ALK inhibitors fficients for RESV andQUERwith normalized best fit drug elution profiles, the arterial retention profile was estimated for the combination coatings. For all distributions, drug mass in the polymer coating decreases monotonically, whereas arterial drug levels first increases to a maximum, then decreases to a minimum. The arterial predictions show that coatings associated with high burst phases initiallyproduce high arterial drug levels, at the expense of lower drug levels following the burst release phase. Conversely, coatings featuring low burst phases initially deliver less drug to the tissue but are associated with greater tissue drug levels during the sustained phase. Relative to RQ1, drug release from the RQ2 coating was predicted to produce higher arterial levels of RESV and QUER during the burst phase, but lower tissue levels during the sustained phase. Relative to QUER, the level of RESV was estimated to be approximately 100 fold bcl-2 higher in the arterial tissue over 28 days. DISCUSSION Despite early indications of success, uncertainty still remains regarding the overall safety of DES.
Recent evidence suggests that the topoisomerase culprit in a majority of problems associated with DES is delayed vascular healing.39 Delayed healing is thought to be due to the nonspecific action of the antimitogenic drugs on endothelial cells. This phenomenon is mediated, at least in part, by high local levels of drug accumulating in the tissue during burst phase release.2,40 Thus, compounds associated with a narrow TI should be used with caution because stent based drug delivery establishes large concentration gradients. These gradients can lead to drug levels several fold higher or lower than the mean tissue concentration depending on tissue proximity to stent struts,21 highlighting the importance of using drugs with a wide margin of safety. Resveratrol and QUER are two red wine polyphenols that are associated with well known vascular protective effects.10,12,13,41 Importantly, these polyphenols have been shown to interfere with the sirolimus pathogenesis of neointimal hyperplasia after arterial injury.42,43 In this study, we found the window between efficacy and toxicity of Taxol, a drug used in clinically available DES, to be relatively narrow compared with the polyphenols RESV or QUER.
This finding of Taxol,s narrow therapeutic window is supported by prior reports of local toxicity in arteries receiving paclitaxel eluting stents.2 These data suggest that a stent releasing RESV and QUER may carry a lower risk of arterial toxicity due to higher TI values. In addition to considering TI, understandingthe multivariate factors that contribute to drug delivery from a polymer film, as well as the influence of arterial tissue on drug distribution, is of chief parallel importance in designing DES that deliver therapeutic levels of drug. Movement of drug from the stent into the tissue depends on many variables that are inherent to both the drug and arterial architecture. The binding of drug to protein carriers may allow drug to be retained within the tissue for extended periods of time compared with drugs associated with low protein binding.4 Results from plasma protein binding experiments suggest that the physicochemical properties of Taxol and RESV favor prolonged tissue retention.