In the previous tutorial we turned to the birth of microbiology, but immediately prior,
we told the story of how the young British chemist William Perkin, while trying to prepare quinine,
accidentally started the artificial dye revolution, which sparked the birth of huge
dyestuff conglomerates in Germany. And as we mentioned, toward the end of the 19th century,
these dyestuff companies switched their focus, and gave rise to the first modern pharmaceutical
companies, some of which are still around today. One future giant was the company Farbwerke Höchst,
founded in 1863 in the town of Höchst, which is now part of Frankfurt, Germany.
The company became a huge player in the dye business through the second half of the 19th
century, growing its workforce to over 2,000 workers and scientists. Near the end of the
century, as the dye business became saturated, the company moved into synthetic drugs, and
over the years 1888 and 89, it introduced to the market two analgesics, antipyrine and amidopyrine.
These were the first synthetic drugs to be developed to treat fever and pain.
The chemistry is quite simple, consisting of two trivial chemical steps, but this turn to synthetic
chemistry as opposed to exclusively utilizing natural products was decisive and represents
the paradigm shift that led to the modern pharma industry. The new drugs were supplied as tablets,
since around 1860, machinery that could compress powders into tablets had been developed in France.
This practice of combining the drug with inactive substances called excipients and compressing the
powerdered mixture into a tablet had been slowly perfected, and was then available worldwide.
Another important area of research was the field of anaesthetics. It is difficult to
imagine that throughout most of human history, there was little to no relief from pain,
and even surgeries were typically performed without applying any kind of anaesthesia.
Historically, only a handful of substances with anaesthetic properties had been stumbled upon. The
power of poppy extracts was apparently discovered by the Sumerians 6,000 years ago. The great
Indian surgeon Sushruta introduced anaesthesia via hemp smoke, or cannabis, around 600 BCE.
Mixtures of alcohol and other herbal extracts were used in Rome. These herbs included opium,
mandrake, henbane, and hemlock. These were allowed to be used to alleviate the pain of crucifixion.
During the 19th century cocaine was commonly used, after the Inca discovered the properties of coca
leaves in the 14th century. And ether was also commonly used, after Paracelsus introduced it
in the 16th century. This was often mixed with chloroform, which produced some very nasty side
effects. Laughing gas, or nitrous oxide, was also effective but of short duration. None
of these procedures was completely effective and free of side effects. Not surprisingly,
chemists turned to organic synthesis to prepare better substances, and modern anaesthetics
are now all synthetic. Höchst introduced Novocain, also called Procaine, in 1905.
Surgeons preferred to stick with cocaine, but Novocain turned out to be extremely successful for
dental procedures, which finally became painless. Höchst grew to become a huge company. In 1913,
the year when the company celebrated its 50th birthday, there were 9,000 workers at the Höchst
site in Frankfurt, and the company reached a turnover of $100 Million. It had factories all
over Europe, including Russia, France and the UK. The Höchst site grew over the years to a
size of over 60,000 workers, including a large division devoted to research and development.
Another extremely successful German giant was Bayer. It was also founded in 1863 near Wuppertal,
much like other companies, in order to enter the immensely profitable dye business. Its
history somewhat parallels that of Höchst. Around 1880, Bayer also entered the pharma business,
and introduced phenacetin, an analgesic, which competed with the Höchst products as the first
synthetic analgesics devoid of addictive properties. In 1880 the company already
employed over 1,000 workers and had an R&D department with dozens of organic chemists.
This was essentially unheard of outside of Germany. The company got so big that
it eventually created its own city, the modern Leverkusen, which currently has 160,000 residents.
Bayer is most famous for the drug Aspirin, which was introduced to the market in 1898.
This drug is described in detail over in the pharmacology series, but to cover the basics,
the drug has anti-inflammatory properties, and its mechanism of action was not elucidated until 1971,
by Nobel-Prize winning British biochemist John Vane.
The drug is still widely used today for its diverse biochemical and medicinal properties, and
has been called “the wonder drug”. This is rather astounding, given its structural simplicity.
The lead for this structure comes from willow extracts, later known to contain salicylates.
The synthetic version, aspirin, also commonly called acetylsalicylic acid,
is a more active and safer version with respect to the extracts it is inspired from.
Aspirin is currently the most utilized drug in the world, on a tonnage basis, with a volume of
40,000 metric tons, or 40 million kg per year, an amount equivalent to 50-120 billion pills.
In many countries, including Germany, Aspirin is still Bayer’s brand name, and acetylsalicylic acid
is the generic name, whereas in other countries, like the US, aspirin has become the generic
name of the drug because of procedural complications with the trademark office.
In the same year that it launched aspirin, 1898,
Bayer launched a simple derivative of morphine named heroin, as a cough suppressant. It was
available over the counter, and it remained so for decades, until people started to realize
the addictive properties of the drug. We will discuss the history of heroin later.
Other important, and later controversial, market introductions were in the field of hypnotics.
The first barbiturates appeared on the market around the turn of the century. Barbituric acid
was first prepared by German chemist Adolf von Baeyer in 1864 by reacting two compounds called
diethyl malonate and urea. The story goes that the chemists went out to celebrate the discovery
at a tavern where an artillery garrison was also celebrating the feast of Saint Barbara,
their patron saint, hence the name of the new substance, an amalgam of Barbara and urea. The new
substance had no biological properties, however, and it took a few decades until chemists decided
to make some modifications to the molecule, which produced drugs with important hypnotic properties.
Indeed in 1904, Bayer marketed barbital with the trade name of Veronal. The substance quickly
replaced the most common treatment against insomnia, bromide, and enjoyed wild success
all over the world. However, its continued use triggered tolerance, and insomniacs needed
larger and larger doses to achieve the desired effects. The effective dose was around 600 to
1,000 milligrams per day, and the drug could be lethal at 3.5 grams per day. It was inevitable
that people would abuse the drug. Deaths were not uncommon, including some very famous people,
and in addition Veronal became a preferred tool to commit suicide, as the death was
painless. Barbiturates are past their heyday and no longer commonly prescribed. However,
hundreds of people still die each year from barbiturate abuse, whether accidental or planned.
Another German Pharma giant that should be mentioned is E. Merck. This is a Pharma company
which did not originate from the dye business. The company started as a pharmacy in Darmstadt,
in 1668, and evolved into a modern pharma company by sticking to the natural product
business. It made a name for itself by marketing several important alkaloids, including morphine.
Among its key products was Oxycodone, marketed as Eukodal, a synthetic opioid and powerful
painkiller, which recently has become well known for its devastating addictive potential.
Merck established production and R&D sites in many countries, including the US,
and specifically in Rahway, NJ, whereas other German companies thrived by exporting
their new drugs to the growing US market. As one might imagine, World War I changed
the situation dramatically, and signaled the end of the supremacy of the German chemical
and pharmaceutical companies over the rest of the world. Allied countries, including the US and UK,
stopped importing German products, and local branches of German companies were closed down.
The US revoked all German patents, and local producers could start making and selling
German products, which enabled the fledgling US and UK pharma industries to quickly grow. The US
branch of the German company Merck was broken off from the mother company, and Merck became de facto
a US company, later to be renamed Merck, Sharp and Dohme, and this separation from the original
owner, E. Merck Darmstadt, became permanent. The end of World War I saw the German economy
in shambles, with some of its best pharma companies having lost patent protection
worldwide for their most important products. At the same time, the victory in the war was
a great boost for the US pharma industry, which would emerge in the coming decades as the most
innovative and productive worldwide. However, the pharma industry in Germany was not quite dead.
As we will see in the next chapter, the antibiotic revolution actually started, as usual, in Germany.