The clinical developments and future of the COX-2 inhibitor drugs

Abstract

A new era of analgesia began with the discovery of aspirin in 1899. Since that time, many newer NSAIDs (non-steroid anti-inflammatory drugs) have been discovered and utilized in clinical practice. The mechanism of anti-inflammatory action of NSAIDs is believed to result from inhibition of the enzyme cyclooxygenase (COX), discovered in the 1970s. This enzyme represents the key ratelimiting step in the production of prostaglandins (PGs) from arachidonic acid. Since PGs are essential for normal gastrointestinal, renal, and platelet function, as well as mediating the inflammatory process, inhibition of cyclooxygenase has both beneficial and deleterious effects. The beneficial effect, obviously, is inhibition of the inflammatory process, while the harmful effects comprise an increased incidence of upper gastrointestinal toxicity (ulceration, perforation, and bleeding) as well as possible renal and platelet dysfunction. In the late 1980s, it was discovered that two isoforms of cyclooxygenase existed (COX-1 and COX-2). COX-1 represents a constitutive form that is expressed in most tissues. In contrast, COX-2 is induced at sties of inflammation and also occurs under normal circumstances in the brain and renal tissues. Since COX-2 levels increase dramatically during acute and chronic inflammation, it was hypothesized that the COX-2 inhibitors might offer significant antiinflammatory qualities with reduced toxicity and may have utility in central nervous system mediated conditions other than peripheral pain, including dementias such as Alzheimer's disease and headache, specifically, migraine headache.