Chitkara Kamal, Hogrefe Kai, Vasa-Nicotera Mariuca, Swanson Neil, Gershlick Anthony H
University of Leicester, Cardiovascular Medicine, Clinical Sciences, Glenfield Hospital, Leicester, United Kingdom.
J Invasive Cardiol. 2006 Sep;18(9):417-22.
Stent thrombosis and in-stent restenosis remain problematic despite drug-eluting stents (DES), especially in diabetic patients and in those with small-vessel disease. Eptifibatide inhibits the platelet glycoprotein IIb/IIIa and smooth muscle cell (SMC) avb3 receptor, thus potentially influencing both thrombosis and proliferation. The aim of the present studies was to examine the absorption and elution characteristics of eptifibatide on polymer-coated stents and investigated their effect on SMC proliferation, platelet deposition and platelet aggregation in vitro.
Polymer-mixed eptifibatide and H3-labeled eptifibatide were loaded onto bare metal stents. A maximum of 111 mcg of eptifibatide was loaded onto 3.0 x 18 mm stents. Drug elution characteristics were tested in a PBS perfusion circuit. Elution profile consisted of an early rapid phase (24% +/- 0.03 loss over 1 hour) followed by a sustained release with 44% +/- 2.30 still present on the stent after 30 days. Eluted eptifibatide significantly inhibited adenosine diphosphate (ADP)-induced platelet aggregation by 95% +/- 0.70 (p < 0.01). Efficacy of stents eluting eptifibatide for antiplatelet effect was determined by measuring deposition of 111indium-labeled platelets on stents. Platelet deposition was significantly reduced by 48% +/- 6 in comparison to controls (p = 0.0065). Finally, drug-loaded stents were placed in SMC culture and showed a distinct zone of cell growth inhibition within 1 mm2 (88 +/- 22 vs. 208 +/- 23 SMCs in control), and within 2 mm2 of stent (131 +/- 32 vs. 191 +/- 23 SMCs in control) (both p < 0.01).
Eptifibatide can be successfully loaded onto stents. It elutes in a predictable manner, significantly inhibiting platelet deposition, aggregation and SMC proliferation in vitro. These studies pave the way to developing stent-based delivery of a potent antiplatelet agent, which additionally may inhibit SMC activity.
尽管有药物洗脱支架（DES），但支架内血栓形成和支架内再狭窄仍然是问题，尤其是在糖尿病患者和小血管疾病患者中。依替巴肽可抑制血小板糖蛋白IIb/IIIa和平滑肌细胞（SMC）的αvβ3受体，从而可能影响血栓形成和增殖。本研究的目的是检测依替巴肽在聚合物涂层支架上的吸收和洗脱特性，并研究其在体外对SMC增殖、血小板沉积和血小板聚集的影响。
将聚合物混合的依替巴肽和H3标记的依替巴肽加载到裸金属支架上。在3.0×18mm的支架上最多加载111μg的依替巴肽。在PBS灌注回路中测试药物洗脱特性。洗脱曲线包括一个早期快速阶段（1小时内损失24%±0.03），随后是持续释放，30天后支架上仍有44%±2.30的药物。洗脱的依替巴肽可显著抑制二磷酸腺苷（ADP）诱导的血小板聚集，抑制率为95%±0.70（p<0.01）。通过测量111铟标记的血小板在支架上的沉积来确定洗脱依替巴肽的支架的抗血小板效果。与对照组相比，血小板沉积显著减少48%±6（p=0.0065）。最后，将载药支架置于SMC培养中，在1mm2内显示出明显的细胞生长抑制区（对照组为208±23个SMC，载药组为88±22个），在支架的2mm2内也有明显抑制（对照组为191±23个SMC，载药组为131±32个）（均p<0.01）。
依替巴肽可成功加载到支架上。它以可预测的方式洗脱，在体外可显著抑制血小板沉积、聚集和SMC增殖。这些研究为开发基于支架的强效抗血小板药物递送方法铺平了道路，这种方法还可能抑制SMC活性。
