Objective-The risk of in-stent restenosis can be considerably reduced by stents eluting cytostatic compounds. We created a novel drug-eluting stent system that includes several new features in the rapidly evolving field of stent-based drug delivery. Methods and Results-The aim of the present study was the preclinical evaluation of a stent-coating system permitting individual, on-site coating of stents with a unique microporous surface allowing for individualizable, dose-adjustable, and multiple coatings with identical or various compounds, designated ISAR (individualizable drug-eluting stent system to abrogate restenosis). Stents were coated with 0.75% rapamycin solution, and high-performance liquid chromatography (HPLC)-based determination of drug release profile indicated drug release for Ͼ21 days. Rapamycin-eluting microporous (REMP) stents implanted in porcine coronary arteries were safe. To determine the efficacy of REMP stents, this novel drug-eluting stent platform was compared with the standard sirolimus-eluting stent. At 30 days, in-stent neointima formation in porcine coronary arteries was similar in both groups, yielding a significant decrease of neointimal area and injury-dependent neointimal thickness compared with bare-metal stents. Conclusion-The ISAR drug-eluting stent platform as a novel concept for stent coating allows for a safe, effective, on-site stent coating process, thus justifying further clinical evaluation to decrease in-stent restenosis in humans. Key Words: drug-eluting stent Ⅲ rapamycin Ⅲ sirolimus Ⅲ stent platform I n-stent restenosis, the major adverse outcome after percutaneous coronary stent placement, 1 can be successfully reduced by drug-eluting stents (DES) releasing cytostatic compounds. Numerous large clinical trials consistently revealed an impressive reduction of in-stent restenosis in de novo lesions by DES. 2-4 However, in specific patient subsets, such as insulin-dependent diabetic subjects, 5 or in challenging interventional scenarios, like bifurcation stenting, 6 the rate of restenosis remains to be substantial at this point. Moreover, the outcome of treatment of in-stent restenosis within DES is currently not satisfactorily solved. 7 Dose adjustments at the discretion of the interventional cardiologist to individualize the dosage of the compound on the drug-eluting stent may be desirable to enable an individual dose adjustment for specific lesion or patient subsets, eg, higher rapamycin doses for diabetic patients. Further, in future scenarios, stent-coating with multiple compounds, for instance to inhibit smooth muscle cell proliferation and promote re-endothelialization, may be desirable. In addition, the presently approved drugeluting stent platforms use a polymer-based coating for retardation of drug release. There is evidence that application of polymers may lead to hypersensitivity reactions and, in few cases, late cardiac death. 8 Furthermore, the issue of late-stent thrombosis in DES, particularly after discontinuation of antiplatelet therapy, is currently s...

Background— Enteroviridae such as coxsackievirus B3 (CVB3) are important infectious agents involved in viral heart disease, hepatitis, and pancreatitis, but no specific antiviral therapy is available. Methods and Results— The aim of the present study was to evaluate the impact of RNA interference on viral replication, cytopathogenicity, and survival. Small interfering RNA (siRNA) molecules were designed against the viral 2A region (siRNA-2A), which is considered to be highly conserved and essential for both virus maturation and host cytopathogenicity. siRNA-2A exhibited a significant protective effect on cell viability mediated by marked inhibition of CVB3 gene expression and viral replication. In highly susceptible type I interferon receptor–knockout mice, siRNA-2A led to significant reduction of viral tissue titers, attenuated tissue damage, and prolonged survival. Repeated siRNA-2A transfection was associated with a further improvement of survival. Various control siRNA molecules had no protective effect in vitro or in vivo. Conclusions— RNA interference directed against the 2A protease encoding genomic region effectively confers intracellular immunity toward CVB3-mediated cell injury and improves survival, suggesting a potential role for RNA interference for future treatment options targeting enteroviral diseases.

As proof of principle, our study provides evidence that local application of a HMG-CoA reductase inhibitor on a drug-eluting stent platform can efficiently limit neointima formation. Consequently, these compounds warrant further clinical evaluation to confirm this finding. Our data further suggest that the anti-restenotic effect of local statin administration might be associated with a more protective interaction with the endothelium than that observed with compounds currently employed on drug-eluting stents.

Novel drug release microimplants (0.8 × 1.14 mm; custom-made by Leiras, now Schering OY, Finland) of slow- and fast-release types containing either 0.9 mg beclomethasone or no drug at all were placed unilaterally onto the round-window membrane (RWM) of 45 guinea pigs for a maximum duration of 28 days. The following parameters were tested on days 1, 14 and 28 after implantation: threshold levels of beclomethasone in the perilymph of the scala tympani, auditory brain stem responses (ABR thresholds and ABR threshold shifts), RWM morphology and hair cell loss (cytocochleograms). None of the animals in the non-implanted control group (n = 5) or placebo implant group (n = 15), but all animals in the slow-release-type implant group (n = 15) and fast-release-type implant group (n = 15) revealed the presence of beclomethasone on day 1 (34.9 and 64.3 pg/µl, respectively), day 14 (43.8 and 46.9 pg/µl, respectively) and day 28 after implantation (4.7 and 60.5 pg/µl, respectively). Histology of the RWMs appeared normal, and cytocochleograms revealed no inner hair cell loss and outer hair cell loss within normal ranges (from 0.5 ± 0.4 to 0.8 ± 0.2% per cochlea) in both ears in all experimental groups at any time during examination (days 1, 14 and 28). Initial values of ABR thresholds at 3, 6, 9 and 12 kHz did not differ significantly in any of the experimental groups. In non-implanted controls, no significant differences of ABR thresholds were observed in all frequencies tested in either ear on days 1, 14 and 28 compared to initial values, and ABR threshold shifts ranged from –3 ± 5 dB (min.) to +5 ± 7 dB (max.). On day 28 after implantation, there were no significant differences of ABR threshold shifts between this and the implant groups, except for 6 kHz of the slow-release device. Therefore, the placebo implants, the slow-release and the fast-release beclomethasone implants appear suitable for further experiments.

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