The Taxus drug-eluting stent: a new paradigm in controlled drug delivery.

The advent of drug-eluting stents (DES) has provided the medical community with a technology that is transforming the treatment of coronary artery disease. As the newest treatment modality available to the interventional cardiologist, drug-eluting stents have not only significantly reduced the risk of restenosis, but they are also allowing the interventionalists to treat more complex lesions in patients that would otherwise require more invasive bypass surgery. Development of these drug-device combination products has presented considerable challenges to the device industry because it involves a multi-disciplinary approach that combines conventional device design and manufacturing with the principles of controlled local drug delivery. This review article provides an in-depth discussion of the key elements of drug-eluting stents, focusing on the TAXUS paclitaxel-eluting stent as an example of this new class of product. Specific sections will review the drug and polymer matrix components, formulation development and evaluation, pre-clinical studies and clinical trial results.

Paclitaxel induces primary and postmitotic G1 arrest in human arterial smooth muscle cells.

Paclitaxel (PTX), a microtubule-active drug, causes mitotic arrest leading to apoptosis in certain tumor cell lines. Here we investigated the effects of PTX on human arterial smooth muscle cell (SMC) cells. In SMC, PTX caused both (a) primary arrest in G(1) and (b) post-mitotic arrest in G(1). Post-mitotic cells were multinucleated (MN) with either 2C (near-diploid) or 4C (tetraploid) DNA content. At PTX concentrations above 12 ng/ml, MN cells had 4C DNA content consistent with the lack of cytokinesis during abortive mitosis. Treatment with 6-12 ng/ml PTX yielded MN cells with 2C DNA content. Finally, 1-6 ng/ml of PTX, the lowest concentrations that affected cell proliferation, caused G(1) arrest without multinucleation. It is important that PTX did not cause apoptosis in SMC. The absence of apoptosis could be explained by mitotic exit and G(1) arrest as well as by low constitutive levels of caspase expression and by p53 and p21 induction. Thus, following transient mitotic arrest, SMC exit mitosis to form MN cells. These post-mitotic cells were subsequently arrested in G(1) but maintained normal elongated morphology and were viable for at least 21 days. We conclude that in SMC PTX causes post-mitotic cell cycle arrest rather than cell death.