Kuji T, Masaki T, Goteti K, Li L, Zhuplatov S, Terry C M, Zhu W, Leypoldt J K, Rathi R, Blumenthal D K, Kern S E, Cheung A K
Department of Medicine, University of Utah, Salt Lake City, Utah 84112, USA.
Kidney Int. 2006 Jun;69(12):2179-85. doi: 10.1038/sj.ki.5000383. Epub 2006 May 3.
Perivascular delivery of antiproliferative drugs has been proposed as an approach to prevent neointimal hyperplasia associated with hemodialysis polytetrafluoroethylene (PTFE) grafts. We examined this approach to deliver dipyridamole in a porcine graft model. PTFE grafts were implanted between the carotid artery and external jugular vein bilaterally in pigs. During the surgery or 1 week post-graft placement, dipyridamole (0.26-52 mg) alone or incorporated in microspheres was mixed with an injectable polymeric gel and applied to the graft-arterial and graft-venous anastomoses on one side, whereas the contralateral control graft received no treatment. Three or four weeks after operation, the grafts and adjacent vessels were explanted en bloc and cross-sections of the anastomoses were examined histologically. The degree of neointimal hyperplasia was quantified by planimetry. In separate experiments, dipyridamole was extracted from the explanted tissues and assayed by spectrofluorometry. The normalized median hyperplasia areas of the treated and control graft-venous anastomoses were 0.45 (25th-75th percentile, 0.30-0.86) and 0.24 (0.21-0.30), respectively (N=7; P=0.08). The median hyperplasia areas of the treated and control graft-arterial anastomoses were 0.12 (0.07-0.39) and 0.11 (0.09-0.13), respectively (N=7; P=0.31). The dipyridamole levels in the vascular walls around the anastomoses were at or above the in vitro inhibitory concentrations for approximately 3 weeks. These results suggest that the local perivascular sustained delivery of dipyridamole, even at high dosages, was ineffective in inhibiting neointimal hyperplasia associated with PTFE grafts in a porcine model.
血管周围递送抗增殖药物已被提议作为一种预防与血液透析聚四氟乙烯（PTFE）移植物相关的内膜增生的方法。我们在猪移植物模型中研究了这种递送双嘧达莫的方法。将PTFE移植物双侧植入猪的颈动脉和颈外静脉之间。在手术期间或移植物放置后1周，将单独的双嘧达莫（0.26 - 52毫克）或包封于微球中的双嘧达莫与可注射的聚合凝胶混合，并应用于一侧的移植物 - 动脉和移植物 - 静脉吻合口，而对侧对照移植物不进行处理。术后三到四周，将移植物和相邻血管整块取出，并对吻合口的横截面进行组织学检查。通过平面测量法定量内膜增生的程度。在单独的实验中，从取出的组织中提取双嘧达莫，并通过荧光分光光度法进行测定。处理组和对照组移植物 - 静脉吻合口的标准化中位数增生面积分别为0.45（第25 - 75百分位数，0.30 - 0.86）和0.24（0.21 - 0.30）（N = 7；P = 0.08）。处理组和对照组移植物 - 动脉吻合口的中位数增生面积分别为0.12（0.07 - 0.39）和0.11（0.09 - 0.13）（N = 7；P = 0.31）。吻合口周围血管壁中的双嘧达莫水平在大约3周内达到或高于体外抑制浓度。这些结果表明，即使在高剂量下，双嘧达莫的局部血管周围持续递送在猪模型中对抑制与PTFE移植物相关的内膜增生无效。
