TY - JOUR
T1 - Tyrphostin AGL-2043 eluting stent reduces neointima formation in porcine coronary arteries
AU - Banai, Shmuel
AU - Gertz, S. David
AU - Gavish, Lilach
AU - Chorny, Michael
AU - Perez, Louise S.
AU - Lazarovichi, Galila
AU - Ianculuvich, Mickey
AU - Hoffmann, Michael
AU - Orlowski, Michael
AU - Golomb, Gershon
AU - Levitzki, Alexander
PY - 2004/10/1
Y1 - 2004/10/1
N2 - 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.
AB - 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.
KW - Angioplasty
KW - Coronary intervention
KW - Restenosis
KW - Stents
KW - Tyrosine protein kinases
UR - http://www.scopus.com/inward/record.url?scp=4444231182&partnerID=8YFLogxK
U2 - 10.1016/j.cardiores.2004.06.013
DO - 10.1016/j.cardiores.2004.06.013
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C2 - 15364624
AN - SCOPUS:4444231182
SN - 0008-6363
VL - 64
SP - 165
EP - 171
JO - Cardiovascular Research
JF - Cardiovascular Research
IS - 1
ER -
