Laboratory of Molecular Pharmacology, Department of Pharmacological Sciences, Università degli Studi di Milano, Via Balzaretti, 9, 20133 Milano, Italy.
Trends Pharmacol Sci. 2010 Mar;31(3):102-7. doi: 10.1016/j.tips.2009.11.007. Epub 2010 Feb 1.
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'.
20 世纪 90 年代，在鉴定出两种催化前列腺素和血栓素 A2（TXA2）合成的环氧化酶（COX）同工酶后，出现了一类新型非甾体抗炎药（COX-2 抑制剂，或 COXIBs）。由于 COXIBs 与 NSAIDs 相比具有胃肠道安全性，因此成为最畅销的药物之一。同时，越来越多的证据表明 COXIBs 可能存在潜在的心血管危害。这表明，选择性抑制 COX-2 衍生的前列腺素的合成可能导致复杂的类二十烷酸网络的不必要破坏。因此，有必要进一步改进 COXIBs，一种潜在的策略可能涉及靶向 TXA2 受体以平衡 COXIBs 产生的不良心血管作用。最近已经证明，一种传统的 NSAID 和一种选择性的 COXIB 具有额外的活性：在 TXA2 受体上具有弱的竞争性拮抗作用。充分利用双靶向化合物可能代表“NSAID 药理学的新转折”。
