Experimental and clinical data suggest that
stents eluting antiproliferative agents can be used for the prevention of in-
stent restenosis. Here we investigate in vitro the antiproliferative and apoptotic effect of
D-24851 and evaluate the safety and efficacy of D-24851-eluting
polymer-coated
stents in a rabbit restenosis model (n = 53). Uncoated
stents (n = 6),
poly (DL: -lactide-co-glycolide) (PLGA)-coated
stents (n = 7), and PLGA-coated
stents loaded with 0.08 +/- 0.0025 microM (31 +/- 1 mug; low dose; n = 7), 0.55 +/- 0.02 microM (216 +/- 8 mug; high dose; n = 6), and 4.55 +/- 0.1 microM (1774 +/- 39 mug; extreme dose; n = 5) of
D-24851 were randomly implanted in New Zealand rabbit right iliac arteries and the animals were sacrificed after 28 days for histomorphometric analysis. For the assessment of endothelial regrowth in 90 days, 12 rabbits were subjected to PLGA-coated (n = 3), low-dose (n = 3), high-dose (n = 3), and extreme-dose (n = 3)
stent implantation. In vitro studies revealed that
D-24851 exerts its growth inhibitory effects via inhibition of proliferation and induction of apoptosis without increasing the expression of heat shock protein-70, a cytoprotective and antiapoptotic
protein. Treatment with low-dose
D-24851 stents was associated with a significant reduction in neointimal area and percentage
stenosis only compared with bare
metal stents (38% [P = 0.029] and 35% [P = 0.003] reduction, respectively). Suboptimal healing, however, was observed in all groups of D-24851-loaded
stents in 90 days in comparison with PLGA-coated
stents. We conclude that low-dose D-24851-eluting
polymer-coated
stents significantly inhibit neointimal
hyperplasia at 28 days through inhibition of proliferation and enhancement of apoptosis. In view of the suboptimal re-endothelialization, longer-term studies are needed in order to establish whether the inhibition of intimal growth is maintained.