西罗莫司及紫杉醇药物洗脱支架的过敏反应

一项美国研究结果提示，西罗莫司及紫杉醇药物洗脱支架（DES）可发生过敏反应。为评估药物洗脱支架是否会引起过敏反应，研究者分析了2003年4月至2004年12月期间报告至FDA生产及使用器械经验中心（MAUDE）的所有西罗莫司药物洗脱支架（Cypher）及紫杉醇药物洗脱支架（Taxus）的不良事件；其他Cypher及Taxus过敏反应报告来自电子数据库的回顾分析和研究者的临床实践。     

药物洗脱支架在糖尿病患者中的对比试验

根据一项多中心随机试验,在糖尿病和多发冠脉病变患者中,西罗莫司（sirolimus）洗脱支架（Ⅰ）比紫杉醇（paclitaxel）洗脱支架（Ⅱ）发生晚期管腔丢失的风险要低。     

FDA顾问委员会将评估药物洗脱支架的安全性

一个美国FDA顾问委员会在2006年12月上旬召开会议，讨论安装了药物洗脱性支架冠心病病人发生支架血栓的问题。最近的一些研究已经对药物洗脱性支架的长期安全性提出了质疑。与裸金属支架相比，Cordis公司（J＆J）的西罗莫司（sirolimus）洗脱支架和Cypher／Boston Scientific公司的Taxus（paclitaxel，紫杉醇洗脱支架）都与较高的死亡率和心梗发生率有关。     

世界药物新闻(七十一)

最近一篇对11项药物洗脱支架(DES)临床试验荟萃分析结果表明，对于DES在治疗中的地位有待进一步证实。发表在本周《柳叶刀》杂志(8月14日583页)上的这一分析结果显示，与使用无药物涂层的传统金属支架(BMS)比较，植入西罗莫司(sirolimus)洗脱支架和聚合紫杉醇(polymeric paclitaxel)洗脱支架的病人虽然再狭窄和主要心血管不良事件的发生率降低，但是它们对于降低心肌梗死率和死亡率尚缺乏证据。     

用于冠状动脉支架内再狭窄的西罗莫司类药物的研究进展

随着经皮冠状动脉介入术在临床治疗上的广泛应用，支架内再狭窄已成为制约该技术发展的一个重要因素，药物洗脱支架的问世给这一临床难题带来了新的曙光。本文对目前广为关注的洗脱支架涂层药物西罗莫司及其衍生物的研究进展作一综述性的回顾。     

西罗莫司在药物洗脱支架中的应用

西罗莫司洗脱支架(SES)的应用使支架内再狭窄率降到了10%以下,但西罗莫司本身的药理特点使药物洗脱支架(DES)存在诸多缺陷,对两罗莫司的药理学研究将有利于SES的一步改进.本文根据大量的中外文献资料,着重介绍了西罗莫司在DES中的作用机制及其应用.     

RP-HPLC法测定复合洗脱支架中西罗莫司和普罗布考的含量

目的:建立以反相高效液相色谱法测定复合洗脱支架中西罗莫司和普罗布考含量的方法。方法:色谱柱为Kromasil C18,流动相为乙腈-水(梯度洗脱),流速为1.0mL·min-1,检测波长为277nm,柱温为55℃,进样量为20μL。结果:西罗莫司和普罗布考检测浓度的线性范围均为1.0~20.0μg.mL-1(r=0.9999);平均加样回收率分别为99.47%、98.35%,日内、日间RSD均小于5%。结论:本方法简便、准确,可用于西罗莫司-普罗布考复合洗脱支架的含量测定。     

西罗莫司脂质体的体外释放研究

目的:研究西罗莫司脂质体的体外释放特性。方法:建立反相高效液相色谱法测定西罗莫司含量;采用反透析法,以500mL 20%乙醇为释放介质,考察24 h不同时间西罗莫司脂质体的体外累积释放率,利用药物释放模型方程拟合释放曲线。结果:西罗莫司检测浓度的线性范围为0.5～20 μg.mL~(-1)(r=0.999 8),平均回收率为99.42%,RSD=1.23%;脂质体前4 h的释药速率快,累积释放率为50%,之后释药相对缓慢,24 h的累积释放率为80%,释放曲线符合一级动力学方程。结论:西罗莫司脂质体具有一定缓释效应,其体外释放属于浓度依赖型渗透释药。     

西罗莫司洗脱支架与其他冠脉支架治疗冠心病的临床安全性比较

目的 对西罗莫司洗脱支架(SES)和其他冠脉支架治疗冠心病的临床安全性进行比较.方法 通过文献检索国内外大型数据库如pubmed、OVID medline、sciencedirect、CNKI、万方数据库等,检索近5年发表的关于SES与裸金属支架及其他药物洗脱支架术后主要心脏不良事件(MACE)、靶血管重建率和靶病变重建率等终点的对比性研究.结果 SES与裸金属支架相比,术后MACE明显下降,靶血管重建率和靶病变重建率也显著下降.SES与其他药物洗脱支架相比,临床安全性与紫杉醇洗脱支架(PES)相当,在某些患者(如合并糖尿病或冠脉分叉病变)可能优于佐他莫司洗脱支架(ZES).对于合并肾功能不全的患者,SES同样优于BES,安全性与PES相当.C反应蛋白对于SES术后发生MACE可能具有预测价值.结论 SES与裸金属支架相比,安全性明显提高,与PES相当.     

预防肾同种器官移植排斥反应新药西罗莫司

综述了西罗莫司的药理学、药代动力学、临床疗效及不良反应。西罗莫司作为一种新型强效免疫抑制剂,预防肾移植术后急性排斥反应有确定疗效,并在保证疗效的同时可减少环孢素和皮质激素用量。西罗莫司也常被作为一种辅助药物,与环孢素和皮质激素合用预防肾同种器官移植排斥,为移植者的治疗提供了一种新的方案。     

Role of stent design and coatings on restenosis and thrombosis

More than 15 years have passed since stent technology was introduced by Sigwart et al. [U. Sigwart, J. Puel, V. Mirkovitch, F. Joffe, et al. Intravascular stents to prevent occlusion and restenosis after transluminal angioplasty. N. Engl. J. Med. 316 (1987) 701-706.] among interventional cardiologists. Recently drug eluting stents have assumed dominance in the interventional world as positive trial results revealed their efficacy for preventing restenosis. Stent design, delivery-vehicle materials, and drug properties affect the function of these stents. Stainless steel stents with tubular and multicellular design have proven superior to coil or hybrid stent models. This chapter describes stents which have subtle influences of modular design, metal coverage, strut thickness, strut shape, surface smoothness, and coating materials like an alloy composition.     

Sirolimus-eluting coronary stent.

PURPOSE: The mechanism of action and pharmacokinetics of sirolimus when used as part of a drug-eluting stent (DES) and the efficacy and cost of using DESs versus bare-metal stents are discussed. SUMMARY: The use of balloon angioplasty with or without coronary artery stenting is limited by the phenomenon of in-stent restenosis (ISR). Until very recently, most efforts to overcome ISR had been ineffective. The search to prevent or reduce the frequency of ISR has led to the recent development of novel coronary artery stents designed to deliver a drug that acts locally. The first DES was approved by FDA in April 2003. This stent releases sirolimus, an agent that inhibits vascular smooth-muscle-cell proliferation. To date, four major clinical trials have demonstrated the sirolimus-eluting stent to be safe and effective in preventing restenosis in de novo coronary artery lesions. CONCLUSION: The sirolimus-eluting coronary stent is associated with less ISR than non-drug-containing stents, but further investigation is needed to determine its exact place in the treatment of coronary artery occlusion.     

药物洗脱支架载药涂层研究进展

药物洗脱支架自2002年在欧洲面世以来极大地改变了心血管介入术,与裸支架单一的机械支撑作用相比,药物洗脱支架在病灶处释放的药物能显著地降低再狭窄率。支架表面涂层作为一种重要药物靶向输送载体,能够最大程度地降低药物对系统的毒副作用,同时在药物的控制释放方面发挥重要的调节作用。涂层材料和制备技术不仅影响支架表面的生物相容性和支架植入过程的表面完整性,也决定了药物的输送传递方式和释放速率。本文介绍了血管载药支架作为临床治疗器械类产品的结构、技术、应用现状及具体面临的问题,在此基础上,分析提炼了相关涂层设计原则,阐述了近年来涂层材料和覆膜技术的研究进展,并展望了该领域的发展前景。     

The Taxus drug-eluting stent: a new paradigm in controlled drug delivery

The advent of drug-eluting stents (DES) has provided the medical community with a technology that is transforming the treatment of coronary artery disease. As the newest treatment modality available to the interventional cardiologist, drug-eluting stents have not only significantly reduced the risk of restenosis, but they are also allowing the interventionalists to treat more complex lesions in patients that would otherwise require more invasive bypass surgery. Development of these drug-device combination products has presented considerable challenges to the device industry because it involves a multi-disciplinary approach that combines conventional device design and manufacturing with the principles of controlled local drug delivery. This review article provides an in-depth discussion of the key elements of drug-eluting stents, focusing on the TAXUS paclitaxel-eluting stent as an example of this new class of product. Specific sections will review the drug and polymer matrix components, formulation development and evaluation, pre-clinical studies and clinical trial results.     

Clinical studies with paclitaxel - eluting stent systems

Coronary artery stents mechanically buttress the arterial wall and prevent negative remodeling, leading to increased lumen gain and less angiographic and clinical restenosis as compared with balloon angioplasty alone. Although stents prevent negative remodeling, they do not eliminate restenosis, as they cause complex arterial injury triggering responses that culminate in the induction of neointimal hyperplasia. For many years after the development of balloon angioplasty and stenting, many unsuccessful attempts were made to find methods to prevent neointimal hyperplasia. In 1995, Sollot and colleagues were first to recognize the ability of the antineoplastic compound paclitaxel to limit neointimal hyperplasia formation. In 1997, Axel and colleagues were the first to demonstrate that paclitaxel locally delivered locally to the arterial wall limited neointimal hyperplasia in an animal model. After success in preclinical and human trials, the FDA approved the use of paclitaxel-eluting coronary stents in 2004 on the strength of the pivotal TAXUS trials, which demonstrated that stents utilizing a polymer coating as a paclitaxel delivery vector were effective in the prevention of restenosis. Subsequent trials have confirmed the effectiveness of paclitaxel in restenosis prevention. In these trials, paclitaxel was delivered using both polymer-coated stents and stents directly impregnated with drug, and on different stent platforms by different manufacturers. Paclitaxel eluting stents have been shown to be effective in a variety of cardiovascular lesion and patient subsets in randomized trial and registry data sets. Although there are concerns that locally delivered paclitaxel and/or its polymer delivery vehicle may lead to impaired vascular healing that may predispose to the development of stent thrombosis, pooled data analyses have confirmed an acceptable safety profile for paclitaxel-eluting coronary stents. The current generation of paclitaxel eluting stents have different performance profiles shen compared to first generation and second generation coronary stents eluting sirolimus or related compounds, especially in regard to target lesion revascularization rates. However, whether these difference translates into clinically relevant benefits remains debatable. In addition, newer paclitaxel elution techniques and newer paclitaxel-eluting stent architecture may improve the performance of paclitaxel-eluting stents. As the only approved non-limus based antiproliferative agent currently available, paclitaxel is uniquely positioned in the future of interventional vascular medicine.     

Drug eluting stents based on Poly(ethylene carbonate): optimization of the stent coating process

First generation drug eluting stents (DES) show a fivefold higher risk of late stent thrombosis compared to bare metal stents. Therefore, new biodegradable and biocompatible polymers for stent coating are needed to reduce late stent thrombosis. In this study, a reproducible spray-coating process for stents coated with Poly(ethylene carbonate), PEC, and Paclitaxel was investigated. PEC is a biocompatible, thermoelastic polymer of high molecular weight. The surface degradation of PEC is triggered by superoxide anions produced by polymorphonuclear leukocytes and macrophages during inflammatory processes. Stents with different drug loading were reproducibly produced by a spray-coating apparatus. Confocal laser scanning micrographs of fluorescent dye loaded stents were made to investigate the film homogeneity. The abluminal stent site was loaded more than the luminal site, which is superior for DES. The deposition of the layers was confirmed by TOF-SIMS investigations. Referring to the stent surface, the drug loading is 0.32 μg (± 0.05) (once coated), 0.53 μg (± 0.11) (twice coated), or 0.73 μg (± 0.06) (three times coated) Paclitaxel per mm(2) stent surface. The in vitro release mechanism during non-degradation conditions can be explained by diffusion-controlled drug release slightly influenced by swelling of PEC, revealing that 100% of the loaded Paclitaxel will be released via diffusion within 2 months. So, the in vivo release kinetic is a combination of diffusion-controlled drug release and degradation-controlled drug release depending on the presence or absence of superoxide anions and accordingly depending on the presence or absence of macrophages. We conclude that the specific release kinetics of PEC, its biocompatibility, and the favorable mechanical properties will be beneficial for a next generation drug eluting stent meriting further investigations under in vivo conditions.     

Drug delivery via nano-, micro and macroporous coronary stent surfaces

Drug-eluting stents (DESs) have revolutionized the treatment of occlusive coronary artery disease via marked reduction of in-stent restenosis. One critical feature for successful DESs is the sustained release of drugs, which is achieved using a polymer coating in the present generation of DESs. However, recent studies have raised a concern that polymers may trigger allergic reactions and/or prolonged inflammation in some patients. These untoward reactions may eventually lead to undesirable clinical events, including stent thrombosis and sudden cardiac death. A new drug delivery technology, using a porous stent surface, may offer desirable drug elution properties without the use of polymers, and may translate into an improved safety profile for the next-generation DESs.     

Advances in stent drug delivery: the future is in bioabsorbable stents

This expert opinion review offers a perspective on the future developments in drug-eluting stent design. Initial efforts were focused on reduction of in-stent restenosis, which the drug-eluting stents addressed effectively. Current concerns are predominantly with regard to risk of stent thrombosis and delayed endothelialization. All three components of the stent have been modified to achieve the goal of endothelialization and vessel healing: drug, polymer and the platform. We review different approaches to reduce this risk from design of different drug combinations, through less traumatic metallic stent platforms, via biodegradable polymers and, finally, fully biodegradable stents. It seems at this time that fully biodegradable solutions to stenting hold the greatest promise, but larger long-term studies are needed to evaluate fully their safety and efficacy in ‘all-comer’ patient populations. At the time of this review, design of a safe drug-eluting stent still remains a challenge.     

Cypher versus Taxus: the stent war

Cypher (sirolimus-eluting stent) and Taxus (paclitaxel-eluting stent) have been approved for use in percutaneous coronary intervention. Both of the stents have shown superiority over bare metal stents in reducing major adverse cardiac events, restenosis rates and target vessel revascularisation. Results of clinical trials with head-to-head comparison of Taxus and Cypher stents in patients with obstructive coronary artery diseases have recently been reported. This review compares the performance of Cypher and Taxus stents as noted in observational studies and clinical trials in various types of coronary artery lesions.     

Drug eluting stents: friend or foe? A review of cellular mechanisms behind the effects of Paclitaxel and sirolimus eluting stents

Coronary artery disease continues to be an important cause of mortality and morbidity. Sirolimus and paclitaxel eluting stents have become an important treatment for patients undergoing revascularization from coronary blockages. These drug eluting stents have enjoyed great success initially in preventing recurrences of adverse cardiac events and decreasing the incidences of repeat revascularizations. However, adverse effects, such as thrombosis, emanating from the use of these drug eluting stents has recently come to focus. Hence a better understanding of the mechanism of action of these drugs in preventing restenosis is important for the long term success and potential betterment of drug eluting stent technology. Herein we review and discuss the pathophysiology of restenosis, the basic mechanism of action of sirolimus and paclitaxel eluting stents and their limitations so as to create a scope for more efficient and novel drug eluting stents in the future.