Adventitial Paclitaxel to Delay Post-Intervention Dialysis Graft Stenosis

描述(申请人提供)：透析通路移植物血管吻合狭窄导致的血液透析血管通路功能障碍目前是美国大约350,000名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。透析通道狭窄是由于新生内膜增生，传统上认为是由于平滑肌细胞从中膜向内膜迁移所致。最近的数据表明，外膜在这一过程中也起着重要的作用，它促进了新生内膜细胞的体积和不利的血管重构。在目前的提案中，我们假设透析通路移植物是使用创新的药物输送平台(墨卡托药物系统公司的MicroSyringe Infusion Caeter(Tm))局部外腔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，当球囊充气时，它会将针穿过血管壁，从而允许直接进入血管外膜。在特定的目标1中，我们计划在验证的猪动静脉移植物狭窄模型中评估紫杉醇的血管摄取的幅度和持续时间，同时使用三种不同剂量的紫杉醇。这一信息将使我们能够确定适当剂量的紫杉醇，能够在局部或全身毒性最小的情况下在血管壁内实现抗增殖浓度。确定的剂量随后将用于第二组实验(特定目标2)，在该实验中，将比较通过微型注射器向移植物静脉吻合口注入紫杉醇，以控制血管成形术后动静脉移植物狭窄模型的血管周围输注(使用各种组织形态计量学和分子终点)。我们认为，这项建议的意义在于：(A)我们计划针对顽固性临床问题测试一种新颖和创新的局部药物输送装置(B)透析通路移植物可能是测试如本方案中所述的新型局部疗法的理想临床模式(C)与血管内疗法相比，血管周围或外膜疗法在预防和治疗血管狭窄方面可能更有效(尤其是考虑到最近对药物洗脱支架环境中晚期血栓形成的担忧)以及(D)在透析通路功能障碍的治疗方面的成功可以迅速转化为其他以血管狭窄为特征的临床环境，如冠状动脉和外周狭窄。事实上，如果这些初步的初步研究取得成功，上述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.