ABSTRACT
PURPOSE: To investigate if a platelet inhibitor (aurintricarboxylic acid [ATA]) and a heparin-mimicking antagonist (RG-13577) of basic fibroblast growth factor 2 (bFGF2) could be combined as a stable compound and attached to conventional bare metal stents to hinder thrombus formation and inflammatory reactions of stenting. METHODS: Fifteen domestic pigs were stented with RG-13577/ATA-coated (n=6), ATA-coated (n=12), and bare metal stents (n=12) in the left anterior descending (LAD) and left circumflex (LCX) coronary arteries. All surviving pigs were evaluated with contrast angiography and intravascular ultrasonography (IVUS) after 4 weeks. Histological analysis of the stented arteries was performed after hematoxylin-eosin staining. Tissue factor (TF) staining and scanning electron microscopy (SEM) were performed in animals with acute stent thrombosis. RESULTS: Five of the 6 animals receiving an RG-13577/ATA-coated stent experienced acute stent thrombosis, while no adverse events occurred in the animals of the other 2 groups. Follow-up angiography did not show significant in-stent stenosis in either bare or ATA-coated stents. However, histomorphometry revealed larger neointimal area (3.54+/-0.69 mm2 versus 1.82+/-0.27 mm2, p<0.05) and outward plaque area (1.56+/-0.34 mm2 versus 0.61+/-0.12 mm2, p<0.05) in ATA-coated stents. Three-dimensional IVUS analysis showed analogous results, with significantly larger neointimal volume and outward plaque volume in ATA-coated stents. There was a slight increase in TF staining around the stent struts, while SEM showed increased platelet adhesion and activity in RG-13577/ATA-coated stents versus the ATA-coated and bare metal stents. CONCLUSION: RG-13577/ATA-coated stents lead to acute stent thrombosis. The ATA coating alone did not lead to acute events, but resulted in higher neointimal hyperplasia and expansive remodeling. These results underline the importance of preclinical studies before using new coated stents in human arteries.
Subject(s)
Aurintricarboxylic Acid/pharmacology , Aurintricarboxylic Acid/toxicity , Coronary Vessels/drug effects , Fibroblast Growth Factor 2/antagonists & inhibitors , Phenoxyacetates/pharmacology , Phenoxyacetates/toxicity , Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation Inhibitors/toxicity , Polymers/pharmacology , Polymers/toxicity , Stents , Thrombosis/etiology , Animals , Aurintricarboxylic Acid/administration & dosage , Coronary Angiography , Coronary Restenosis/prevention & control , Coronary Vessels/pathology , Drug Combinations , Drug Evaluation, Preclinical , Hyperplasia , Microscopy, Electron, Scanning , Phenoxyacetates/administration & dosage , Platelet Aggregation Inhibitors/administration & dosage , Polymers/administration & dosage , Stents/adverse effects , Swine , Thrombosis/diagnostic imaging , Thrombosis/pathology , Treatment Failure , Tunica Intima/drug effects , Tunica Intima/pathologyABSTRACT
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: 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 mm(2), p=0.004), and the absolute luminal area was increased by 57% (2.19+/-1.09 versus 3.39+/-0.59 mm(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.
