Muller D W, Gordon D, Topol E J, Levy R J, Golomb G
Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor 48109-0022, USA.
Am Heart J. 1996 Feb;131(2):211-8. doi: 10.1016/s0002-8703(96)90343-9.
Adventitial heparin delivery has been shown to inhibit thrombosis and neointimal thickening in a rat carotid injury model. To determine whether sustained, local delivery of hirulog, a potent antithrombin agent, inhibits thrombus formation and neointimal thickening after arterial stenting, silicone polymers containing hirulog were formulated at a concentration of 5.8% by weight and were tested in vitro to determine the rate of drug release. An oversized metallic stent was implanted in the carotid artery of 18 juvenile farm pigs. Hirulog-impregnated silicone polymers were placed around the adventitial surface of one stented segment of each animal and a control polymer was placed contralaterally. Intravenous hirulog (4 mg/kg/hr) was infused for the duration of the procedure to maintain the activated clotting time of > 300 sec. Ex vivo testing estimated the release of hirulog to be 1.54 micrograms/mg matrix/day with no loss of anticoagulant activity of the released peptide. In four pigs killed on days 3 through 5, macroscopic thrombus was very faintly visible on the stent struts of one arterial segment treated with sustained-release hirulog but was readily evident in all control arteries. However, electron microscopy showed platelet adhesion and microscopic thrombus formation on each stent of both treated and untreated sides. Fourteen pigs were killed 32 +/- 4 days after stenting. Histologic analysis showed no difference between hirulog-treated and control sides in the volume of neointima (540 +/- 129 units vs 357 +/- 95 units, p = 0.27) or in the average intima to media ratio (0.44 +/- 0.12 vs 0.34 +/- 0.24, p = 0.47) over the length of the stented segment. Late thrombotic occlusion occurred in two hirulog-treated and two control arteries. In this model, local adventitial hirulog delivery at the dose and delivery rate used may reduce, but does not prevent, thrombus formation and does not reduce the severity of neointimal thickening after carotid stent implantation.
在大鼠颈动脉损伤模型中，已证实外膜给予肝素可抑制血栓形成和新内膜增厚。为了确定强效抗凝血酶药物水蛭素的持续局部给药是否能抑制动脉支架置入术后的血栓形成和新内膜增厚，制备了含5.8%（重量）水蛭素的硅聚合物，并进行体外测试以确定药物释放速率。将一个尺寸过大的金属支架植入18只幼年农场猪的颈动脉。将含水蛭素的硅聚合物放置在每只动物一个支架段的外膜表面周围，对侧放置对照聚合物。在手术过程中持续静脉输注水蛭素（4mg/kg/小时），以维持活化凝血时间>300秒。体外测试估计水蛭素的释放量为1.54微克/毫克基质/天，释放的肽的抗凝血活性无损失。在第3至5天处死的4只猪中，在接受持续释放水蛭素治疗的一个动脉段的支架支柱上，肉眼可见的宏观血栓非常模糊，但在所有对照动脉中都很明显。然而，电子显微镜显示，治疗侧和未治疗侧的每个支架上均有血小板粘附和微观血栓形成。14只猪在支架置入后32±4天处死。组织学分析显示，在支架段长度上，水蛭素治疗侧和对照侧在新内膜体积（540±129单位对357±95单位，p = 0.27）或平均内膜与中膜比值（0.44±0.12对0.34±0.24，p = 0.47）方面没有差异。在两只接受水蛭素治疗的动脉和两只对照动脉中发生了晚期血栓闭塞。在该模型中，以所用剂量和给药速率进行局部外膜水蛭素给药可能会减少但不能预防血栓形成，并且不会降低颈动脉支架置入术后新内膜增厚的严重程度。
