LB30057, A Direct Thrombin Inhibitor, Inhibits Vascular Smooth Muscle Cell proliferation in vitro and the Neointimal Hyperplasia in Rat Carotid Injury Model

ABSTRACT

BACKGROUND: Recent data showed prolonged administration of direct thrombin inhibitor might be needed to counteract the persistent thrombin activity and reduce the neointimal hyperplasia after arterial injury. We hypothesized that prolonged administration of LB30057, orally active direct thrombin inhibitor, might inhibit the vascular smooth muscle cell (SMC) proliferation in vitro and neointimal hyperplasia in rat carotid injury model. METHODS: In phase I, thrombin stimulated [methyl-3H] thymidine uptake was measured after LB30057 administration in cell culture study using rat aortic SMC. In phase II, LB30057 (low-dose 5mg/kg, bid mid-dose 25mg/kg, bid high-dose 50mg/kg, bid) or placebo was administrated orally twice a day starting from 30minutes before injury until sacrifice for 14days in separated 2 sets of experiment. The histo-morphometric analysis for lumen area, intimal area, medial area, intima-to-medial ratio was performed. RESULTS: In vitro rat aortic SMC culture study, LB30057 inhibited thrombin-induced thymidine uptake. The mean neointimal area was significantly less in high-dose and mid-dose group than placebo group (high-dose vs. placebo 0.14+/-0.02mm2 vs. 0.25+/-0.02mm2 mid-dose vs. placebo 0.16+/-0.02mm2 vs. 0.29+/-0.03mm2, p<0.005) respectively and the mean ratio of neointima to medial area were significantly less in high-dose and mid-dose group than in placebo group (high-dose vs. placebo 1.20+/-0.57 vs. 1.94+/-0.67, mid-dose vs. placebo 1.58+/-0.29 vs. 2.39+/-0.27, p<0.05). There was no significant difference in the mean area of internal elastic lamina, external elastic lamina and mean luminal area between groups. In 2nd set experiment, the mean neointimal area (placebo 0.29+/-0.03mm2, mid-dose 0.16+/-0.02mm2 p<0.005), the mean area of internal elastic lamina and external elastic lamina were significantly less in mid-dose group than in placebo group. The mean ratio of neointima to medial area was significantly less in mid-dose group(1.58+/-0.29) than in placebo group (2.39+/-0.27) (p<0.05). CONCLUSION: LB30057 inhibits SMC proliferation in a dose dependent manner. Prolonged 14-day oral administration of LB30057 is effective in reducing the neointimal hyperplasia in rat carotid balloon injury model.