β-cyclodextrin tetradecasulfate, a novel cyclic oligosaccharide, inhibits thrombus and neointimal formation after coronary vascular injury

Background: Neointimal formation is a major cause of restenosis after interventional vascular procedures. β-Cyclodextrin tetradecasulfate (β-CDT) has been shown to inhibit fibroblast growth factor activity and we hypothesized that β-CDT would reduce intimal formation. Design: Three studies were performed: (1) pharmacokinetics of oral and intravenous β-CDT and determination of optimal dose, (2) determination of efficacy of oral and intravenous β-CDT in reducing neointimal formation after balloon-overstretch injury and (3) determination of the effect of β-CDT on cellular proliferation, factor Xa activity, activated clotting time, activated partial thromboplastin time and thrombus formation. Methods: Pharmacokinetics were determined in eight domestic swine following administration of oral β-CDT and intravenous β-CDT at three doses each. In the efficacy study, balloon-overstretch injury of 37 pigs (69 arteries) was performed and randomized into three groups (n = 23 arteries/group): control, oral administration of 300 mg β-CDT/kg per day or intravenous infusion of 100 mg β-CDT/kg per day. Animals were sacrificed 14 days later. Cellular proliferation and mural thrombus were determined in six arteries/group at 5 days and endothelial coverage was evaluated at 5 and 14 days. Results: Oral and intravenous β-CDT reduced the intimal hyperplasia area normalized to injury index by 24 and 48%, respectively: control, 3.03 ± 0.75 mm², oral, 2.31 ± 0.83 mm² (P = 0.004) and intravenous, 1.67 ± 0.73 mm² (P = 0.0000002). β-CDT reduced cellular proliferation (control, 55 ± 18%, oral, 35 ± 7%, P = 0.03 and intravenous, 30 ± 12%, P = 0.01) and mural thrombus formation (control, 0.84 ± 0.4 mm², oral, 0.44 ± 0.14 mm², P = 0.04, intravenous, 0.42 ± 0.09 mm², P = 0.03). Endothelial coverage was increased in the experimental groups (P = 0.008, oral versus control, P < 0.0001, intravenous versus control). Factor Xa activity was inhibited 9-10 fold following intravenous administration while oral administration demonstrated no effect. Conclusions: Both oral and intravenous formation of β-CDT reduced intimal hyperplasia with the greatest reduction in the intravenous group. We postulate that β-CDT was effective by the combination of increasing endothelial coverage, reducing mural thrombus formation, inhibiting factor Xa activity and reducing cellular proliferation.