Perivascular administration: The outside-in concept.

Perivascular administration has attracted increasing attention since intimal hyperplasia was identified as the main cause for coronary and peripheral bypass graft occlusion. For preventing the graft occlusion, a local treatment using a sustained drug delivery system would be ideal, as the vessels are readily exposed to the vascular surgeons [1]. However, neither local nor oral formulations have been developed, not tomention clinically available products, to prevent the advance of this pathological condition. A drug delivery system that wouldmeet the needs of this pathology will help those undergoing bypass surgeries greatly. The paper by Doctor Florence Delie and her coworkers in this issue is a collaborative effort between the Geneva-Lausanne School of Pharmacy and the Vascular Surgery Department of Lausanne's University Hospital [2]. They investigated the optimal release kinetics necessary to decrease the development of intimal hyperplasia in a murine model. Based on the time course of the evolution of the pathology, three different atorvastatin releasing profiles were tested in vivo: short-term release over 3 days (fast), sustained release over 45 days (sustained) and a combination of both (biphasic). Poly(D,L-lactic-co-glycolic acid) microparticles were used to sustain the release of atorvastatin, a compound known to inhibit human smooth muscle cell proliferation in vitro. A cross-linked hyaluronic acid gel, also used for fast release, ensured ease of application and retention of the formulation at the site of action. The biodistribution of atorvastatin over adjacent and distal organs was investigated. An ex vivo test was set up to ensure permeability of atorvastatin through human saphenous veins, the graft of choice for bypass interventions. The study by the Delie team draws significant conclusions. First, the biphasic releasing system, combining fast and sustained release of atorvastatin, was demonstrated to be optimal. In vivo, after four weeks, this biphasic formulation reduced by 68% the occurrence of intimal hyperplasia compared with the untreated control group. Fast or sustained release formulations did not provide such an efficacy. This observation indicates that there may be a synergistic effect: an initial bolus release of atorvastatin is necessary to prevent smooth muscle cell proliferation at the very early stage of the pathology, and the sustained release inhibits later events such as smooth muscle cell migration from the media to the subintimal level. Second, the endotheliumwas not affected