SRL-eluting stents favorably modulate neointimal formation for 30 days in the porcine coronary model. Long-term inhibition of neointimal hyperplasia is not sustained presumably due to delayed cellular proliferation despite increased levels of the cyclin-dependent kinase p27(kip1) in the vessel wall.
Millions of patients worldwide have received drug-eluting stents to reduce their risk for in-stent restenosis. The efficacy and toxicity of these local therapeutics depend upon arterial drug deposition, distribution, and retention. To examine how administered dose and drug release kinetics control arterial drug uptake, a model was created using principles of computational fluid dynamics and transient drug diffusion-convection. The modeling predictions for drug elution were validated using empiric data from stented porcine coronary arteries. Inefficient, minimal arterial drug deposition was predicted when a bolus of drug was released and depleted within seconds. Month-long stent-based drug release efficiently delivered nearly continuous drug levels, but the slow rate of drug presentation limited arterial drug uptake. Uptake was only maximized when the rates of drug release and absorption matched, which occurred for hour-long drug release. Of the two possible means for increasing the amount of drug on the stent, modulation of drug concentration potently impacts the magnitude of arterial drug deposition, while changes in coating drug mass affect duration of release. We demonstrate the importance of drug release kinetics and administered drug dose in governing arterial drug uptake and suggest novel drug delivery strategies for controlling spatio-temporal arterial drug distribution.
Controlled-release local delivery of a cell-cycle inhibitor from a nonerodable polymer-coated stent reduced neointimal formation in rabbit iliac arteries in a dose-dependent manner and represents a promising strategy for preventing restenosis.
Arterial drug concentrations determine local toxicity. As such the emergent safety concerns surrounding drug-eluting stents mandate an investigation of the factors contributing to fluctuations in arterial drug uptake. Drug-eluting stents were implanted into porcine coronary arteries, arterial drug uptake was followed and modeled using 2-dimensional computational drug transport. Arterial drug uptake in vivo occurred faster than predicted by free drug diffusion, thus an alternate, mechanism for rapid transport has been proposed involving carrier-mediated transport. Though there was minimal variation in vivo in release kinetics from stent to stent, arterial drug deposition varied by up to 114% two weeks after stent implantation. The extent of adherent mural thrombus also fluctuated by 113% within 3 days after implantation. The computational drug transport model predicted that focal and diffuse thrombi elevate arterial drug deposition in proportion to the thrombus size by reducing drug washout subsequently increasing local drug availability. Fluctuations in arterial drug uptake are commonly reported. We now explain that variable peristrut thrombus can explain such observations even in the face of a narrow range of drug release from the stent. The mural thrombus effects on arterial drug deposition may be circumvented by forcing slow, rate limiting arterial transport that cannot be further hindered by mural thrombus. Keywords stents; drug delivery; restenosis; thrombus II. IntroductionThere is increasing concern for the risk of thrombosis in drug-eluting stents late after implantation. It was reported that drug-eluting stents clot at 0.6% each year after implantation for up to 3 years 1 and remain an issue even years after implantation 2,3 . Documentation of delayed healing and re-endothelialization suggest that the unhealed tissue state might provide a nidus for thrombosis [4][5][6] . Drug-eluting stents may delay recovery of endothelial function *Corresponding author. Phone: 617 253 1569 Fax: 617 253 2514 innga@mit.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript compared to their bare metal counterparts even 6 months after implantation 7,8 . Heightened local arterial drug levels may be responsible for these observations and may be an especially potent problem given the narrow therapeutic window for paclitaxel and sirolimus and their selective effects on smooth muscle and endothelial cells 9,10 . Complete appreciation of the role and limitations of drug eluting stents requ...
This study was conducted to assess the systemic drug release and distribution of sirolimus-eluting stents. Early results with sirolimus-eluting stents have demonstrated a favorable outcome for reducing restenosis post coronary intervention. However, the clinical systemic pharmacokinetics of sirolimus released from these stents has not been investigated. Sirolimus-eluting stents (150-178 mcg/18 mm stent) were implanted in 19 patients with coronary artery disease using standard techniques. Blood samples were obtained at multiple times to determine the kinetics of sirolimus release and elimination. Non-compartmental analysis showed that the maximum blood concentration of sirolimus occurred between 3 and 4 hr after implantation, with a peak concentration of 0.57 +/- 0.12 ng/mL (mean +/- SD) and 1.05 +/- 0.39 ng/mL in patients receiving one or two stents, respectively. Terminal-phase elimination half-life was independent of the number of stents and averaged at 213 hr, a value longer than that seen in patients following oral dosing. The apparent clearance was 1.46 +/- 0.45 L/hr with an apparent volume of distribution in the terminal phase of 407 +/- 111 L (data for both stent doses pooled). Minimal measurable blood levels were detectable at 7 days. Peak whole blood level following sirolimus stent implantation in humans is proportional to the number of stents implanted. The prolonged terminal half-life may reflect kinetics of blood clearance combined with continued drug elution and secondary local tissue release.
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