Tyrphostin AGL-2043 eluting stent reduces neointima formation in porcine coronary arteries

Shmuel Banai, S. David Gertz, Lilach Gavish, Michael Chorny, Louise S. Perez, Galila Lazarovichi, Mickey Ianculuvich, Michael Hoffmann, Michael Orlowski, Gershon Golomb, Alexander Levitzki

Research output: Contribution to journalArticlepeer-review

Abstract

Objective: Tyrphostin AGL-2043 is a potent tricyclic quinoxaline inhibitor of PDGF β-receptor tyrosine kinase (PTK), Kit, and Flt3. We have shown previously that selective inhibition of PDGF β-receptor PTK by tyrphostins markedly reduces SMC proliferation and migration in vitro, reduces neointima formation in balloon-injured porcine femoral arteries, and reduces neointimal stenosis in stented porcine coronary arteries when administered intramurally within biodegradable nanoparticles. The present study was designed to determine the effect of AGL-2043 delivered from a stent-based, biodegradable polymeric coating on neointima formation in the porcine coronary artery model. Methods and Results: Stents coated with biodegradable, polylactic/glycolic acid (PLGA) polymer, with (n=13) or without (n=11) 180 mcg AGL-2043 were implanted into the proximal LAD of 24 Sinclair mini-pigs (34±4 kg) to achieve a 1.1:1 stent/artery diameter ratio. The delivery of drug from stent to tissue was confirmed by high-performance liquid chromatography. After 28 days, histomorphometric analysis showed that in-stent stenosis in animals treated with AGL-2043 was reduced by 50% (51±21% versus 26±10%, p=0.001), the absolute neointimal area was reduced by 44% (2.38±1.04 versus 1.31±0.43 mm2, p=0.004), and the absolute luminal area was increased by 57% (2.19±1.09 versus 3.39±0.59 mm2, p=0.003). There were no significant differences between control and AGL-2043 in injury score (1.24±0.11 vs. 1.15±0.12, p=0.07) or inflammation score (1.19±0.35 vs. 1.07±0.33, p=0.41). Moreover, the difference in % in-stent stenosis between control and treated animals remained highly significant even after normalizing the % stenosis to the degree of injury (p=0.0008) or to the inflammation score (p=0.001). Mortality for this study was zero. Tissue concentration in segments 1 cm proximal and distal to the stents, were negligible or zero at 1 h, 24 h, and 4 weeks after stent implantation. Conclusion: Stent-based delivery of tyrphostin AGL-2043 from a biodegradable polymeric coating reduces in-stent neointimal hyperplasia in porcine coronary arteries by 50% after 28 days and preserves lumen area. Long-term studies should be the next step in testing applicability to the human interventional setting.

Original languageEnglish
Pages (from-to)165-171
Number of pages7
JournalCardiovascular Research
Volume64
Issue number1
DOIs
StatePublished - 1 Oct 2004
Externally publishedYes

Keywords

  • Angioplasty
  • Coronary intervention
  • Restenosis
  • Stents
  • Tyrosine protein kinases

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