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   INFLAMMATION
 

Combating inflammation in arthritis and cardiovascular disease
Michael G. Malkowski, Ph.D.

malkowskiAspirin, ibuprofen, and other nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the cyclooxygenase enzymes COX-1 and COX-2 and provide relief to individuals suffering from inflammation, swelling, and pain associated with rheumatoid arthritis and osteoarthritis. These "classical" NSAIDs do not discriminate between COX-1 and COX-2 and thus many individuals experience adverse side effects, such as stomach ulceration and kidney failure, with chronic administration.

The recently approved "COX-2 selective" NSAIDs Celebrex®, Vioxx®, and Bextra® do not cause these gastrointestinal side effects.  While COX-2 inhibitors have provided individuals with a drug that allows them to better manage the painful symptoms of arthritis, many still suffer from potentially dangerous NSAID-induced gastrointestinal bleeding.

The goal of this Malkowski Lab research project is to: provide insight into how these NSAID-dependent compounds affect the inflammatory process; and lead to the exploration and development of new therapeutic approaches for the treatment of rheumatoid arthritis, osteoarthritis, and other inflammatory diseases.

Worldwide, cardiovascular disease and atherosclerosis (hardening of the arteries) are the primary cause of illness and death among adults. The leading cause of coronary artery disease is atherosclerosis.  It is well established that inflammation and the accumulation of fat in arterial walls represents the early stages of vascular inflammatory damage that ultimately leads to vessel blockage.  The reduction of such blockages through low-dose aspirin treatment is a well-established therapy.  An enzyme (known as COX-2) is active during the kind of inflammation that occurs in cardiovascular disease. Drugs such as Vioxx® have been developed to target COX-2. Those drugs were designed to control arthritis symptoms. Unfortunately, the drugs were causing heart attacks and other residual health problems.  No one truly understand why, so the Malkowski Lab is working toward a better understanding at the molecular level of how these drugs interact with COX-2 and how to stop the problems that are occurring as a result.

This project is supported by a grant, "Structural Biology of Oxylipin Biosynthesis", from the National Institutes of Health.

 
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