Adventitial Paclitaxel to Delay Post-Intervention Dialysis Graft Stenosis

描述（由申请人提供）：透析通道移植物-静脉吻合口狭窄导致的血液透析血管通路功能障碍是目前美国约35万血液透析患者面临的一个巨大的临床问题。尽管这个问题很严重，但目前还没有有效的治疗方法。透析通路狭窄是由于新内膜增生，传统上认为是由于平滑肌细胞从介质迁移到内膜。最近的数据表明，外膜在这一过程中也起着重要的作用，通过促进新内膜细胞体积和不利的血管重构。在目前的建议中，我们假设透析通道移植物是使用创新药物输送平台（Mercator MedSystems micro注射器输注导管（tm））局部体外输送抗狭窄药物的理想临床模型。这是一种血管内球囊导管，当球囊膨胀时，通过血管壁挤出一根针，从而允许直接治疗外膜。在具体目标1中，我们计划在使用三种不同剂量的紫杉醇的情况下，评估动静脉移植狭窄猪模型中紫杉醇血管摄取的大小和持续时间。这些信息将使我们能够确定适当剂量的紫杉醇，使其能够在血管壁内达到抗增殖浓度，同时使局部或全身毒性最小。确定的剂量将用于第二组实验（Specific Aim 2），在动静脉移植狭窄血管成形术后模型中，通过micro注射器将紫杉醇输注到移植物-静脉吻合处将与对照血管周围输注（使用各种组织形态学和分子终点）进行比较。我们认为，这一建议的意义在于：(a)我们计划测试一种新的和创新的局部药物输送装置，以解决顽固性临床问题；(b)透析通道移植物可能是测试新型局部治疗的理想临床模型，如本提案中描述的；(c)与血管内治疗相比，血管周围或血管外治疗在预防和治疗血管狭窄方面可能更有效(特别是在最近对药物洗脱支架的晚期血栓形成的担忧和透析通路功能障碍的治疗成功可以迅速转化为其他以血管狭窄为特征的临床环境，如冠状动脉和外周血管狭窄。事实上，如果这些初步的试验研究成功的话，所有这些都表明墨卡托医疗系统公司的设备具有巨大的商业潜力。

DESCRIPTION (provided by applicant): Hemodialysis vascular access dysfunction as a result of stenosis at the graft-vein anastomosis of dialysis access grafts is currently a huge clinical problem for the estimated 350,000 patients on hemodialysis in the United States. Despite the magnitude of the problem there are currently no effective therapies for this condition. Dialysis access stenosis is due to neointimal hyperplasia which has traditionally been thought to be due to the migration of smooth muscle cells from the media into the intima. Recent data suggests that the adventitia also plays an important role in this process by contributing to both neointimal cell volume and adverse vascular remodeling. In the current proposal we hypothesize that dialysis access grafts are the ideal clinical model for local adventitial delivery of anti-stenotic drugs using an innovative drug delivery platform (the Mercator MedSystems MicroSyringe Infusion Catheter(tm)). This is an endovascular balloon catheter which extrudes a needle through the vessel wall when the balloon is inflated, thus allowing direct therapeutic access to the adventitia. In Specific Aim 1 we plan to assess the magnitude and duration of vascular uptake of paclitaxel in a validated pig model of arteriovenous graft stenosis, while using three different doses of paclitaxel. This information will allow us to identify an appropriate dose of paclitaxel that is able to achieve antiproliferative concentrations within the vessel wall with minimal local or systemic toxicity. The identified dose will then be used in a second set of experiments (Specific Aim 2), in which paclitaxel infused through the MicroSyringe device into the graft-vein anastomosis will be compared to control perivascular infusions (using a variety of histomorphometric and molecular end points) in a post-angioplasty model of arteriovenous graft stenosis. We believe that the significance of this proposal lies in the fact that (a) we plan to test out a novel and innovative local drug delivery device for a recalcitrant clinical problem (b) dialysis access grafts could be the ideal clinical model for testing out novel local therapies such as those described in this proposal (c) perivascular or adventitial therapy may be more effective in the prevention and treatment of vascular stenosis as compared to endovascular therapies (particularly with regard to recent concerns about late thromboses in the setting of drug eluting stents) and (d) therapeutic success in the setting of dialysis access dysfunction could be rapidly translated to other clinical settings characterized by vascular stenosis such as coronary and peripheral stenoses. Indeed, all of the above suggest a huge commercial potential for the Mercator MedSystems device, if these initial pilot studies are successful.