Beta-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. Beta-cyclodextrin tetradecasulfate (beta-CDT) has been shown to inhibit fibroblast growth factor activity and we hypothesized that beta-CDT would reduce intimal formation.


METHODS
Three studies were performed: (1) pharmacokinetics of oral and intravenous beta-CDT and determination of optimal dose, (2) determination of efficacy of oral and intravenous beta-CDT in reducing neointimal formation after balloon-overstretch injury and (3) determination of the effect of beta-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 beta-CDT and intravenous beta-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 beta-CDT/kg per day or intravenous infusion of 100 mg beta-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 beta-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). beta-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 beta-CDT reduced intimal hyperplasia with the greatest reduction in the intravenous group. We postulate that beta-CDT was effective by the combination of increasing endothelial coverage, reducing mural thrombus formation, inhibiting factor Xa activity and reducing cellular proliferation.
Meneveau
Nicolas F
NF
Department of Medicine, University of Pennsylvania, USA.
Klugherz
Bruce D
BD
Chaqour
Brahim
B
Anand
Vibha
V
Tomaszewski
John E
JE
Joullié
Madeleine M
MM
Macarak
Edward
E
Golden
Michael
M
Weisz
Paul B
PB
Wilensky
Robert L
RL
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003328:Coronary Thrombosis / Q000097:blood / Q000188:drug therapy*; D003331:Coronary Vessels / Q000187:drug effects / Q000293:injuries*; D003505:Cyclodextrins / Q000097:blood / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D015951:Factor Xa / Q000187:drug effects / Q000378:metabolism; D008274:Magnesium / Q000097:blood; D008955:Models, Cardiovascular; D009844:Oligosaccharides / Q000097:blood / Q000494:pharmacology*; D016032:Randomized Controlled Trials as Topic; D013223:Statistics as Topic; D013552:Swine; D016896:Treatment Outcome; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology*; D014914:Whole Blood Coagulation Time; D047392:beta-Cyclodextrins
D001786:Blood Glucose; D003505:Cyclodextrins; D009844:Oligosaccharides; D047392:beta-Cyclodextrins; C064089:beta-cyclodextrin tetradecasulfate; D015951:Factor Xa; D008274:Magnesium