[Specific cyclooxygenase-2 inhibitors. Basis and options of a pharmacotherapeutic concept]

Abstract

The therapeutic and unwanted side effects of non-steroidal antiinflammatory drugs (NSAIDs) are attributable to inhibition of the cyclooxygenase (COX) enzyme which catalyzes the first step of the synthesis of prostanoids. In the early 1990s, COX was demonstrated to exist as two distinct isoforms. COX-1 is constitutively expressed as a 'housekeeping' enzyme in most tissues. In contrast, COX-2 can be upregulated by various proinflammatory agents, including endotoxin, cytokines and growth factors. Whereas many of the side effects of NSAIDs (e.g. gastrointestinal ulceration and bleeding, platelet dysfunctions) are due to a suppression of COX-1 activity, inhibition of COX-2-derived prostanoids facilitates the anti-inflammatory, analgesic and antipyretic effects of NSAIDs. Thus, the hypothesis that specific inhibition of COX-2 might have therapeutic actions similar to those of NSAIDs, but without causing the unwanted side effects, was the rationale for the development of specific inhibitors of the COX-2 enzyme as a new class of anti-inflammatory and analgesic agents with improved gastrointestinal tolerability. However, the simple concept that COX-2 is an exclusively proinflammatory and inducible enzyme cannot be supported any longer. Recently, COX-2 was shown to be also expressed under basal conditions in organs such as the ovary, uterus, brain, spinal cord, kidney and bone, suggesting that this isoenzyme may play a more complex physiological role than was expected. The present review assesses concept and molecular mechanism underlying specific COX-2 inhibition as well as indications, pharmakokinetics and unwanted side effects of the recently approved specific COX-2 inhibitors celecoxib and rofecoxib. Moreover, recent advances in COX-2 research, with particular emphasis on new insights into physiological functions of this isoenzyme will be discussed.