Inhibition of neointimal hyperplasia in vascular grafts by sustained perivascular delivery of paclitaxel

Masaki, Takahisa; Rathi, Ramesh; Zentner, Gaylen M.; Leypoldt, John K.; Mohammad, Sameer; Burns, Gregory L.; Li, L.I.; Zhuplatov, Sergey; Chirananthavat, Thanit; Kim, Seung-Jung; Kern, Steven E.; Holman, John; Kim, Sung Wan; Cheung, Alfred K.

doi:10.1111/j.1523-1755.2004.00985.x

Cited by 79 publications

(61 citation statements)

References 29 publications

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“…Paclitaxel has been incorporated into these thermosensitive polymers, injected into the perivascular area of hemodialysis grafts several weeks after graft placement, and shown to inhibit neointimal hyperplasia in a canine model (32). An alternative approach that involves the placement of paclitaxel-loaded wraps around the graft-vein anastomosis also has been shown to be effective in reducing neointimal hyperplasia and luminal stenosis (99).…”

Section: Local Drug Deliverymentioning

confidence: 99%

Hemodialysis Vascular Access Dysfunction

Roy‐Chaudhury

Sukhatme

Cheung³

2006

Journal of the American Society of Nephrology

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Hemodialysis vascular access dysfunction is a major cause of morbidity and hospitalization in the hemodialysis population. The major cause of hemodialysis vascular access dysfunction is venous stenosis as a result of neointimal hyperplasia. Despite the magnitude of the clinical problem, however, there has been a paucity of novel therapeutic interventions in this field. This is in marked contrast to a recent plethora of targeted interventions for the treatment of arterial neointimal hyperplasia after coronary angioplasty. The reasons for this are two-fold. First there has been a relative lack of cellular and molecular research that focuses on venous neointimal hyperplasia in the specific setting of hemodialysis vascular access. Second, there have been inadequate efforts by the nephrology community to translate the recent advances in molecular and interventional cardiology into therapies for hemodialysis vascular access. This review therefore (1) briefly examines the different forms of hemodialysis vascular access that are available, (2) describes the pathology and pathogenesis of hemodialysis vascular access dysfunction in both polytetrafluoroethylene grafts and native arteriovenous fistulae, (3) reviews recent concepts about the pathogenesis of vascular stenosis that could potentially be applied in the setting of hemodialysis vascular access dysfunction, (4) summarizes novel experimental and clinical therapies that could potentially be used in the setting of hemodialysis vascular access dysfunction, and, finally, (5) offers some broad guidelines for future innovative translational and clinical research in this area that hopefully will reduce the huge clinical morbidity and economic costs that are associated with this condition.

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Section: Local Drug Deliverymentioning

confidence: 99%

Hemodialysis Vascular Access Dysfunction

Roy‐Chaudhury

Sukhatme

Cheung³

2006

Journal of the American Society of Nephrology

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505

283

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“…Some of these models use peripheral locations, but others use central vascular locations, where the suture sites are less likely to be disturbed by the animal. However, this benefit is counteracted by higher blood flow rates in the central arteries and the possibility of lower resistance in (17), suggesting that the dog AV access provides a better representation of the human AV access; however, this finding also means that longer studies are required to evaluate effects of interventions that target intimal hyperplasia. The vascular system of swine is similar in size and flow parameters to that of humans.…”

Section: Animal Models Of Av Accessmentioning

confidence: 67%

“…A single application of a biodegradable polymer gel containing dipyridamole to the vein-graft anastomosis in a porcine model of AVG achieved tissue drug concentrations in the therapeutic range but did not inhibit neointimal hyperplasia (68). A single application of a polymer gel incorporated with the antiproliferative agent, paclitaxel, did inhibit neointimal hyperplasia in AVG in a dog model (17). Repeat application of a sirolimus-laden polymer gel through ultrasoundguided injection to the vein-graft anastomosis significantly inhibited neointimal hyperplasia at 6 weeks in the swine AVG model (63,69).…”

Section: Perivascular Approachesmentioning

confidence: 99%

Novel Therapies for Hemodialysis Vascular Access Dysfunction

Terry

Dember

2013

Clinical Journal of the American Society of Nephrology

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SummaryHemodialysis vascular access dysfunction is a major source of morbidity for patients with ESRD. Development of effective approaches to prevent and treat vascular access failure requires an understanding of the underlying mechanisms, suitable models for preclinical testing, systems for targeted delivery of interventions to maximize efficacy and minimize toxicity, and rigorous clinical trials that use appropriate outcome measures. This article reviews the substantial progress and ongoing challenges in developing novel treatments for arteriovenous vascular access failure and focuses on localized rather than systemic interventions.

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“…This approach using the sustained-release polymeric gel to deliver paclitaxel has been shown to be effective in inhibiting neointimal hyperplasia in a canine femoral artery-to-femoral vein PTFE graft model [25]. Another study was performed to examine this strategy to deliver dipyridamole in a porcine carotid artery-to-jugular vein PTFE graft model.…”

Section: Local Sustained Drug Deliverymentioning

confidence: 99%

Pathogensis and Local Drug Delivery for Prevention of Vascular Access Stenosis

Cheung

Terry

2008

Journal of Renal Nutrition

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Native fistulae and polytetrafluoroethylene (PTFE) grafts are preferred over intravenous catheters as hemodialysis vascular access. Stenosis plagues both types of arteriovenous conduits, although PTFE grafts are more prone to such complication. In PTFE grafts, stenosis develops commonly around the graft-venous anastomosis, and less frequently at the graftarterial anastomosis [1]. In native fistulae, stenosis occurs in both the outflow vein as well as the inflow artery. An incidence as high as 40% of inflow arterial stenosis has been reported in a study of chronic dialysis patients referred for vascular access intervention [2].The pathology of neointimal hyperplasia associated with arteriovenous PTFE grafts has been well characterized [3.4]. The lesion is comprised of smooth muscle-like cells in disarray, extracellular matrices and neovasculature. There is substantial adventitial angiogenesis and a large number of macrophages lining the peri-graft region. Also present are various growth factors, such as platelet-derived growth factor, vascular endothelial growth factor and basic fibroblast growth factor. Pathogensis of neointimal hyperplasia in vascular accessA number of factors contribute to the development of neointimal hyperplasia in vascular access. The local trauma produced by the surgical procedure of creating the anastomoses, altered hemodynamics and the bioincompatibility of the graft material are likely to be important contributing factors for the hyperplasia at the anastomoses. In distinct contrast to the coronary or peripheral arterial grafts, the dialysis graft is repeatedly punctured by large-bore needles as part of the hemodialysis procedure. This trauma induced by the needle puncture attracts and activates platelets and various leukocytes, leading to a sequence of pro-inflammatory and proliferative events.It is highly likely that the trauma of angioplasty of the stenotic lesion of the native fistulae or PTFE grafts further promotes neointimal hyperplasia formation, because of injury to the endothelium and medial layer. Neointimal hyperplasia is a well-recognized and frequent complication following angioplasty of the coronary artery. This complication and its early

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Inhibition of neointimal hyperplasia in vascular grafts by sustained perivascular delivery of paclitaxel

Abstract: These results suggest that the local delivery of antiproliferative agents using a thermosensitive, injectable biodegradable copolymer (ReGel) for sustained delivery is a promising strategy to inhibit neointimal hyperplasia of arteriovenous hemodialysis grafts.

Cited by 79 publications

References 29 publications

Hemodialysis Vascular Access Dysfunction

Hemodialysis Vascular Access Dysfunction

Novel Therapies for Hemodialysis Vascular Access Dysfunction

Pathogensis and Local Drug Delivery for Prevention of Vascular Access Stenosis

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