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Complementary and Alternative Medicine: Fair and Balanced

Arthritis: Why COX-2 matters

Drugs and herbals that can separate COX-2 and COX-1 effects can relieve or prevent joint pain and swelling while maintaining GI mucosal integrity.

By John Russo Jr. Vicus.com

VICUS.COM (4 May 2000) -- In March 1999, seven weeks after being launched, the number of daily prescriptions for Celebrex (celecoxib), Monsanto's new arthritis pain drug, had surpassed the daily prescriptions for Viagra (sildenafil), the widely publicized impotence drug from Pfizer, at the same point in its life span. Celebrex was on its way to becoming the top-selling drug ever and on track to become a $2 billion dollar drug in its first year.

One year later, the numbers are in. Celebrex sales reached $1.5 billion in 1999, and sales of Vioxx (rofecoxib), the other COX-2 inhibitor, totaled $472 million. These drugs have not only met a need for safer treatment of rheumatoid arthritis and osteoarthritis, but they have expanded the potential role of non-steroidal inflammatory drugs (NSAIDs) in areas such as  Alzheimer's disease, colon cancer and the prevention of colonic polyps and tumors.

The concept behind COX      

Figures 1 and 2 show why Celebrex and Vioxx have had such a significant effect on the treatment of rheumatoid arthritis and osteoarthritis. It also illustrates the reason for the growing interest in the Chinese traditional herbal preparation Tripterygium wilfordii Hook (TWHF) extract, which appears to reduce COX-2 by blocking the gene for COX-2 rather than by inhibiting the enzyme after it is produced.

In Figure 1, the pathway to prostaglandin synthesis shows that tissue damage activates phospholipase A2 (PL-A2). From here, there are two main pathways that are activated. The lipo-oxygenase pathway leads to formation of leukotrienes and lipoxins, while the cyclo-oxygenase (COX) enzymes (COX-1 and/or COX-2) convert arachidonic acid to prostaglandin G(PGG2), which is later converted to prostaglandin H2. Other enzymes then convert prostaglandin H2 to prostaglandins D2, E2  or F2. The E2 molecule is the one most closely involved in the inflammatory response.

Figure 2 provides a closer look at the alternative COX pathways. Physiologic stimuli lead to expression of COX-1, the "good COX," which is secreted within the gastrointestinal tract, the kidneys and elsewhere, and is involved in physiological "housekeeping" -- maintaining cellular integrity. For example, COX-1 is continuously secreted within the stomach and duodenum where it catalyzes PGE2 and PGI2 synthesis, which have cytoprotective effects that help maintain GI mucosal integrity. By comparison, COX-2, the "bad COX," is induced only at sites of inflammation. It is found mainly in inflammatory and immune cells (i.e., neutrophils, macrophages, mast cells, etc.) and cells lining the joints in rheumatoid arthritis. 

Reducing production of COX-2 or interfering with COX-2 activity can relieve or prevent the joint pain and swelling that occur in rheumatoid arthritis and osteoarthritis. However, reducing production of COX-1, which is done by NSAIDs, removes an important source of GI mucosal protection. 

 

Figure 1. When tissue damage activates phospholipase A2 (PL-A2), two pathways are activated. The lipo-oxygenase pathway leads to formation of leukotrienes and lipoxins, while the cyclo-oxygenase (COX) enzymes (COX-1 and/or COX-2) convert arachidonic acid to prostaglandin G2 (PGG2), which is later converted to prostaglandin H2. Other enzymes then convert prostaglandin H2 to prostaglandins D2, E2  or F2. The E2 molecule is the one most closely involved in the inflammatory response. 

Figure 2. A closer look at the alternative COX pathways reveals that physiologic stimuli lead to expression of COX 1, which is secreted within the gastrointestinal tract, the kidneys and elsewhere, and is involved in maintenance of cell integrity. By comparison, COX-2 is induced only at sites of inflammation. It is found mainly in inflammatory and immune cells (e.g., neutrophils, macrophages, mast cells, etc.) and cells lining the joints in rheumatoid arthritis. 

Reducing COX-2 activity can relieve or prevent the joint pain and swelling that occurs in rheumatoid arthritis and osteoarthritis. However, reducing production of COX-1, removes an important source of GI mucosal protection: [ = inhibitory pathway; COX = cyclo-oxygenase; PG = prostaglandin. 

 

John Russo Jr. is senior vice president of medical communications at Vicus.com. He is a pharmacist and medical writer with more than 20 years of experience in medical education.

 

References:


Burton TM. Technology & health: Monsanto arthritis-pain drug, Celebrex, surpasses Viagra's early sales success. The Wall Street Journal, March 5, 1999