Krotz Florian, Schiele Thomas M, Klauss Volker, Sohn Hae-Young
Institute of Cardiology, Medical Polyclinic, Ludwig Maximilians University, Munich, Germany.
J Vasc Res. 2005 Jul-Aug;42(4):312-24. doi: 10.1159/000086459. Epub 2005 Jun 20.
Selective inhibitors of cyclooxygenase-2 (COX-2, 'coxibs') are highly effective anti-inflammatory and analgesic drugs that exert their action by preventing the formation of prostanoids. Recently some coxibs, which were designed to exploit the advantageous effects of non-steroidal anti-inflammatory drugs while evading their side effects, have been reported to increase the risk of myo cardial infarction and atherothrombotic events. This has led to the withdrawal of rofecoxib from global markets, and warnings have been issued by drug authorities about similar events during the use of celecoxib or valdecoxib/parecoxib, bringing about questions of an inherent atherothrombotic risk of all coxibs and consequences that should be drawn by health care professionals. These questions need to be addressed in light of the known effects of selective inhibition of COX-2 on the cardiovascular system. Although COX-2, in contrast to the cyclooxygenase-1 (COX-1) isoform, is regarded as an inducible enzyme that only has a role in pathophysiological processes like pain and inflammation, experimental and clinical studies have shown that COX-2 is constitutively expressed in tissues like the kidney or vascular endothelium, where it executes important physiological functions. COX-2-dependent formation of prostanoids not only results in the mediation of pain or inflammatory signals but also in the maintenance of vascular integrity. Especially prostacyclin (PGI(2)), which exerts vasodilatory and antiplatelet properties, is formed to a significant extent by COX-2, and its levels are reduced to less than half of normal when COX-2 is inhibited. This review outlines the rationale for the development of selective COX-2 inhibitors and the pathophysiological consequences of selective inhibition of COX-2 with special regard to vasoactive prostaglandins. It describes coxibs that are current ly available, evaluates the current knowledge on the risk of atherothrombotic events associated with their intake and critically discusses the consequences that should be drawn from these insights.
环氧化酶-2（COX-2）的选择性抑制剂（“昔布类药物”）是高效的抗炎和镇痛药，通过阻止前列腺素的形成发挥作用。最近，一些旨在利用非甾体抗炎药的有益作用同时避免其副作用而设计的昔布类药物，已被报道会增加心肌梗死和动脉粥样血栓形成事件的风险。这导致罗非昔布从全球市场撤市，药品监管机构已就使用塞来昔布或伐地昔布/帕瑞昔布期间的类似事件发出警告，引发了关于所有昔布类药物是否存在固有动脉粥样血栓形成风险以及医疗保健专业人员应从中吸取何种后果的问题。鉴于选择性抑制COX-2对心血管系统的已知影响，这些问题需要得到解决。尽管与环氧化酶-1（COX-1）亚型相比，COX-2被认为是一种仅在疼痛和炎症等病理生理过程中起作用的诱导型酶，但实验和临床研究表明，COX-2在肾脏或血管内皮等组织中组成性表达，在这些组织中它执行重要的生理功能。COX-2依赖性前列腺素的形成不仅导致疼痛或炎症信号的介导，还维持血管完整性。特别是前列环素（PGI₂），它具有血管舒张和抗血小板特性，很大程度上由COX-2形成，当COX-2被抑制时，其水平会降至正常水平的一半以下。本综述概述了选择性COX-2抑制剂的开发原理以及选择性抑制COX-2的病理生理后果，特别关注血管活性前列腺素。它描述了目前可用的昔布类药物，评估了关于摄入这些药物与动脉粥样血栓形成事件风险的现有知识，并批判性地讨论了应从这些见解中得出的后果。
