Cornelius Celsus, a Roman writer who lived during the reign of the emperor Caligula, included in his compendium of medicine what he called "inflammation's four cardinal signs" -- redness, swelling, heat and pain. Until the l9th century, when aspirin was developed, doctors were relatively powerless to cope with any of these signs.
Now scientists have discovered a whole new class of compounds, called anti-leukotrienes, which they hope may treat a variety of inflammatory illnesses ranging from asthma to rheumatoid arthritis. Several giant pharmaceutical companies are vying for potential multimillion dollar royalties from this class of drugs.
So far, the only compound that has been tested in humans is zileuton, manufactured by the Chicago-based Abbott Laboratories. In tests earlier this year involving 69 patients, zileuton relieved symptoms of three kinds of inflammatory conditions -- asthma, hay fever and ulcerative colitis, a debilitating bowel disease that afflicts about one million Americans.
"Zileuton has significant potential as a therapeutic agent," said William Stenson, associate professor of medicine at Washington University in St. Louis. Stenson's group was one of several laboratories participating in a controlled study of zileuton as a treatment for ulcerative colitis. In clinical trials, 28 patients treated with zileuton improved, while those given a placebo did not.
However, Stenson noted, it is not clear whether zileuton is better than other drugs already available for ulcerative colitis. Patients who were given zileuton in addition to sulfasalazine or 5-ASA, two drugs currently used to treat ulcerative colitis, showed no additional improvement.
Researchers have begun experimenting with different dosages of zileuton, hoping to increase its effectiveness.
"We're quite excited about zileuton," said James Kesterson, vice president of pharmaceutical development for Abbott Laboratories. Kesterson said Abbott expects to file a new drug application with the Food and Drug Administration in the next two years. After an approval process that takes about two to three years, the drug would be available to physicians.
Zileuton also has shown some effectiveness in treating asthma, a respiratory condition that affects 9 million Americans, as well as hay fever, a seasonal allergy to pollen from which 23 million Americans suffer. Researchers also are studying the effect of zileuton on people who have rheumatoid arthritis and psoriasis.
Other pharmaceutical companies, including Wellcome Research Laboratories, Merck Sharp & Dohme, Boehringer Ingelheim Corp. and Wyeth-Ayerst Laboratories, are testing anti-leukotrienes of their own, but these drugs have not reached human clinical trials, according to company officials.
The anti-leukotrienes are the latest in a long line of anti-inflammatory drugs developed since aspirin, the most widely used drug in the world with estimated U.S. sales of $388 million.
Aspirin became a potent drug in the mid-1800s, when chemists discovered it was an active ingredient in a popular ointment used by herbalists -- the extract from the bark of the willow tree.
More recent discoveries of drugs that have similar properties include the nonsteroidal anti-inflammatory drugs -- NSAIDs -- such as ibuprofen and Motrin. Both aspirin and the NSAIDs interfere with cyclo-oxygenase, an enzyme that helps cause inflammation. They limit the amount of prostaglandins, powerful chemicals with a range of biological functions, manufactured naturally in the body.
During inflammation, prostaglandins make veins and arteries stretch wider, thus allowing more blood to flow to inflamed areas. More blood bathes the afflicted area with redness and warmth, which, as Celsus noted, are two of the hallmarks of inflammatory disease. But aspirin and NSAIDs are only partly effective in reducing pain and don't affect swelling.
The anti-leukotrienes interfere with a different enzyme, lipoxygenase, thereby stemming production of another family of chemicals that are closely related to prostaglandins, the leukotrienes.
Leukotrienes wreak havoc on the walls of veins and arteries, by making the blood vessel walls more permeable to water and causing water to leak out of the blood vessels and into the surrounding tissue. This causes the tissues to swell.
The hope is that the anti-leukotrienes will stop the swelling, which contributes in part to the pain -- Celsus's fourth sign of inflammation -- as does action by the prostaglandins, which directly affect the nerve endings.
Although inflammation occurs normally when the body fights infection, it can be a symptom of a crippling disease, such as rheumatoid arthritis.
Scientists don't know what causes rheumatoid arthritis, which affects more than 2 million people. They speculate it is an inapproriate response of the immune system.
When the body's first line of defense, the skin, is compromised by anything ranging from a mosquito bite to a deep cut, an army of white blood cells is dispatched to the wound.
As the white blood cells attack foreign particles and germs in the bloodstream, some also manufacture prostaglandins, leukotrienes and many other chemicals that together cause inflammation.
By stopping the manufacture of prostaglandins, aspirin and NSAIDs quell inflammation. However, they also interfere with the beneficial roles prostaglandins play, such as helping blood to clot.
Leukotrienes, on the other hand, do not appear to perform any bodily function other than aiding inflammation, which causes pain.
Anti-leukotrienes, researchers hope, will affect only the inflammatory response and have few, if any, side effects.
Researchers hope that anti-leukotrienes will assuage the swelling and pain of inflammation that aspirin does not touch. But whether doctors will be able to prescribe these drugs depends on an expensive approval process involving extensive clinical trials that is likely to take several years.