OF WORK A major complication facing 40-50% of patients undergoing percutaneous transluminal coronary angioplasty (PTCA) for symptomatic coronary artery disease is restenosis, a condition characterized by neointimal proliferation and vascular remodeling. Efforts to develop a therapeutic approach for preventing restenosis have focused on the local administration of drugs that prevent neointimal hyperplasia. One of these agents is paclitaxel, a hydrophobic anti-neoplastic drug with proven efficacy in the rat model of restenosis. Local intravascular paclitaxel delivery was tested in the minipig model by implanting paclitaxel-coated Cordis (wire) and Palmaz-Schatz (slotted) stents in the LAD coronary artery following overinflation balloon injury. Lumenal narrowing was assessed by angiography and histology/morphometry 4 weeks post-implantation. Stents coated with ethylene vinyl acetate for sustained paclitaxel release elicited either acute thrombosis and death in 50% of animals tested or significant (70-95%) late lumenal narrowing. To avoid polymer-induced thrombotic complications, PS stents were coated by immersion in ethanolic paclitaxel and air-dried. Compared to control (no drug), stents coated with 90 miciogram paclitaxel caused a reduction in angiographic late loss index (65%; p<0.003; n=8) and histologic neointimal area (36%; p<0.05) and an increase in histologic lumenal area (68%; p<0.002). Smaller, insignificant changes in these indices were detected at an intermediate paclitaxel level (15 miciogram/stent; n=7). Evidence of cytotoxicity (inflammation, focal intimal herrorhage, necrosis) was found only at the higher drug dose. To test the efficacy of intravascular paclitaxel in the peripheral circulation, stainless steel stents coated with a paclitaxel-containing polymer (1% chondroitin sulfate and gelatin; CSG) were deployed in the rabbit iliac artery. Animals receiving the highest drug dose (42 micogram/stent) showed a significant reduction in neointimal thickness (43%; p<0.001) compared to the other groups (no coating, CSG alone, CSG with 1.5 or 8.6 miciogram/stent), but also displayed evidence of cytotoxicity (neovascularization, inflammation, focal dissection). Polymeric coatings were nonthrombogenic in the iliac artery in contrast to their effects in the coronary circulation.. These studies demonstrate that 1) paclitaxel is effective at reducing neointimal formation when applied locally by an intravascular route; 2) polymeric drug delivery systems are better tolerated in the peripheral than in the coronary circulation; 3) further studies are needed to establish a therapeutically effective paclitaxel dosing range for treating coronary and peripheral restenosis.
