Specific COX-2 Therapy Is the Future

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used drugs throughout the world, with an estimated 17 million persons in the United States using them on a daily basis [1,2]. These drugs have been proven to be effective in the treatment of acute and chronic painful and inflammatory musculoskeletal conditions. However, due to widespread use of NSAIDs, the incidence of NSAID-induced adverse effects has become a problem. The most common toxic effects induced by NSAIDs are gastric and/or duodenal ulcers; ulcer complications, potentially including bleeding, perforation, or obstruction of the gastrointestinal tract; and alterations in kidney function [3–6]. These serious complications of ulcer disease can lead to death. For many years clinicians have been tantalized by announcements of “new and safer” NSAIDs. Unfortunately, the hoped-for increased safety was typically associated with some sacrifice in efficacy, and when more of the safe drug was used by the individual patient to attain an improved clinical effect, the incidence of NSAID-induced gastrointestinal damage increased (although less than observed with the older NSAIDs). Many of the important toxic effects of NSAIDs are primarily due to their primary mechanism of action: the inhibition of prostaglandin synthesis through the inhibition of the rate-limiting synthetic enzyme cyclooxygenase (COX). With the discovery of the COX isoforms, the reasons for the problems with traditional NSAIDs became more clear, and we now have available drugs that provide efficacy through the inhibition of COX-2 only. In this editorial, I will review the evidence that shows that COX-2–specific inhibitors provide efficacy equal to that of traditional NSAIDs without conveying the same risk to the gastrointestinal tract or platelet. The NSAIDs currently available effectively reduce pain and inflammation due to many different conditions and diseases, including the chronic arthritis seen in rheumatoid arthritis and osteoarthritis. This effect is by inhibition of the activity of COX, the enzyme that catalyzes the synthesis of cyclic endoperoxides from arachidonic acid to form proinflammatory and other forms of prostaglandins [5,6]. Prostaglandins, when synthesized at sites of inflammation, are clearly important in increasing local inflammation and enhancing pain sensation. Yet, in the gastric mucosa, prostaglandins promote the generation of a protective barrier of mucous and bicarbonate, decrease the synthesis of gastric acid, stimulate glutathione production (which acts to scavenge superoxides), and promote adequate blood flow to meet the needs of the cells of the gastric mucosa [7–10]. All of these positive effects serve to protect the cells that comprise the gastric lining from the extreme conditions found within the gastric lumen. These include not only the normally highly acidic contents of the gastric lumen but also potential ingested toxins such as alcohol or NSAIDs. In the kidney, prostaglandins act to modulate intrarenal plasma flow and water and electrolyte balance [5,6]. Thus, there are both good and bad effects with the inhibition of prostaglandin synthesis. Recently, 2 isoenzymes of COX were identified: COX-1 and COX-2 [9–17]. Although they are products of 2 different genes, there is 60% homology between the enzymes. There is 95% homology in the active site of the 2 peptides, which differ only in 1 of 25 amino acids within the binding site for arachidonate or NSAID. COX-1 acts predominantly as a constitutive enzyme in the gastric mucosa, producing prostaglandins that generate the protective barrier in the gastric lumen and probably those prostaglandins active in the renal parenchyma, particularly in the glomerulus. It is the only available isoform in platelets. Thromboxane is the important prostaglandin in promoting platelet aggregation; inhibition of its synthesis by decreasing COX-1 activity leads to a decreased ability to clot, a prolonged bleeding time, and an increased propensity to bleed. Inhibition of COX-1 activity is considered a major cause of the gastrointestinal toxic effects of NSAIDs, although COX-2 activity is upregulated when there is injury [13,18], perhaps associated with the attempt to repair. COX-2 is present in most tissues constitutively in small amounts, particularly in the brain, ovulating ovum, vas deferens, bone near the periosteum, macula densa, and tubules of the kidney. It is highly inducible at sites of inflammation. Cytokines and growth factors have been demonstrated to increase COX-2 mRNA and thus more COX-2 protein,