Background-The purpose of this study was to determine the efficacy of stent-based delivery of sirolimus (SRL) alone or in combination with dexamethasone (DEX) to reduce in-stent neointimal hyperplasia. SRL is a potent immunosuppressive agent that inhibits SMC proliferation by blocking cell cycle progression. Methods and Results-Stents were coated with a nonerodable polymer containing 185 g SRL, 350 g DEX, or 185 g SRL and 350 g DEX. Polymer biocompatibility studies in the porcine and canine models showed acceptable tissue response at 60 days. Forty-seven stents (metal, nϭ13; SRL, nϭ13; DEX, nϭ13; SRL and DEX, nϭ8) were implanted in the coronary arteries of 16 pigs. The tissue level of SRL was 97Ϯ13 ng/artery, with a stent content of 71Ϯ10 g at 3 days. At 7 days, proliferating cell nuclear antigen and retinoblastoma protein expression were reduced 60% and 50%, respectively, by the SRL stents. After 28 days, the mean neointimal area was 2.47Ϯ1.04 mm 2 for the SRL alone and 2.42Ϯ1.04 mm 2 for the combination of SRL and DEX compared with the metal (5.06Ϯ1.88 mm 2 , PϽ0.0001) or DEX-coated stents (4.31Ϯ3.21 mm 2 , PϽ0.001), resulting in a 50% reduction of percent in-stent stenosis. Conclusions-Stent-based delivery of SRL via a nonerodable polymer matrix is feasible and effectively reduces in-stent neointimal hyperplasia by inhibiting cellular proliferation.

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.

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Immobilized polyethylene glycol (PEG) reduced the amount of bovine serum albumin (BSA) adsorbed on polyvinyl alcohol (PVA) hydrogel, but did not reduce the platelet reactivity of the hydrogel surface. PEG, molecular weight (MW) 2000 or 5000, with or without a monomethoxy end group, was covalently bound to glutaraldehyde-crosslinked PVA either through a cyclic acetal or an urethane functional group with a surface coverage of 70% (as measured by x-ray photoelectron spectroscopy [XPS]). Immobilization of monomethoxy-PEG via a cyclic acetal reduced BSA adsorption to PVA from 11 +/- 2 nmol/m2 to 3.9 +/- 0.3 nmol/m2 and 3.3 +/- 0.3 nmol/m2 for MW 2000 and 5000, respectively. Similarly, urethane bound PEG reduced adsorption to 3.5 +/- 1.6 nmol/m2 for MW 2000 and 5.4 +/- 1.0 nmol/m2 for MW 5000. Whole blood clotting times of PVA (using a Chandler loop) were not affected by covalently linked PEG, although the initial rate of thrombin generation at the surface, measured using a fluorogenic substrate, was marginally reduced; a rate constant of 4.2 +/- 0.1 cm/sec and 3.5 +/- 0.1 cm/sec were obtained for MW 2000 and 5000, respectively, compared to 5.6 +/- 1.0 cm/sec for PVA. Ex vivo evaluation using a canine arteriovenous shunt revealed that the hydrogel, with or without bound PEG, reduced circulating platelet levels by 35-70% after 4 days. The initial fractional rate of platelet destruction determined from measurement of platelet cyclooxygenase activity, indicated that cyclic acetal or urethane bound PEG of either molecular weight had no effect on platelet consumption produced by PVA.(ABSTRACT TRUNCATED AT 250 WORDS)

Raman spectroscopy was used to differentiate each component found in the CYPHER Sirolimus-eluting Coronary Stent. The unique spectral features identified for each component were then used to develop three separate calibration curves to describe the solid phase distribution found on drug-polymer coated stents. The calibration curves were obtained by analyzing confocal Raman spectral depth profiles from a set of 16 unique formulations of drug-polymer coatings sprayed onto stents and planar substrates. The sirolimus model was linear from 0 to 100 wt % of drug. The individual polymer calibration curves for poly(ethylene-co-vinyl acetate) [PEVA] and poly(n-butyl methacrylate) [PBMA] were also linear from 0 to 100 wt %. The calibration curves were tested on three independent drug-polymer coated stents. The sirolimus calibration predicted the drug content within 1 wt % of the laboratory assay value. The polymer calibrations predicted the content within 7 wt % of the formulation solution content. Attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectra from five formulations confirmed a linear response to changes in sirolimus and polymer content.