The janus face of cyclooxygenase-2 in ischemic stroke - Shifting toward downstream targets
The janus face of cyclooxygenase-2 in ischemic stroke - Shifting toward downstream targets
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DOI：
10.1161/01.str.0000153797.33611.d8
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发表时间：
2005-02-01
期刊：
影响因子：
8.3
通讯作者：
Gorelick, PB
中科院分区：
文献类型：
--
作者：
Iadecola, C;Gorelick, PB
20世纪70年代，Vane提出非甾体抗炎药（NSAIDS）的生物学效应是由COX介导的。21在发现COX的不同亚型后，研究表明这些药物的镇痛和抗炎作用是通过阻断COX-2的能力介导的。然而，非选择性非甾体抗炎药可能是有害的，因为它们也会阻断COX-1，导致胃肠道功能改变、粘膜溃疡、疼痛和出血。选择性COX-2抑制剂的开发有望缓解疼痛和炎症，而不会出现COX-1抑制相关的不良事件。在美国，塞来昔布和罗非昔布是FDA批准使用的首批COX-2抑制剂。24塞来昔布用于治疗类风湿性关节炎，罗非昔布用于治疗急性疼痛和经期疼痛。对COX-2抑制剂进行了严格的研究，以确定它们是否具有抗炎和镇痛作用而没有胃肠道并发症。在一项RA患者的研究中，塞来昔布（100 ~ 400mg BID）是有效的，与萘普生相比，内窥镜溃疡的发生率更低。另一项针对类风湿性关节炎和骨关节炎患者的研究检查了与传统非甾体抗炎药相比，塞来昔布是否与较低的显著胃肠道并发症和其他不良反应发生率相关。26与非甾体抗炎药布洛芬和双氯芬酸相比，高剂量塞来昔布（BID 400mg）的胃肠道副作用和其他并发症发生率较低。26同样，与萘普生相比，罗非昔布具有良好的胃肠功能。COX-2抑制剂的成功使这些药物大受欢迎，每年销售额达数十亿美元。是否存在被忽视的不良事件信号？
In the 1970s, Vane suggested that the biological effects of nonsteroidal anti-inflammatory drugs (NSAIDS) were mediated by COX. 21 After the discovery of the different isoforms of COX, studies revealed that the analgesic and antiinflammatory effects of these drugs were mediated by their ability to block COX-2. 22 However, nonselective NSAIDS might be harmful because they also block COX-1, leading to altered gastrointestinal function, mucosal ulceration, pain, and bleeding. 23 The development of selective COX-2 inhibitors promised to relieve pain and inflammation without the adverse events associated with COX-1 inhibition. 24 In the United States, celecoxib and rofecoxib were the first COX-2 inhibitors approved for use by the FDA. 24 Celecoxib was labeled for treatment of RA and rofecoxib for treatment of acute pain and menstrual pain. COX-2 inhibitors were studied rigorously to determine whether they provided antiinflammatory and analgesic effects without gastrointestinal complications. In a study of patients with RA, Celecoxib (100 to 400 mg BID) was effective, with lower incidence of endoscopic ulcers compared with naproxen. 25 Another study in patients with RA and osteoarthritis examined whether celecoxib was associated with a lower incidence of significant gastrointestinal complications and other adverse effects compared with conventional NSAIDS. 26 Celecoxib at high doses (400 mg BID) was associated with a lower incidence of gastrointestinal side effects and other complications compared with the NSAIDS ibuprofen and diclofenac. 26 Similarly, rofecoxib was shown to have a favorable gastrointestinal profile when compared with naproxen. 27, 28 The successes of the COX-2 inhibitors led to the popularity of these drugs and billions of dollars in sales per year. 29 Was there an ominous adverse event signal that had been ignored?