FROM THE JAMES LIND

LIBRARY

The introduction of ‘chemotherapy’

KJ Williams
5 Maplewood Road, Wilmslow, Cheshire SK9 2RY, UK
E-mail: [email protected]

DECLARATIONS Paul Ehrlich and studies of the Syphilis was a scourge affecting a significant
effects of dyes on infectious proportion of men and women in the early 20th
Competing interests
century. Routine therapy for the disease had been
None declared organisms
with mercury, both as an ointment and internally,
but this was quite toxic.3 In 1905, Fritz Schaudinn
Funding In the late 19th century, Paul Ehrlich (1854–1915)
and Erich Hoffmann identified the causative or-
None developed an early interest in the specific staining
ganism of syphilis – a spirochaete – which be-
of tissues with dyes, first with methylene blue and
Ethical approval longed to the same group of organisms as the
then with trypan red and atoxyl. He reasoned this
Not applicable trypanosomes. So it was that another arsenical –
might allow the detection of a substance that
diamino dihydroxy arsenobenzol (arsphenamine)
Guarantor
would specifically bind to and kill microbes with-
– was discovered, synthesized in 1907 by Alfred
out harming human cells. After working initially
KJW Bertheim, and tested on spirochaetes by Ehrlich’s
under Robert Koch in Berlin, Ehrlich moved to his
assistants. The two assistants who first tested it
Contributorship own institute in Frankfurt (Main). After it had been
concluded that it was useless, and it was therefore
KJW is the sole shown in 1905 that atoxyl, an arsenical, had some
put aside until Ehrlich asked his Japanese assist-
contributor activity against trypanosomes, his chemists, led by
ant, Sahashiro Hata, to repeat the experiments.
Alfred Bertheim, synthesized a series of arsenical
Acknowledgements Hata found that arsphenamine was superior to all
derivatives.
The author is
the other drugs that had been tested, prompting
Over this period Ehrlich developed a close rela-
Ehrlich’s fury that the inadequate methods used
grateful to Tilli tionship with Professor August Laubenheimer,
by his former assistants had resulted in the delay in
Tansey and Ulrich who had joined the pharmaceutical arm of the
this discovery.3
Troehler for Meister, Lucius and Bruening dyeworks, now bet-
Arsphenamine was known first by the number
comments on an ter known by their location (Hoechst). Ehrlich’s
606, as the 606th preparation tested in Ehrlich’s
earlier version of work expanded in 1906 after he moved his labora-
laboratory, and subsequently by its trade name
tory into the Georg Speyer Haus, near Frankfurt,
this commentary. Salvarsan when it was marketed in 1910. Ehrlich
close to the dye factories. There were some partial
Additional material continued to evaluate further compounds and
successes, for example, compound 418 (arseno-
for this article is improved upon Salvarsan with compound 914,
phenylglycine), which was tested clinically by the
available from the Neosalvarsan, which was more soluble and had a
dermatologist Alfred Neisser (whose name we now
James Lind Library lower arsenical content and appeared more active.
associate with the gonococcus). Compound 418
website (www. also had some activity when tested in Africa against
jameslindlibrary.org), trypanosomes, which cause sleeping sickness, but it Dramatic effects of Salvarsan in
where it was orig- was not as powerful as atoxyl. Ehrlich was looking
patients
inally published for an agent that could achieve sterile cultures in
animals with a single dose. He coined the terms Salvarsan was tested in patients for the first time in
‘chemotherapy’ and ‘magic bullet’ to characterize the spring of 1909. Ehrlich was cautious because of
the processes he had in mind. He first used the term the disaster that had followed Robert Koch’s to-
‘magic bullet’ at a Harben Lecture in London in tally unsystematic clinical testing of his presump-
1908,1 although the concept (Zauberkugel) had ap- tive wonder drug, Tuberculin. Ehrlich therefore
peared earlier in his writings in German.2 arranged for carefully recorded clinical studies to

J R Soc Med 2009: 102: 343–348. DOI 10.1258/jrsm.2009.09k036 343

be done by a small group of doctors in Uchtspringe (1) Does it have a specific effect in syphilis, and if
(Alt), Magdeburg (Schneider), Bonn (Hoffmann), so, does it exceed that of already known drugs;
St Petersburg (Iversen) and Pavia (Ascoli), giving (2) Does it cure syphilis;
guidance on dose and selection of patients. Later (3) Is the eventual risk of the drug in an acceptable
the same year, Ehrlich’s friend Konrad Alt pro- balance with the size of its [beneficial] effects?’
vided the first published report of the dramatic
‘Concerning the first point, there can no longer
effects of Salvarsan in patients.4 be any doubt at all, even when judging with the
‘In total, 31 patients with progressive paralysis greatest scepticism, that the new drug acts on the
were treated, all of whom had previously had a symptoms of syphilis in all infectious forms with a
definite positive Wassermann reaction (repeatedly speed and thoroughness which no other drug so far
demonstrated); 7 of them lost the [positive] reaction known can match, even approximately. We have
completely, in one it returned after 5 weeks, [but] in tried this out in 80 cases and the effects occur with
the others it remained negative. In a larger number, the certainty of an experiment .’
the Wassermann reaction decreased substantially, ‘The curative effects are so rapid that one cannot
but returned to its former level after some time. demonstrate patients because after a few days there
Initially we had not treated patients with high is no longer anything to be seen on them, and they
doses, so some of the cases may not have responded leave the hospital.’
for this reason. It seems that it was cases of less than Still, like Konrad Alt, Wechselmann concluded
2 years duration of paralysis who were mostly optimistically but cautiously:
influenced .’
‘We are aware that everything I have presented
Alt recognized the need for a larger case series: today still leaves many gaps; however, this is
‘The question of whether and how the clinical inevitable in such a new situation. We shall have to
course of paralysis has been affected is obviously continue working quietly and critically in order to
crucial. It would be premature to make a judgement determine the exact indication and contraindica-
in so changeable a disease on the grounds of such a tions of the drug. However, one may safely say
small number. We have seen a rapid and noticeable today that Ehrlich’s genius has won a big battle in
improvement not only in some patients who lost the the war against syphilis. But because the path
[positive] Wassermann reaction, but also in many which has led to today’s results has been based on
others. Whether this was due to the treatment can firm scientific experimental foundations, we can be
only be decided after a larger test series and a longer quietly confident that this path is the right one, and
observation period .’ express our hope that it will lead us to final victory.’
‘Our treatment trials with arsenophenylglycine By the end of 1910 – the year the drug was given
in patients with progressive paralysis are being its trade name Salvarsan – some 65,000 doses had
extended to a larger series. One may claim already, been administered to over 20,000 patients, a pre-
without being overhasty, that our preliminary re- viously unheard of series before marketing, as was
sults support the hope that it should not be com- noted at the first presentation of the clinical results
pletely ruled out that, sooner or later, we will no in Wiesbaden in 1910.6
longer be forced to confront entirely with folded Salvarsan was prepared at Hoechst in stainless
arms the future course of patients with an early steel containers by a complex chemical process
diagnosis of progressive paralysis. As the remis- with a yield just under 16%, avoiding explosions
sions of such patients show clearly, the paralytic and fires due to volatile ether. It was a fine yellow
process can at least be brought a standstill, even if powder, soluble in water, ether and glycerine,
not to a cure.’ which had to be packaged under carbon dioxide in
The year after Alt’s report, Wilhelm Wechsel- ampoules, to prevent oxidation to a toxic form. By
November 1910, Hoechst was producing 12,000–
mann’s lecture to the Berlin Medical Society on 22
14,000 ampoules per day and Ehrlich was able
June was published.5
to offer small amounts to the many doctors who
‘The questions which one had naturally to ask when requested a supply, but only after quality controls
examining a new preparation were: and further tests in his laboratory. Tests were

344 J R Soc Med 2009: 102: 343–348. DOI 10.1258/jrsm.2009.09k036

developed to assess the drug’s state of oxidation doses. Also, although Salvarsan eliminated para-
and to test for its presence in the urine of patients. sites in the tertian form of malaria, they recurred
and did not respond as well to a second course,
McDonagh and the evaluation of though Salvarsan therapy made them more sus-
ceptible to quinine. McDonagh also recognized
Salvarsan in Britain that Salvarsan was somewhat variable in action,
In Britain, the most substantial early experience depending on its solubility and acidity. Already
with Salvarsan was obtained at the Lock Hospital, some discrepancies had been observed between
London, by James McDonagh (1881–1965), who effects in animals and humans, and skin tests
was the outpatient surgeon at the hospital from to evaluate the likelihood of reactions (as with
1909 to 1929.7–11 The hospital had been founded in tuberculin) were poorly predictive.
1746 as the first voluntary hospital for venereal By 1912 some problems had emerged with
diseases, and was originally in a building in Gros- Salvarsan.7,13 In his book, McDonagh referred to
venor Place, near Hyde Park.12 By McDonagh’s Wechselmann’s suggestion that dead bacteria
time, male outpatients were seen in a building in and fungi in the distilled water caused the fever
Dean Street, female patients in one in Harrow Road. and rigors that sometimes followed admin-
McDonagh published a book about Salvarsan in istration of the drug, and he confirmed Wechsel-
1912.7 It describes the drug’s history, explains its mann’s 1910 observations by using re-distilled
method of administration, and provides estimates water to avoid the problems. The inflammatory
of its potency against Spirochaete pallida (Treponema condition caused by Salvarsan injection also made
pallidum). McDonagh explained what the drug did it theoretically unwise to use the drug in people
and did not do and its uses and abuses, observing with epilepsy, in case the inflammation gave rise
that, like all new remedies, it had to pass through to seizures. However McDonagh treated a case
the two stages of initial extravagant laudation and who not only recovered his memory but had no
then extravagant abuse. He illustrated these with further seizures. Salvarsan had its most marked
many case reports and pictures of genital and ex- toxic effect on patients already suffering from
tragenital chancres, and the complications associ- meningitis or even alcohol poisoning, which was
ated with syphilis. deemed to have ‘weakened the tissues’. Another
McDonagh’s book is more of a review of his issue relating to the patients under evaluation
extensive experience with illustrated cases rather was the development of concurrent conditions
than a numerical summary. The early chapters give such as Herpes genitalis or chest infections. Sum-
an overall account of his experience, without tabu- marizing the drug’s safety profile, McDonagh
lated data or numbers, written in the usual ‘authori- stated that ‘there is no drug which has not at some
tative’ style, supported by detailed case histories. time or another given rise to toxic symptoms, so
Chapters are devoted to toxic reactions, neuro- differently constituted in each human frame’. He
recurrences, fatal cases following injection and con- considered humans to be more sensitive than ani-
traindications. The emphasis of the text then turns mals to these effects, and that it was impossible to
to methods of administration, effects on the syphilis predict who would be affected.
test developed by August von Wassermann and the McDonagh’s book was important in confirming
excretion of arsenic. Case histories are used to illus- the early promise of Salvarsan and establishing its
trate results in the primary, secondary and tertiary efficacy, which contrasted with the exorbitant
stages stage of syphilis, syphilis of the nervous sys- claims made for several other German patent
tem, congenital syphilis and then conditions other medicines at the time. This work became an im-
than syphilis. The book ends with a short postscript portant milestone in demonstrating the growing
on early experience with Neosalvarsan. importance of the German dye industry, which
McDonagh described some general observa- produced 90% of the world’s synthetic dyes, and
tions that had already been made in earlier the diversification into pharmaceuticals of firms
studies in Germany, including the ‘immunity’ to such as Hoechst, Bayer and others. These develop-
Salvarsan that could occur in patients already ments had already given rise to phenol antiseptics,
pre-treated with other arsenicals, observing that phenacetin, aspirin and a growing number of syn-
‘immunity’ was more likely after intramuscular thetic drugs.

J R Soc Med 2009: 102: 343–348. DOI 10.1258/jrsm.2009.09k036 345

In addition to his book, McDonagh commented Research Committee (MRC) had incorporated
frequently on these issues in the medical literature, several Burroughs Wellcome staff, leaving the firm
as it was clear that not everyone shared his views. with a shortage of experience to perform assays, so
Regarding the toxic effects of Salvarsan he wrote: the MRC became involved in the process of assay
and standardization.
‘As all of us require an unbiased opinion upon
However, McDonagh, who had read the pat-
Salvarsan, it would have been better to have given
ents and literature, remarked that ‘because they
a summary of the whole of the Fifth German
are chemically identical it does not follow that
Congress of Neurologists held last October in
they are similar in other respects.’ He pointed out
Frankfurt, as then we could have heard both sides.
that German patents were written in a way to
Hearing only one side leaves this side widely open
deceive so how could British products be the
to criticism. In this country more than any other
same. Many of his complex arguments about in-
we have heard so much as to what the “great” or
complete linkages and side reactions confused
“well-known” syphilologists think of Salvarsan.
Notice that their greatness has increased since the his main point, which was that clinical data
advent of the drug, although as often as not they rather than animal tests of purity were needed.14
have never given an injection. Why an able clini- He wrote:
cian or a reader of many books should be able to ‘I am fairly of the opinion from several toxic effects
judge a subject of which his experience is nil must I have seen following the use of the new products
be an enigma for many.’8 that the successful manufacture has not been solved
and that the medical profession would be well
advised to await the reports of clinicians before
Manufacture of arsphenamine in using the product.’9
Britain
This was not the message that the MRC wanted
Recognition of the reliance on Germany for drugs to convey, as all they had was British and some
was brought home dramatically two years later French arsphenamine.
with the sudden outbreak of World War I, when The MRC played a prominent role in support-
German drugs became unavailable.11 My research ing the British synthetic drug industry. Initially
on the origins of the synthetic drug industry in they focused on the manufacturing and assay con-
England14 showed that Burroughs Wellcome was, trols but following the heated discussions with
to the surprise of Hoechst, able to synthesize and McDonagh they realized they needed data on clini-
produce arsphenamine and other synthetic drugs cal efficacy and safety, particularly as the Select
within weeks of the outbreak of war, when the Committee on Patent Medicines had recently chal-
patents of the drugs were abrogated. Although lenged the many unsubstantiated reports of cures
synthetic chemistry had begun on a small scale in of venereal diseases.14 The MRC appealed to mem-
Britain in the 1890s and Burroughs Wellcome had bers of the medical profession, who:
synthesised various alkaloids to show that they
had extracted and purified the active ingredients ‘would be performing a service of national impor-
from plants, Britain had failed to produce synthetic tance, in the present emergency, by keeping accu-
drugs on a large scale.15 The British firms were rate records of cases in which the new preparations
many times smaller than the German dye firms were used, and by placing such records at the
and could not compete with them in producing disposal of the committee for their private infor-
synthetic drugs. Furthermore, Britain was also re- mation and guidance. Particular stress must be laid
liant on the German firms for many of the raw upon the desirability of recording in every case, the
materials required. name of the preparation used and the serial number
Throughout the early stages of the war, great applied by the manufacturer to the particular batch
emphasis was placed upon demonstrating that the employed together with such details as to dosage,
arsphenamine produced by Burroughs Wellcome, the precautions taken to ensure purity of the water
and marketed as Kharsivan, was as good as the used and finally the results of the administration,
German products Salvarsan, Neosalvarsan and later both as regards therapeutic efficacy and the presence
Silver Salvarsan. The recently established Medical or absence of special incidental symptoms.’16

346 J R Soc Med 2009: 102: 343–348. DOI 10.1258/jrsm.2009.09k036

One of the most important of the reports stimu- This had immediate benefits in 1922–1923 in
lated by this call was published by HC Lucey, who the production of insulin,19 which, although not
worked at the Royal Herbert Hospital, Woolwich. synthetic, required elaborate control procedures
Recording his experience with 600 injections of the for large scale manufacture. These developments
British arsphenamine, he concluded ‘I believe were driven particularly by Francis Carr, a chemi-
Kharsivan to be every bit as potent as the original cal engineer who had been involved in producing
German preparation in the incidence of adverse arsphenamine at Burroughs Wellcome, who
reactions and the bactericidal power of the blood’.17 moved first to Boots and then to British Drug
The British army in France studied Kharsivan Houses. It is often not appreciated that, as early as
(the Burroughs Wellcome trade mark for its ver- 1921, industry (through Carr in particular) asked
sion of arsphenamine) and Galyl (the Poulenc the Medical Research Council to establish a sys-
Frères version of the drug imported by the Anglo tem of clinical trials to test its products.14 Though
French Drug Company).14 Collected under con- clinical trials remained unregulated, they were
ditions of war, these data were not as extensive as overseen by committees of the Medical Research
those that seemed to have been collated earlier in Council, and subsequently by its Therapeutic
Germany.14 Although cure rates were high, esti- Trials Committee.19,20
mates of adverse reactions were very variable, and As far as the treatment of syphilis was con-
valid comparisons between the French, British and cerned, arsenicals remained the mainstay of treat-
German versions of arsphenamine were imposs- ment of syphilis, later in combination with
ible.14 Much as the MRC wanted to prove that bismuth, until penicillin became widely available
British Kharsivan was as effective and as well toler- after World War II. Penicillin then rapidly became
ated as German Salvarsan, the data were insuffi- accepted as the treatment of choice, although peni-
cient to support confident claims – yet the MRC cillin treatment schedules for syphilis were not
still stated publicly that British arsphenamine was standardized until 1960.21
as good as German arsphenamine.
As a result of continued controversy, the MRC
set up a second Salvarsan Committee in 1917. Even References
after the war had ended, the MRC defended British 1 Ehrlich P. Experimental researches on specific therapy. On
immunity with special relationship between distribution and
arsphenamine, although they recognized privately action of antigens. Harben Lecture. London: Lewis; 1908
that it was impossible to provide reliable compara- 2 Witkop B. Paul Ehrlich and his magic bullets – revisited.
tive data with the German product. An annual Lecture given at the Paul Ehrlich Foundation, Frankfurt,
13 November 1998. See http://www.aps-pub.com/
report issued five years later argued that the Com- proceedings/1434/Witkop
mittee had assisted not only in ‘meeting an imme- 3 Abraham JJ. Some account of the history of the treatment
diate national need, but in founding an industry of syphilis. Br J Venereal Diseases 1948;24:153–61
4 Alt K. Behandlungsversuche mit Arsenophenylglyzin bei
which [would] be of increasing importance to the Paralytikern. Muenchener Medizinische Wochenschrift
practice of medicine’.18 1909;56:1457–9
It did indeed prove to be a turning point in the 5 Wechselmann W. Über die Behandlung der Syphilis mit
Dioxydiamido-arseno-benzol. Berliner Klinische
history of the pharmaceutical industry in Britain. Wochenschrift 1910;47:1261–4
Although Burroughs Wellcome had previously 6 Baumler E. Paul Ehrlich. Scientist for life. New York, NY:
synthesized drugs, it had done so only to confirm Holmes & Meier; 1984
7 McDonagh JER. Salvarsan in syphilis and allied diseases.
the properties of their alkaloidal extracts. The Oxford: Oxford Medical Publications; 1912
company did not attempt to compete on a com- 8 McDonagh JER. Some toxic effects of Salvarsan. BMJ
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9 McDonagh JER. The manufacture of Salvarsan products in
the ‘needs must’ situation of World War I, as others England and France. BMJ 1915;1:697
took up drug synthesis and large scale manufac- 10 McDonagh JER. The manufacture of Salvarsan products in
ture, Burroughs Wellcome shared its experience England and France. BMJ 1915;1:742
11 McDonagh JER. The chemio-therapeutics of Mr
with Allen & Hanburys, Boots, Evans and British McDonagh. BMJ 1916;2:340–1
Drug Houses. Subsequent growth in experience 12 Williams DI. Short History of the London Lock Hospital and
placed Britain in a stronger position when the Rescue Home 1746–1906. London: Lock Hospital; 1906
13 Yakimoff WL, Kohl-Yakimoff N. Der Einfluss von
country next faced the prospect of war with Mikroben auf die Wirkung des Salvarsan. Muenchener
Germany. Medizinische Wochenschrift 1911;58:2601–4

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15 Church RA, Tansey EM. Burroughs, Wellcome & Co., 20 Toth B. Clinical trials in British medicine 1848–1948, with
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16 Editorial. The manufacture of Salvarsan products in 21 Benedek T. The ‘Tuskegee Study’ of syphilis: analysis of
England and France. BMJ 1915;10 April:1091 moral versus methodologic aspects. In: Reverby SM, ed.
17 Lucey HC. The therapeutic and reaction effects of Tuskegee’s truths: rethinking the Tuskegee Syphilis Study.
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18 Medical Research Council. 5th Annual Report. London; p. 213–35
MRC; 1922

348 J R Soc Med 2009: 102: 343–348. DOI 10.1258/jrsm.2009.09k036