allowed Ehrlich to do as much research as he
wanted. Ehrlich began studying atoxyl in 1908, the year he won
jointly with Metchnikoff the Nobel Prize in Physiology or Medicine
for his work on immunity. Atoxyl was effective against trypanosome—
a parasite responsible for a variety of infections, notably
sleeping sickness—but also imposed serious side effects upon the
patient, not the least of which was blindness. It was Ehrlich’s study
of atoxyl, and several hundred derivatives sought as alternatives to
atoxyl in trypanosome treatment, that led to the development of derivative
606 (Salvarsan). Although compound 606 was the first
chemotherapeutic to be used effectively against syphilis, it was discontinued
as an atoxyl alternative and shelved as useless for five
years.
The discovery and development of compound 606 was enhanced
by two critical events. First, the Germans Fritz Schaudinn and Erich
Hoffmann discovered that syphilis is a bacterially caused disease.
The causative microorganism is a spirochete so frail and gossameric
in substance that it is nearly impossible to detect by casual microscopic
examination; Schaudinn chanced upon it one day in March,
1905. This discovery led, in turn, to German bacteriologist August
von Wassermann’s development of the now famous test for syphilis:
the Wassermann test. Second, a Japanese bacteriologist, Sahachiro
Hata, came to Frankfurt in 1909 to study syphilis with
Ehrlich. Hata had studied syphilis in rabbits in Japan. Hata’s assignment
was to test every atoxyl derivative ever developed under
Ehrlich for its efficacy in syphilis treatment. After hundreds of tests
and clinical trials, Ehrlich and Hata announced Salvarsan as a
“magic bullet” that could cure syphilis, at the April, 1910, Congress
of Internal Medicine in Wiesbaden, Germany.
The announcement was electrifying. The remedy was immediately
and widely sought, but it was not without its problems. Afew deaths
resulted fromits use, and it was not safe for treatment of the gravely ill.
Some of the difficulties inherent in Salvarsan were overcome by the development
of neosalvarsan in 1912 and sodium salvarsan in 1913. Although
Ehrlich achieved much, he fell short of his own assigned goal, a
chemotherapeutic that would cure in one injection.


Impact

The significance of the development of Salvarsan as an antisyphilitic
chemotherapeutic agent cannot be overstated. Syphilis at
that time was as frightening and horrifying as leprosy and was a virtual
sentence of slow, torturous death. Salvarsan was such a significant
development that Ehrlich was recommended for a 1912 and
1913 Nobel Prize for his work in chemotherapy.
It was several decades before any further significant advances in
“wonder drugs” occurred, namely, the discovery of prontosil in 1932
and its first clinical use in 1935. On the heels of prontosil—a sulfa
drug—came other sulfa drugs. The sulfa drugs would remain supreme
in the fight against bacterial infection until the antibiotics, the
first being penicillin, were discovered in 1928; however, they were
not clinically recognized untilWorldWar II (1939-1945).With the discovery
of streptomycin in 1943 and Aureomycin in 1944, the assault
against bacteria was finally on a sound basis. Medicine possessed an
arsenal with which to combat the pathogenic microbes that for centuries
before had visited misery and death upon humankind.


See also : Abortion pill ; Antibacterial drugs ; Artificial insemination ; Birth control pill ; Penicillin ; Reserpine ;  Arsphenamine