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'.
Rovati
G Enrico
GE
Laboratory of Molecular Pharmacology, Department of Pharmacological Sciences, Università degli Studi di Milano, Via Balzaretti, 9, 20133 Milano, Italy.
Sala
Angelo
A
Capra
Valérie
V
Dahlén
Sven-Erik
SE
Folco
Giancarlo
G
D000818:Animals; D002318:Cardiovascular Diseases / Q000139:chemically induced*; D052246:Cyclooxygenase 2 Inhibitors / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology; D004008:Diclofenac / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors*
D052246:Cyclooxygenase 2 Inhibitors; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D004008:Diclofenac; C473384:lumiracoxib