Wessely Rainer, Blaich Birgit, Belaiba Rachida Siham, Merl Sabine, Görlach Agnes, Kastrati Adnan, Schömig Albert
Deutsches Herzzentrum, Department of Cardiology / 1. Medizinische Klinik rechts der Isar, University of Technology, Munich, Germany.
Thromb Haemost. 2007 Jun;97(6):1003-12.
Pleiotropic anti-restenotic properties of drugs that are eluted from coated stents are critical for efficacy and safety. Little is known about comparative drug properties in appropriate human coronary target cell lines for the two compounds that are utilized on FDA-approved drug-eluting stent (DES) platforms, paclitaxel (PTX) and sirolimus (SRL). Target cell lines that play a pivotal role for the pathogenesis of restenosis and vascular healing include human coronary artery smooth muscle (CASMC) and endothelial cells (CAEC). PTX and SRL inhibited CASMC and CAEC proliferation and migration efficiently. However, there was a differential effect on proliferation and migration in CAEC with a more profound inhibition of both parameters by PTX, even at low dosages. Induction of cytotoxicity and apoptosis was pronounced in PTX- and very modest in SRL-treated CASMC and CAEC. PTX increased eNOS activity and nitric oxide (NO) release from CAEC. Neutrophilic leukocyte activation and transmigration, which should be avoided since it may precipitate adverse coronary events such as restenosis and stent thrombosis, was suppressed by SRL, whereas PTX tended to increase neutrophilic leucocyte activity. Therefore, although the primary drug target, inhibition of mitogen-mediated CASMC proliferation, is effectively accomplished by both drugs, auxiliary pharmacological properties that are crucial for the anti-restenotic drug effect and vascular healing are considerably different between PTX and SRL. In comparison with PTX, SRL shows minor interference with endothelial cell proliferation and migration, lower levels of cytotoxicity and apoptosis, a broader therapeutic range and distinctive immunosuppressive properties.
从涂层支架洗脱的药物的多效抗再狭窄特性对疗效和安全性至关重要。对于美国食品药品监督管理局（FDA）批准的药物洗脱支架（DES）平台上使用的两种化合物紫杉醇（PTX）和西罗莫司（SRL），在合适的人冠状动脉靶细胞系中的比较药物特性知之甚少。在再狭窄发病机制和血管愈合中起关键作用的靶细胞系包括人冠状动脉平滑肌（CASMC）和内皮细胞（CAEC）。PTX和SRL有效抑制CASMC和CAEC的增殖和迁移。然而，对CAEC的增殖和迁移存在差异效应，即使在低剂量下，PTX对这两个参数的抑制作用也更显著。PTX处理的CASMC和CAEC中细胞毒性和凋亡的诱导明显，而SRL处理的则非常轻微。PTX增加CAEC的eNOS活性和一氧化氮（NO）释放。SRL抑制中性粒细胞的活化和迁移，这是应该避免的，因为它可能引发不良冠状动脉事件，如再狭窄和支架血栓形成，而PTX则倾向于增加中性粒细胞活性。因此，尽管两种药物都能有效实现主要药物靶点，即抑制丝裂原介导的CASMC增殖，但对于抗再狭窄药物效应和血管愈合至关重要的辅助药理学特性在PTX和SRL之间存在很大差异。与PTX相比，SRL对内皮细胞增殖和迁移的干扰较小，细胞毒性和凋亡水平较低，治疗范围更广，且具有独特的免疫抑制特性。
