A single short contact of tissue with a small dose of paclitaxel has been shown to efficaciously inhibit local cell proliferation. Paclitaxel is a natural compound found in the bark of Pacific yew trees. It binds to tubulin and thus inhibits the regular separation of chromosomes in dividing cells. It belongs to the group of cytostatic agents. Antiproliferative taxanes such as paclitaxel seem to be suitable due to their high lipophilicity and tight binding to various cell constituents, resulting in effective local retention at the site of delivery.¹ Paclitaxel as a hydrophobic compound possesses preferential tissue binding. Two recently published papers documented effective convection and diffusion mechanisms of paclitaxel into the arterial wall from the lumen.^2,3 In addition, competitive binding - for example by albumin and other plasma proteins - was identified as the main reason for diminished paclitaxel accumulation.³ Plasma concentrations of paclitaxel in the general circulation sufficient to inhibit restenosis would probably reach toxic levels.⁴ The coating of angioplasty balloons with paclitaxel allows for arterial uptake not hindered by protein binding due to the direct exposure of the drug to the luminal surface and short-lasting high local concentrations.

Adhesion of paclitaxel to the balloon surface is of great importance for successful coating delivery. The coating must adhere to the balloon during its passage through the introductory sheath or guiding catheter in the bloodstream, as well as during its passage through tortuous and sometimes calcified arteries. Upon inflating the balloon, the coating must be immediately released to the vessel wall. Ultravist® 370 is added to the coating in order to facilitate the release of paclitaxel from the balloon surface and enhance the solubility of paclitaxel in aqueous media.

Non-clinical Studies
The efficacy of paclitaxel locally administered by implanted drug-eluting stents (DES) in inhibiting restenosis following coronary angioplasty has been proved in animal experiments and clinical trials.⁵ Unlike DES, the drug is released from coated balloons upon contact within seconds to a minute. Studies have investigated the effectiveness of short exposure times of the drug on the tissue. Cell culture experiments provided the first hint that short exposure times may be sufficient to achieve persistent effects. The exposure of cells for three minutes was sufficient to inhibit cell proliferation for the following 12 days without impairing cell survival. In vivo studies of coronary overstretch in the porcine model showed that the paclitaxel-coated balloons effectively inhibited neointimal proliferation at all dose levels tested. Doses between 2.5 and 10μg paclitaxel/mm2 balloon surface were equally effective. No difference was found between a 10-second and the standard 60-second inflation time. Efficacy compares favourably with the best-known DES on the market.

Experience with DES - although different because of the sustained drug supply - indicate the risk of delayed healing of the vessel wall after dilatation. Delayed healing, particularly delayed endothelialisation and coverage of the stent struts by endothelial cells, increases the risk of late thrombosis, which may result in vessel occlusion and myocardial infarction. Theoretically, paclitaxel administration to a coronary vessel may cause damage to the myocardial tissue supplied by this artery, whereas effects after further dilution and recirculation can be excluded because of the low dose. The risk of delayed healing and local damage to the treated vessel and myocardium has been assessed in various studies in pigs after implantation of the paclitaxel-coated balloons. No differences in the acute tolerance of coated and conventional non-coated balloon catheters were found during the interventional procedures. No signs of delayed thrombotic events possibly caused by delayed healing could be detected. Even if the highest dose was applied, histology revealed complete healing and endothelialisation four to five weeks after balloon dilatation and stent implantation. In order to obtain the clinical benefit of restenosis inhibition, it is important that the coating is not lost or washed off during catheter use. Potential areas of loss include passage through the introductory sheath, use with the guiding catheter while on its way to the stenotic lesion and contact with flowing blood and tortuous vessels before the balloon is expanded and pressed against the vessel wall. The transfer of the drug from the balloon surface to the vessel wall during balloon inflation has been investigated and found to be sufficient.⁶ The pharmacokinetics and biotransformation of paclitaxel reaching the general circulation are well-known from clinical use.