COX-1 and COX-2 products in the gut: therapeutic impact of COX-2 inhibitors.

Despite the considerable range of newly identified disease modifying approaches to the control of the inflammatory process reported over the past 10–20 years, only a few have yet gained widespread clinical acceptance. In contrast, the very recent advent of the class of anti-inflammatory agents termed COX-2 selective inhibitors is already having a significant impact on current clinical prescribing practice and market share in those territories that they are available. That these COX-2 selective inhibitors have become so successful within the same year of their launch attests to the perceived need for novel agents that can control the signs and symptoms of inflammatory diseases, but with minimal risk of gastrointestinal side eVects. Extensive epidemiological studies have well documented the so-called stealth epidemic of the gastropathy with non-steroidal antiinflammatory drugs (NSAIDs) that has developed over the period since the non-aspirin NSAIDs were introduced. 2 The massive growth of the market for such products, which has involved diVerent patients populations and the prescription of high doses, has led to the current substantial problem of some 103 000 hospitalisations and 16 500 deaths per year in the USA alone. The impact of such events on health care budgets is therefore substantial, and the risk of serious side eVects from these agents is an important consideration in long term anti-inflammatory therapy, especially in the elderly. Individual assessment of personal risk from taking NSAIDs can be obtained from a questionnaire accessed at www.seniors.org/score. This initial success of the COX-2 selective agents, unprecedented in the area of anti-inflammatory analgesics, has probably arisen from the general perception that they are a superior form of non-steroidal anti-inflammatory drug rather than a completely novel therapeutic approach of unknown clinical consequences. Moreover, the very reasonable scientific rationale proposed for their enhanced safety has been backed up by relatively extensive and well conducted clinical trials that have addressed the important pharmacological features of these agents. These factors have allowed their rapid appraisal and subsequent registration by regulatory bodies with minimal delay. The development of the scientific rationale for the eYcacy and safety of these agents covers some 30 years, beginning with the identification of cyclo-oxygenase (COX) inhibition by aspirin and the other classical non-steroidal anti-inflammatory drugs in 1971 by John Vane, as a mechanism of both their anti-inflammatory analgesic actions and their side eVects on the gut. This was followed 10 years later by identification of site selective inhibition of COX as a rational basis for the development of less gut injurious anti-inflammatory agents. The beginning of the 1990s saw the molecular identification and characterisation of two isoforms of COX, upon which the current focus for selective inhibitors of the COX-2 isoform is based. A decade later, the initial regulatory approval of celecoxib (Celebrex; Searle), the first specially designed selective COX-2 inhibitor, was granted in the USA, followed rapidly by its launch onto the market in early 1999. It has subsequently gained marketing authorisation in many diVerent territories, with approval in the UK in May 2000, being launched by Pharmacia/Pfizer. Within a few months of the commercialisation of celecoxib, another selective COX-2 inhibitor, rofecoxib (Vioxx; Merck), was approved and launched in the USA, and was similarly approved in the UK in June 1999. The present article reviews the background to the development of these gut sparing anti-inflammatory agents, as well as their therapeutic promise.