Anti-Proliferative Compounds for the Prevention of Restenosis: Anti-Restenotic Mechanisms of Paclitaxel Action

Mark      C. Lavigne; Michael      J. Eppihimer; Ruth      Cheng; James      J. Barry

doi:10.2174/138161210794454888

Abstract

Coronary artery disease is commonly characterized by atherosclerotic obstruction of vessels responsible for providing adequate blood supply to the myocardium. Disruption of atheromatous plaques can promote thrombosis, significant reductions in cardiac perfusion, and devastating acute (i.e, death) or chronic (i.e., congestive heart failure) consequences. Minimally invasive, catheter-based techniques have been implemented throughout the past three decades and include balloon angioplasty and stent implantation, to alleviate occlusive plaque burden in coronary vessels. Yet, these techniques have not come without complication, namely the tendency for vessels to re-occlude, or undergo restenosis. This manifestation is characterized by acute physical and longer-lasting cellular/biochemical components. To maximize clinical effectiveness, researchers and clinicians have exploited recognition that use of a rigid bare metal stent bound to a drug-bearing polymer, or so-called drug-eluting stent (DES), is best to combat the mechanical and biological contributors to restenosis. In this report, we review restenosis factors in detail, the corresponding rationale for drug choice for DES, and the results of trials conducted with such DES agents. Particular emphasis is given to paclitaxel, a natural compound included in a first-generation DES (Taxus® Express2®) made available for clinical use by Boston Scientific Corporation. We use paclitaxel as a model to illustrate alternatives for drug delivery to coronary vessels, broad concerns about DES use in the context of disease backgrounds, such as diabetes, and suggestions related to the continuing evolution of DES.

Keywords: Drug eluting stent (DES), local drug delivery, biostable, bioabsorbable, drug delivery, stent, Restenosis, Paclitaxel Action, Coronary artery disease, myocardium, thrombosis, congestive heart failure, drug-eluting stent, Angioplasty, vascular smooth muscle, endothelial, balloon, diabetes, Paclitaxel, Cardiovascular disease, bare metal stents, anti-cancer drugs, neutrophils, platelet-derived growth factor, CCR2, MCP-1, ICAM-1, GPIb, active pharmaceutical ingredient, BiodVysio stents, (“M”)-phase, TAXOL, Paclitaxel-induced apoptosis, DNA fragmentation, neointimal hyperplasia, MHC II, TGF-, SMAD3, diabetics, rosiglitazone, sirolimus