| AIM Drug eluting stent is the most significant progress in prevernting restenosis in recent yeaIRS and the best stent is rapamycin eluting stent. The efficacy and safety of the rapamycin eluting stent had been proved by a lot of muLticenter, extensive , randomized, double-blind trials and the restenosis rate in stent had been reduce to 5-10% since it was used generally in 2003. Drug eluting stent shares the liability of impairing endothelial recovery and increasing the associated risk of stent thrombosis as well as inhibiting SMC and intima proliferation. Patients who accepted PCI need to take antiplatelet drug for half or one year to prevent the incidence of in-stent thrombosis,which wouLd bring them not only major bleeding complications but also economic burden.To explore new and effective drug eluting stent which can prevent in-stent thrombosis and restenosis is still a hot spot in nowadays research.Tirofiban is one of glycoprotein IIb/IIIa receptor antagonists which can inhibit platelet aggregation,inhibit the thrombus formation,inhibit the contraction of blood vessel, improve endothelial dysfunction, decrease platelet-mediated inflammation.Tirofiban and rapamycin have synergistic action and compatibility.We developed a new drug eluting stent by combining rapamycin with tirofiban.By observing their influences on in-stent thrombosis and newly formed coronary artery endothelium,we both assessed whether the compound drug eluting stent cound prevent the in-stent thrombosis and restenosis and evaluated the biocompatibility of the stent.METHODS①RAPM and tirofiban loaded in RTES were determined by high-performance liquid chromatography(HPLC).In vitro, drug released from RTES was performed by HPLC.②Twelve miniature pigs were randomly divided into rapamycin eluting stent group(RES)and rapamycin-tirofiban eluting stent(RTES) group.Each group had six pigs. By experiment time,each group was divided into three-month subgroup(four pigs) and six-month subgroup(two pigs). Two stents were implanted in the coronary artery with the precise positioning determined by predeployment angiographic measurements to achieve 1.1:1 to 1.2:1 stent-to-artery ratio compared with the baseline vessel diameter in each pig. Animals in RTES group were treated with clopidogrel in a dose of 75mg/d orally for a week after stent implantation, while animals receiving RES in control group were treated orally with clopidogrel (75mg/d) for three months and six months. All animals were administered orally aspirin (300mg/d) for three months and six months. Quantitative coronary arteriographies were taken before, immediately after stents were implanted and before the pigs were sacrificed. Indexes of ethology and complication of hemorrhage were determined. Three momths and six months later, arteries were compared in angiography, histopathology and histomorphometry analysis. Reference vessel diameter, minimal lumen diameter, percent diameter stenosis were measured. The stented coronary artery segments were processed for plastic embedding,HE staining and histomorphometric analysis of representative cross sections per stent from the proximal aspect through the distal margin of the stent. The evaluated parameteIRS were luminal area, neointimal area and the rate of lost luminal area. Blood vessel endothelium and platelet activation were detected by scanning electron microscope(SEM).The whole blood cell counts,biochemical indexes of liver and kidney before implantation of stents and sacrifice were analyzed.Lungs,liveIRS,kidneys and the ventricuLar walls which infused by the stents supported arteries were also observed histologically.RESULTS①The amount of RAPM loaded in RTES was 149.9±3.4ug,while tirofiban was 86.7±2.6ug.The RTES had the characteristic of slow release.②All stents were implanted successfuLly. All animals survived.The changes of ethology weren't observed during the trial. Neither thrombosis nor pseudoangeioma was observed in both groups when quantitative coronary angiography performed on third month and sixth month after stent implantation.There wasn't mural thrombosis in sectiones of blood vessel in both groups.③On third month,there was no significant difference in reference vessel diameter between three-month RTES subgroup[(2.85±0.19) mm] and three-month RES subgroup[(2.81±0.21 )mm]as well as minimal lumen diameter[(2.62±0.20)mm vs(2.56±0.17)mm] and percent diameter stenosis[(7.9±2.0)% vs (8.7±2.3)%,( P>0.05)]. The side effects were not found in both groups. Histomorphometric analysis:The lumen area in three-month RTES subgroup was similar with those in three-month RES subgroup (4.96±0.35 vs 4.89±0.46 mm2). The neointlmal area in three-month RTES subgroup was similar with those in three-month RES subgroup (1.12±0.10 vs 1.05±0.09 mm2). Both type of stents had similar effect on lumen stenosis rates (19%±9% vs 21%±7%).④On sixth month,there was no significant difference in reference vessel diameter between six-month RTES subgroup[(2.86±0.21) mm] and six-month RES subgroup[(2.83±0.18 )mm]as well as minimal lumen diameter[(2.50±0.22)mm vs(2.45±0.19)mm] and percent diameter stenosis([12.8±2.4)% vs (14.1±2.7)%,( P>0.05)]. The side effects were not found in both groups. Histomorphometric analysis:The lumen area in six-month RTES subgroup was similar with those in six-month RES subgroup (4.74±0.43 vs 4.49±0.51 mm2). The neointlmal area in six-month RTES subgroup was similar with those in six-month RES subgroup (1.42±0.13 vs 1.54±0.11 mm2). Both type of stents had similar effect on lumen stenosis rates (22%±6% vs 26%±8%).⑤Outcomes of SEM:the blood vessel endothelium in three-month subgroup was integrated, but endothelial cells were arranged disorderly. The blood vessel endothelium in six-month subgroup was integrated and endothelial cells were arranged orderly. Platelet activation and thrombus weren't observed in both groups.⑥Bone marrow suppression , liver and kidney disfunction were not found in both groups. There was no significant difference in heart rate , blood pressure and body weight in both groups. Behavior was not influenced. There were no pathological damages related to RTES in lungs , liveIRS , kidneys and the ventricuLar walls infused by the stent supported arteries.CONCLUSIONS①The RTES is a sort of significantly slow release drug eluting stent.②The rapamycin tirofiban eluting stent can prevent in-stent thrombosis effectively after PCI..③The efficacy of the rapamycin tirofiban eluting stent preventing in-stent restenosis is not significantly different with the rapamycin eluting stent.④The blood compatibility and histocompatibility were good after RTES were implanted in coronary arteries of miniature pigs. |
