Happy 100th, Aspirin

Take two aspirin and call the doctor in the morning.

This may not have been such bad advice. On its 100th anniversary, that little white pill keeps on coming up with new uses.

Well beyond its traditional roles for killing pain, reducing fever and controlling inflammation, aspirin has proved to be a potent medication for a wide variety of ailments, from halting heart attacks to preventing strokes.

The National Library of Medicine has logged more than 23,000 scientific papers on aspirin, with 880 published this year alone on various aspects of its use. Aspirin can soothe migraine headaches, stop premature labor in some pregnant women and control lung inflammation caused by a common respiratory virus that is a major hazard for premature infants.

Aspirin is one of the most widely used medications in the world. Each year, 58 billion doses of aspirin are swallowed, sipped in fizzling concoctions or taken in suppositories, according to the Bayer Co., one of the largest manufacturers. Americans pop 80 million aspirin tablets daily--29 billion per year--a figure that works out to 117 aspirin tablets annually for every man, woman and child in the country, according to Joe Graedon, author of “The Aspirin Handbook” (Bantam Books, 1993).

Experts say yearly aspirin consumption could rise even higher in its second century as researchers uncover new applications. The latest scientific findings suggest aspirin can help in preventing colon cancer and in treating Alzheimer’s disease and other forms of senility. It might even play a role in preventing cataracts.

“It’s mind-boggling how many new applications this simple drug has,” said Paul Lietman, professor of pharmacology at the Johns Hopkins Medical Institutions in Baltimore. “It seems that each year we hear of a new therapeutic application for the drug.”

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Acetyl salicylic acid is one of the original members of a group of more than four dozen chemical compounds called nonsteroidal anti-inflammatory drugs (NSAIDs). Among the better-known NSAIDs are ibuprofen, such as Advil and Motrin; and sodium naproxen, sold as the prescription drug Naprosyn and the over-the-counter medication Aleve. Another popular pain killer, acetaminophen, most often sold as Tylenol, is not an NSAID.

As a group of drugs, NSAIDs help to control fever, swelling and pain. How well they exert these effects--and with what number of complications--varies from drug to drug. But “aspirin is still the gold standard that all the others are compared to,” Lietman said.

Researchers did not begin to understand how aspirin exerts its powerful effects until the 1970s, although there were many intriguing clues beforehand. Kidney researchers had found that low doses of aspirin blocked the production of uric acid in the kidneys. Pharmacologists had research proving that aspirin reduced pain by acting on tissues and nerves throughout the body instead of working like morphine to block nerves in the brain that transmit pain signals.

Evidence also showed that aspirin lowered fever by affecting key centers in the hypothalamus rather than by affecting blood vessels throughout the body. In the blood, aspirin halted platelet function and blood-clot formation as well as caused salt and water retention. It also caused indigestion and in a small number of people could produce nasal polyps.

But there was no common thread to explain these varied effects until British pharmacologist John Vane wove them together with the discovery that aspirin halts production of a potent group of chemicals in the body called prostaglandins.

Prostaglandins, which are synthesized from fatty acids, are manufactured in every cell of the body except red blood cells. They are key ingredients in a host of essential body reactions from muscle contraction to ovulation. But unlike other hormones such as insulin that are released from organs, prostaglandins are released when cells are injured or otherwise stimulated. They, in turn, can cause tissue damage.

Vane found that aspirin was able to halt the release of prostaglandins. The linchpin in this process, Vane and his colleagues at the Royal College of Medicine later found, was aspirin’s ability to regulate an enzyme called cyclo-oxygenase-2 or COX-2. The discovery about prostaglandins won him a Nobel Prize in medicine in 1982 and led to an explosion of scientific research on aspirin.

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“Aspirin now has a whole host of possibilities that were never envisioned,” said Charles Hennekens, chief of the Physicians Health Study, an ongoing research project at Harvard that has examined aspirin use closely. “It really has the extraordinary potential to have benefits on a wide range of disease.”

As researchers learn more about the many actions of aspirin in the body, new and unexpected possible benefits are emerging.

“Aspirin has spawned a huge amount of research into the mechanisms of the inflammatory response,” said Lee Simon, associate professor of medicine at Harvard Medical School and chairman of the committee on education for the American College of Rheumatology. “It has been an incredible field of development.”

* Alzheimer’s disease. Aspirin may be helpful for preventing Alzheimer’s disease and other forms of senility. The Baltimore Longitudinal Study of Aging, involving nearly 1,700 participants, reported earlier this year that aspirin users had a significantly lower risk of Alzheimer’s disease than people who took acetaminophen. A 1995 study of 210 patients treated at the Johns Hopkins Alzheimer’s Disease Research Center found that patients who took aspirin on a daily basis showed less decline in speaking, spatial recognition and orientation than patients who did not take aspirin.

* Colon cancer. Large epidemiological studies have found a 40% to 50% reduction in the death rate from colorectal cancer in people who took aspirin or other NSAIDs on a regular basis. A 1996 study of nearly 10,000 people in Finland found a significantly lower colorectal cancer rate among people with rheumatoid arthritis who regularly took aspirin or other NSAIDs. Animal studies by researchers at Vanderbilt University, the University of Texas Health Science Center and the University of Michigan, among others, suggest aspirin may inhibit key enzymes in the intestine, which are also linked to the development of precancerous polyps.

* Preventing premature labor. Because prostaglandins help contract the uterus during childbirth, aspirin and its new derivatives may also be used one day to help prevent premature labor and to treat preeclampsia. This use is still experimental as current recommendations are for women to avoid aspirin use during the third trimester of pregnancy because of potential bleeding problems.

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But aspirin does have its dark side. High doses of aspirin have been linked to the risk of gastrointestinal ulcers and bleeding, and many aspirin users consume it in high doses: 20% of the users consume 80% of the drug.

“About 2% to 4% of people will develop important complications of aspirin and other NSAID use,” said Simon. In a study involving nearly 9,000 participants, Simon and his colleagues found that 1% to 2% of aspirin users experience the worst bleeding complications. “There are about 2,600 excess deaths due to gastrointestinal complications from NSAID use and about 20,000 hospitalizations annually,” said Simon. “It’s not an inconsequential problem.”

Aspirin use can also be a problem for about 10% of people who have asthma. Studies have found that in this group of asthmatics, the drug can trigger attacks, may cause facial swelling and may produce polyps--small benign growths--in the nasal passages.

High doses of aspirin--a dozen or more regular strength tablets taken over several days--have also been linked to ringing in the ears.

Most importantly, aspirin is not recommended at all for children 16 and younger because of its link to an often-fatal neurological problem called Reye’s syndrome that can develop after a child has a viral infection.

No one knows exactly what causes this condition, but researchers at the federal Centers for Disease Control and Prevention in Atlanta found that the number of cases declined markedly from 1980 to 1985 after public-health warnings about the link between Reye’s syndrome and use of aspirin in children.

The challenge for researchers is to develop preparations that retain aspirin’s beneficial effects while decreasing its complications.

Recent studies by Vane and by Philip Needleman of the chemical company Monsanto have found that the COX enzymes may hold the key to reducing aspirin complications. COX-1 is linked to the greatest amount of bleeding complications. Under development are new aspirin derivatives that produce COX-2 enzymes, which appear to protect the stomach and intestines from ulcers and bleeding.

As aspirin marks its first century, experts rank the drug as one of the most useful available and one of the best bargains around. Aspirin still costs just pennies per dose. “If aspirin were half as effective and 10 times more expensive, we would take it far more seriously,” Hennekens said.

“Considering how many people use it, which numbers in the millions, and the low level of toxicity, it is a pretty good drug,” said Simon. “It has stood the test of time.”

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A History of Helping

* 400 B.C.: Hippocrates prescribes willow bark and leaves to relieve pain and fever. Willow bark contains salicylic acid, a key ingredient of aspirin.

* 1853: Chemist Charles Frederic von Gerhardt synthesizes a crude form of salicylic acid from the bark of a willow tree.

* 1897: Chemist Felix Hoffmann, an employee of the Bayer Co., finds an improved way to make acetyl salicylic acid, a compound that proves helpful in controlling pain of arthritis. Unable to get the drug patented, the company registers a trade name for the new medicine, aspirin.

* 1900: Aspirin becomes available in water-soluble tablets--a new way of taking medicine.

* 1915: Aspirin becomes a non-prescription drug.

* 1920: Use of aspirin expands to include treatment of rheumatism, lumbago and neuralgia or nerve pain.

* 1948: Dr. Lawrence Craven of California notes that 400 men to whom he prescribed daily doses of aspirin have not suffered heart attacks. He proposes a possible protective effect of aspirin for the heart.

* 1980: The Food and Drug Administration approves the use of aspirin to reduce the risk of stroke after a so-called mini-stroke, or transient ischemic attack, in men.

* 1985: The FDA expands the use of aspirin to include prevention of heart attacks in people who have suffered one heart attack or who experience chronic, unstable chest pain.

* 1988: The FDA requires warning label on all aspirin products for children because of the increased risk of the rare, but often fatal Reye’s syndrome.

* 1990: The FDA requires all oral and rectal aspirin products to include a label warning against use during the last three months of pregnancy without a doctor’s approval.

* 1996: The FDA approves the use of aspirin during a suspected heart attack.

* 1997: The FDA committee recommends approval of aspirin for the prevention of stroke in women who have had a mini-stroke as well as for use after a minor stroke. Also recommends aspirin for use in doses lower than previously recommended.

Sources: Food and Drug Administration; Bayer; “Aspirin Wars,” by Charles C. Mann and Mark L. Plummer (Knopf, 1991).