Elsevier

Atherosclerosis

Volume 125, Issue 2, 6 September 1996, Pages 171-182
Atherosclerosis

Research paper
Controlled delivery of a tyrphostin inhibits intimal hyperplasia in a rat carotid artery injury model

https://doi.org/10.1016/0021-9150(96)05868-6Get rights and content

Abstract

We examined the inhibitory effect of AG-17, a potent inhibitor of protein tyrosine kinase activity on injury-induced vascular SMC proliferation by polymeric-based, periadventitial controlled release implant in the balloon catheter carotid injury model in rats. The AG-17 delivery system was formulated from ethylenevinyl acetate copolymer and the release kinetics as well as drug stability were determined. Polymeric matrices containing 2 or 10% AG-17 were implanted perivascularly in rats following balloon catheter injury. Western blot analysis of explanted arterial segments revealed enhanced tyrosine phosphorylation in injured arteries that was essentially reduced to normal levels in treated arteries. The mean neointima to media ratios were significantly reduced in both 2% (0.79 ± 0.17, n = 9, P < 0.02) and 10% AG-17 (0.59 ± 0.09, n = 12, P < 0.001) groups in comparison to the control group (1.38 ± 0.18, n = 16). The mean areas of the media in the control and the 2% AG-17 group did not differ significantly but a significant reduction of the mean area of the media was observed in 10% AG-17 group. Embedding of the unstable tyrphostin compound, AG-17, in a hydrophobic matrix stabilizes the drug both in vitro and in vivo, and allows delivery-rate modulation as well as protracted site-specific therapy. Perivascular controlled release delivery of the tyrphostin AG-17 inhibits neointimal formation in the rat carotid injury model.

References (71)

  • TJ Roseman et al.

    Release of medroxyprogesterone acetate from a silicone polymer

    J Pharm Sci

    (1970)
  • ES Miller et al.

    Morphological changes of ethylene/vinyl acetate-based controlled delivery systems during release of water soluble solutes

    J Memb Sci

    (1983)
  • G Golomb et al.

    Controlled-release drug delivery of diphosphonates to inhibit bioprosthetic heart valve calcification: release rate modulation with silicone matrices via drug solubility and membrane coating

    J Pharm Sci

    (1987)
  • RL Wilensky et al.

    Direct intraarterial wall injection of microparticles via a catheter: a potential drug delivery strategy following angioplasty

    Am Heart J

    (1991)
  • RL Wilensky et al.

    Methods and devices for local drug delivery in coronary and peripheral arteries

    Trends Cardiovasc Med

    (1993)
  • RL Wilensky et al.

    Regional and arterial localization of radioactive microparticles after local delivery by unsupported or supported porous balloon catheters

    Am Heart J

    (1995)
  • I Gradus-Pizlo et al.

    Local delivery of biodegradable microparticles containing colchicine or a colchicine analogue: effects on restenosis and implications for catheter-based drug delivery

    J Am Coll Cardiol

    (1995)
  • G Wolbring et al.

    Inhibition of GTP-utilizing enzymes by tyrphostins

    J Biol Chem

    (1994)
  • I Melamed et al.

    Tyrosine phosphorylation is essential for microfilament assembly in B lymphocytes

    Biochem Biophys Res Commun

    (1991)
  • JJ Pompa et al.

    Clinical trials of restenosis after coronary angioplasty

    Circulation

    (1991)
  • M Ferrell et al.

    A dilemma for the 1990s: choosing appropriate experimental animal model for the prevention of restenosis

    Circulation

    (1992)
  • PW Serruys et al.

    Restenosis after coronary angioplasty: a proposal of new comparative approaches based on quantitative angiography

    Br Heart J

    (1992)
  • R Ross

    The pathogenesis of atherosclerosis: a perspective for the 1990s

    Nature

    (1993)
  • T Kakuta et al.

    Differences in compensatory vessel enlargement, not intimal formation, account for restenosis after angioplasty in the hypercholesterolemic rabbit model

    Circulation

    (1994)
  • SD Gertz et al.

    Geometric remodeling is not the principal pathogenic process in restenosis after balloon angioplasty

    Circulation

    (1994)
  • V Fuster et al.

    The three processes leading to post-PTCA restenosis: dependence on the lesion substrate

    Thromb Haemost

    (1995)
  • J-PR Herrman et al.

    Pharmacological approaches to the prevention of restenosis following angioplasty: part II

    Drugs

    (1993)
  • J-PR Herrman et al.

    Pharmacological approaches to the prevention of restenosis following angioplasty: part I

    Drugs

    (1993)
  • KE Bornfeldt et al.

    Insulin-like growth factor-I and platelet-derived growth factor-BB induce direct migration of human arterial smooth muscle cells via signaling pathways that are distinct from those of proliferation

    J Clin Invest

    (1994)
  • PC Adams et al.

    Role of platelets in atherogenesis: relevance to coronary arterial restenosis after angioplasty

    Cardiovasc Clin

    (1987)
  • MW Majesky et al.

    PDGF ligand and receptor gene expression during repair of arterial injury

    J Cell Biol

    (1990)
  • GAA Ferns et al.

    Inhibition of neointimal smooth muscle accumulation after angioplasty by an antibody to PDGF

    Science

    (1991)
  • A Jawien et al.

    Platelet-derived growth factor promotes smooth muscle migration and intimal thickening in a rat model of balloon angioplasty

    J Clin Invest

    (1992)
  • LW Kraiss et al.

    Regional expression of the platelet-derived growth factor and its receptors in a primate graft model of vessel wall assembly

    J Clin Invest

    (1993)
  • R Weinstein et al.

    Growth factor responses of human arterial endothelial cells in vitro

    Cell Dev Biol

    (1986)
  • Cited by (0)

    View full text