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

• Published in: Trends in pharmacological sciences (Regular ed.) Vol. 31; no. 3; pp. 102 - 107
• Main Authors: Rovati, G. Enrico, Sala, Angelo, Capra, Valérie, Dahlén, Sven-Erik, Folco, Giancarlo
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.03.2010
• Subjects: Advanced Basic Science; Animals; Cardiovascular Diseases - chemically induced; Cyclooxygenase 2 Inhibitors - adverse effects; Cyclooxygenase 2 Inhibitors - chemistry; Cyclooxygenase 2 Inhibitors - pharmacology; Diclofenac - adverse effects; Diclofenac - analogs & derivatives; Diclofenac - chemistry; Diclofenac - pharmacology; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Humans; Medicin och hälsovetenskap; Receptors, Thromboxane A2, Prostaglandin H2 - antagonists & inhibitors
• ISSN: 0165-6147; 1873-3735; 1873-3735
• DOI: 10.1016/j.tips.2009.11.007

In the 1990s, after identification of two cyclo-oxygenase (COX) isoforms catalyzing the synthesis of prostaglandins and thromboxane A2 (TXA2 ), 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 TXA2 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 TXA2 receptor. Full exploitation of dual-targeted compounds may represent a ‘new twist in NSAID pharmacology’.