title: Improving arteriovenous fistula patency: Transdermal delivery of diclofenac reduces cannulation-dependent neointimal hyperplasia via AMPK activation.
abstract: Creation of an autologous arteriovenous fistula (AVF) for vascular access in haemodialysis is the modality of choice. However neointimal hyperplasia and loss of the luminal compartment result in AVF patency rates of ~60% at 12months. The exact cause of neointimal hyperplasia in the AVF is poorly understood. Vascular trauma has long been associated with hyperplasia. With this in mind in our rabbit model of AVF we simulated cannulation autologous to that undertaken in vascular access procedures and observed significant neointimal hyperplasia as a direct consequence of cannulation. The neointimal hyperplasia was completely inhibited by topical transdermal delivery of the non-steroidal anti-inflammatory (NSAID) diclofenac. In addition to the well documented anti-inflammatory properties we have identified novel anti-proliferative mechanisms demonstrating diclofenac increases AMPK-dependent signalling and reduced expression of the cell cycle protein cyclin D1. In summary prophylactic transdermal delivery of diclofenac to the sight of AVF cannulation prevents adverse neointimal hyperplasic remodelling and potentially offers a novel treatment option that may help prolong AVF patency and flow rates.
authors: Strathclyde Institute of Pharmacy and Biomedical Science, University of Strathclyde Glasgow, UK.
authors: Mark G
authors: MG
authors: MacAskill
authors: Strathclyde Institute of Pharmacy and Biomedical Science, University of Strathclyde Glasgow, UK.
authors: David G
authors: DG
authors: Watson
authors: Institute of Cardiovascular & Medical Sciences, University of Glasgow, UK.
authors: Marie-Ann
authors: MA
authors: Ewart
authors: Strathclyde Institute of Pharmacy and Biomedical Science, University of Strathclyde Glasgow, UK.
authors: Roger
authors: R
authors: Wadsworth
authors: Department of Renal Surgery, Western Infirmary, Glasgow, UK.
authors: Andrew
authors: A
authors: Jackson
authors: Department of Renal Surgery, Western Infirmary, Glasgow, UK.
authors: Emma
authors: E
authors: Aitken
authors: Strathclyde Institute of Pharmacy and Biomedical Science, University of Strathclyde Glasgow, UK.
authors: Graeme
authors: G
authors: MacKenzie
authors: Department of Renal Surgery, Western Infirmary, Glasgow, UK.
authors: David
authors: D
authors: Kingsmore
authors: Strathclyde Institute of Pharmacy and Biomedical Science, University of Strathclyde Glasgow, UK.
authors: Susan
authors: S
authors: Currie
authors: Strathclyde Institute of Pharmacy and Biomedical Science, University of Strathclyde Glasgow, UK. Electronic address: paul.coats@strath.ac.uk.
authors: Paul
authors: P
authors: Coats
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000279:Administration, Cutaneous; D000818:Animals; D001164:Arteriovenous Fistula / Q000201:enzymology / Q000517:prevention & control*; D002404:Catheterization / Q000009:adverse effects*; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004008:Diclofenac / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006965:Hyperplasia / Q000201:enzymology / Q000517:prevention & control; D058426:Neointima / Q000188:drug therapy* / Q000201:enzymology; D011817:Rabbits; D014654:Vascular Patency / Q000187:drug effects* / Q000502:physiology
chemical_list: D004008:Diclofenac; D055372:AMP-Activated Protein Kinases
keywords: Arteriovenous fistula Vascular; Cell proliferation; Pharmacotherapy; Re-stenosis