COX-2-specific inhibitors - the emergence of a new class of analgesic and anti-inflammatory drugs

The prostaglandin series of bioactive compounds is formed by the interactio n of two distinct but related enzymes, cyclo-oxygenase-l (COX-1) and cyclo- oxygenase-2 (COX-2). COX-I is a constitutive form which is present mainly i n the gastric mucosa, kidney and platelets. COX-2 is mainly an inducible fo rm, although also to some extent present constitutively in the CNS, the jux taglomerular apparatus of the kidney and in the placenta during late gestat ion. Both isoforms contribute to the inflammatory process, but COX-2 is of considerable therapeutic interest as it is induced, resulting in an enhance d formation of prostaglandins, during acute as well as chronic inflammation . Conventional NSAIDs inhibit both isoforms to a similar extent and in an a pproximately equal dose and concentration range. The two recently developed and clinically available selective COX-2 inhibitors, celecoxib and rofecox ib, are about 100-1000 times more selective on the COX-2 than on the COX-1 isoform. Ln Europe rofecoxib is today indicated for the symptoms and signs of osteoarthritis, whereas celecoxib is indicated for both osteoarthritis a nd rheumatoid arthritis. The major clinical interest of these drugs has bee n related to the lower incidence of gastrointestinal bleeding which, with t he conventional COX-1/COX-2 agents has been a source of hospitalisation, di sablement and death, especially in the elderly. Clinical trials have convin cingly demonstrated that celecoxib and rofecoxib in clinical use induce ver y few gastrointestinal complications compared to conventional and non-selec tive NSAIDs. However, the well known contraindications for NSAIDs, such as late pregnancy, aspirin-induced asthma, congestive heart failure and renal dysfunction, will so far apply also to the COX-2 inhibitors. Compared to th e traditional and non-selective NSAIDs, COX-2 inhibitors may provide an ins ight into additional therapeutic areas, such as gastrointestinal cancer and dementia, where the potential relevance to COX-2 mechanisms are currently being explored and clinical trials being performed. With the rapid clinical acceptance of celecoxib and rofecoxib, knowledge about their clinical usef ulness in various inflammatory disease states and pain disorders is increas ing. For the many patients suffering from such conditions, the selective CO X-2 inhibitors are likely to become a significant addition to the therapeut ic arsenal of analgesic and anti-inflammatory drugs.