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

Abstract

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.

DESIGN:

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.

• Authors: Nicolas F Meneveau, Bruce D Klugherz, Brahim Chaqour, Vibha Anand, John E Tomaszewski, Madeleine M Joullié, Edward Macarak, Michael Golden, Paul B Weisz, Robert L Wilensky
• Journal: Coronary artery disease (Coron Artery Dis) Vol. 13 Issue 3 Pg. 189-97 (May 2002) ISSN: 0954-6928 [Print] England
• PMID: 12131024 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Glucose
• Cyclodextrins
• Oligosaccharides
• beta-Cyclodextrins
• beta-cyclodextrin tetradecasulfate
• Factor Xa
• Magnesium

Topics

• Animals
• Blood Glucose (drug effects, metabolism)
• Coronary Thrombosis (blood, drug therapy)
• Coronary Vessels (drug effects, injuries)
• Cyclodextrins (blood, pharmacology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Evaluation
• Endothelium, Vascular (cytology, drug effects)
• Factor Xa (drug effects, metabolism)
• Magnesium (blood)
• Models, Cardiovascular
• Oligosaccharides (blood, pharmacology)
• Randomized Controlled Trials as Topic
• Statistics as Topic
• Swine
• Treatment Outcome
• Tunica Intima (drug effects, pathology)
• Whole Blood Coagulation Time
• beta-Cyclodextrins