Local drug delivery systems and prevention of restenosis.

Abstract

Time for primary review 38 days. It is somewhat incongruous that the successful performance of percutaneous transluminal coronary revascularization, a technically challenging and somewhat delicate endeavour, is predicated on the delivery of a traumatic insult to the vascular wall. This injury incites a cascade of compensatory responses, involving thrombosis and inflammation, vascular smooth muscle proliferation and migration, and matrix production and deposition. Although this reparative process usually stabilizes the site of injury and ensures a successful long term result, in 30 to 50% of cases it is excessive [1], resulting in compromise of the lumen with the potential for recurrent ischemia. Our understanding of the process of restenosis, although not yet complete, has evolved considerably in recent years. There is a complex interplay of vessel wall remodeling and neointimal proliferation. Remodeling refers to a contracture or ‘shrinkage’ of the vessel, primarily related to the inflammatory process in the vessel wall which involves the media and adventitia. The neointimal proliferative process appears to be linked to vascular smooth muscle cell activation, proliferation and migration [2, 3]. The deployment of an intracoronary stent at the site of injury, by providing a scaffold within the vessel wall, can reduce the impact of vascular remodeling, but may be accompanied by an exhuberant intimal hyperplastic response [4]with consequent restenosis in a persistent 20–30% of cases [5, 6]. Thus, over recent years there has been a widespread intensive research effort directed towards identifying pharmacotherepeutic regimens targeting primarily (but not exclusively) the smooth muscle cell, to prevent the neointimal restenotic process. These have involved conventional pharmacological agents, as well as novel gene therapies, and many of these have been found to be effective in preventing restenosis in animal models of vascular injury following systemic administration. However, when these agents have progressed to clinical … * Corresponding author. Tel.: +1 216 4459490; Fax: +1 216 4459595; E-mail: topole@cesmtp.ccf.org