FitzGerald Garret A
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Am J Cardiol. 2002 Mar 21;89(6A):26D-32D. doi: 10.1016/s0002-9149(02)02234-8.
Cyclooxygenase (COX)-2 inhibitors have been developed with the goal of providing similar efficacy and greater safety compared with traditional nonsteroidal anti-inflammatory drugs. Development was based on the hypothesis that COX-1 is the housekeeping enzyme necessary for production of prostaglandins (PGs) with homeostatic functions, whereas COX-2 is a mediator of pathophysiologic processes. However, later research has demonstrated a role of COX-2 in production of PGs that have functions under normal physiologic conditions. In the vasculature, COX-2 seems to be the main enzyme responsible for the production of prostacyclin. Increased synthesis of this vasodilatory and antithrombotic PG represents a homeostatic response during periods of accelerated platelet-vessel wall interactions and counteracts increased synthesis of COX-1-derived prothrombotic prostanoid thromboxane A(2) (TXA(2)). The clinical sequelae of inhibiting prostacyclin activity in the absence of concomitant inhibition of TXA(2) are not currently clear. Animal studies show that inhibition of prostacyclin activity does not lead to spontaneous thrombosis but may increase response to thrombotic stimuli. Therefore, prostacyclin synthesis may be important for limiting thrombotic events in patients who are at an increased cardiovascular risk. Overviews of clinical studies in arthritis and Alzheimer's disease have not demonstrated increased cardiovascular risk associated with specific COX-2 inhibition in most patients. However, data from 1 clinical trial revealed a 5-fold divergence in rates of myocardial infarction between a coxib and a nonsteroidal anti-inflammatory drug comparitor. Credible explanations for the results of this trial have been proposed and further studies are necessary to clarify the relative risk-to-benefit ratio of COX-2 inhibition in patients at increased risk for cardiovascular events, and the effects of concomitant aspirin therapy.
环氧化酶（COX）-2抑制剂的研发目的是与传统非甾体抗炎药相比，提供相似的疗效并具有更高的安全性。其研发基于这样的假设：COX-1是产生具有稳态功能的前列腺素（PGs）所必需的看家酶，而COX-2是病理生理过程的介质。然而，后来的研究表明COX-2在产生正常生理条件下起作用的PGs中也发挥作用。在血管系统中，COX-2似乎是负责产生前列环素的主要酶。这种血管舒张和抗血栓形成的PG合成增加代表了血小板与血管壁相互作用加速期间的一种稳态反应，并抵消了COX-1衍生的促血栓形成类前列腺素血栓素A2（TXA2）合成的增加。在没有同时抑制TXA2的情况下抑制前列环素活性的临床后果目前尚不清楚。动物研究表明，抑制前列环素活性不会导致自发血栓形成，但可能会增加对血栓形成刺激物的反应。因此，前列环素的合成对于限制心血管风险增加的患者的血栓形成事件可能很重要。关节炎和阿尔茨海默病临床研究的综述表明，在大多数患者中，特定的COX-2抑制与心血管风险增加无关。然而，一项临床试验的数据显示，一种环氧化酶抑制剂与一种非甾体抗炎药对照物之间的心肌梗死发生率相差5倍。已经对该试验结果提出了可信的解释，需要进一步研究以阐明心血管事件风险增加的患者中COX-2抑制的相对风险效益比，以及联合使用阿司匹林治疗的效果。
