Scheller Bruno, Speck Ulrich, Romeike Bernd, Schmitt Alexander, Sovak Milos, Böhm Michael, Stoll Hans Peter
Internal Medicine III, University of Saarland, D-66421 Homburg/Saar, Germany.
Eur Heart J. 2003 Aug;24(15):1462-7. doi: 10.1016/s0195-668x(03)00317-8.
Lipophilic taxanes can be dissolved in contrast media at significantly higher concentration than in saline. As contrast media have occasionally been observed to delineate the contour of coronary arteries for some seconds they may serve as a matrix for an antiproliferative drug aimed at preventing restenosis. The aim of this study was to test a novel taxane-contrast agent formulation for this new approach in the setting of coronary stenting.
In cell culture experiments (bovine vascular smooth muscle cells), 60-min incubation with contrast agent-taxane formulations (iopromide-paclitaxel, iopromide-protaxel) induced a significant, concentration-dependent inhibition of vascular smooth muscle cell (VSMC) proliferation over 12 days. Shorter incubation times of 10 and 3 min showed the same efficacy. For in vivo investigation, 16 stents were implanted into the coronary arteries of eight pigs using a 1.3 to 1 overstretch ratio. A control group received iopromide 370 alone while the treatment group was injected with a iopromide-protaxel formulation at a dose of 74 micromol/l, which is far below protaxel levels inducing systemic toxicity. Quantitative angiography and histomorphometry of the stented arteries asserted statistic equality of the baseline parameters between the control and treatment groups. After 28 days, the treatment group showed a marked reduction of the parameters characterizing in-stent restenosis, especially a 34% reduction of the neointimal area.
First evidence is provided that using a contrast agent as solvent for a taxane constitutes a new drug delivery mechanism able to inhibit in-stent restenosis in the porcine restenosis model.
亲脂性紫杉烷在造影剂中的溶解浓度显著高于在盐水中的浓度。由于偶尔观察到造影剂能在数秒内勾勒出冠状动脉轮廓，它们可作为一种抗增殖药物的载体，用于预防再狭窄。本研究的目的是在冠状动脉支架置入的背景下，测试一种新型紫杉烷 - 造影剂制剂用于这种新方法。
在细胞培养实验（牛血管平滑肌细胞）中，用造影剂 - 紫杉烷制剂（碘普罗胺 - 紫杉醇、碘普罗胺 - 原紫杉醇）孵育60分钟，在12天内诱导了血管平滑肌细胞（VSMC）增殖的显著浓度依赖性抑制。10分钟和3分钟的较短孵育时间显示出相同的效果。对于体内研究，使用1.3至1的过度扩张比例，将16个支架植入8头猪的冠状动脉中。对照组仅接受370碘普罗胺，而治疗组以74微摩尔/升的剂量注射碘普罗胺 - 原紫杉醇制剂，该剂量远低于诱导全身毒性的原紫杉醇水平。支架置入动脉的定量血管造影和组织形态计量学表明，对照组和治疗组之间的基线参数在统计学上相等。28天后，治疗组显示出支架内再狭窄特征参数的显著降低，尤其是新生内膜面积减少了34%。
首次提供证据表明，使用造影剂作为紫杉烷的溶剂构成了一种新的药物递送机制，能够在猪再狭窄模型中抑制支架内再狭窄。
