Aspirin's 100th Anniversary: CHEMICAL & ENGINEERING NEWS, AUGUST 18, 1997
Germany's Bayer was not looking for a drug to relieve the pain of rheumatism
100 years ago, but a 29-year-old Bayer chemist and pharmacist named Felix
Hoffmann was looking for a way to relieve his father's suffering. Sodium
salicylate used to treat rheumatism victims at the time not only tasted
awful, but the acid also attacked the mouth and stomach linings. Working
in Bayer's Elberfeld, Germany, pharmaceutical laboratory , Hoffmann acetylated
salicylic acid in August 1897. The resultant acetylsalicylic acid powder,
aspirin, had few of sodium salicylate's drawbacks, and besides relieving
father Hoffmann's rheumatoid aches and pains, it had some additional benefits
as well Bayer scientists found aspirin helped relieve headaches and toothaches,
reduced fever, and combated inflammation. Bayer first sold aspirin powder
to the public in 1899, and brought out a water soluble tablet in 1900.
The company estimates that today consumers worldwide swallow 50 billion
tablets of this wonder drug annually. Bayer still supplies 11 billion or
22% of those tablets. And physicians are still finding new uses for this
old drug. It is used, for example, to help prevent heart attacks and strokes
and investigators are looking into its potential to treat certain types
of cancer and Alzheimer's disease.
An aspirin a day keeps the doctor at bay: THE ECONOMIST AUGUST 9TH 1997
ON AUGUST 10th 1897, Felix Hoffmann, a chemist in the employ of a German
dyestuffs company called Bayer managed to acetylate the phenol group of
a compound called salicylic acid. Not, on the face of it, the stuff for
which front pages are held. But acetylsalicylic acid has two claims to
fame. First, as the world's first truly synthetic drug and not merely an
artificial copy of a naturally occurring compound, it paved the way for
the modern pharmaceuticals industry. Second, it is probably the most successful
medicine in history. For acetylsalicylic acid is better known as aspirin.
Since Hoffmann's synthesis, aspirin has gone from strength to strength.
It has not suffered proscription, as happened to its near contemporary,
heroin. Nor has it been overtaken by more modern substances. Paracetamol
and ibuprofen may have nibbled at its share of the over-the-counter painkiller
market, but aspirin still outsells them both, in Germany, for instance,
half of the OTC market belongs to aspirin-based products. Moreover as time
passes, aspirin looks more and more useful. It was first marketed mainly
as an antiinflammatory, particularly for people suffering from rheumatism,
but its popularity as a general-purpose painkiller followed quickly. Lately
it has come to be seen as a life-saver; prescribed to those at risk of
heart attacks and strokes as a way of preventing the blood clots that cause
them. And the future may be even more thrilling, for current research is
lining aspirin up to treat one of the nastier types of cancer.
Barking up the right tree
All this springs ultimately from a substance that accumulates in willow
trees. Rheumatism has plagued the human race at least since the flowering
of the great river cultures of the Middle East. Clay tablets from the Sumerian
period describe the use ofwillow leaves to treat it. The Egyptians were
also aware of the pain-relieving effects of potions made from myrtle or
willow leaves.
Extracts from the bark and leaves of the willow, myrtle and a number
of other plants rely for their effect on the presence of salicylic acid,
an organic compound composed of seven carbon atoms, six hydrogens and three
oxygens. Edward Stone, a vicar from Chipping Norton in Oxfordshire, is
generally recognised as the man who gave the first scientific description
of the effects of willow bark. in 1763 he wrote a letter to the Earl of
Macclesfield, then president of the Royal Society in London, in which he
describes treating patients suffering from ague (fever) with 20 grains
(ap proximately a gram) of powdered willow bark in a dram of water every
four hours.
Stones interest in willows was due to the ancient "Doctrine of Signatures",
whereby the cause of a disease offers a clue to its treatment. According
to Stone:
"As this tree delights in a moist or 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."
In 1829 the action moved to France. Henri Leroux, a pharmacist, obtained
a compound of salicylic acid, known as salicin, in crystalline form for
the first time, and Raffaele Piria an Italian chemist, then succeeded in
splitting it up to obtain the acid in its pure state. Reports of its beneficial
properties spread quickly and demand grew. Hermann Kolbe, professor of
chemistry at Marburg University, in north-western Germany, discovered the
compound's chemical structure and succeeded in making it artificially in
1859. This allowed salicylic acid to be produced on an industrial scale,
and by 1874 a factory in Dresden was able to sell it at a tenth of the
price of material extracted from willow bark.
However, salicylic acid has unpleasant side-effects. Most notably, it
irritates the stomach and many patients were simply unable to tolerate
its unpleasant taste. One such patient was the father of Felix Hoffmann,
and it was his father's complaints that stimulated the younger Hoffmann
to play around with salicylic acid in order to produce something as effective
as a treatment for rheumatism, but more palatable.
The head of Bayer's pharmacology laboratory, Heinrich Dreser, quickly
tested Hoffmann's new compound on himself. He then set up a series of animal
experiments (another first for aspirin; the testing of drugs on animals
had never before been done in an industrial setting) and soon demonstrated
the anti-inflammatory and analgesic effects of acetylsalicylic acid on
his experimental animals. Tests on people began soon afterwards in the
Deaconess Hospital in Halle an der Saale.
Following an enthusiastic report from the medical staff there, Bayer
realized that it had a major discovery on its hands. In yet another first,
the first mass marketing of any drug; the company sent information aboutaspirin
to 30,000 doctors. By 19l4, aspirin was making a healthy contribution to
Bayer's profits. And although many of its foreign rights were confiscated
by Germany's enemies after the first world war, Bayer still leads the world
in aspirin production selling ~1 billion tablets a year.
Unlike many centenarians, though, aspirin is not ready to retire. In
fact, its future seems brighter than ever following a number of clinical
trials stimulated by the discovery, in 1976, of how it actually works.
Keep on taking the tablets
In a piece of research for which he was awarded both a Nobel prize and
a knighthood, John Vane, who was then employed by the Royal College of
Surgeons in London, showed that aspirin suppresses the production of local
hormones known as prostaglandins.
These are found in most tissues of the body, and they have a number
of different functions including regulating the contraction of the so-called
"smooth" muscle that is found in the blood vessels, the stomach the intestines
and the bladder, and mediating pain and inflammation. But they also regulate
the aggregation of platelets scraps of cells in the bloodstream that help
to form clots. Suppress the prostoglandins in platelets, therefore, and
you suppress the formation of the sort of clots that trigger heart attacks
and strokes.
The Physicians' Health Study organised by Charles Hennekens of Harvard
University and published in 1989 involved more than 22,000 healthy American
doctors. It showed that an aspirin a day reduces the incidence of heart
attacks by half, and that the drug can also help to prevent thrombosis
and strokes.
This was followed up by a so-called "meta-analysis" of clinical trials
of aspirin published in 1994 by Richard Peto and Rory Collins of Oxford
University. They reviewed the results of 300 published trials of aspirin,
involving some 140,000 patients the largest number of patients ever reviewed
at one time. The message was clear: if people under 70 who are at risk
of heart disease were to take aspirin regularly, the number of deaths from
such disease across the world could be reduced by 1oo,ooo a year. Many
people, including a lot of doctors, now begin their day with an aspirin.
That aspirin's uses may not stop there has been suggested by Sam Shapiro
and his colleagues at Boston University. About five years ago they developed
a hypothesis, based on data from experimental animals, that bowel cancer
might be prevented by a regular dose of aspirin. Some 15 -20 studies of
this idea have since been carried out, and they suggest that it is correct_the
reduction being somewhere between 30% and 50%. Aspirin, Dr Shapiro believes,
interferes with the biochemical mechanism that causes cells lining the
bowel to become cancerous. This mechanism appears to involve prostoglandins
in at least two of its stages. Keeping them suppressed keeps the cancer
suppressed as well. There is clearly life in the old drug yet.
Stomach turning
Sales of aspirin may be going from strength to strength, but the manufacturers
of anti-peptic-ulcer drugs have suffered from the discovery that such ulcers
are caused not by stress and a consequent excess of stomach acid (of which
such drugs curtail the production), but as a result of the activities of
a wee beastie called Helicohacter pylori. This week sees the publication
in Nature of the complete genetic sequence of this bacterium, and with
it, a better understanding of how it prospers in people's stomachs and
causes them grief.
The H. pylori theory of stomach ulcers was first suggested in
1983 by two Australians, Robin Warren and Barry Marshall. Since acid is
not, according to this theory, the primary problem (although it can be
an aggravating factor), the way to treat ulcers is not with palliatives
that reduce acid levels, but with antibiotics which destroy the agent that
creates ulcers in the first place.
The hypothesis was widely ridiculed at first, partly because the bug
has turned out to be so common (roughly one person in two harbours it,
and stomach ulcers are not that frequent). But the association has been
nailed down and it is now generally accepted. The genetic sequence (worked
out by a group of researchers led by Craig Venter, Claire Eraser and Jean-
Erancois Tomb of the Institute for Genomic Research, in Rockville, Maryland)
has strengthened it still further.
According to this team, the bacterium has 1,590 genes (people, for comparison,
have about 80,000). Among these, the researchers have identified several
that help it to be an effective agent of disease. Eive genes, for example,
make proteins that help H. pylori to stick specifically to the cells
of the stomach lining. A number of others, clustered together in a so-called
"pathogenicity island", stimulate cells of the stomach wall to produce
interleukin 8, a substance that then causes them to become inflamed. And
40 genes were identified as being responsible for proteins that contribute
to the propeller-like flagellae the bacteria use to move around.
One other gene is of particular interest. It is the one that seems to
allow H. pylori to thrive in the acidic environment of the stomach,
which is there, in the view of most biologists, precisely to kill incoming
bacteria. This gene is the blueprint for an enzyme called urease, which
converts urea into ammonium ions. These ions, like the hydrogen ions that
are the heart of every acid, have a single positive charge. Like charges
repel. So by building up the concentration of ammonium ions inside its
retaining membrane, H. pylori is able to fend off the destructive
attentions of the hydrogen ions in stomach acid and thus live free from
competition by less hardy germs.
Whether any of the institute's discoveries will lead directly to better
anti-ulcer drugs remains to be seen. But this sort of whole-genome sequencing,
which has so far been completed on five bacteria, should allow a much better
understanding of how bacteria work, what they have in common, and what
makes individual species unique. That will, in turn, allow nasty ones to
be attacked more vigorously and useful ones to be engineered to be of still
greater service.
