Paclitaxel and cyclosporine A show supra-additive antiproliferative effects on smooth muscle cells by activation of protein kinase C

We intended to establish a pharmacologic concept of synergistic antiproliferative effects on smooth muscle cells (SMC) by using paclitaxel and cyclosporine A at clinically applicable doses. Coronary SMC were incubated with paclitaxel and cyclosporine A at concentrations of 10 – 20 nmol/L and 83 – 415 nmol/L, respectively. Antiproliferative effects were assessed by cell counts, [³H]thymidine incorporation and cell cycle analysis. In addition, apoptosis was studied by cytoplasmic histone-associated DNA fragments and in vitro protein kinase C activity (PKC) was determined by immunoassay. We found paclitaxel and cyclosporine A to exert a highly supra-additive antiproliferative effect on SMC with significant reductions of cell counts (p < 0.01) and [³H]thymidine incorporation (p < 0.05). SMC were found to be arrested at the G2/M transition. This antiproliferative effect was observed in the absence of DNA fragmentation above values obtained for single compound treatment, which had virtually no impact on cell proliferation. DNA fragmentation started to increase at a drug combination comprising paclitaxel at the higher dose of 20 nmol/L. Under the treatment with both paclitaxel and cyclosporine A, PKC activity showed a 1.8-fold increase (p < 0.05) compared with untreated controls. In conclusion, PKC mediates supra-additive antiproliferative effects of paclitaxel and cyclosporine A on SMC. The data demonstrate a highly efficient pharmacologic concept for the inhibition of SMC proliferation. Further studies are needed to test this concept under in vivo conditions for the prevention of restenosis or transplant vasculopathy by systemic application of cyclosporine A – when already applied for immunosuppressive purposes – and local delivery of paclitaxel. Received: 28 August 2001, Returned for revision: 25 September 2001, Revision received: 20 November 2001, Accepted: 4 December 2001     

益气活血解毒方和血府逐瘀胶囊抑制再狭窄中细胞外基质的对比研究

目的比较益气活血解毒方和血府逐瘀胶囊抑制再狭窄中细胞外基质的作用特点.方法用电刺激兔颈总动脉,喂饲高脂饲料,再用球囊原位扩张造成动脉粥样硬化再狭窄模型,病理取材,HE、Masson染色及平滑肌细胞肌动蛋白α-SM-actin免疫组化分析和图像分析.结果益气活血解毒方能显著减少内膜增生,尤其是降低血管局部胶原含量的作用最显著.而血府逐瘀胶囊可明显降低血清转化生长因子(TGF-β)的含量,也可减少血管局部的胶原含量.同时两组对内膜平滑肌细胞数均无影响.结论两种中医治则治法对再狭窄均有一定程度的抑制作用,但二者作用的病理环节有所不同.     

氧化低密度脂蛋白、高敏C反应蛋白与冠状动脉支架置入术后再狭窄的关系

目的:探讨氧化低密度脂蛋白(ox-LDL)、高敏C反应蛋白(hs-CRP)与经皮冠状动脉介入治疗(PCI)术后支架内再狭窄的相关性。方法:45例患者PCI术后6~12个月内接受冠状动脉造影复查,其中18例有再狭窄作为再狭窄组,27例无再狭窄作为对照组。2组术后均接受阿司匹林、波立维、他汀类等药物治疗。取2组患者PCI术前、后冠状动脉造影复查时血浆标本,采用酶联免疫吸附法(ELISA)检测血浆ox-LDL水平,超敏免疫比浊法检测血浆hs-CRP水平,酶法测定血脂水平。结果:①再狭窄组PCI术后ox-LDL、hs-CRP水平较术前均明显升高[(1.32±0.35)∶(0.53±0.17)mg/L、(4.82±1.44)∶(3.50±1.18)mg/L],均P0.01;对照组PCI后ox-LDL、hs-CRP水平较术前明显下降[(0.32±0.13)∶(0.55±0.13)mg/L、(2.28±0.71)∶(3.37±1.25)mg/L],均P0.05。②再狭窄组和对照组PCI术前ox-LDL、hs-CRP水平差异无统计学意义,再狭窄组PCI术后ox-LDL、hs-CRP水平显著高于对照组(均P0.01)。③再狭窄组和对照组术后TC、TG、LDL-C水平均较术前明显下降(P0.05),但2组间PCI术前和术后比较均差异无统计学意义(P0.05)。④再狭窄组和对照组术前、术后ox-LDL和hs-CRP水平均呈正相关。结论:PCI术后再狭窄患者血浆ox-LDL及CRP水平明显升高,二者可作为PCI术后再狭窄的预测指标。     

Effect of Tongguan Capsules(通冠胶囊)on Restenosis after Coronary Stent Implantation:Study Protocol for A Randomized Controlled Trial

Background:Although percutaneous coronary intervention(PCI)had become widely employed therapeutic procedure for coronary artery disease,stent restenosis limited the benefits of this revascularization and the question how to prevent such events remained unresolved.While numerous empirical observations suggested Tongguan Capsules(通冠胶囊),a patented Chinese Medicine,could decrease frequency and duration of angina pectoris attacks,evidence supporting its efficacy on restenosis remained inadequate.Objective:This trial was designed to determine whether Tongguan Capsules would reduce restenosis rate in patients after successful stent implantation.Methods:Approximately 400 patients undergoing percutaneous coronary stent deployment were enrolled and randomized to control group or Tongguan Capsules(4.5 g/d)for 3 months.All patients received standard anti-platelet,anti-coagulation and lipid-decreasing treatments,concurrently.The primary clinical endpoint was the 12-month incidence of the major adverse cardiovascular events(defined as cardiac death,myocardial infarction,and recurrence of symptoms requiring additional revascularization).The angiographic end point was restenosis rate at 6 months.Conclusion:This study would provide important evidence for the use of Tongguan Capsules in patients after stent implantation in combination with routine therapies,which may significantly reduce incidence of the restenosis so as to potentially improve the clinical outcomes.(registration number:ChiCTR-TRC-ChiCTR-IIR-17011407)     

MMP-9在大鼠动脉损伤后表达的研究

目的 观察基质金属蛋白酶-9（MMP-9）在大鼠动脉损伤后不同时间的表达,探讨MMP-9在大鼠动脉损伤后发挥的作用.方法采用大鼠胸主动脉损伤模型,应用免疫组织化学（IHC）染色及图像分析方法,对MMP-9在动脉损伤后不同时间点的含量变化进行分析.结果MMP-9在球囊损伤组大鼠动脉内膜及中膜呈强阳性表达.动脉损伤后第1天表达开始增加,第10天达到最高峰,第28天仍有少量表达.结论MMP-9在动脉球囊损伤术后合成、分泌增多,在早期再狭窄形成过程中发挥其降解Ⅳ型基底膜胶原的作用,在再狭窄早期平滑肌细胞的迁移与增殖中起重要作用.     

大鼠动脉损伤后MMP-2表达变化的实验研究

目的观察球囊导管损伤大鼠主动脉内膜以后基质金属蛋白酶一2在内膜表达的变化过程。方法70只SD大鼠按照不同的时间段分为七个实验组及对照组,实验组从颈总动脉切开应用2F Fogarty导管损伤主动脉内膜至肾动脉水平,球囊充放气3次,然后结扎颈总动脉,对照组只切开然后结扎颈总动脉而不损伤内膜,然后于不同的时间段处死大鼠取主动脉以及内膜,处死前30min从尾静脉注入Evansblue以便证实为主动脉内膜,分别进行HE染色,Gelatin Zymography来分析动脉内膜损伤以后MMP-2表达的变化。结果MMP-2于损伤后开始升高,至5天时达到顶点,而后逐渐下降,内膜增生则是28天最为显著。结论动脉内膜损伤以后MMP-2表达有着规律的变化且与内膜增生并不成比例,MMP-2的升高先于内膜增生,为治疗动脉损伤后血管再狭窄提供一种新方法。     

Value of M2BP in predicting in‐stent restenosis in patients after coronary drug‐eluting stent implantation

ObjectiveWe evaluated the association between plasma levels of mac‐2 binding protein (M2BP) with the risk of in‐stent restenosis (ISR) after percutaneous coronary intervention (PCI).MethodsPlasma M2BP levels were compared between 258 patients who experienced ISR at 12‐months post‐PCI and 258 patients, matched for age and sex, without angiographic evidence of ISR.ResultsThe plasma M2BP level was significantly higher in the ISR than in the non‐ISR group. On multivariate analysis, adjusted for potential clinical, biochemical, and angiography characteristics, M2BP remained as an independent significant predictor of ISR.ConclusionsM2BP may be an important predictive biomarker of ISR and may be useful in identifying at‐risk patients.     

三维超声检查在评估CEA后再狭窄中的作用

目的 探讨三维超声在评估颈动脉内膜斑块切除术(CEA)后再狭窄中的价值.方法 回顾性分析2016年3月至2020年2月CEA治疗的272例颈动脉狭窄的临床资料.采用三维超声定量检测术前颈动脉斑块灰阶中位数值(GSM)、总体积(TPV)、GSM/TPV和最大横截面积,以及手术前后残余管腔面积.术后随访6～53个月,中位时...     

The endovascular approach for in-stent restenosis in femoropopliteal disease

In-stent restenosis remains one of the main drawbacks of stenting the femoropopliteal segment, and leads to stent failure and repeated interventions. A variety of endovascular techniques have been investigated so far to reduce this phenomenon, including plain angioplasty, atherectomy, new stent deployment, cutting balloons and cryoplasty but without satisfactory mid- and long-term results. More recently drug-eluting devices have been applied in femoropopliteal in-stent restenosis with promising results. The aim of this review is to analyse the indication and effectiveness of those endovascular techniques for the treatment of in-stent restenosis.     

Targeting stents with local delivery of paclitaxel-loaded magnetic nanoparticles using uniform fields

The use of stents for vascular disease has resulted in a paradigm shift with significant improvement in therapeutic outcomes. Polymer-coated drug-eluting stents (DES) have also significantly reduced the incidence of reobstruction post stenting, a disorder termed in-stent restenosis. However, the current DESs lack the capacity for adjustment of the drug dose and release kinetics to the disease status of the treated vessel. We hypothesized that these limitations can be addressed by a strategy combining magnetic targeting via a uniform field-induced magnetization effect and a biocompatible magnetic nanoparticle (MNP) formulation designed for efficient entrapment and delivery of paclitaxel (PTX). Magnetic treatment of cultured arterial smooth muscle cells with PTX-loaded MNPs caused significant cell growth inhibition, which was not observed under nonmagnetic conditions. In agreement with the results of mathematical modeling, significantly higher localization rates of locally delivered MNPs to stented arteries were achieved with uniform-field–controlled targeting compared to nonmagnetic controls in the rat carotid stenting model. The arterial tissue levels of stent-targeted MNPs remained 4- to 10-fold higher in magnetically treated animals vs. control over 5 days post delivery. The enhanced retention of MNPs at target sites due to the uniform field-induced magnetization effect resulted in a significant inhibition of in-stent restenosis with a relatively low dose of MNP-encapsulated PTX (7.5 μg PTX/stent). Thus, this study demonstrates the feasibility of site-specific drug delivery to implanted magnetizable stents by uniform field-controlled targeting of MNPs with efficacy for in-stent restenosis.