Aspirin

Despite being one of the world's oldest and most common drugs--perhaps the oldest drug used solely for therapeutic reasons--aspirin has been reluctant to give up its secrets. For more than four millennia, people have been using aspirin or naturally occurring analogs to treat pain and inflammation, but it was only in the 1970s that scientists finally cracked the medicine's biochemical mode of action.

With understanding has come a second renaissance for aspirin, whose storied history has come full circle from ancient painkiller to legal leper, through adventures on the Napoleonic high seas and in interbellum Europe, and finally to a still-burgeoning set of new and preventative uses. It accompanied astronauts to the moon and has been mentioned in the "Guinness Book of World Records," and the 20th century was even dubbed "the age of aspirin" by Spanish philosopher Jose Ortega y Gasset.

In 1971, Sir John Vane, then working at the Royal College of Surgeons of England, uncovered the mode of action of aspirin and related compounds, known as NSAIDs (nonsteroidal anti-inflammatory drugs). This achievement ultimately garnered the scientist both the Nobel Prize in Physiology or Medicine (1982) and a knighthood. The drugs, he found, inhibit the synthesis of a group of hormonelike substances known as prostaglandins. Aspirin and most other NSAIDs inhibit cyclooxygenase enzymes, which normally drive prostaglandin production.

Prostaglandins have a wide variety of effects, acting as messenger molecules for inflammation and being involved in pain transmission to the brain and in internal temperature regulation. Their suppression explains the analgesic (pain-relieving), anti-inflammatory, and fever-reducing effects that make NSAIDs so popular. NSAIDs also thin the blood and inhibit blood-clot formation through a similar mechanism, which is why aspirin has recently taken on a new and significant role in the prevention and treatment of heart attacks and strokes.

NSAIDs can have serious side effects when taken regularly or in large doses, most notably gastrointestinal symptoms, including ulcers and stomach bleeding. Not only do the acidic molecules irritate the gastrointestinal tract, but cyclooxygenase enzymes are found in abundance in the stomach lining, where the prostaglandins they release play a protective role for the stomach mucosa. Aspirin has also been linked to Reye's syndrome, a deadly illness associated with viral infections, which is why aspirin is no longer used to treat flulike symptoms in children.

Since the development of aspirin at the end of the 19th century, a host of other NSAIDs have flooded the market, including the common over-the-counter drug ibuprofen. Paracetamol, or acetaminophen, closely related in structure to aspirin, has also become quite popular as an analgesic, in part because it causes little irritation to the stomach lining. But even though scientists have found that paracetamol also affects cyclooxygenase enzymes, it is not properly an NSAID: It works in a different manner and has no anti-inflammatory or clot-reducing properties.

Aspirin's new role in circulatory health has cemented its place as one of the world's most popular drugs. Studies have even hinted at additional preventative uses for aspirin--though they have yet to be properly substantiated.

It's been a strange journey for the wonder drug. People have been using salicylic acid, found naturally in willow and myrtle, for almost as long as civilization has been around. Ancient Sumerian clay tablets mention using willow leaves to treat rheumatoid arthritis, and the Ebers papyrus, one of the world's oldest preserved medical texts, indicates that the Egyptians knew of the analgesic properties of dried myrtle leaves from at least the middle of the second millennium B.C. The Greek physician Hippocrates wrote in the 5th century B.C. of willow bark's curative powers, sentiments later echoed by Galen and other Roman and Greek luminaries, and some evidence also suggests that ancient Chinese, Native American, and African groups were aware of the drug.

WILLOW CONTINUED to be used well into the Middle Ages in Europe, only to run into a major obstacle: the lumber business. The budding wicker industry needed the willow for itself; in fact, demand was so high that in some places using willow for medicinal reasons was banned outright. Even then, scientists were still making some progress; in the mid-1700s, the Reverend Edward Stone wrote a note to the president of the Royal Society of London describing quantitatively the treatment of fever with powdered willow bark. He was motivated in part by the Doctrine of Signatures, a philosophical tenet that holds that plants offered external clues to the kinds of maladies they might treat; willow is often found in moist soils, which were associated with fevers.

But it would take war for aspirin to really return to the limelight. After the colonization of the New World, Europe had taken to treating pain and fever with quinine imported from South America. When Napoleon Bonaparte's rise to power plunged Europe into more than a decade of internecine conflict, however, naval clashes between Britain and France cut off much of the continental mainland from maritime trade. Napoleon and other leaders were forced to return to readily available sources of analgesics, such as willow.

In the 1820s and 1830s, scientists succeeded in isolating the active ingredient, salicin, from willow bark. The bitter extract garnered its name from the Latin designation for white willow, Salix alba; because of its acidity in water, the compound became more commonly known as salicylic acid. The compound was eventually produced industrially from coal tar through a process discovered by Herman Kolbe, but its nasty side effects--an unpalatable taste and stomach irritation--led many users to comment that the cure was worse than the disease.

In 1897, a scientist at German firm Bayer, Felix Hoffman, created the modern form of aspirin by acetylating the hydroxyl group of salicylic acid, creating acetylsalicylic acid. Hoffman's father had been complaining about the side effects of the salicylic acid he had been taking--the official story from Bayer goes--spurring Hoffman's interest. Hoffman also has another claim to fame: Physicians at the time were growing increasingly concerned over the addictiveness of morphine, and Hoffman synthesized the morphine derivative diacetylmorphine, named and sold by Bayer for a number of years as the "nonaddictive" heroin for the "heroic" feeling it inspired in users.

Recently, though, the exact nature of acetylsalicylic acid's discovery has become a source of controversy. In 1949, Arthur Eichengrn, Hoffman's sometime-boss at Bayer, claimed that it was his idea to acetylate salicylic acid and that he was never given credit for this work. And it turns out that acetylsalicylic acid had already been invented decades previously: French chemist Charles Gerhardt made an impure version in 1853, and German chemist Karl J. Kraut made a more pure version shortly thereafter. But neither scientist picked up on the medicinal potential of his work.

Heinrich Dreser, the head of Bayer's pharmacology division at the time, was unimpressed with acetylsalicylic acid at first, dismissing the compound. But eventually clinical trials in animals and then humans were conducted, and their success quickly inspired Bayer to market its new drug; they dubbed it aspirin: "a" for acetyl; "spir" for the spiraea flower, another natural source of salicin; and "in," a common drug ending at the time.

In 1899, Bayer sent information on aspirin to nearly 30,000 doctors. Soon, it was the world's best-selling drug, and Bayer began branching out its production to capitalize on its success, including a plant in New York. But aspirin would once again have a fateful encounter with world war.

In 1914, the assassination of Austrian Archduke Franz Ferdinand triggered a tangled web of alliances that pulled almost all of Europe into conflict. The guns of August shattered continental tranquility in a war that soon ballooned to encompass Africa, Asia, and the Americas. Bayer found itself the unfortunate victim of its location; its foreign assets (including patents and trademarks) were seized by the victorious Allied powers--Britain, France, the U.S., and Russia--as part of reparations mandated by the 1919 Treaty of Versailles. The company estimates that its total sales in 1919 were only two-thirds of those of 1913.

In the U.S. and Canada, Sterling Drug won the auction for Bayer's assets, including the right to its name and its famous cross-shaped logo, for about $5 million. When generic competitors flooded the market soon thereafter, aspirin also became a generic and unprotected name in the U.S. and some other countries. Bayer managed to retain its trademark in more than 70 other nations, where acetylsalicylic acid is used to refer to the generic form, but the war auctions forced it to sell its own aspirin under a different name for dozens of years in the U.S., the world's largest market. Finally, in 1994, SmithKline Beecham, the new owners of Sterling Winthrop, sold Bayer's over-the-counter line back to the company through Bayer's wholly owned Miles subsidiary--for $1 billion. It was a steep price for Bayer to pay to once again secure worldwide rights to its own name and logo.

Aspirin

Name
◾ 2-(Acetyloxy)benzoic acid

Other Names
◾ Acetylsalicylic acid, ASA, Aspergum, Empirin, Ecotrin, Measurin

CAS Registry
◾ 50-78-2

Did you know that pharmacist Harold J. DeMonaco, author of "How Drugs Work" and senior editor for Harvard Health Publications, believes that if aspirin had been launched recently, it would not be sold over the counter because of its side effects?