Gregory A. Kopia

Twenty-eight-day efficacy and phamacokinetics of the sirolimus-eluting stent.

BackgroundIn-stent restenosis is caused by neointimal hyperplasia. Sirolimus (rapamycin; Wyeth Research, Radnor, Pennsylvania, USA) inhibits vascular smooth muscle cell proliferation and we evaluated the efficacy of sirolimus in reducing neointimal formation in a rabbit iliac model and in-vivo pharmacokinetics in the porcine coronary model. DesignRandomized, blinded, prospective animal study. MethodsBilateral rabbit iliac artery stent implantation was performed using crossflex stents (Cordis Corporation, Warren, New Jersey, USA) coated with sirolimus incorporated in a nonerodable polymer. Arteries were randomized to one of four stent groups: uncoated stents (n  = 8); polymer control stents (n  = 10); low-dose sirolimus-eluting stents (n  = 9); and high-dose sirolimus-eluting stents (n  = 10). Histomorphometry was performed at 28 days. Arterial tissue and stents were retrieved at 8, 14 and 28 days and blood samples were obtained daily during the first week. ResultsTreatment with low-dose sirolimus was associated with a 23% (P  = NS) reduction in neointimal area and treatment with high-dose sirolimus with a 45% (P  < 0.05) reduction. Sustained drug release from the stent and prolonged intramural arterial deposition were confirmed for up to 28 days. No detectable sirolimus was found in the blood after 2 days. ConclusionControlled-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.

Sirolimus PK trial: A pharmacokinetic study of the sirolimus-eluting Bx Velocity stent in patients with de novo coronary lesions

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.

Thrombus causes fluctuations in arterial drug delivery from intravascular stents

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.

Safety and Pharmacokinetics of Sirolimus-eluting Stents in the Canine Cerebral Vasculature: 180 Day Assessment

OBJECTIVE:We evaluated local and systemic pharmacokinetics and pharmacodynamics of sirolimus-eluting stents (SES) in canine cerebral vessels. METHODS:SES (1.5 × 8 mm, 79 &mgr;g/479 &mgr;g sirolimus) and control stents (1.5 × 8 mm stainless steel with or without polymer) were implanted in canine basilar and ventral spinal arteries. Animals were sacrificed for local pharmacokinetic (36 animals at 1, 3, 8, 30, 90, 180 days) and pharmacodynamic (60 animals at 3, 30, 90, 180 days) assessment. RESULTS:Postrecovery adverse clinical events were not serious, requiring no unscheduled treatment. Histologically, brain and spinal cord sections revealed scattered microinfarcts and minimal gliosis consistent with postprocedure changes in all four stent-treatment groups. All stented vessels at all time points demonstrated good luminal patency with low injury and inflammation scores and no thrombosis of either stented or branch arteries. Endothelialization was complete in all stent groups by 30 days. Intimal smooth muscle cell scores were reduced in both SES groups at 30, 90, and 180 days. Systemic sirolimus levels peaked between 1 and 7 hours postimplant (maximum concentration, 1.2 ± 1.47, 79 &mgr;g; 4.5 ± 1.23 ng/ml, 479 &mgr;g), then declined rapidly to 1 ng/ml or less by 96 hours. Peak local tissue sirolimus levels were 41.5 ng/mg (79 &mgr;g) and 65 ng/mg (479 &mgr;g). CONCLUSION:SES in canine cerebral vessels were associated with good luminal patency to 180 days, with complete endothelialization and no evidence of acute thrombosis. This model has shown that SES deployed within the brain do not cause neurotoxicity during a 180-day time course, even when exaggerated doses are used. The findings support the contention that SES are safe to use and maintain patency in cerebral vessels.

1139-49 Sirolimus-eluting stents: Pharmacokinetics in blood, vessel, and myocardium in a porcine coronary model

Background: Our objective was to evaluate the range of programmable parameters of the Conor Medsystems MedStentTM loaded with lipophilic paclitaxel (PXL) in an in vitro elution experiment. We examined: 1) spatial homogeneity, 2) the breadth of multiple temporal and directional kinetic profiles, and 3) simultaneous combination of PXL with water soluble 2-chlorodeoxyadenosine (CDA), a potent macrophage inhibitor. Methods: Stents (9 formulations of 4 stents each) were immersed in aliquots of agitated N, N-diethylnicotinamide, and released drug was measured by HPLC for up to 30 days. Results: Spatial homogeneity for PXL varied by <3.5%. Graph A shows cumulative release curves for 100% of the loaded PXL over 5-30 days. Seven unique first and zero order temporal profiles were achieved with doses from 10-30 μg released either at the vessel wall or at the wall and lumen. Graph B shows cumulative simultaneous release from stents containing PXL and CDA. Conclusions: This stent’s layered multi-drug/polymer inlay technology permits precise control of spatial and temporal first and zero order pharmacokinetic elution profiles. A novel feature is the ability to simultaneously deliver water soluble and lipid soluble combination chemotherapy from a simple polymer carrier structure. These capabilities are undergoing further investigation in animal and human clinical trials.

Evaluation of an intramedullary bone stabilization system using a light‐curable monomer in sheep

Percutaneous intramedullary fixation may provide an ideal method for stabilization of bone fractures, while avoiding the need for large tissue dissections. Tibiae in 18 sheep were treated with an intramedullary photodynamic bone stabilization system (PBSS) that comprised a polyethylene terephthalate (Dacron) balloon filled with a monomer, cured with visible light in situ, and then harvested at 30, 90, or 180 days. In additional 40 sheep, a midshaft tibial osteotomy was performed and stabilized with external fixators or external fixators combined with the PBSS and evaluated at 8, 12, and 26 weeks. Healing and biocompatibility were evaluated by radiographic analysis, micro-computed tomography, and histopathology. In nonfractured sheep tibiae, PBSS implants conformably filled the medullary canal, while active cortical bone remodeling and apposition of new periosteal and/or endosteal bone was observed with no significant macroscopic or microscopic observations. Fractured sheep tibiae exhibited increased bone formation inside the osteotomy gap, with no significant difference when fixation was augmented by PBSS implants. Periosteal callus size gradually decreased over time and was similar in both treatment groups. No inhibition of endosteal bone remodeling or vascularization was observed with PBSS implants. Intramedullary application of a light-curable PBSS is a biocompatible, feasible method for fracture fixation.

Particulates from hydrophilic-coated guiding sheaths embolise to the brain

AIMS We sought to evaluate the incidence of embolic material in porcine brains following vascular interventions using hydrophilic-coated sheaths. METHODS AND RESULTS A new self-expanding stent and delivery system (SDS) was deployed through a hydrophilic-coated (Flexor Ansel; Cook Medical, Bloomington, IN, USA) guiding sheath into the iliac and/or carotid arteries of 23 anaesthetised Yucatan mini swine. The animals were euthanised at three, 30, 90 and 180 days and their brains were removed for histological analysis. In an additional single control animal, the guiding sheath was advanced but no SDS was deployed. Advancement of the coated guiding sheath with or without the SDS was associated with frequent foreign material in the arterioles of the brain. The embolic material was amorphous, non-refractile, non-crystalline, non-birefringent and typically lightly basophilic with a slightly stippled appearance on haematoxylin and eosin (H&E) stain. Material was observed at all time points involving 54% of all study animals (i.e., test and control) and in vitro after incubation in 0.9% saline. CONCLUSIONS The hydrophilic coating on a clinically used guiding sheath readily avulses and embolises to the brain during deployment in a porcine model. Further documentation of this effect and monitoring in clinical scenarios are warranted.

Angiographic and histological results following implantation of a novel stent-on-a-wire in the animal model.

AIMS The Svelte Stent-On-A-Wire (SOAW) is a thin strut novel device consisting of a balloon-expandable cobalt-chromium stent premounted onto a single lumen fixed-wire delivery catheter platform. We evaluated the performance of the novel Svelte SOAW in comparison with the MultiLink Vision (ML Vision) balloon-expandable stent, in porcine coronary arteries. METHODS AND RESULTS Eight Yorkshire swine (30-day follow-up cohort) and eight Yucatan mini-swine (90-day follow-up cohort) were implanted with either Svelte or control ML Vision. Acute performance characteristics were graded by interventionalists during implantation. Angiographic assessments were performed at the index procedure and at 30 or at 90 days post implantation. Scanning electron microscopy (SEM), histological and histomorphometric analysis of stented segments were performed after angiographic follow-up. Acute implantation performance was similar between the two stents; however, deflation time was significantly lower in the Svelte stent group (Svelte 4.70±0.93 s vs. ML Vision 9.56±0.96 s, p <0.05). Angiographic late loss was similar for both stents at 30 (Svelte 0.83±0.59 mm vs. ML Vision 0.88±0.71 mm, p=0.969) and at 90 days (Svelte 0.76±0.35 mm vs. ML Vision 0.83±0.35 mm, p=0.679). SEM analysis showed complete endothelialisation at 30 days in both stent types. Histopathological assessment demonstrated minimal injury and inflammation at 30 and 90 days with Svelte and ML Vision stents as well as similar endothelialisation, neointimal maturation, adventitial fibrosis and neointimal fibrin. No evidence of in-stent thrombus was reported in either stent group. Histomorphometric analysis showed no differences between the two groups in lumen, stent, media or neointimal areas at either 30 or 90 days post implantation. CONCLUSIONS At 30 and 90 days after implantation in porcine coronary arteries, the Svelte Stent-On- A-Wire showed vascular healing and tissue response equivalent to that observed with ML Vision stent.

Biocompatibility, bone healing, and safety evaluation in rabbits with an IlluminOss bone stabilization system

Bone healing, biocompatibility, and safety employing the IlluminOss System (IS), comprised of an inflatable balloon filled with photopolymerizable liquid monomer, was evaluated in New Zealand white rabbits. Successful bone healing and callus remodeling over 6 months was demonstrated radiologically and histologically with IS implants in fenestrated femoral cortices. Biocompatibility was demonstrated with IS implants in brushed, flushed femoral intramedullary spaces, eliciting no adverse, local, or systemic responses and with similar biocompatibility to K‐wires in contralateral femurs up to 1 year post‐implant. Lastly simulated clinical failures demonstrated the safety of IS implants up to 1 year in the presence of liquid or polymerized polymer within the intramedullary space. Polymerized material displayed cortical bone and vasculature effects comparable to mechanical disruption of the endosteum. In the clinically unlikely scenario with no remediation or polymerization, a high dose monomer injection resulted in marked necrosis of cortical bone, as well as associated vasculature, endosteum, and bone marrow. Overall, when polymerized and hardened within bone intramedullary spaces, this light curable monomer system may provide a safe and effective method for fracture stabilization.