Sirolimus and its Analogs and its Effects on Vascular Diseases

Steven      J. Adelman

Abstract

Sirolimus (rapamycin), a macrolide antibiotic approved for use as an immunosuppressive agent in the prevention of organ rejection, is a cell proliferation inhibitor and regulator of the immune response which acts through inhibition of TOR (target of rapamycin), a kinase essential to cell cycle progression. Recent studies suggest that the TOR pathway is critical to overall cell function, and at a basic mechanistic level, may be a regulator and potential therapeutic target involved in many of the major (and minor) disorders seen in man today. Cardiovascular diseases including restenosis following percutaneous coronary intervention as well as the more widespread condition of atherosclerosis, share this common involvement of TOR. The present report addresses the current state of intervention in cardiovascular disorders with Sirolimus and similar inhibitors of TOR, including the rationale for this approach and the successes observed to date. Success of the first drug-eluting stent to locally treat restenosis in the clinic is discussed, as are preclinical studies addressing a role in overall atherosclerosis in animal models. In addition, due to the known toxicities when given systemically, an approach for targeted delivery to local areas of vascular disease is discussed.

Keywords: Drug-eluting stents, Sirolimus, Rapamycin derivatives, Paclitaxel, Eluting Stent Systems, Coronary artery, neointimal hyperplasia, restenosis, taxol, coronary artery disease, drug-eluting stent, clinical trials, bare metal stent, angioplasty, sirolimus-eluting stents, Chemotherapy, -tubulin, lipophilicity, Palmaz-Schatz stents, intraintimal hemorrhage, Antiplatelet therapy, clopidogrel, angiographic stenosis, myocardial infarction, Academic Research Consortium, thrombosis, Stenting of Saphenous Vein Grafts, vascular brachytherapy, brachytherapy, chronic total occlusions, SYNTAX trial, XIENCE V stent, femoropopliteal disease