From prostaglandin replacement to specific COX-2 inhibition: a critical appraisal.
Nonsteroidal antiinflammatory drugs (NSAID) are among the most widely prescribed medications worldwide. While these agents are efficacious for the relief of both pain and the signs and symptoms of inflammation, the use of traditional NSAID is associated with a high prevalence of toxic events. It is estimated that 2-4% of traditional NSAID users will have a serious adverse gastrointestinal (GI) event per year, with a point prevalence of GI ulcers at any given time of 10-30%. The mortality rate associated with these NSAID is one of the highest attributed to the use of any agent. Prostaglandin replacement with misoprostol has been shown to significantly reduce the incidence of serious GI toxicity related to the use of conventional NSAID. All conventional NSAID inhibit both cyclooxygenase-1 (COX-1) and COX-2 enzymes. As COX-1 is constitutively expressed in many tissues and contributes to the maintenance of the normal physiologic state in the GI tract, the kidney, and platelets, an agent that specifically inhibits COX-2, an inducible enzyme associated with the inflammatory response, would be highly desirable. Specific COX-2 inhibition would have the advantage of improving the signs and symptoms of inflammation, while avoiding the possibly significant toxicity of traditional NSAID. This article describes the biology of eicosanoids and the effects of NSAID, the toxicity profile of conventional NSAID, and the rationale for the use of gastroprotective agents or agents that specifically inhibit the COX-2 isozyme.