Inhibition of smooth muscle cell proliferation after local drug delivery of the antimitotic drug paclitaxel using a porous balloon catheter

Bristol Royal Infirmary Percutaneous transluminal coronary angioplasty is a n accepted treatment fbr coronary artery disease. The major limitation, how ever, is the high incidence of restenosis which limits the long-term benefi t of this intervention. Paclitaxel is a new antiproliferative agent that ha s generated considerable scientific interest since it was introduced in cli nical trials in the early 1980s. Recent in vitro studies have shown that pa clitaxel has considerable antiproliferative activity in human coculture sys tems. In the present study the efficacy of paclitaxel was investigated afte r development of an intimal plaque by electrical stimulation and additional cholesterol diet and subsequent balloon angioplasty in 63 New Zealand Whit e rabbits. Local drug delivery of paclitaxel was accomplished in 30 rabbits with a porous balloon catheter (35 holes, hole diameter 75 mum, 2 5 mm cat heter diameter). Paclitaxel was administered locally with 4 ml (solution 10 (-5) mol/L) using an injection pressure of 2 atm. To study the extent of re stenosis and morphological changes, the animals were sacrificed 7, 28 or 56 days after intervention. After staining procedures quantification of SMC p roliferation, intimal macrophages and morphological analyses were performed . Paclitaxel plasma concentrations were measured using HPLC technique. One week after balloon angioplasty the arteries treated with local paclitaxel d elivery showed an insignificant trend towards a reduction in intimal smooth muscle cell proliferation (untreated 8.4 +/- 4.9 % vs paclitaxel treated 2 .4 +/- 2.4 %, p = NS). However, this resulted Bristol Royal Infirmary in a significant reduction of stenosis degree of 66 % 8 weeks after intervention compared to the untreated group (untreated 41 +/- 18 % vs paclitaxel treat ed 14 +/- 11 %, p = 0.005). In conclusion, locally delivered paclitaxel pre vented neointimal thickening in the rabbit carotid artery after balloon ang ioplasty. Local paclitaxel treatment may therefore be a clinical option for the prevention of restenosis after coronary interventions. However, furthe r preclinical studies have to prove long-term efficacy and safety.