Lysitsas Dimitrios N, Katsouras Christos S, Papakostas John C, Toumpoulis Ioannis K, Angelidis Charalampos, Bozidis Petros, Thomas Christopher G, Seferiadis Konstantin, Psychoyios Nikolaos, Frillingos Stathis, Pavlidis Nikolaos, Marinos Euaggelos, Khaldi Lubna, Sideris Dimitris A, Michalis Lampros K
Michailideion Cardiac Center, Ioannina, Greece.
Cardiovasc Intervent Radiol. 2007 Nov-Dec;30(6):1192-200. doi: 10.1007/s00270-007-9027-4. Epub 2007 Sep 8.
Experimental and clinical data suggest that stents eluting antiproliferative agents can be used for the prevention of in-stent restenosis. Here we investigate in vitro the antiproliferative and apoptotic effect of D-24851 and evaluate the safety and efficacy of D-24851-eluting polymer-coated stents in a rabbit restenosis model (n = 53). Uncoated stents (n = 6), poly (DL: -lactide-co-glycolide) (PLGA)-coated stents (n = 7), and PLGA-coated stents loaded with 0.08 +/- 0.0025 microM (31 +/- 1 mug; low dose; n = 7), 0.55 +/- 0.02 microM (216 +/- 8 mug; high dose; n = 6), and 4.55 +/- 0.1 microM (1774 +/- 39 mug; extreme dose; n = 5) of D-24851 were randomly implanted in New Zealand rabbit right iliac arteries and the animals were sacrificed after 28 days for histomorphometric analysis. For the assessment of endothelial regrowth in 90 days, 12 rabbits were subjected to PLGA-coated (n = 3), low-dose (n = 3), high-dose (n = 3), and extreme-dose (n = 3) stent implantation. In vitro studies revealed that D-24851 exerts its growth inhibitory effects via inhibition of proliferation and induction of apoptosis without increasing the expression of heat shock protein-70, a cytoprotective and antiapoptotic protein. Treatment with low-dose D-24851 stents was associated with a significant reduction in neointimal area and percentage stenosis only compared with bare metal stents (38% [P = 0.029] and 35% [P = 0.003] reduction, respectively). Suboptimal healing, however, was observed in all groups of D-24851-loaded stents in 90 days in comparison with PLGA-coated stents. We conclude that low-dose D-24851-eluting polymer-coated stents significantly inhibit neointimal hyperplasia at 28 days through inhibition of proliferation and enhancement of apoptosis. In view of the suboptimal re-endothelialization, longer-term studies are needed in order to establish whether the inhibition of intimal growth is maintained.
实验和临床数据表明，洗脱抗增殖剂的支架可用于预防支架内再狭窄。在此，我们在体外研究了D-24851的抗增殖和凋亡作用，并在兔再狭窄模型（n = 53）中评估了载有D-24851的聚合物涂层支架的安全性和有效性。将未涂层支架（n = 6）、聚（DL-丙交酯-共-乙交酯）（PLGA）涂层支架（n = 7）以及载有0.08±0.0025微摩尔（31±1微克；低剂量；n = 7）、0.55±0.02微摩尔（216±8微克；高剂量；n = 6）和4.55±0.1微摩尔（1774±39微克；极高剂量；n = 5）D-24851的PLGA涂层支架随机植入新西兰兔右髂动脉，28天后处死动物进行组织形态计量分析。为评估90天时的内皮再生情况，对12只兔子进行了PLGA涂层（n = 3）、低剂量（n = 3）、高剂量（n = 3）和极高剂量（n = 3）支架植入。体外研究表明，D-24851通过抑制增殖和诱导凋亡发挥其生长抑制作用，而不增加热休克蛋白-70（一种细胞保护和抗凋亡蛋白）的表达。与裸金属支架相比，低剂量D-24851支架治疗仅使内膜面积和狭窄百分比显著降低（分别降低38%[P = 0.029]和35%[P = 0.003]）。然而，与PLGA涂层支架相比，在90天时所有载有D-24851的支架组均观察到愈合欠佳。我们得出结论，低剂量载有D-24851的聚合物涂层支架在28天时通过抑制增殖和增强凋亡显著抑制内膜增生。鉴于再内皮化欠佳，需要进行长期研究以确定内膜生长的抑制作用是否持续存在。
