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.

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 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 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.