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.


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.


CONCLUSIONS
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.
Banai
Shmuel
S
Department of Cardiology, Hadassah University Hospital, P.O. Box 12000, Jerusalem 91120, Israel.
Gertz
S David
SD
Gavish
Lilach
L
Chorny
Michael
M
Perez
Louise S
LS
Lazarovichi
Galila
G
Ianculuvich
Mickey
M
Hoffmann
Michael
M
Orlowski
Michael
M
Golomb
Gershon
G
Levitzki
Alexander
A
D000818:Animals; D001673:Biodegradation, Environmental; D003327:Coronary Disease / Q000188:drug therapy / Q000628:therapy*; D003331:Coronary Vessels; D003692:Delayed-Action Preparations; D004343:Drug Implants; D023421:Models, Animal; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D015607:Stents; D013552:Swine; D013556:Swine, Miniature; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology*; D020032:Tyrphostins / Q000008:administration & dosage* / Q000627:therapeutic use
D003692:Delayed-Action Preparations; D004343:Drug Implants; D020032:Tyrphostins; C494191:tyrphostin AGL-2043; D011505:Protein-Tyrosine Kinases