title: Inhibition of neointimal hyperplasia in vascular grafts by sustained perivascular delivery of paclitaxel.
abstract: BACKGROUND
  Neointimal hyperplasia occurs commonly at the anastomoses of arteriovenous grafts for chronic hemodialysis, causing stenosis and occlusion. Antiproliferative drugs may be effective in inhibiting hyperplasia, but local drug delivery would be required to minimize systemic side effects. We examined the feasibility of local drug delivery to inhibit neointimal hyperplasia at dialysis grafts in a canine model.
  
  
  METHODS
  Bilateral polytetrafluoroethylene loop grafts (10-cm length and 6-mm internal diameter) were placed between the femoral artery and ipsilateral femoral vein of five mongrel dogs. At the time of surgery or 1 to 5 weeks later, 2 mL of a thermosensitive biodegradable copolymer (ReGel) mixed with 0.26 mg or 0.65 mg paclitaxel were applied to the external surface of one graft around the anastomoses to provide a depot for sustained release of the drug. ReGel alone without paclitaxel was applied to the contralateral graft as a control. The grafts and the connecting vessels were explanted at eight or nine weeks, and the cross-sections were examined histologically. The degree of hyperplasia at the anastomoses was graded by five blinded independent reviewers, with scores ranging from 0 to 5.
  
  
  RESULTS
  The median (25th-75th percentile) hyperplasia score of both arterial and venous anastomoses was 1.80 (0.90-3.05) in the grafts treated with ReGel alone, and 0.95 (0.70-1.50) in the grafts treated with ReGel/paclitaxel (N= 8; P < 0.05 by Wilcoxon signed rank test). There were no noticeable localized or systemic complications attributed to the treatments in these animals. Paclitaxel levels in the plasma obtained from forelimb veins were undetectable (<10 ng/mL).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Departments of Medicine, Bioengineering, Pathology, Pharmaceutics, and Surgery, and Animal Resource Center, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Masaki
authors.forename: Ramesh
authors.initials: R
authors.lastname: Rathi
authors.forename: Gaylen
authors.initials: G
authors.lastname: Zentner
authors.forename: John K
authors.initials: JK
authors.lastname: Leypoldt
authors.forename: Syed F
authors.initials: SF
authors.lastname: Mohammad
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Burns
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Sergey
authors.initials: S
authors.lastname: Zhuplatov
authors.forename: Thanit
authors.initials: T
authors.lastname: Chirananthavat
authors.forename: Seung-Jung
authors.initials: SJ
authors.lastname: Kim
authors.forename: Steven
authors.initials: S
authors.lastname: Kern
authors.forename: John
authors.initials: J
authors.lastname: Holman
authors.forename: Sung Wan
authors.initials: SW
authors.lastname: Kim
authors.forename: Alfred K
authors.initials: AK
authors.lastname: Cheung
mesh_terms: D000818:Animals; D001807:Blood Vessel Prosthesis; D004285:Dogs; D005260:Female; D006083:Graft Occlusion, Vascular / Q000517:prevention & control*; D006965:Hyperplasia / Q000517:prevention & control; D008297:Male; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D011108:Polymers; D011138:Polytetrafluoroethylene; D006435:Renal Dialysis; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology*
chemical_list: D011108:Polymers; D011138:Polytetrafluoroethylene; D017239:Paclitaxel