SCIENCE: ASPIRIN THE WONDERDRUG

One of the most successful medicines of all time; aspirin continues to astonish doctors with its powers to relieve pain and treat major killers. And all this from the drug that was nearly never marketed. Peter Sweasey celebrates the approach of its centenary A 1994 REPORT SUGGESTED THAT PREVENTATIVE USE OF ASPIRIN COULD SAVE AROUND 100,000 LIVES EACH YEAR
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The Independent Culture
WHEN FELIX Hoffman first created acetylsalicylic acid (aspirin) in 1897, his bosses at Bayer rejected it as useless and probably dangerous. The German chemical company was far more excited by Hoffman's other discovery that year, diacetylmorphine. The factory workers who sampled it reported that it made them feel "heroic". Bayer gave the new wonder- drug the brand-name Heroin, and enthusiastically promoted it as an excellent cough remedy and a "non-addictive alternative" to morphine.

When Bayer eventually decided there might be a market for acetylsalicylic acid after all, they chose a brand name which had the same ending as their big-selling opiate, and promoted the pair together in adverts. The ultimate drug cocktail: Aspirin for your headache, Heroin for your cough.

Bayer stopped advertising Heroin when they worked out why so many people were coming back for repeat prescriptions - severe addiction. (Though in the US you could still buy it over the counter as late as the 1920s.) The modest Aspirin, however, carried on generating sales - and medical uses - far beyond anyone's initial expectations. Today we consume 100 billion tablets of aspirin worldwide, every year.

Aspirin was the first "scientific" medicine to be mass-marketed, and the first major product to be sold as a tablet instead of a powder. It went on to become the drug of the century. It is consumed across the globe and has infiltrated the whole spectrum of human behaviour - found in the works of Thomas Mann and Graham Greene, but also with Neil Armstrong on Apollo 11 and in the more mythical space travel of Doctor Who (for whom a single pill is fatal). Spanish philosopher Jose Ortega y Gasset dubbed the 20th century "the age of aspirin".

Few drugs from the Victorian pharmacy remain in use today; yet with the 100th anniversary of its launch only months away, aspirin - now a generic name in Britain and the US - can still be found not only in bathroom cabinets across the land, but also on the pages of scientific journals announcing the latest major killer it can treat. Aspirin is now being used to prevent heart attacks, strokes, bowel cancers, leg thromboses, dementia, pre- eclamptic toxaemia in pregnant mothers, the formation of cataracts, and blindness in diabetics. It is still unsurpassed as an anti-inflammatory treatment for sufferers of rheumatoid arthritis, and turns out to be as effective as opiates for relieving many types of severe pain. It's also pretty good for a hangover.

A primitive form of aspirin has been discovered and then forgotten again at regular intervals over several millennia. Ancient Egyptians took an infusion of dried myrtle leaves for muscular pain, while the father of modern medicine, Hippocrates, prescribed tea made from willow bark for the aches of the Greeks. The active ingredient of both these preparations is salicylic acid - which is also aspirin's active ingredient.

By the Middle Ages, salicylic acid was lost to the medical profession, and survived only as a popular herbal remedy until modern science rediscovered it in the 18th century. Chipping Norton earned a place in medical history thanks to a local clergyman, Edward Stone, who conducted one of the earliest recorded clinical trials in 1763: giving willow bark extract to 50 feverish patients, and reporting the positive results in the Royal Society's Journal. By 1859, salicylic acid had been successfully synthesised in the laboratory - so ending dependence on plants for its ingredients and enabling mass production for the first time. But successful though it was in treating rheumatic pain and fever, salicylic acid had serious side effects. Its repulsive taste made many patients vomit, and it corroded the mucous membranes of the mouth, throat and stomach. All attempts to neutralise these effects failed - until Felix Hoffman came along.

Felix was a 29 year-old pharmaceuticals graduate who worked in Bayer's chemical sciences department, one of the world's first industrial laboratories. He had a walrus moustache, a predilection for wearing bowler hats, and a severely arthritic father who couldn't stomach salicylic acid. According to scientific legend, he asked the young Felix to create a more palatable palliative, and it was filial devotion which led to the invention of the most successful drug in history. In fact, Felix had been set to work on improving salicylic acid by his boss, and was following the notes of two earlier scientists who'd attempted to modify it by acetylation. Charles Gerhardt had created acetylsalicylic acid (ASA) as far back as 1853; what Felix managed to do for the first time was produce it in a pure and stable form. And because salicylic acid was "bound" in the new compound, it no longer provoked emetic and caustic side effects.

But for a while, it looked as though no-one would benefit from Hoffman's achievement, due to the negative judgement of Heinrich Dreser, whose moustache was even bigger than Hoffman's. Dreser nearly became the scientific equivalent of the Decca executive who turned down the Beatles. He was the head of Bayer's testing laboratories; for a company to test its own products was a welcome innovation in an age when it was more usually left to doctors to find out whether a drug actually had any effect. Dreser decided not to submit ASA to any further testing after an unsuccessful experiment involving frogs' hearts, and in any case, he was being kept busy enough by the runaway success of Heroin, which by contrast had done brilliantly in trials (some of which were conducted on babies).

So the most successful drug of all time languished in a desk drawer until Hoffman and his boss arranged for clinical trials in Berlin hospitals, which were kept secret from Bayer. Only when these generated glowing reports did Dreser, and Bayer, change their minds. ASA was given its brand name in January 1899 (the "A" stands for acetyl, the "spir" is from Spiraea ulmaria, the meadowsweet plant which is a source of salicylic acid) and was launched a few months later, at first in powder form. Initially sold only to doctors and hospitals - rather than direct to the public - it was an instant success.

Hoffman didn't profit from his discovery. He couldn't patent something which had, technically speaking, already been discovered and he eventually retired to Switzerland to study art history. Dreser, however, received a royalty from all medicines tested in his laboratory, and so earned a fortune from the drug he'd written off as "worthless". And it turned Bayer into a hugely profitable multi-national conglomerate. Aspirin is still a Bayer trademark in more than 80 countries - outside Britain, America and France, this article would have to be peppered with ... ... . Aspirin became a generic term here as a result of anti-German feeling during the First World War: enemy "property", including Bayer's rights to the drug, was confiscated. The Treaty of Versailles enshrined this punishment in international law; Germany was even obliged to supply a quarter of all the ASA it produced, at a low price, to the victorious Allies.

More humiliating still, when the American government entered the war it seized not only the rights to aspirin, but also Bayer's New York factory and its name. These were sold off for a ridiculously low price to a company best known at the time for its laxatives and dandruff treatments. Sterling Products was delighted with its purchase, until it realised that it couldn't decipher the German instructions for making aspirin - and didn't know how to operate its new factory either. In 1919 it had to ask the Germans - still technically the enemy - for advice, and do a deal on international rights in return. Sterling soon learned to make Bayer Aspirin in America, however, and for more than seven decades there were two Bayer Aspirins in the world, made by entirely different companies. It wasn't until 1994 that the German Bayer company finally managed to buy back its own name and product.

As more manufacturers joined the fray in the years between the First and Second World Wars, aspirin colonised the world. It reached the remotest places, such as the highlands of Latin America, thanks to a medicine show for the modern age. Bayer's agents sent out touring trucks, with loudspeakers and film projectors, which set up shop in the middle of even the tiniest villages, proclaiming the virtues of this magical new cure-all. The first time thousands of people witnessed moving pictures, it was images of aspirin that they saw.

By the late 1930s, these advertisements were mixed with less healthy propaganda. Bayer, commercial victim of the First World War, became a villain of the second as part of the chemical conglomerate IG Farben - leading industrial supporters of the Nazi party, and eventually suppliers of Zyklon B gas to concentration camp chambers. The aspirin roadshows now became vehicles for educating people about the drug's glorious fatherland, and the trucks were accordingly decorated with swastikas as well as little white pills.

But aspirin was too useful to be tainted even by Nazi associations, and it reigned supreme as the most popular everyday painkiller until the 1950s, when it encountered its first serious analgesic competition. Paracetemol - the generic name in Britain for proprietory drugs like Panadol - was as effective at killing pain, but didn't cause aspirin's major side effect: gastrointestinal blood loss. Although ASA doesn't corrode the stomach on the same scale as unacetylated salicylic acid, it does have some effect, causing upsets in roughly 6 per cent of users, aggravating ulcers, and leading to routine slight blood loss. This is no more than you'd lose from a small graze, though in a highly influential advertising campaign Panadol helpfully calculated that if everyone in Britain suffered this effect every time they took aspirin, then "swimming pools of blood" must be lost each year. Paracetemol could afford to take the medical high ground, since its own major downside - liver toxicity - had yet to be discovered.

Other adverse effects of aspirin emerged. After decades of being prescribed to pregnant women and feverish children, it was linked with miscarriages in the former and the rare but fatal condition Reye's Syndrome (encephalitis and degeneration of the liver) in the latter: both groups are now advised to take it only with medical approval. Aspirin sales declined, further diminished by the appearance of another major analgesic, ibuprofen (which was discovered by a couple of British chemists working for Boots).

What cured aspirin of its commercial ill-health was science. After seven decades of use, people finally started to figure out how it actually worked - and to realise that it had barely begun to reach its full medical potential. The breakthrough was made by a portly lecturer from the Royal College of Surgeons, Professor John Vane, who earned a knighthood and the Nobel Prize for his work. Vane specialised in prostaglandins, hormone- like fatty acids which are secreted by almost every cell in the body, and which regulate various bodily functions - including inflammation, temperature and muscle contraction. He discovered that aspirin blocks the formation of cyclooxygenase, an enzyme which triggers the creation of prostaglandins. Without these cyclooxygenase, prostaglandins cannot be produced, so the symptoms of pain, fever and inflammation can't be produced either. Prostaglandins in the central nervous system, which amplify the transmission of pain signals, are also disabled, so aspirin has an effect both globally and locally. The drug is indiscriminate about which prostaglandins it switches off - which is why it can harm as well as heal, because the stomach needs prostaglandins to provide a protective lining against acids.

In addition to killing pain, the suppression of cyclooxygenase is central to the new uses which have been found for aspirin. The enzyme doesn't just bring prostaglandins to life: it also switches on a similar substance, thromboxane, which plays a crucial role in causing blood to clot. Clotting is vital when there is a hole in the body that needs to be plugged, otherwise we'd bleed to death. But clots (or thrombi) can also form in blood vessels which have been narrowed by fat and cholesterol, or where tears have occurred due to high blood pressure. When a thrombus blocks an artery which supplies the heart's muscles, the heart can no longer get the oxygen it needs from the blood and stops beating, causing cardiac arrest.

Aspirin, by preventing thromboxane from being formed, prevents blood platelets from clumping together, which is how clots begin to grow. Readers can see this effect for themselves by repeating an experiment first conducted in the 1960s: Harvey Weiss found that people who consumed an aspirin tablet bled three minutes longer from a pinprick than people who hadn't. For some people - haemophiliacs for instance - preventing clots is a bad idea, but for people at high risk of a heart attack (especially people who have already had one, or sufferers of angina), it has been proven to significantly reduce both the chances of cardiac arrest, and the chances of dying if you're unfortunate enough to have one. Many doctors go so far as to recommend that aspirin be taken as an emergency remedy during a heart attack, and ensure people at risk always have a pack to hand.

It was only when John Vane discovered how aspirin works in the body that medical science accepted it could have uses other than killing pain, although the notion that it "thinned the blood" had been part of surgery folklore for decades, and as far back as 1950, an American doctor named Lawrence Craven reported that he had eliminated all cases of coronary thrombosis among his many patients by prescribing aspirin to them. Unfortunately, no one paid much heed to his discovery. His experiments weren't scientifically conducted and he published his results in obscure magazines like the Mississippi Valley Medical Journal. Then he severely damaged his own case by dying suddenly in 1957 - of a heart attack.

But Craven had correctly deduced the principle which also explains aspirin's new role in fighting other major diseases: by preventing clots it helps keep constricted vessels open. Most strokes occur when a thrombus stops oxygen from reaching the brain. Regular doses of aspirin have been shown to reduce strokes by between 20 and 35 per cent for high-risk patients - although it also increases the chances of the rarer type of stroke, which is caused by blood haemorrhaging from a weak vessel. Prescribing aspirin to prevent these conditions vindicates the advice of Hippocrates, who recommended salicylic acid (in the form of willow bark extract) to pregnant Greeks.

Less clear is why aspirin should prevent bowel cancer; yet a major study of American nurses suggested that regular long-term use reduces the risk of death from colonic cancer by 44 per cent. One possible explanation lies in aspirin's inhibition of prostaglandins, high levels of which have been associated with tumours. Aspirin also stimulates production of interleukin (a component of the immune system which may play a part in fighting cancer) as well as a newly-identified group of compounds, the 15-epilipoxins, which, at least in the laboratory, prevent the growth of tumour cells.

More research needs to be completed before there is conclusive proof that aspirin fights cancer, or a definitive explanation of how it does so. As with aspirin's other new uses, it is currently only recommended to people at high risk of developing the disease, and under strict medical supervision. Even the drug's manufacturers warn healthy people off taking a pill every day just to be on the safe side - research has yet to prove it is useful for "primary prevention". If you were to take ordinary over- the-counter aspirin like a daily vitamin supplement, you would be overdosing yourself. Only very low quantities of aspirin are required to prevent clotting, far lower than are required to relieve pain. High blood pressure sufferers are often prescribed "coated" aspirin that helps protect the stomach. At higher doses its effects are counterproductive.

Notwithstanding such medical caution, the range of aspirin's uses, and the complexity of its operation within the body, are little short of miraculous. A comprehensive report published in the British Medical Journal in 1994 suggested that preventative use of the drug could save 100,000 lives worldwide each year. The National Health Service alone would be pounds 70m a year better off.

For decades, aspirin's very familiarity and availability, as well as its age and low cost, prevented it from being taken seriously. It was often seen as little more than a placebo - lax doctors, like Reginald Perrin's Doc Morrissey, would respond to any symptom by telling you to take two aspirins and call them in the morning. They turn out to have been right all along: aspirin is much more effective than many newer and more expensive drugs, from beta-blockers to hi-tech painkillers, and may be better at keeping the doctor at bay than anything since the proverbial apple. Today, 100 years after it was first tested secretly against the wishes of its manufacturers, aspirin is again the subject of clinical trials - this time on an unprecedented scale. It's the most researched drug in medical history, but only now are we beginning to unlock its mysteries. As aspirin completes its first century, there's every chance it's going to be healing us - and probably surprising us - well into the next millennium. !

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