The year 2017 marks 120 years since the first non-steroidal anti-inflammatory (NSAID) drug, aspirin, became commercially available.¹ NSAIDs quickly become mainstay treatment for non-narcotic pain relief² and are now some of the most widely marketed and commonly used drugs in the world. Millions of patients have benefited from relief of pain and inflammation. However, this has come at a human price. Upper gastrointestinal ulceration leading to haemorrhage and occasionally perforation was detected early although, with the development of proton pump inhibitors, this is now preventable to a degree.³ It was not until 2000 that the possibility of a pro-thrombotic effect of NSAIDs became widely recognized.² Superficially, this seemed counter-intuitive as aspirin is used widely to prevent thrombosis. However, more detailed pharmacology provided an explanation. In the vascular system NSAIDs, to variable degree, inhibit both cyclo-oxygenase 1 (COX-1), which reduces production of pro-thrombotic thromboxane, and cyclo-oxygenase 2 (COX-2), which reduces production of the anti-thrombotic prostacyclin. It is believed that the balance between these, but particularly the degree of COX-2 inhibition, determines the net effect.⁴ NSAIDs differ in the degree of COX-2 inhibition achieved during regular use, which in turn depends on dose and pharmacokinetic/ pharmacodynamic relationships.⁵ This helps explain the apparent variability in vascular effects of NSAIDS: for example, the protective effect of aspirin (a COX-1 inhibitor at low doses) and an increased risk of major vascular events with rofecoxib (a potent COX-2 inhibitor with low inhibition of COX-1), which led to its withdrawal from world markets in 2004.⁶

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评论：有关非甾体类抗炎药的心血管风险的新争议

自第一种非甾体类抗炎药（NSAID）阿司匹林市售以来，2017年已过去120年。¹ NSAID迅速成为非麻醉性止痛药的主要治疗药物²，现在已成为世界上最广泛销售和最常用的药物。数以百万计的患者受益于疼痛和炎症的缓解。但是，这是要付出人力的代价。尽早发现上消化道溃疡，导致出血和偶尔穿孔，尽管随着质子泵抑制剂的发展，现在在一定程度上是可以预防的。³直到2000年，非甾体抗炎药具有促血栓形成作用的可能性才广为人知。^2个从表面上看，这似乎与直觉相反，因为阿司匹林被广泛用于预防血栓形成。但是，更详细的药理学提供了解释。在血管系统中，NSAIDs在不同程度上抑制环氧化酶1（COX-1）和环氧化酶2（COX-2），环氧化酶1（COX-1）减少血栓前血栓素的产生，环氧化酶2（COX-2）减少抗血栓素的产生。前列环素。据信，两者之间的平衡，尤其是COX-2抑制的程度，决定了净效应。^4种非甾体类抗炎药在常规使用期间获得的COX-2抑制程度不同，这又取决于剂量和药代动力学/药效关系。⁵这有助于解释NSAIDS在血管作用方面的明显变化：例如，阿司匹林（低剂量的COX-1抑制剂）的保护作用以及罗非考昔（一种低抑制作用的强效COX-2抑制剂）的发生重大血管事件的风险增加（COX-1），导致其在2004年退出世界市场^。6