Effect of Anti-Oxidant (Carvedilol and Probucol) Loaded Stents in a Porcine Coronary Restenosis Model

Abstract

he long-term clinical efficacy of intracoronary stenting is limited by restenosis, which occurs in 15-30% of patients 1,2 and is caused solely by neointimal hyperplasia. [3][4][5] Stent-induced mechanical arterial injury and a foreign body response to the prosthesis incite acute and chronic inflammation in the vessel wall, with elaboration of cytokines and growth factors that induce multiple signaling pathways for activation of smooth muscle cell (SMC) migration and proliferation. [3][4][5] Therefore, the delivery of agents inhibiting cell cycle progression within the stent platform should produce an effective inhibition of instent neointimal hyperplasia. [6][7][8][9][10][11] Carvedilol is a neurohumoral antagonist with multiple actions. 12,13 It was originally discovered to be a -adrenoreceptor antagonist, 14 but subsequent research revealed that it has potent antioxidant and free radical scavenger properties. 15 In addition, carvedilol inhibits vascular SMC proliferation induced by a broad group of mitogens, such as platelet-deCirculation Journal Vol.69, January 2005 rived growth factor, fibroblast growth factor, endothelin-1, serum and thrombin, 15,16 and it has produced 84% suppression of neointimal hyperplasia in rat carotid injury model. 17 Recently, the mechanism of the antimitogenic action of carvedilol on vascular smooth muscle was shown to be inhibition of mitogen-activated protein kinase activity and regulation of cell cycle progression. 18,19 Carvedilol is highly lipophilic, which promotes a rapid cellular uptake, 20 and a stent containing carvedilol should result in a high local concentration in the vessel walls with which it is in contact.Since probucol was discovered, it has been developed and sold as a lipid-lowering agent. 21 It is also an antioxidant 22 and reduces restenosis after percutaneous transluminal coronary angioplasty (PTCA), [23][24][25][26] and has recently been identified as a vascular protectant. 27 A multicenter study recently reported that post-stenting restenosis was reduced by probucol via a mechanism improving the dimension of the vessel's lumen. 28 The combination of probucol and candersatan has the potential effects of both anti-oxidant and vascular protectant. 29 In the present study, we tested whether loading of carvedilol or probucol onto phosphorylcholine (PC)-coated stents was feasible and which one most effectively inhibits neointimal hyperplasia in a porcine model of stent restenosis. Methods Carvedilol and Probucol Loading and in Vitro Release KineticsCarvedilol or probucol was loaded onto 3.0×15 mm Background The long-term clinical efficacy of intracoronary stenting is limited by restenosis and delivery by the stent of agents inhibiting cell cycle progression should prevent in-stent neointimal hyperplasia. Carvedilol is an antioxidant that inhibits smooth muscle cell proliferation and migration, whereas probucol is a vascular protectant and reduces stent restenosis by improving the lumen dimension at the stent placement site. Methods and ResultsBiodivYsio ® phospho...

Inflammation and Delayed Endothelization With Overlapping Drug-Eluting Stents in a Porcine Model of In-Stent Restenosis

“…[23][24][25][26] Future generations of stents will likely be engineered for optimal drug delivery to specific lesions while continuing to refine the BMS platform to enhance acute procedural success. Furthermore, it is likely that novel polymer materials and pharmacologic agents will be chosen for biological activity in specific disease states or vascular beds.…”

Pro-healing drug-eluting stents: a role for antioxidants?

“…Preliminary work has been done with carvedilol, a β-blocker with potent antioxidant activity. It has been shown recently that implantation of a carvedilol-coated stent in a porcine model is capable of inhibiting ISR and providing complete re-endothelialization [90]. The same study failed to demonstrate a beneficial effect with a probucol-coated stent, although there were serious concerns about adequate drug delivery.…”

The effects of granulocyte-colony stimulating factor in bare stent and sirolimus-eluting stent in pigs following myocardial infarction

“…Animal studies were carried out as previously described [14]. All animal experimental protocols were approved by the Ethics Committee of Chonnam National University Medical School and Chonnam National University Hospital, and conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No.…”