COLUMN ONE : The Little White Pill That Could : Newer, more expensive pain relievers pushed aspirin out of the spotlight. But it is making a comeback after researchers link it to the fight against heart disease, cancer and AIDS.

TIMES MEDICAL WRITER

In Joe Graedon's view, the scandal of the century wasn't the fixing of the 1919 World Series or even Watergate. It was the giant, collective yawn that greeted the great aspirin experiment of 1948.

In that year, Dr. Lawrence Craven, a general practitioner in Glendale, began telling his male patients to take aspirin every day. He had noticed that aspirin made his tonsillectomy patients bleed, suggesting that it somehow prevented clotting. And so he wondered: Might it also prevent heart attacks?

More than 400 men took Craven's advice; two years later, he announced that there had not been a single heart attack in the bunch. Soon, he was singing the praises of aspirin to everyone he knew. By 1956, he had chronicled the health of 8,000 aspirin-popping California men. Still no heart attacks, Craven claimed. It sounded too good to be true, and his peers thought Craven was probably a tad too enthusiastic about his evidence.

So nobody listened.

"The medical community, for the most part, seemed oblivious, if not antagonistic," complains Graedon, a pharmacologist and author of "The Aspirin Handbook," published last year and dedicated to Craven. "If only we would have paid attention to Dr. Craven. . . . Tens of thousands, perhaps hundreds of thousands, of lives were lost while we sat on our hands."

Indeed, four decades later, scientists and physicians are just beginning to discover the wonders of ordinary aspirin. The long-ignored little white pill--often passed over at the drugstore counter in favor of sexier, and far more expensive, pain relievers--is turning out to be good for a lot more than curing headaches.

Made from salicylic acid, aspirin was designed to reduce pain and fever but it also controls inflammation and inhibits blood clotting. From heart disease to cancer to cataracts to Alzheimer's and even AIDS, researchers are finding new and surprising uses for the century-old standby.

With so many functions, "Take two aspirin and call me in the morning" may be better advice than most people think.

Just last month, a team at Harvard University reported that men who took aspirin at least twice a week had a 32% lower risk of colon cancer than those who did not, and scientists at Yale University conducted test-tube studies that indicate that aspirin may delay the onset of AIDS by preventing the human immunodeficiency virus from replicating. Their work adds to a considerable body of evidence showing that, just as Craven suspected, aspirin is a cheap and effective way to treat and prevent heart disease.

"No little white pill does everything, that's for sure," said Dr. Garret FitzGerald, a professor of cardiovascular medicine at the University of Pennsylvania and one of the world's top experts on aspirin. "But the strength of the evidence for aspirin working where it has been shown to work is probably greater than the strength of the evidence for any drug for human disease."

All this from a medicine whose origins date to Hippocrates and which now costs less than a penny a pill--so familiar that most people do not even think of it as a real drug.

It is a pill, moreover, with a bad rap. Who could forget all those commercials for aspirin alternatives that hinted, not so subtly, that the real thing would only give you a stomachache?

All that advertising has had an effect; although an estimated 80 million aspirin tablets are taken in the United States each day, the drug has clearly become passe in the eyes of many.

Aspirin sales have been plunging since 1984, when ibuprofen--the key ingredient in Advil, Motrin and other newer "non-steroidal anti-inflammatory drugs" (NSAIDS)--was introduced over the counter. In a different class is Tylenol, whose key ingredient is acetaminophen, which went over the counter in 1960, when aspirin dominated the market.

Ten years ago, aspirin's share of the analgesic market was more than 50%, according to Mike Perlmutter, a consultant for Kline & Co., which tracks aspirin sales.

Today, Perlmutter said, aspirin--the original NSAID--accounts for 23% of the $2.6 billion in annual sales of pain relievers--a figure that comes as little surprise to Graedon.

"If it were a vitamin, if it were a new prescription drug, you would see headlines, you would see lines at the pharmacy, you would see doctors prescribing this new wonder drug," he said. "But because it's aspirin, somehow it hasn't sunk in."

*

Respect may come if science continues on its current course. The reports about colon cancer and AIDS are the latest among dozens of studies that hint at a wide range of surprising benefits.

For instance: Pregnant women are routinely told to avoid aspirin; it blocks an important chemical that helps prepare the uterus for delivery, and could cause hemorrhaging. Yet there is growing evidence that aspirin may be beneficial to the small number of pregnant women who suffer from a condition known as preeclampsia, which causes dangerously high blood pressure.

Scientists are also exploring whether aspirin can prevent migraine headaches, besides alleviating the pain. Testing is under way to see whether aspirin might prevent cataracts in the elderly, and whether it might help prevent a recurrence of gallstones.

And based on preliminary studies, experts in Alzheimer's disease believe that stronger NSAIDS--in essence, souped-up alternatives to aspirin--can delay the onset of the debilitating brain disorder.

At the moment, such research is evolving. But in the arena of heart disease, the evidence is solid: Taking aspirin is a cheap and effective form of prevention and treatment.

If a heart attack victim is given a standard-dose, 325-milligram tablet within 24 hours of being stricken, and another dose every day for 30 days, the patient's chances of dying are reduced 23%, studies show. The risk drops another 19% when aspirin is combined with newer "clot-busting" medications, according to Dr. Charles Hennekens of Brigham and Women's Hospital in Boston, who conducted much of the research.

Aspirin can also prevent subsequent heart attacks in those who have had one attack and cuts the risk of stroke in those who have had previous "transient ischemic attacks"--temporary, stroke-like episodes caused by clots in the brain.

But the most startling news came in 1988, when Hennekens discovered that aspirin could prevent heart attacks in the healthy too.

In a landmark study, he tracked 22,071 male physicians over age 40; half took an aspirin every other day and half took a placebo. The men taking aspirin cut their risk of heart attack 44%--a finding so surprising that five years into the 10-year study, a safety monitoring committee shut down the clinical trial to publicize the findings and allow the doctors taking the placebo to switch to aspirin.

As a result, an estimated 25% of healthy, middle-aged and older Americans take a small daily dose of aspirin. The amount found in one baby aspirin--80 milligrams--is sufficient, Hennekens says. So many people started taking baby aspirin, in fact, that the nation's largest aspirin manufacturer has introduced a product--"Adult Low Strength Bayer"--to appeal to this market.

Ironically, the company cannot advertise that the low-dose pill could prevent heart attacks--the Food and Drug Administration won't allow it.

The FDA--which controls the labeling and marketing of all drugs, prescription or over the counter--has still not approved the use of aspirin to prevent heart attacks. Nor has the agency given approval for using aspirin to treat acute heart attacks. In both cases, the agency is considering the recommendation of an advisory committee that has urged approval.

Even without the FDA's blessing, the percentage of heart attack patients getting aspirin has nearly doubled in recent years--from 39% to 72%. That is an improvement, Hennekens said, but he is more concerned with the flip side of this equation: The statistics mean that nearly one-third of heart attack victims are not getting this inexpensive, potentially life-saving treatment.

Angrily, he rattles off his own calculations: If every heart attack patient underwent angioplasty--in which a balloon is inserted into the arteries to clear blockages--it would cost the nation's health care system $250,000 to save a single life, given current success rates.

Saving one life by giving every patient FDA-approved clot-busting drugs would cost $12,000 to $88,000, Hennekens said.

And aspirin? A mere $13.

"When I give this speech (to doctors)," Hennekens said, "and I give the cost-benefit data, I say: 'This makes me wonder if aspirin were half as effective and 10 times as expensive and on prescription, maybe we'd take it more seriously.' "

*

Of course, no drug is perfect. Like any medication, aspirin has side effects.

It does irritate the stomach lining, although experts agree that just taking two for a headache--as opposed to long-term, regular use--is not enough to cause gastrointestinal distress in otherwise healthy people. Coated, or buffered, aspirin helps prevent an upset stomach, but it will not work for a headache--the drug takes too long to get into the bloodstream.

Moreover, aspirin has been linked to Reye's syndrome, a rare disorder in children that is characterized by brain and liver damage. Reye's syndrome occurs after viral infections; as a result, doctors advise that children who have chicken pox, flu or other viruses be given acetaminophen.

"Aspirin does have side effects, and there are some people who should never take it," said Graedon, the aspirin handbook author. "Anyone who is contemplating a lifelong regimen of aspirin needs to be under medical supervision. This is not a do-it-yourself project."

The origins of aspirin can be traced to the 5th Century BC, to the Greek physician generally regarded as the father of medicine.

It was Hippocrates who first noticed that a potion made from the bark and leaves of the willow tree could relieve the pain of childbirth and control fever. In 1758, an English clergymen stumbled upon the same discovery, and soon willow bark was being prescribed to treat fevers.

In the early 1820s, chemists discovered the secret of the willow's success: its bark and leaves contain salicin, a substance with analgesic properties from which salicylic acid is derived. By this time, scientists had found another natural source of salicylic acid--the queen of the meadow plant, known in Latin as Spiraea ulmaria .

Although salicylic acid reduced fever and relieved common aches and pains, it upset the stomach so badly that, according to one account, some Europeans who sought relief with it complained that they felt as though they were "crawling with ants."

Efforts to neutralize salicylic acid with sodium--producing a compound called sodium salicylate--flopped. In 1853 a French chemist named Charles Frederic Gerhardt tried to improve on sodium salicylate by combining it with acetyl chloride. That resulted in a new compound that was less irritating to the stomach. But it was so tedious to make that Gerhardt abandoned the concoction.

The aspirin story might have ended there, were it not for Felix Hoffman, a young chemist who in the 1890s worked for a German pharmaceutical company named Bayer. Hoffman's father, aspirin legend has it, suffered from arthritis, and he asked his son to come up with a drug to bring him some relief.

Hoffman decided to try Gerhardt's compound. His father did so well on the drug that he supplied it to two doctors, who urged Bayer to market it. In 1899, the company did so, under the name aspirin, after the Spiraea plant.

*

It was not until decades later, in the 1960s and '70s, that scientists began to figure out precisely how aspirin works inside the body. Their discoveries have opened up whole new avenues of investigation.

The key is prostoglandin, a chemical made by all the body's tissues and cells. Prostoglandin plays a role in many important functions--digestion, circulation, reproduction and the immune system. It triggers fever, which fights off bacteria. It prepares a pregnant woman's uterus for delivery of the fetus. It prompts platelets, a component of blood, to clump together, assisting in clotting.

Excess prostoglandin can cause headaches, fever and arthritic inflammation, as well as production of blood clots that lead to cardiovascular disease. Tumor cells, particularly in colon cancer, have high levels of prostoglandins. Prostoglandin has also been found, at least in the test tube, to boost the ability of HIV to replicate. Prostoglandin also helps the stomach maintain its lining.

Aspirin inhibits prostoglandin, which explains why it works for so many different conditions, and at the same time irritates the stomach.

"One could say, 'How could something work for cancer and for heart attack and for pain and for fever?' " said Steven Weisman, director of clinical research for Sterling Winthrop, which manufactures and markets Bayer aspirin in North America. "The common link is that they are all prostoglandin-mediated."

The prostoglandin theory has evoked interest around the country and the world, as medical researchers probe new uses for aspirin.

At Harvard, Dr. Edward Giovannucci is continuing to investigate the link between aspirin and reduced rates of colon cancer. One crucial unanswered question: What is the right dose? Although his recent study concluded that one full-strength 325-milligram aspirin a day is probably enough, he said, it will be several years before the data will be precise enough to say whether people at risk for colon cancer should take aspirin to prevent it and, if so, at what dosage.

In New York, Dr. Donald Kotler is about to begin a small clinical trial comparing aspirin to a placebo in HIV-infected patients. Like the researchers at Yale, Kotler, a gastroenterologist, has conducted laboratory studies that show aspirin slows the ability of HIV to replicate. Now, he wants to see if what works in a petri dish also works in people.

"If it works," Kotler said, "it is probably the first drug that has been tested that could be used worldwide that people could actually afford."

Not all the research efforts have turned up evidence in aspirin's favor. In Vancouver, Canada, Dr. Patrick McGeer of the University of British Columbia has abandoned his hope that aspirin could work for Alzheimer's patients.

McGeer came up with his theory after noticing that people with rheumatoid arthritis--who often take aspirin to combat joint inflammation--seemed to be spared the degenerative brain disease. Reasoning that aspirin might help prevent inflammatory reactions that kill brain cells, he began putting Alzheimer's patients on aspirin.

"It was my hope," McGeer said, "that you might be able to treat Alzheimer's disease just by going into your local supermarket and buying bottles of aspirin. But then we realized we were going to have to give doses that would be beyond what could safely be taken on a casual basis."

Since then, McGeer has experimented with indomethacin, a stronger non-steroidal anti-inflammatory. In a test involving 14 patients, he found that indomethacin "completely arrested" the progression of Alzheimer's. In a few years, he said, "these agents will routinely be used to treat Alzheimer's disease."

To pharmacologist Graedon, it makes little difference that the treatment comes from a newer generation of non-aspirin drugs. The fact is, McGeer's research would never have been possible without the little white pill. Graedon's fondest wish is that others would see what he sees.

"People need to give aspirin its due," he said. "They need to give it respect."

The Little White Pill

Over the past decade, medical researchers have come up with new and surprising uses for aspirin, as the following data suggests. But the little white pill, developed a century ago to relieve pain and fever, also has side effects.

THE PROS

* Heart Disease: Cuts the risk of a first heart attack 44%, according to a 1988 Harvard University study. Also reduces deaths 23% when administered during a heart attack.

* Stroke: Substantially reduces the chances of a second stroke, according to a 1994 Tel Aviv University study that also found that patients receiving 325 milligrams of aspirin a day are more than three times less likely to die from a stroke than those not taking aspirin.

* Colon Cancer: Cuts the risk of colon cancer 32% among those who take aspirin at least twice a week, according to a recent Harvard University study of 47,900 male health professionals. Long-term chronic users of aspirin have a 65% lower risk, the study found.

* Preeclampsia: Among women at risk for this pregnancy-related disorder, 2.2% of those taking aspirin become afflicted, compared to 15% not taking aspirin, according to a 1993 study by Memphis researchers.

THE CONS

* Reye's syndrome: Aspirin should never be given to children who have chicken pox or the flu because it poses a risk of this rare disorder. Reye's syndrome causes brain and liver damage, and is fatal 20% to 30% of the time.

* Gastrointestinal disorders: An estimated 2% to 6% of people who take aspirin suffer upset stomach; coated aspirin relieves this problem for some. Ulcers are common among those who take aspirin frequently over a long period of time. Gastrointestinal risk is highest among people taking very high doses, such as rheumatoid arthritis patients, who require 12 to 18 tablets a day. Most arthritis patients now take other anti-inflammatories.

* Allergies: About 1 in 500 people suffer allergic reactions to aspirin. Some complain of rash, including itchy red hives; others have asthma-like attacks. People with asthma, nasal polyps or a history of hives should be extremely cautious with aspirin.

Sources: The Aspirin Foundation of America; The Aspirin Handbook, by Joe Graedon and Tom Ferguson.

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