Clinical aspects of COX-2 inhibitors

Inflammation is the body's response to tissue damage. The signs of inflammation are pain, swelling and edema. One of the major chemical mediators involved in the inflammatory response is the group of prostaglandins (PGs) synthesized by the enzyme cyclooxygenase (COX). There are two isoforms of COX, the constitutive enzyme COX-1, which is responsible for the production of PGs with general housekeeping functions such as maintenance of renal perfusion and a protective effect on the gastric mucosa against ulceration; and the inducible enzyme COX-2, which is responsible for the production of proinflammatory PGs. Non-steroidal antiinflammatory drugs (NSAIDs), by inhibiting the COX enzyme, are able to reduce the pain and swelling associated with inflammation. In theory, new molecules that preferentially inhibit the inducible enzyme alone would not affect the housekeeping function of COX-1 but would retain the antiinflammatory action. Currently, there are a number of molecules available which claim to have some selectivity for the COX-2 enzyme. These have been labeled COX-2 preferential drugs. Highly selective COX-2 enzyme inhibitors are being assessed in phase II and phase III clinical studies. What are the issues these drugs will create and will they be successful? The first question is whether they are truly COX-2-selective. The balance of evidence suggests that they are. There is less gastric ulceration by the preferential drugs and there is very little evidence of gastric damage with the COX-2-selective drugs. All these drugs seem to maintain renal perfusion better than other NSAIDs and platelet aggregation is not affected. The second question is whether these drugs are as effective as conventional NSAIDs. From the preliminary data available it appears that the inhibition of COX-2 is effective in reducing inflammation. There are some doubts from studies in animal models as to whether some inhibition of COX-1 is also required, but this has not yet been shown in humans. There are concerns regarding the cerebral function of COX-2 and the expression of COX-2 in the kidney and gut. Thirdly, will new benefits arise from the use of these drugs? It seems likely that selective COX-2 inhibition will have the same beneficial effects on Alzheimer's disease and colonic cancer as nonselective drugs. In fact, these may even become new indications. What are the likely hazards? There will probably be individual problems with particular drugs but these cannot be predicted. The crucial issue is that patients who benefit most from NSAIDs are those who will be most likely to have side effects from the nonselective COX-1 and COX-2 inhibitors. Therefore, once there is good evidence of their efficacy and safety they will become widely used drugs.