11: Industrial Roots of Drug Production

Recap:
 Medical laboratories emerged in France and Germany in the mid nineteenth
century
 They were places where physiological phenomena were investigated, especially
the processes of metabolism
 Where debates over spontaneous generation and vitalism were conducted
 Where new technology for registering and recording phenomena such as pulse,
temperature and blood pressure were developed
 Where bacterial microbes were identified (1 per year between 1879 and 1900) and
controlled for virulence
 Where vaccines were produced
 The first therapeutic application of the laboratory was preventive, i.e. vaccination.

This lecture will explore the curative breakthroughs in the lab, looking at the historical
roots of chemotherapy and the modern pharmaceutical industry: i.e. how laboratories
became sites for producing drugs.

We are going to look at two of the first blockbuster drugs: Aspirin and Salvarsan.

Aspirin
 First came on the market in 1900 – the quintessential twentieth-century drug and
the world’s first and greatest blockbuster drug.
 Truly a wonder drug, now used for all kinds of preventive applications including
against heart-attack and stroke.
 An introductory organic chemistry textbook has this to say about Aspirin: ‘…we
have much to learn about this enigmatic remedy. No one yet knows exactly how
or why it works, yet more than 15 billion aspirin tablets are consumed each year
in the United States.’ (Pavia, Donald. (2005) Introduction to Organic Laboratory
Techniques, p. 55)
White Willow Bark
 Ancient remedy – It is mentioned as an analgesic in ancient Egyptian medical
texts; one of the Hippocratic physicians left a record of using a powder of white
willow bark to treat pain; Galen recommended it.
 Medieval physicians seem to have forgotten about its properties, but it may have
existed as a folk remedy.
 In 1758 an English vicar called Edward Stone idly broke off a leaf of the white
willow tree and tasted it.
 It was powerfully bitter and reminded him of the taste of cinchona bark that was
used to treat malaria.
 Accordingly, he ground up the bark to make powder and administered it to some
fever patients, finding that it seemed to alleviate their symptoms.
 This is how he rendered his train of thought in a letter to the Royal Society:
“There is the bark of an English tree, which I have found by experience to be a
powerful astringent, and very efficacious in curing agues and intermitting
disorders. About six years ago I accidentally tasted it and was surprised at its
extraordinary bitterness; which immediately raised in me a suspicion of its having
the properties of the Peruvian bark. As this tree delights in a moist or a wet soil,
where agues chiefly abound, the general maxim, that many natural maladies carry
their cures along with them, or that their remedies lie not far from their causes,
was so very apposite to this particular case, that I could not help applying it; and
that this might be the intention of Providence here I must own had some little
weight with me.” (Quoted in Jeffreys, Diarmuid. (2005) Aspirin: the remarkable
story of a wonder drug. London: Bloomsbury)
 By the end of the eighteenth century, the idea of a scientific pharmacology via
chemical isolation and analysis of the active ingredients of medicinal substances
was taking shape.
 In 1804, for example, two French pharmacists isolated a crystalline substance
from opium; nicotine, strychnine, caffeine and finally quinine followed, and were
refashioned into potent drugs, known as the alkaloids.
 Willow bark was by then used as a cheap domestic alternative to cinchona bark,
and it was a natural candidate for this kind of investigation.
 In 1828 by a Bavarian professor of pharmacy called Joseph Buchner, managed to
extract some yellowish, bitter crystals, which he named salicin after the Latin
name for willow, later renamed salicylic acid.
 A Swiss pharmacist working on another plant with anti pyretic properties,
meadowsweet, managed to isolate some crystals, and found that it was the same
substance.
 The stuff was medically potent but had very severe side-effects, producing gastric
irritation.
 Because of these side-effects, the synthesis of a really useful version of salicylic
acid had to take a serious detour through the new industrial economy.

 It was actually not traditional medicine at all, but the dyestuffs industry that first
provided the materials and the infrastructure for the emergence of the
pharmaceutical industry in the form in which we recognize it today.

 The connections between labs, dyes, medicine and industrial drug production
were forged by the systematic investigation of novel compounds produced by
 other industrial activities. Molecules move between these different sites, creating
new alliances and axes of power and knowledge.

Aniline molecules

 The molecules in question were organic compounds derived from coal tar – a by-
product of the new coal-fired industrial economy in England.

 It is produced when coal is carbonized to make coal gas. Sticky, black, strong-
smelling, volatile stuff, available in vast quantities.

 Complex chemical compound, varying greatly, depending on the type of coal

used and the method of distillation.

 It was intriguing, partly because of its potent smell, and it was quickly determined
that all sorts of useful substances might be made of it.

 The first application was as a preservative for wood that was in contact with
moisture: creosote. A Scottish chemist called Mackintosh used one of its
derivatives to treat fabric. Solvents for varnish and paint were fractionated out of
it. Carbolic acid is produced by successive distillations of coal tar, and was used
by Joseph Lister as the first surgical antiseptic. Coal tar is still used as a treatment
for dandruff, psoriasis, and head lice, and as an ingredient in soap.

 By far the most economically important derivatives, however, were the aniline
dyes. Dyestuffs are the pivot of the origins of the pharmaceutical industry.

William Perkin

 William Perkin’s career stands as an example of the movements between dyeing

industry and medicine

 Perkin was a chemistry student in London, working under a German chemist

called August von Hofman who was the first person to use ball and stick
molecular models in his chemistry lectures.

 Hofman was analyzing coal tar, and trying to separate it into its various
components.

 Inspired by the potential for medicinal applications, his student, William Perkin
set up a home laboratory.
  Perkin wanted to synthesize quinine, because of problems with supply – political,
topographical.

 Attempting to synthesize quinine, Perkin started to tinker with coal tar (like his
mentor von Hofman), as it seemed a likely candidate for bioactivity

 Perkin heats it, distills it, breaks it down. He fails to synthesize quinine but finds
that one of its fractions is an incredible bright, brilliant purple, which dyes silk
without fading.

 Perkins starts with a medical aim – synthesis of quinine, one of the only effective
drugs in the world at the time – ends up in the dyeing industry.

 He sets up a dyestuffs factory, but sells it to some people who have no idea how
to run it, and the centre of the industry moves to Germany.

 In Germany, the reverse movement from the dyeing industry to medicine

happens.

German dyestuffs industry

 Great Britain had long had a stranglehold on the dyeing industry because the
empire gave British merchants access to sources of natural dyes such as indigo.

 Germany had the labs because of the reforms in German research after the
Napoleonic Wars.

 When news of Perkin’s discovery leaked out, coal-dye companies sprang up all
over Germany, and before long they were masters of the new industry.

 In 1886 two Strasbourg hospital doctors ordered from an industrial chemist some
naphthalene (aromatic coal tar derivative, main ingredient in mothballs) for a
patient suffering from intestinal worms, as part of an experimental study. There
was a mix-up with the order and the pharmacy ended up giving the patient another
common by-product of the coal tar industry, acetanilide, that was used by the
dyeing industry.

 The worms did not go away, but the patient’s temperature dropped. The doctors
discovered the mix-up and decided to conduct some tests on the substance.
 The tests confirmed that it worked as an anti-pyretic (anti-fever), so they
approached a chemical company to see if they were interested in producing
quantities of the stuff to sell as medicine.

 Only problem was that the stuff – acetanilide – was very common, so they
renamed it ‘Antifebrine’ and made a lot of money.

 This inspired a chemist called Carl Duisberg at Freidrich Bayer dyestuffs

company to try the same trick, and he developed an anti-pyretic from a waste
substance that was lying around one of their plants waiting to be disposed of,
which he called Phenacetin.

 Both drugs were effective but pretty toxic, turning patients’ skin blue, but Bayer’s
one was a bit less bad. Influenza epidemic ensured high sales and Bayer was
launched into the drug business.

 They started to employ young chemists to tinker around with compounds and to
try and make therapies.

 Perhaps recalling the mix-up that had led to Antifebrine, Duisberg had a liberal
attitude to scientific discoveries, saying to new employees that a technical
breakthrough ‘depends more often than not on coincidences that no-one can
predict. Each individual is merely required to work inventively and create
innovation.’

 One of the new employees was a young chemist named Felix Hoffman, who
decided to try and make a version of salicylic acid that did not corrode the
stomach lining.

 He succeeded in developing the basic chemistry of aspirin, the same fortnight as

he derived a chemical derivative of opium that he called ‘heroin’ for the heroic
way it made people feel.

 Heroin was more potent and faster acting than morphine because it passes more
rapidly from blood to brain.

 The new drug was presented as a cough chest and lung medicine on the grounds
that it helped people with TB to sleep. Bayer advertised it in German, English,
Italian, Russian and other languages.

 In a typical early report of 1898, G. Strube of the Medical University Clinic of

Berlin tested oral doses of 5 and 10 mg of heroin on fifty phthisis patients and
found it effective in relieving their coughs and producing sleep. He noted no
 unpleasant reactions; indeed the patients liked it and continued to take the heroin
after he ceased to prescribe.

 It was considered so much less addictive than morphine, that it was actually used
to treat morphine dependence!

 By 1903, the wisdom of this was being questioned, and the stuff began to be
heavily regulated, but as late as 1911 one Kentucky physician was quoted as
saying that “bringing charges against heroin is almost like questioning the fidelity
of a good friend. I have used it with good results.” The story of Oxycontin is
somewhat similar.

 Aspirin, however, turned out to be fabulous stuff, and became, in the words of a
popular medical historian “one of the most amazing creations in medical history.”

Salvarsan

 The second drug that illustrates the origins of the pharmaceutical industry is
Salvarsan, a drug against syphilis, which did not have any botanical origin.

Paul Ehrlich

 Paul Ehrlich, medical student who loves the lab.

 Works in Leipzig at a famous German research facility (unification of Germany

1871 after the Franco-Prussian War) and writes a dissertation on histological
staining

 Histological staining exploited the chemical properties of the new aniline dyes.

 The fact that they stained some components of the tissue leaving others uncolored
was what made them valuable.

 Ehrlich was working in hospital laboratories, and was interested in chemical

approaches to biological problems.

 He decided that the selective action of the aniline dyes on the tissue looked like
just the kind of bioactivity that might translate into a therapeutic application.

 As a result, he coined one of the key terms of modern pharmacology – ‘receptor’.

Theorized that cells have structures that enable different chemicals to ‘dock’. Also
coins the term ‘chemotherapy’ (as opposed to immunotherapy of vaccines).
  Observed, for example, that the recently-discovered malaria parasite specifically
took up the aniline dye methylene blue.

 In 1891 he showed that methylene blue had a modest therapeutic effect on two
patients with malaria. By this time the Dutch had established quinine plantations
on their territories in the East Indies, so Ehrlich’s industrial substitute didn’t catch
on.

 The report that he wrote on it is the reading for this week, along with a piece on
the background.

Salvarsan

 Ehrlich did, however, develop the some of the most enduring techniques for drug
development.

 With the support of the huge corporation I. G. Farbenindustrie (‘color industry’),

in 1907 he engaged in a search for a drug to treat syphilis.

 Arsenic killed the syphilis spirochete in vitro, but was a poison.

 Ehrlich therefore engaged in the systematic testing of hundreds of arsenic

compounds looking for a magic bullet that would kill the syphilis parasite but
leave the host unaffected, (like the selective staining of histology samples).

 This systemic screening technique became one of the lynchpin techniques of the
modern pharmaceutical industry.

 In 1909 Japanese chemist Sahachiro Hata joined Ehrlich and introduced animal
testing to the laboratory. He had developed a technique for inducing syphilis in
rabbits. Hata’s animal testing was crucial to the method.

 The 606th compound that Ehrlich had initially tested had little bioactivity in vitro
but was shown to be effective in vivo (it has to be metabolized to work).

 He began human trials (unsystematic by today’s standards), sending samples of

the drug to his physician friends. Good results, especially when compared with
mercury, which was the only therapy available.

 Announced the cure at an international medical congress in 1910, and was

swamped with requests
  Salvarsan (salvation thru arsenic) was unstable and unpredictable, lots of
problems with manufacture and delivery. Intravenous technique was still not
standardized.

 Salvarsan is only toxic to the syphilis spirochete and not to the human host if it is
used at exactly the right dose and right phase of its chemical breakdown. Ehrlich’s
idea of the ‘magic bullet’ not quite as simple as he had hoped.

 Salvarsan was distributed in powdered form; doctors had to dissolve it in several

hundred milliliters of pure, sterilized water and then inject it intravenously, taking
care to minimize air exposure.

 Some of the side effects attributed to Salvarsan turned out to be due to improper
handling and administration of the drug, causing Ehrlich to observe that "the step
from the laboratory to the patient's bedside ... is extraordinarily arduous and
fraught with danger."

 He poured himself into helping doctors standardize handling and administration

of the drug and eventually developed an easier-to-handle derivative of Salvarsan
with improved water solubility.

 606, and its less chemically volatile successor Neo-Salvarsan, nevertheless

became the first commercially viable drugs made with the screening compounds
methods, and an industry was born.

Medicine, molecules and industry:

 Just as substances can be broken down and reassembled in the lab, so the products
of the lab can rearrange the social and political order.

 New kind of industrial medicine was made by forging links between labs, where
new molecules like anilines were created, and factories, where they were mass-
produced for dyeing, and hospitals, where they were used for staining tissues.

 The concept of the cell ‘receptor’ then facilitates the passage of these molecules
from histology labs to experimental physiology. Therapeutic successes, such as
using methylene blue to treat malaria, encourage this work.

 Search for magic bullets is on. Animal testing hundreds of arsenic compounds
leads to the discovery of the therapeutic effect of 606.

 Announcement of the drug creates great demand, and the mass-production of 606
is undertaken by the same German chemical industry involved in making dyes.