Principal Investigators:
C. Lotan MD, A. Haji-Yehia PhD, R. Jabara MD, G. Golomb PhD, T. Nassar PhD

Collaboration:
Biocompatibles Ltd., England
EuroCor GMBH, Germany

Abstract:

The problem of restenosis has long been the Achilles' heel of interventional procedures. Although intracoronary stenting has significantly lowered the rate of restenosis compared with balloon angioplasty, in-stent restenosis continues to be an important clinical problem. Unfortunately, despite intensive research on how to suppress cell proliferation, no pharmacological agent has been proven effective in inhibiting in-stent restenosis in humans.
Over the last years it was shown that both nitric-oxide (NO) and antioxidants play an important role in vascular injury. NO is critical for maintaining vascular homeostasis and is depleted after coronary angioplasty, leading to endothelial denudation. Anti-oxidants were found to be vital in the preservation of endothelium-dependent functions and to have beneficial effects on cell proliferation and arterial remodeling.
We have shown in preliminary studies using a rabbit model, that administration of a novel anti-superoxide-nitric-oxide donor (TEMPOL) after experimental balloon angioplasty, decreased significantly the percent of restenosis and the amount of neointimal formation, in addition it has a positive effect on vessel remodeling.
The objective of this study is to assess the effect of TEMPOL on cellular proliferation after experimental balloon angioplasty and implantation of a stent. Using the hypercholesterolemic rabbit as a model of iliac arterial endothelial denudation, we will test the hypothesis that a stent coated with TEMPOL inserted into a commercially available polymer will decrease restenosis and have a beneficial effect on vessel remodeling. We will also assess the oxidative stress, as measured by the total antioxidant capacity of the plasma and oxidized LDL at baseline and after surgery. On the 30th day post operation, both iliacs will be isolated and prepared for histological and immuno-cytochemical analysis. In addition to measuring the intima to media ratio and the percent of luminal narrowing, immuno-cytochemical identification of proliferating cells will also be carried out.
This unique approach of combining antioxidants and NO-donors may prove useful for partially restoring endothelial functions after vascular injury and for new pharmacological interventions to reduce in-stent restenosis.

Status:

Pharmacokinetic studies of drug release
Pre-clinical trials with large animals (pigs)