A successful experimental model for intimal hyperplasia prevention using a resveratrol delivering balloon.

Restenosis due to intimal hyperplasia is a major clinical problem that compromises the success of angioplasty and endovascular surgery. The pathogenesis of restenosis is multifactorial, involving such events as endothelial injury, inflammation, platelet activation, and hyperplasia of the intima, primarily due to vascular smooth muscle cell replication (vSMC). The incidence of intimal hyperplasia varies in different risk populations, e.g., diabetic patients, up to 35% of whom require bare metal stent implantation; clinical evidence has shown that this value is reduced but continues to cause problems after the implantation of drug-eluting stents (DES). Overall, however, despite many years of clinical experience with drug-eluting balloons (DEB), the number of large, high-quality, randomised clinical trials is low, and further data are urgently needed across the spectrum of clinical indications. Taxol and other cytostatic drugs destroy a cell's ability to use its cytoskeleton in a flexible manner, and, considering the clinical results, further research on a more physiologic mechanism of action should be pursued. Antioxidants are currently under investigation due to their protective activity within the vessels. Rosenbaum et al. showed that the endothelialisation of prosthetic grafts was significantly reduced, and anastomotic hyperplasia, significantly increased in rabbits on a high cholesterol diet. Treatment with an antioxidant improves endothelial cell coverage, decreases intimal hyperplasia and reduces oxidative stress, promoting the patency of prosthetic grafts. Resveratrol is a polyphenolic phytoalexinic antioxidant that is produced by grapes and other plants in response to injurious infections. The molecular structure of RSV, unfortunately, reduces its immediate clinical application for three main reasons: 1) its status as a highly lipophilic molecule; 2) its fast drifting from the TRANS- to CIS-phase, representing an oxidised and inactive state, respectively; and 3) its low circadian bioavailability for rapid hepatic metabolism. As consequence of these features, the oral bioavailability of RSV is negligible since it is rapidly conjugated to improve the solubility of the compound. The disposition of 14C-labeled RSV, as orally and intravenously administered in normal, healthy volunteers, was evaluated to estimate the extent of the oral dose absorbed, the bioavailability of the unchanged drug, and the drug’s metabolic phase. RSV demonstrated a high oral absorption but a rapid and extensive metabolism, resulting in only trace amounts of unchanged RSV remaining until systemic circulation. Five major metabolites were detected in the urine samples14, plasma and colo-rectal cancer tissues, although all were only measured qualitatively due to a lack of available reference materials. Metabolite 1 (M1) was a RSV monoglucuronide, and metabolite 2, an isomeric RSV monoglucuronide (M2), was found in greater abundance. M3 was a dihydroresveratrol monoglucuronide, whereas M4 and M5 were two poorly resolved RSV sulphates, i.e., a resveratrol monosulphate (M4) and a dihydroresveratrol sulphate (M5). Despite the controversial results on the efficacy of RSV reported in the literature, very recent data obtained in colon cancer cells have supported the notion that RSV, in spite of its low bioavailability, is able to act through its metabolites, mainly the sulpho-conjugate but also the combination of sulphate/glucuronide derivatives. Despite the wide literature on RSV, only few preclinical studies have demonstrated the efficacy of RSV in an animal model or investigated the possibility of locally administering this antioxidant by eluting stents. Based on our experience, we decided to set up a sterile, injectable, and hydrophilic RSV-containing compound (RSV-c). This solution was locally administered in the common iliac artery of adult male New Zeeland white rabbits using a dedicated device.