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

Objective: Tyrphostin AGL-2043 is a potent tricyclic quinoxaline inhibitor of PDGF beta-receptor tyrosine kinase (PTK), Kit, and Flt3. We have shown previously that selective inhibition of PDGF beta-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: Stems 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 2 area was reduced by 44% (2.38 +/- 1.04 versus 1.31 +/- 0.43 mm(2), p = 0.004), and the absolute luminal area was increased by 57% (2.19 +/- 1.09 versus 3.39 +/- 0.59 min(2), 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. (C) 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.