Drug-eluting Stent Solutions: Examining the Anti-Proliferative Drug Paclitaxel

Dr. Heldman was the first to demonstrate effective reduction of coronary restenosis in an animal model with a prototype drug eluting stent. His clinical interests include the treatment and prevention of coronary restenosis; complex coronary interventions, coronary stenting, diseases of the aorta and peripheral vascular disease. His research interests include coronary stent design; coronary local drug delivery for treatment and prevention of restenosis; cardiovascular gene therapy; stem cell myogenesis; and cardiac magnetic resonance imaging (MRI). Dr. Heldman has published extensively in such publications as Circulation, Journal of Interventional Cardiology, Catheterization and Cardiovascular Interventions and Investigative Radiology. Dr. Heldman, paclitaxel is a drug that is eluted from some coronary stent systems. Could you give us a brief history of this drug? The drug paclitaxel was discovered in the course of a systematic screening of naturally occurring compounds done under the auspices of the National Cancer Institute. This molecule, which is now synthesized, was first found as a derivative of the Pacific yew tree and had potent anti- proliferative effects on cells in culture. For the first several decades of its history, it was developed as an anti-cancer anti-proliferative agent. It is essentially insoluble in water, so for intravenous administration to cancer patients, it is dissolved in an oil base, Cremophor ^® Solution, to form the drug Taxol ^®. What is the difference in the form of the drug used to treat cancer patients compared to the form used on drug-eluting stents? Paclitaxel is the active ingredient in the anti-cancer drug Taxol ^®. Because paclitaxel is not soluble in water, it is not suitable alone for systemic therapy, but is more applicable for contact-based, local delivery, as in drug-eluting stents. One obvious example is its use as a local anti-proliferative to reduce restenosis. The chief difference between paclitaxel as used in coronary stenting versus cancer treatment is the dose. Paclitaxel-eluting stents administer tiny doses in comparison to Taxol in cancer treatment. How does paclitaxel work? Paclitaxel works by stabilizing microtubules, cell elements that are responsible for cell division, rendering them nonfunctional. The drug has unique multifunctional effects that inhibit the restenotic process. It promotes the polymerization of stable nonfunctioning mictrotubules and thus inhibits all microtubule-dependent activities. As a result, it can inhibit multiple cellular components of the restenotic process. In addition, paclitaxel is highly lipophilic, which contributes to more efficient drug transfer off the stent and into the tissue. Lastly, paclitaxel has a dose-dependent inhibitory effect on smooth muscle cell proliferation. Because smooth muscle cells are more sensitive to paclitaxel than endothelial cells, it reduces restenosis without compromising the healing of the arterial wall. There has been confusion in the marketplace about whether paclitaxel, as used on the TAXUS Express2 Paclitaxel-Eluting Coronary Stent, is a cytostatic or cytotoxic drug. Can you clear this up for us? When oncologists and drug discovery clinicians examine a drug that inhibits the proliferation of cells, they plot it on a chart, with the concentration of the drug on one axis and the cell proliferation on the other. This kind of assay is called a cytotoxicity assay. Unfortunately, what has been extrapolated from this form of evaluation is the notion that the drug is killing the cells. In fact, this is not the case, as has been well studied, even with human vascular wall cells in culture. Paclitaxel does not kill the cells it is cytostatic in that it merely inhibits, on a dose-dependent basis, their ability to proliferate. What actually happens is that the drug inhibits all the cell processes that depend on microtubule turnover, such as proliferation and migrationimportant components of the restenotic response. How has paclitaxel performed in clinical trials? What’s interesting is that we’ve had, roughly in parallel, two strategies for the clinical development of paclitaxel. The first is non- polymer based, and the second is a polymeric drug. Outcomes in all the trials using the polymeric delivery system (the TAXUS program) have been remarkably consistent: a dramatic and significant reduction in late loss and restenosis events, while retaining safety comparable to that of a bare metal stent. Can you compare paclitaxel to other drugs being used in coronary stenting? There hasn’t been a head-to-head comparison, but that has been discussed and considered. There are currently two drug-eluting stent systems one based on the drug sirolimus and one based on paclitaxel. There are some differences in the clinical development programs for these two drugs, but at the end of the day, their results look more similar than different in their respective studies. With sirolimus, there is greater inhibition of late loss, to around zero and a very small amount of neointimal proliferation. With paclitaxel, there is more positive value of late loss in follow-up. Whether one or another of these approaches results in a clinical advantage has been and will be debated at length. One argument favoring consistent positive value for late loss is that the stent struts are covered. Insufficient levels of late loss may leave the struts exposed, and could lead to platelet aggregation and thrombosis. Neointimal and endothelial tissue growth are evidence of healing, as is demonstrated by a low but positive level of late loss. Further, uniform neointimal and endothelial healing can provide an appropriate amount of strut coverage. Neointima very rarely ruptures, thromboses or causes an infarction; it’s a smooth, slippery lining so, a low but positive value of late loss that ensures apposition is desirable. Why can cath lab staff feel good about treating their patients with stents coated with paclitaxel? Paclitaxel in its current form is an excellent demonstration of successful development from many years of clinical study. For years, we dreamed of a reliable system for revascularization in the cath lab. The history of interventional cardiology is full of ideas for trying to achieve this. So, the development of the paclitaxel stent system is all that we had hoped it would be because the compound profoundly limits proliferative activity. This means that we can treat lesions with a great degree of confidence that our patients will have a long-term benefit. Sponsored by Boston Scientific Corporation. Taxol is a trademark of Bristol-Meyers Squibb Company. Cremaphore is a trademark of Basf Aktiengesellschaft. TAXUS is a trademark of Boston Scientific Corporation or its affiliates.

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