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Separate and Combined Effects of Local and Continuous Intravenous Administration of ß-Cyclodextrin Tetradecasulfate on Intimal Hyperplasia after Angioplasty in Porcine Coronary Arteries

Bruce D. Klugherz, MD

Departments of Medicine, Cardiovascular Division

Brahim Chaquor, PhD

Anatomy and Histology, School of Dental Medicine, University of Pennsylvania

Michael A. Golden, MD

Departments of Medicine, Surgery

Madeleine M. Jouille, PhD

Bioengineering of the University of Pennsylvania

Edward Macarek, PhD

Anatomy and Histology, School of Dental Medicine, University of Pennsylvania

Paul B. Weisz, PhD

Bioengineering of the University of Pennsylvania

Robert L. Wilensky, MD

Departments of Medicine, Cardiovascular Division; Laboratory for Experimental Interventional Cardiology, 3400 Spruce Street, 9 Gates, Hospital of the University of Pennsylvania, Philadelphia, PA 19104

Background: Beta-Cyclodextrin tetradecasulfate binds fibroblast growth factors and possesses anticoagulant properties. This study was designed to assess the separate and combined effects of local intramural delivery and intravenous administration of ß-cyclodextrin tetradecasulfate on neointimal formation and arterial damage following angioplasty.

Methods and Results: Fifty-two pigs randomized into four groups underwent coronary artery angioplasty: 1) control, 2) continuous intravenous infusion of 100 mg/kg/d of ß-cyclodextrin tetradecasulfate, 3) intramural delivery of 1250 mg ß-cyclodextrin tetradecasulfate, 4) intramural delivery of 1250 mg ß-cyclodextrin tetradecasulfate followed by continuous intravenous infusion of 100 mg/kg/d. Fourteen days after injury, morphometric analysis revealed that arteries randomized to the intravenous ß-cyclodextrin tetradecasulfate groups had a decreased normalized neointima area: control, 3.03 ± 0.75 mm²; intravenous, 1.67 ± 0.73 mm² (40% decrease; P < 10-7); intravenous plus local, 1.95 ± 0.76 mm² (30% decrease; P < 10-5). There was no difference in neointimal response following local ß-cyclodextrin tetradecasulfate delivery only (2.82 ± 1.14 mm²). Coronary arterial damage, defined as aneurysm, dissection, adventitial rupture, and retromedial hematoma was similar in all groups (12% in control and local groups, 10% in the intravenous group, 14% in the intravenous plus local; NS). Bleeding complications were more frequent in the intravenous and intravenous plus local groups compared to the local and control groups (23%vs 7.6% and 0%, respectively; P < 0.05).

Conclusions: Continuous intravenous administration of ß-cyclodextrin tetradecasulfate substantially reduced intimal hyperplasia, while intramural delivery had no effect, indicating that a single bolus of ß-cyclodextrin tetradecasulfate did not reduce intimal hyperplasia. There was no additive effect of local intramural delivery of ß-cyclodextrin tetradecasulfate. However, local delivery of ß-cyclodextrin tetradecasulfate induced less bleeding complications and did not lead to additional arterial injury, indicating that local delivery of an anticoagulant does not cause additional arterial injury.

Key Words: restenosis • local drug delivery • coronary artery disease

Journal of Cardiovascular Pharmacology and Therapeutics, Vol. 8, No. 1, 53-60 (2003)
DOI: 10.1177/107424840300800i108


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