Dual COXIB/TP antagonists: a possible new twist in NSAID pharmacology and cardiovascular risk

In the 1990s, after identification of two cyclo-oxygenase (COX) isoforms catalyzing the synthesis of prostaglandins and thromboxane A(2) (TXA(2)), a new class of non-steroidal anti-inflammatory drug (NSAID) became available (COX-2 inhibitors, or COXIBs). COXIBs have become among the best-selling drugs because of their gastrointestinal safety compared with NSAIDs. Concomitantly, increasing evidence for a potential cardiovascular hazard associated with COXIBs emerged. This suggested that selective inhibition of the synthesis of COX-2-derived prostanoids could lead to undesired disruption of the intricate inter-eicosanoid network. Further improvement of COXIBs is therefore necessary, and a potential strategy might involve targeting the TXA(2) receptor to balance the undesired cardiovascular effects of COXIBs. It has recently been demonstrated that a traditional NSAID and a selective COXIB possess an additional activity: weak competitive antagonism at the TXA(2) receptor. Full exploitation of dual-targeted compounds may represent a 'new twist in NSAID pharmacology'.