Tardif Jean-Claude
Department of Medicine, Montreal Heart Institute, Montreal, Quebec, Canada.
Am J Cardiol. 2003 Feb 6;91(3A):41A-49A. doi: 10.1016/s0002-9149(02)03149-1.
A large body of evidence points to oxidative stress as an important trigger in the complex chain of events leading to atherosclerosis. Reactive oxygen species have also been implicated in the pathophysiology of restenosis after percutaneous coronary interventions (PCI). The powerful antioxidant probucol has been shown to prevent coronary restenosis after balloon angioplasty in the MultiVitamins and Probucol (MVP) trial and other clinical studies. Probucol has also induced regression of carotid atherosclerosis in the Fukuoka Atherosclerosis Trial (FAST). However, prolongation of the QT interval with probucol remains a long-term safety concern. AGI-1067, a metabolically stable analog of probucol, is a vascular protectant (V-protectant) with strong antioxidant properties, equipotent to those of probucol. This V-protectant has been effective at preventing atherosclerosis in all tested animal models, including the low-density lipoprotein receptor-deficient and apolipoprotein E-knockout mice and the hypercholesterolemic primate. AGI-1067 improved luminal dimensions of the PCI site and reduced restenosis in the Canadian Antioxidant Restenosis Trial (CART-1). In contrast to probucol, AGI-1067 did not induce prolongation of the QT interval. AGI-1067 also improved luminal dimensions of the reference segments in the PCI vessels in CART-1, an effect that suggests a direct antiatherosclerosis effect. This has potentially important implications, as local approaches to prevent restenosis, such as coated stents, are not expected to prevent atherosclerosis progression, myocardial infarction, and cardiovascular death. Considering that oxidative stress and inflammation may persist for a prolonged period after stenting, treatment with AGI-1067 for the entire period of risk after PCI (instead of only 4 weeks in CART-1) may result in enhanced protection against luminal renarrowing in the ongoing multicenter CART-2 trial. Because the ultimate goal of therapy for patients with coronary artery disease must remain prevention of disease progression and atherosclerosis-related events, CART-2 will test the value of AGI-1067 for the reduction of both post-PCI restenosis and atherosclerosis progression.
大量证据表明，氧化应激是导致动脉粥样硬化的复杂事件链中的一个重要触发因素。活性氧也与经皮冠状动脉介入治疗（PCI）后再狭窄的病理生理学有关。在多项维生素和普罗布考（MVP）试验及其他临床研究中，强效抗氧化剂普罗布考已被证明可预防球囊血管成形术后的冠状动脉再狭窄。普罗布考在福冈动脉粥样硬化试验（FAST）中也可使颈动脉粥样硬化消退。然而，普罗布考导致QT间期延长仍然是一个长期的安全问题。AGI-1067是普罗布考的一种代谢稳定类似物，是一种具有强大抗氧化特性的血管保护剂（V-保护剂），其抗氧化能力与普罗布考相当。这种V-保护剂在所有测试的动物模型中都能有效预防动脉粥样硬化，包括低密度脂蛋白受体缺陷小鼠、载脂蛋白E基因敲除小鼠和高胆固醇血症灵长类动物。AGI-1067在加拿大抗氧化剂再狭窄试验（CART-1）中改善了PCI部位的管腔尺寸并减少了再狭窄。与普罗布考不同，AGI-1067不会导致QT间期延长。AGI-1067还改善了CART-1中PCI血管参考节段的管腔尺寸，这一效应表明其具有直接的抗动脉粥样硬化作用。这具有潜在的重要意义，因为诸如涂层支架等预防再狭窄的局部方法预计无法预防动脉粥样硬化进展、心肌梗死和心血管死亡。考虑到支架置入后氧化应激和炎症可能会持续很长时间，在正在进行的多中心CART-2试验中，用AGI-1067在PCI后的整个风险期进行治疗（而不是像CART-1中那样仅治疗4周）可能会增强对管腔再狭窄的预防作用。由于冠心病患者治疗的最终目标必须始终是预防疾病进展和动脉粥样硬化相关事件，CART-2将测试AGI-1067在降低PCI后再狭窄和动脉粥样硬化进展方面的价值。
